Publications by authors named "George J Kahaly"

134 Publications

Inhibition of TSH/IGF-1 receptor crosstalk by Teprotumumab as a treatment modality of Thyroid Eye Disease.

J Clin Endocrinol Metab 2021 Nov 12. Epub 2021 Nov 12.

Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

Context: We previously presented evidence that TSH receptor (TSHR)-stimulating autoantibodies (TSAbs) bind to and activate TSHRs but do not bind to IGF1 receptors (IGF1Rs). Nevertheless, we showed that IGF1Rs were involved in thyroid eye disease (TED) pathogenesis because TSAbs activated crosstalk between TSHR and IGF1R. Teprotumumab, originally generated to inhibit IGF1 binding to IGF1R, was recently approved for the treatment of TED (Tepezza®).

Objective: To investigate the role of TSHR/IGF1R crosstalk in teprotumumab treatment of TED.

Design: We used orbital fibroblasts from patients with TED (TEDOFs) and measured stimulated hyaluronan (HA) secretion as a measure of orbital fibroblast activation by TED immunoglobulins (TED-Igs) and monoclonal TSAb M22. We previously showed that M22, which does not bind to IGF1R, stimulated HA in a biphasic dose-response with the higher-potency phase dependent on TSHR/IGF1R crosstalk and the lower-potency phase independent of IGF1R. Stimulation by TED-Igs and M22 was measured in the absence or presence of Teprotumumab Biosimilar (Tepro) or K1-70, an antibody that inhibits TSHR.

Results: We show: 1) Tepro dose-dependently inhibits stimulation by TED-Igs; 2) Tepro does not bind to TSHRs; 3) Tepro inhibits IGF1R-dependent M22-induced HA production, which is mediated by TSHR/IGF1R crosstalk, but not IGF1R-independent M22 stimulation; and 4) β-arrestin 1 knockdown, which blocks TSHR/IGF1R crosstalk, prevents Tepro inhibition of HA production by M22 and by a pool of TED-Igs.

Conclusion: We conclude that Tepro inhibits HA production by TEDOFs by inhibiting TSHR/IGF1R crosstalk and suggest that inhibition of TSHR/IGF1R crosstalk is the mechanism of its action in treating TED.
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http://dx.doi.org/10.1210/clinem/dgab824DOI Listing
November 2021

Graves' Autoantibodies Exhibit Different Stimulating Activities in Cultures of Thyrocytes and Orbital Fibroblasts Not Reflected by Clinical Assays.

Thyroid 2021 Nov 29. Epub 2021 Nov 29.

Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

The pathogenesis of Graves' hyperthyroidism (GH) and associated Graves' orbitopathy (GO) appears to involve stimulatory autoantibodies (thyrotropin receptor [TSHR]-stimulating antibodies [TSAbs]) that bind to and activate TSHRs on thyrocytes and orbital fibroblasts. In general, measurement of circulating TSHR antibodies by clinical assays correlates with the status of GH and GO. However, most clinical measurements of TSHR antibodies use competitive binding assays that do not distinguish between TSAbs and antibodies that bind to but do not activate TSHRs. Moreover, clinical assays for TSAbs measure stimulation of only one signaling pathway, the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, in engineered cells that are not thyrocytes or orbital fibroblasts. We determined whether measuring TSAbs by a cAMP-PKA readout in engineered cells accurately reveals the efficacies of stimulation by these antibodies on thyrocytes and orbital fibroblasts. We measured TSAb stimulation of normal human thyrocytes and orbital fibroblasts from patients with GO in primary cultures . In thyrocytes, we measured secretion of thyroglobulin (TG) and in orbital fibroblasts secretion of hyaluronan (hyaluronic acid [HA]). We also measured stimulation of cAMP production in engineered TSHR-expressing cells in an assay similar to clinical assays. Furthermore, we determined whether there were differences in stimulation of thyrocytes and orbital fibroblasts by TSAbs from patients with GH alone versus from patients with GO understanding that patients with GO have accompanying GH. We found a positive correlation between TSAb stimulation of cAMP production in engineered cells and TG secretion by thyrocytes as well as HA secretion by orbital fibroblasts. However, TSAbs from GH patients stimulated thyrocytes more effectively than TSAbs from GO patients, whereas TSAbs from GO patients were more effective in activating orbital fibroblasts than TSAbs from GH patients. Clinical assays of stimulation by TSAbs measuring activation of the cAMP-PKA pathway do correlate with stimulation of thyrocytes and orbital fibroblasts; however, they do not distinguish between TSAbs from GH and GO patients. , TSAbs exhibit selectivity in activating TSHRs since TSAbs from GO patients were more effective in stimulating orbital fibroblasts and TSAbs from GH patients were more effective in stimulating thyrocytes.
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http://dx.doi.org/10.1089/thy.2021.0326DOI Listing
November 2021

Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment: OPTIC-X Study.

Ophthalmology 2021 Oct 21. Epub 2021 Oct 21.

Department of Ophthalmology and Visual Sciences and Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.

Purpose: To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare.

Design: The Treatment of Graves' Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial.

Participants: Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC.

Methods: OPTIC nonresponders or those who flared (≥2-mm increase in proptosis, ≥2-point increase in clinical activity score [CAS], or both) during follow-up were treated for the first time (previous placebo patients) or re-treated with teprotumumab in OPTIC-X with 8 infusions over 24 weeks.

Main Outcome Measures: Proptosis response and safety. Secondary outcomes included proptosis, CAS, subjective diplopia, and quality-of-life.

Results: Thirty-three of 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean ± standard deviation, -3.5 ± 1.7 mm) when treated with teprotumumab in OPTIC-X. The responses were equivalent to the OPTIC study. In these responders, proptosis, CAS of 0 or 1, and diplopia responses were maintained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at follow-up week 48. The median TED duration was 12.9 months versus 6.3 months in those treated with teprotumumab in the OPTIC study. Of the 5 OPTIC teprotumumab nonresponders re-treated in OPTIC-X, 2 responded, 1 showed a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatment early. Of the OPTIC teprotumumab responders who experienced flare, 5 of 8 patients (62.5%) responded when re-treated (mean proptosis reduction, 1.9 ± 1.2 mm from OPTIC-X baseline and 3.3 ± 0.7 mm from OPTIC baseline). Compared with published double-masked trials and their integrated follow-up, no new safety signals were identified. Mild hearing impairment was reported; 4 events occurred during first course of treatment, and 2 events reoccurred after re-treatment.

Conclusions: Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.
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http://dx.doi.org/10.1016/j.ophtha.2021.10.017DOI Listing
October 2021

Effect of a biofeedback intervention on heart rate variability in individuals with panic disorder: A randomized controlled trial.

Psychosom Med 2021 Oct 12. Epub 2021 Oct 12.

Medical Psychology and Medical Sociology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany Clinic for Psychotherapy and Psychosomatic Medicine, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany Department of Psychosomatic Medicine und Psychotherapy, University Bonn, Bonn, Germany.

Objective: Some individuals with panic disorder (PD) display reduced heart rate variability, which may result in an increased risk of cardiovascular mortality. Heart rate variability-biofeedback (HRV-BF) training has been shown to improve the modulation of the autonomic activity. Therefore, this randomized controlled trial was conducted to investigate the effect of a four-week HRV-BF intervention in individuals with PD. Heart rate variability-biofeedback (HRV-BF) training improved the modulation of the autonomic activity. Therefore, with this randomized controlled trial we aimed to investigate the effect of a four-week HRV-BF intervention in people with PD.

Methods: Thirty-six women and sixteen men with PD (mean age: 35.85 ± 15.60 years) were randomly allocated either to HRV-BF with 0.1 Hz breathing as intervention group or to HRV-Sham-BF as active control group. HRV-BF was performed over four weeks while HRV was measured both during a short-term resting condition as well as during a paced breathing condition before and after intervention.

Results: HRV-BF with 0.1 Hz breathing increased HRV and reduced panic symptoms in individuals with PD. HRV-BF with 0.1 Hz breathing demonstrated an increase in the time and frequency domain parameters of HRV during the short-term resting condition (ΔPost-Pre RMSSD: 5.87 ± 14.03 ms; ΔPost-Pre SDNN: 11.63 ± 17.06 ms; ΔPost-Pre Total Power: 464.88 ± 1825.47 ms2; ΔPost-Pre LF: 312.73 ± 592.71 ms2), a decrease in the heart rate during the paced breathing condition (ΔPost-Pre: -5.87 ± 9.14 b/min), and a decrease in the Panic & Agoraphobia Scale (ΔPost-Pre: -3.64 ± 6.30). There was no intervention effect in the HRV-Sham-BF group.

Conclusions: HRV-BF as a non-invasive and non-pharmacological treatment seems to be an important intervention option to improve reduced HRV and decrease panic symptoms in individuals with PD. Future studies are needed to establish whether these effects translate to reductions in the risk of cardiovascular disease in PD.
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http://dx.doi.org/10.1097/PSY.0000000000001031DOI Listing
October 2021

Response to comment by Smith on the 2021 EUGOGO guidelines.

Eur J Endocrinol 2021 Oct 25;185(6):L15-L16. Epub 2021 Oct 25.

Department of Medicine and Surgery, University of Insubria, Varese, Italy.

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http://dx.doi.org/10.1530/EJE-21-0967DOI Listing
October 2021

Triiodothyronine alongside levothyroxine in the management of hypothyroidism?

Curr Med Res Opin 2021 Dec 12;37(12):2099-2106. Epub 2021 Oct 12.

Department of Medicine I, Johannes Gutenberg-University Medical Centre, Mainz, Germany.

The current guideline-based management of hypothyroidism recommends monotherapy with levothyroxine (LT4), titrated to maintain the level of thyrotropin within a euthyroid reference range. This has been successful for most people with hypothyroidism, but a substantial minority still report symptoms of hypothyroidism unexplained by a comorbid medical condition. LT4 is essentially a prodrug for triiodothyronine (T3), the thyroid hormone that acts on target tissues in the brain and the periphery. Thyroid hormone replacement with LT4 alone does not restore physiological tissue levels of thyroid hormones, particularly T3. During the last two decades, much interest has focussed on the potential of combinations of LT4 and T3 to provide a superior outcome to LT4 monotherapy for people with hypothyroidism, especially those with residual symptoms despite thyrotropin-optimized LT4. This review seeks to provide an overview of currently available evidence on combination (LT4 + T3) therapy to be used for personalized medicine in patients with hypothyroidism. A number of randomized, controlled trials (RCTs) have failed to demonstrate superiority for the combination therapy approach, largely due to non-physiological T3 doses. However, patients with hypothyroidism are highly heterogeneous in terms of their residual thyroid function, individual set points for optimal thyroid homeostasis and for the presence or absence of polymorphisms in deiodinase enzymes in tissues that activate and deactivate circulating thyroid hormones. Accordingly, these RCTs may have failed to demonstrate benefits of combination therapy in individual hypothyroid phenotypes. The pharmacokinetics of LT4 and T3 also differ, which is a barrier to their co-administration. Future clinical trials using LT4 + T3 tablets better suited for combination therapy will resolve the outstanding research questions relating to the place of LT4 + T3 combination therapy in the management of hypothyroidism.
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http://dx.doi.org/10.1080/03007995.2021.1984219DOI Listing
December 2021

2021 European Thyroid Association Guidelines for the Management of Iodine-Based Contrast Media-Induced Thyroid Dysfunction.

Eur Thyroid J 2021 Jul 16;10(4):269-284. Epub 2021 Jun 16.

Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany.

Given the fact that a large number of radiological examinations using iodine-based contrast media (ICM) are performed in everyday practice, clinicians should be aware of potential ICM-induced thyroid dysfunction (TD). ICM can induce hyperthyroidism (Hyper) or hypothyroidism (Hypo) due to supraphysiological concentrations of iodine in the contrast solution. The prevalence of ICM-induced TD varies from 1 to 15%. ICM-induced Hyper is predominantly found in regions with iodine deficiency and in patients with underlying nodular goiter or latent Graves' disease. Patients at risk for ICM-induced Hypo include those with autoimmune thyroiditis, living in areas with sufficient iodine supply. Most cases of ICM-induced TD are mild and transient. In the absence of prospective clinical trials on the management of ICM-induced TD, an individualized approach to prevention and treatment, based on patient's age, clinical symptoms, pre-existing thyroid diseases, coexisting morbidities and iodine intake must be advised. Treatment of ICM-induced Hyper with antithyroid drugs (in selected cases in combination with sodium perchlorate) should be considered in patients with severe or prolonged hyperthyroid symptoms or in older patients with underlying heart disease. It is debated whether preventive therapy with methimazole and/or perchlorate prior to ICM administration is justified. In ICM-induced overt Hypo, temporary levothyroxine may be considered in younger patients with symptoms of Hypo, with an underlying autoimmune thyroiditis and in women planning pregnancy. Additional clinical trials with clinically relevant endpoints are warranted to further aid in clinical decision-making in patients with ICM-induced TD.
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http://dx.doi.org/10.1159/000517175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314764PMC
July 2021

Teprotumumab for thyroid eye disease: early response is not required for benefit.

Eye (Lond) 2021 Jun 28. Epub 2021 Jun 28.

Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Purpose: In recent trials, 50% of patients treated with teprotumumab for thyroid eye disease had significant improvements in proptosis at 6 weeks. However, a small subgroup of patients did not have a significant response by week 12. We examine the outcomes at week 24 in patients from both trials who had little or no proptosis response at week 12.

Design: In this post hoc analysis, data from teprotumumab-treated patients in the placebo-controlled randomized phases 2 and 3 trials were reviewed.

Methods: Patients treated with teprotumumab or placebo with a ≤2 mm reduction from baseline in proptosis at week 12 and completed assessments at both the weeks 12 and 24 visits were included. The main outcome measures were a change in proptosis, clinical activity score (CAS) and diplopia in response to teprotumumab therapy at baseline and weeks 6, 12, 18, and 24.

Results: From the phases 2 and 3 studies, 24 patients from the treated and placebo groups were included for analysis (48 total). In the teprotumumab group, of the 24 who had no improvement in proptosis (≥2 mm from baseline) at 12 weeks, 15 (63%) demonstrated a clinically significant improvement at week 24. No patients from the 24 placebo patients had a clinically significant improvement in proptosis at 12 weeks, and 24 weeks. At week 12, 22 patients (92%) in the teprotumumab group had a significant reduction in the CAS (≥2 points) and at 24 weeks all patients achieved this reduction. At week 12, 11 (46%) patients from the placebo group had a significant improvement, while 10 (42%) had a significant improvement at 24 weeks. 22 of the 24 patients (92%) in the teprotumumab group had a diplopia grade > 0 at baseline. At week 12, 12 of the 22 (55%) had improvement in diplopia ≥ 1 grade. By week 24, 16 patients (73%) had an improvement in diplopia ≥ 1 grade. In the placebo group, 15 (63%) had significant diplopia. At week 12, 3 (20%) from this group had improvement in diplopia ≥ 1 grade, while at 24 weeks this number rose to 4 (27%).

Conclusions: There is variability in the time taken to manifest a clinically significant response to teprotumumab, some patients my need a longer time to respond.
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http://dx.doi.org/10.1038/s41433-021-01539-5DOI Listing
June 2021

Precision Medicine in Graves' Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody.

Front Endocrinol (Lausanne) 2021 4;12:691781. Epub 2021 Jun 4.

Department of Medicine, Albert Einstein College of Medicine, New York, NY, United States.

Background: CD40, a key co-stimulatory molecule expressed on antigen-presenting cells, is genetically associated with a number of autoimmune diseases including Graves' disease (GD). Therefore, recent therapies targeting CD40 have been developed, including the anti-CD40 monoclonal antibody Iscalimab. In a recent pilot study, Iscalimab was shown to induce clinical remission in ~ 50% of GD patients, but the reason why only 50% of GD patients responded is not known. The aim of our study was to test the hypothesis that specific CD40 single nucleotide polymorphism (SNP) genotypes and haplotypes are associated with clinical response of GD patients to Iscalimab.

Methods: We extracted genomic DNA from the whole blood of 13 GD patients treated with Iscalimab, and genotyped seven CD40 single nucleotide polymorphisms (SNPs) associated with autoimmunity. Additionally, we analyzed CD40 mRNA expression levels in whole blood. The patients' CD40 SNP genotypes and mRNA levels were tested for association with clinical response to Iscalimab.

Results: Three common haplotypes, designated haplotypes A, B, and C, were identified. Haplotypes B and C were associated with higher CD40 mRNA levels and clinical response to Iscalimab (i.e., patients achieving euthyroidism without need for additional medications), while haplotype A was associated with decreased CD40 mRNA levels and no response to Iscalimab.

Conclusion: Our data suggest that genetic polymorphisms in the CD40 gene drive its expression levels and response to Iscalimab. Polymorphisms associated with higher CD40 levels are also associated with clinical response to CD40-targeted therapies. These results set the stage to implementing precision medicine in the therapeutic approach to GD.
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http://dx.doi.org/10.3389/fendo.2021.691781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212124PMC
June 2021

A cyclic peptide significantly improves thyroid function, thyrotropin-receptor antibodies and orbital mucine /collagen content in a long-term Graves' disease mouse model.

J Autoimmun 2021 08 15;122:102666. Epub 2021 Jun 15.

Molecular Thyroid Research Laboratory, Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany. Electronic address:

Background: BALB/c mice which received long-term immunizations of adenovirus (Ad) expressing thyrotropin receptor A-subunits (TSHR) developed stable Graves' disease (GD). TSHR-derived cyclic peptide 19 (P19) was identified as effective therapy in this model.

Methods: In Ad-TSHR mice, we investigated shorter disease intervals up to 4 months for histological alterations of the orbits, fine tuning of anti-TSHR antibodies (Ab) and free thyroxine (fT4) hormone levels by using novel detection methods in an independent laboratory. Therapy (0.3 mg/kg P19 or vehicle) was given intravenously after the fourth Ad-TSHR immunization (week 11) and continued until week 19.

Results: Thyrotropin binding inhibitory immunoglobulins (TBII, bridge immunoassay), blocking (TBAb) and stimulating (TSAb) TSHR-Ab (both cell-based bioassays) and serum levels of fT4 were significantly elevated at week 11 in Ad-TSHR-immunized mice versus none in control mice. For the first time, TSAb, TBAb, and thyroperoxidase-Ab were detected in 17 of 19, 12/19 and 6/19 Ad-TSHR immunized mice, respectively at week 21. Also, for the first time, this study showed that P19 treatment markedly reduced serum TBII (p < 0.0001), serum fT4 (p = 0.02), and acidic mucins and collagen content in the orbital tissue of Ad-TSHR-immunized mice.

Conclusion: P19 significantly improved thyroid function, confirming previous results in an independent second laboratory. A relevant shift of anti-TSHR antibody subpopulations in response to P19 therapy may help explain its immunological effects. Moreover, P19 exerted a beneficial effect on mucine and collagen content of orbital tissue. Hence, P19 offers a potential novel therapeutic approach for GD and associated orbitopathy.
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http://dx.doi.org/10.1016/j.jaut.2021.102666DOI Listing
August 2021

Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials.

Lancet Diabetes Endocrinol 2021 06 15;9(6):360-372. Epub 2021 Apr 15.

Kellogg Eye Center-Michigan Medicine and University of Michigan, Ann Arbor, MI, USA.

Background: Thyroid eye disease manifests inflammation and treatment-resistant proptosis and diplopia. Teprotumumab, an insulin-like growth factor-1 receptor inhibiting monoclonal antibody, was approved in the USA on Jan 21, 2020, on the basis of two randomised trials. In this analysis we evaluated the short-term and long-term aggregate response to teprotumumab from the two trials, focusing on proptosis and diplopia.

Methods: We analysed integrated outcomes and follow-up data from two randomised, double-masked, placebo-controlled, multicentre, trials done at a total of 28 academic referral tertiary specialised centres offering joint thyroid eye clinics, or orbital clinics or practices, or both, in Europe and the USA. Participants were adult patients with a diagnosis of Graves' disease and active moderate-to-severe thyroid eye disease (clinical activity score [CAS] ≥4). Patients received eight intravenous infusions of either teprotumumab (10 mg/kg body weight for the first infusion, 20 mg/kg for subsequent infusions) or placebo every 3 weeks. The final study visit was at week 24, 3 weeks after the final infusion. In our analysis, the prespecified primary outcome was the between-group difference from baseline to week 24 in the proportion of patients with a proptosis response (≥2 mm reduction in the study eye without similar deterioration in the fellow eye at week 24) stratified by tobacco non-use and current use. Secondary endpoints at week 24 were the proportion of patients with improved diplopia (≥1 Bahn-Gorman grade), an overall response (reduction of ≥2 mm in proptosis and reduction of ≥2 points in CAS), mean change from baseline in proptosis measurement in the study eye, mean change from baseline in Graves' ophthalmopathy quality of life (GO-QOL) questionnaire scores (overall, visual functioning, and appearance), and the proportion of patients with disease inactivation (ie, a CAS score of 0 or 1). We also assessed data for the primary and secondary outcomes by patient subgroups (tobacco use; age <65 years or older; sex; time to diagnosis; CAS score 4 or 5, or 6 or 7; and thyrotropin binding inhibiting immunoglobulin [TBII] concentration <10 IU/L or ≥10 IU/L) versus placebo. Additional outcomes included short-term and long-term responses at 7 weeks and 51 weeks after the final dose, and post-hoc assessments of disease severity (more severe baseline disease defined as proptosis ≥3 mm or constant or inconstant diplopia, or both, as compared with all others), and an ophthalmic composite outcome (improvement in ≥1 eye from baseline without deterioration in either eye in ≥2 of the following: absence of eyelid swelling; CAS ≥2; proptosis ≥2 mm; lid aperture ≥2 mm; diplopia disappearance or grade change; or improvement of 8 degrees of globe motility). All outcome endpoint analyses were done by intention-to-treat (ITT) except where noted.

Findings: The pooled ITT population consisted of 84 patients assigned teprotumumab and 87 assigned placebo. More patients receiving teprotumumab achieved a reduction of at least 2 mm in proptosis at week 24 versus placebo (65 [77%] of 84 patients assigned teprotumumab vs 13 [15%] assigned placebo; stratified treatment difference 63%, 95% CI 51-75; p<0·0001). Numbers-needed-to-treat (NNT) were 1·6 for proptosis response, 2·5 for diplopia response (treatment difference 39%, 95% CI 23-55), 1·7 for overall response (treatment difference 60%, 48-72), and 2·5 for disease inactivation (treatment difference 40%, 27-53); all p <0·0001. The post-hoc assessment of the composite outcome showed that it was reached by 68 (81%) patients in the teprotumumab group and 38 (44%) in the placebo group (NNT 2·5, treatment difference 40%, 95% CI 26-53; p<0·0001). There were significantly more proptosis responders with teprotumumab in all subgroups at week 24; the number of diplopia responders was also significantly higher with teprotumumab for all subgroups except tobacco users and patients with TBII less than 10 IU/L at baseline. Integrated treatment differences for proptosis ranged from 47% in tobacco users (95% CI 21-73, p=0·0015; NNT=2·1) to 83% in patients aged 65 years and older (60-100, p<0·0001; NNT=1·2), and for diplopia ranged from 29% in tobacco users (95% CI -3 to 62, p=0·086; NNT=3·4) to 47% in those with baseline CAS of 6 or 7 (95% CI 23-71, p=0·0002; NNT=2·1). All other integrated subgroup results were p≤0·033. Integrated responses were observed at 7 weeks and 51 weeks after final dose for proptosis in 62 (87%) of 71 patients and 38 (67%) of 57 patients respectively; for diplopia in 38 (66%) of 58 and 33 (69%) of 48 respectively; and for the composite outcome in 66 (92%) of 72 and 48 (83%) of 58, respectively. During the 24-week study, compared with placebo, there were moderate-to-large improvements with teprotumumab for GO-QOL total scores (19 vs 6, p<0·0001), visual scores (20 vs 7, p=0·0003), and appearance scores (18 vs 6, p=0·0003), respectively, which were maintained during follow-up. Of all adverse events during the treatment period, 63 (94%) of 67 patients with teprotumumab and 59 (98%) of 60 patients with placebo were mild to moderate (grade 1 or 2), with three (4%) serious adverse events related or possibly related to teprotumumab of diarrhoea, infusion reaction, and Hashimoto's encephalopathy (co-incident with confusion) leading to study discontinuation. Of the most commonly reported adverse events with teprotumumab, muscle spasm (18%, 95% CI 7·3-28·7), hearing loss (10%), and hyperglycaemia (8%, 1·7-15·0) had the greatest risk difference from placebo.

Interpretation: Teprotumumab markedly improved the clinical course of thyroid eye disease in all patient subgroups examined from the two trials, with most patients maintaining responses in the long-term. Analyses of the effect of teprotumumab retreatment on non-responders and those who flare after response, as well as further studies in a broader population of thyroid eye disease are ongoing.

Funding: Horizon Therapeutics.
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http://dx.doi.org/10.1016/S2213-8587(21)00056-5DOI Listing
June 2021

Type 1 Diabetes and Autoimmune Thyroid Disease-The Genetic Link.

Front Endocrinol (Lausanne) 2021 10;12:618213. Epub 2021 Mar 10.

Molecular Thyroid Research Laboratory, Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany.

Type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) are the most frequent chronic autoimmune diseases worldwide. Several autoimmune endocrine and non-endocrine disorders tend to occur together. T1D and AITD often cluster in individuals and families, seen in the formation of autoimmune polyendocrinopathy (AP). The close relationship between these two diseases is largely explained by sharing a common genetic background. The HLA antigens DQ2 () and DQ8 (), tightly linked with DR3 and DR4, are the major common genetic predisposition. Moreover, functional single nucleotide polymorphisms (or rare variants) of various genes, such as the , the , the , the , and the that are involved in immune regulation have been identified to confer susceptibility to both T1D and AITD. Other genes including cluster of differentiation , the , the Class I , , the , the gene, the , and various cytokine genes are also under suspicion to increase susceptibility to T1D and AITD. Further, (, (, (, and ( are found to be associated with T1D and AITD by various independent genome wide association studies and overlap in our list, indicating a strong common genetic link for T1D and AITD. As several susceptibility genes and environmental factors contribute to the disease aetiology of both T1D and AITD and/or AP subtype III variant (T1D+AITD) simultaneously, all patients with T1D should be screened for AITD, and vice versa.
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http://dx.doi.org/10.3389/fendo.2021.618213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988207PMC
March 2021

Predictive Factors for Changes in Quality of Life after Steroid Treatment for Active Moderate-to-Severe Graves' Orbitopathy: A Prospective Trial.

Eur Thyroid J 2021 Feb 2;9(6):313-320. Epub 2020 Jul 2.

Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany.

Objectives: To investigate the predictive factors for changes in the quality of life (GO-QoL) of patients with Graves' orbitopathy (GO) prior to and after specific treatment.

Methods: A prospective follow-up study was conducted at an academic tertiary referral orbital center with a joint thyroid-eye clinic on 100 consecutive patients with GO. Before and after the standard 12-week course of weekly intravenous methylprednisolone (cumulative dose 4.5 g), the GO-QoL questionnaire provided by the European Group on Graves' Orbitopathy (EUGOGO) was completed. Endocrine and ophthalmic assessments were performed at each visit.

Results: All patients were biochemically euthyroid and untreated for GO at baseline and presented with active and moderate-to-severe disease. Both GO-QoL subscales (visual functioning [VF] and appearance [AP]) significantly increased after immunosuppressive therapy and showed a sustained improvement for 6 months. At baseline, demographic variables (sex, age, and smoking) influenced QoL in the stepwise linear regression ( < 0.01, adjusted = 0.24 for VF and < 0.01, adjusted = 0.21 for AP). In contrast, 6 months after treatment, the improved QoL was now exclusively associated with ophthalmic parameters ( < 0.01, adjusted = 0.47 for VF; < 0.01, adjusted = 0.23 for AP).

Conclusions: Predictive factors for GO-QoL differed not only between the 2 subscales but also before and after the first treatment of GO.
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http://dx.doi.org/10.1159/000508071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923875PMC
February 2021

Stimulatory Thyrotropin Receptor Antibodies Are a Biomarker for Graves' Orbitopathy.

Front Endocrinol (Lausanne) 2020 2;11:629925. Epub 2021 Feb 2.

Molecular Thyroid Research Laboratory, Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany.

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http://dx.doi.org/10.3389/fendo.2020.629925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885640PMC
May 2021

Improvement of asymmetric thyroid eye disease with teprotumumab.

Br J Ophthalmol 2021 Feb 12. Epub 2021 Feb 12.

Ophthalmology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Purpose: Teprotumumab, a specific blocking antibody to the insulin like growth factor 1 receptor, significantly reduced proptosis in patients with thyroid eye disease (TED) in recent clinical trials. Given its specificity, we expect it to demonstrate greater efficacy on the worse affected orbit, in patients with asymmetric TED. Herein, we investigate the differential impact of teprotumumab on the orbits of such patients.

Methods: In this pooled analysis of patients who were enrolled in the recent phase 2 (NCT01868997) and phase 3 (NCT03298867) trials, all patients with asymmetric TED (difference in exophthalmometry of ≥3 mm) were screened for eligibility. The primary outcomes of the trials, proptosis, diplopia and Clinical Activity Score (CAS) response, were evaluated in both orbits of patients who had received treatment or placebo, to examine the differential response from baseline to week 24.

Results: From a pooled group of 84 patients randomised to receive teprotumumab and 87 randomised to placebo, 10 (12%) and 12 (14%), respectively, met the inclusion criteria. The teprotumumab-treated patients demonstrated significant reductions in proptosis, CAS and diplopia in both orbits of each patient and this was not seen with placebo. The reduction in proptosis and CAS was significantly greater in the worse affected orbit, improving symmetry. In the placebo arm, while the mean CAS in the study eye reduced over time, proptosis and diplopia did not change in either orbit.

Conclusion: The findings in this study suggest the differential impact of teprotumumab on orbits that are clinically more affected by TED, suggesting that teprotumumab reduces asymmetry.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318314DOI Listing
February 2021

A Novel Long-Term Graves' Disease Animal Model Confirmed by Functional Thyrotropin Receptor Antibodies.

Eur Thyroid J 2020 Dec 23;9(Suppl 1):51-58. Epub 2020 Jul 23.

AdvanceCor GmbH, Martinsried, Germany.

Introduction: A novel long-term murine model for Graves' disease (GD) using repeated, long-term immunizations with recombinant adenovirus expressing the extracellular A-subunit of the human thyrotropin receptor (Ad-TSHR) was applied to evaluate the functional anti-TSHR-antibody (TSHR-Ab) profile.

Methods: BALB/c mice received 7 immunizations with either 10 plaque-forming units of Ad-TSHR or control Ad-GFP. Naïve (nonimmuized native) mice were also studied. Three 3-weekly immunizations were followed by 4-weekly boosts until the 7th immunization. Blocking (TBAb) and stimulating (TSAb) TSHR-Ab were measured with bioassays. Assay cut-offs for TBAb/TSAb were at 34% inhibition and a specimen-to-reference ratio (SRR) of 140%.

Results: Nineteen (8 Ad-TSHR-, 4 Ad-GFP-immunized, and 7 native) mice were investigated. All native mice were negative for TSHR-binding inhibitory immunoglobulins (TBII) prior to immunization. Native and Ad-GFP mice were negative in weeks 17 and 27 for TBII and TBAb/TSAb. In native mice, the free thyroxine (fT4) levels (median [25th percentile; 75th percentile]) were in the upper normal range (1.2 ng/mL [1.1; 1.6]) prior to immunization, at weeks 17 (2.2 ng/mL [2.1; 2.4]) and 27 (1.4 ng/mL [1.1; 1.7]), respectively. In contrast, in Ad-TSHR-immunized mice, fT4 values were markedly increased at weeks 17 (4.4 ng/mL [3.9; 6]) and 27 (4.5 ng/mL [4.2; 6]) compared to those in Ad-GFP mice (2 ng/mL [1.8; 2.1] and 1.4 ng/mL [1.1; 1.6]), respectively ( = 0.0008, = 0.001). In contrast, at week 17, in Ad-TSHR mice, the mean TBII, TBAb, and TSAb levels were 40 IU/L (40; 40); 62% inhibition (38; 69), and 116% SRR (97; 185), respectively; at week 27, they were 40 IU/L (39; 40); 65% inhibition (34; 80) and 95% SRR (63; 187), respectively. Three serum samples from Ad-TSHR mice (38%) demonstrated dual TBAb/TSAb positivity.

Conclusions: TBAb/TSAb were highly prevalent in Ad-TSHR-immunized mice, thus confirming the successful establishment of a novel, long-term murine model for GD. All TBAb- and TSAb-positive Ad-TSHR-immunized mice were TBII-positive. Thus, the binding immunoassay did not differentiate between TSHR-Ab functionality.
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http://dx.doi.org/10.1159/000508790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802450PMC
December 2020

Novel Approaches for Immunosuppression in Graves' Hyperthyroidism and Associated Orbitopathy.

Eur Thyroid J 2020 Dec 10;9(Suppl 1):17-30. Epub 2020 Aug 10.

Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany.

Background: Both 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.

Summary: Immunotherapies 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 Messages: Therapeutic advances will continue to optimize our management of GH and associated orbitopathy in an effective and safe manner.
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http://dx.doi.org/10.1159/000508789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802437PMC
December 2020

Twentieth EUGOGO Anniversary Symposium.

Eur Thyroid J 2020 Dec 8;9(Suppl 1):1-2. Epub 2020 Sep 8.

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http://dx.doi.org/10.1159/000510702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802436PMC
December 2020

Glucocorticoids in Graves' orbitopathy: mechanisms of action and clinical application.

Ther Adv Endocrinol Metab 2020 14;11:2042018820958335. Epub 2020 Dec 14.

Department of Medicine I., Johannes Gutenberg University (JGU) Medical Center, Langenbeckstraße 1, Mainz, 55131, Germany.

Background: Graves' orbitopathy (GO) is the most frequent extrathyroidal manifestation of the autoimmune Graves' disease. GO significantly impacts quality of life and has a psycho-social morbidity. Inflammation and swelling of the orbital tissue often leads to proptosis, diplopia, and decrease of visual acuity. Due to the inflammatory background of the disease, glucocorticoids (GC) have been used as a first-line treatment for decades.

Methods: PubMed and MeSH database were searched for original articles, clinical trials, reviews, and meta-analyses published between 1 January 2000 and 31 March 2020 and pertaining to both the mechanism of action and immunological effects of GC as well as to the treatment of GO by GC. The publications were evaluated according to their setting and study design.

Results: GC act through genomic (trans-activation and trans-repression) and rapid non-genomic mechanisms. GC in general, and the intravenous (IV) administration of GC in particular, markedly decrease the activity and number of the most potent antigen-presenting dendritic cells. According to the internationally acknowledged European Thyroid Association Guidelines for the management of GO, weekly IVGC application over 12 weeks is recommended as first-line treatment for patients with active and severe GO. The daily and cumulative dose should be tailored according to clinical severity, for example, 4.5 g of IV methylprednisolone for the inflammatory component 7.5 g in the presence of diplopia and severe proptosis. Fast and significant improvements in orbital symptoms and signs are noted in 65-70% of patients. Long-term experience over decades, and worldwide availability at low cost, underline the clinical and therapeutic relevance of GC. Adverse events are rarely severe, dose-dependent, and usually reversible, hence easy to handle by medical investigators. Oral GC application on a daily basis is characterized by high bioavailability but reduced efficacy and increased toxicity.

Conclusion: IVGC still represents the standard of care in active/severe GO. Innovative biologicals, like monoclonal antibodies targeting the thyrotropin/Insulin-like growth factor-1 receptors or pro-inflammatory cytokines (e.g., Interleukin-6) should be compared with standard GC treatment with respect to short- and long-term efficacy, safety, costs, and global availability.
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http://dx.doi.org/10.1177/2042018820958335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745544PMC
December 2020

Type 1 diabetes and associated autoimmune diseases.

World J Diabetes 2020 Nov;11(11):527-539

Department of Medicine I, Johannes Gutenberg Medical Center, Mainz 55131, Germany.

Background: Common autoimmune diseases (AID) tend to occur together in the same individual and families. Type 1 diabetes (T1D) is caused by an autoimmune-induced inflammatory destruction of the pancreatic tissue and clusters with several other AID.

Aim: To compare the demographic, clinical, and serological features of patients with single T1D those with T1D and associated AID.

Methods: From October 1999 to February 2020, a total of 665 patients with T1D and their first-degree relatives were evaluated.

Results: Compared to patients with isolated T1D, those with T1D + AID were older and had a higher female: male ratio. Average patient age and age at disease onset were higher in T1D + AID T1D only. The average time interval between T1D onset and the onset of a second glandular AID was markedly shorter than the time interval between T1D and the occurrence of a non-endocrine AID. T1D-specific autoantibodies were more frequent in patients with T1D + AID and relatives those with T1D only. However, the prevalence of AID and autoantibodies against various tissues were found to be higher in relatives of patients with T1D only compared to relatives of patients with T1D + AID.

Conclusion: Annual serological and subsequent functional screening for AID in patients with T1D and their first-degree relatives is recommended.
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http://dx.doi.org/10.4239/wjd.v11.i11.527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672792PMC
November 2020

Management of Graves Thyroidal and Extrathyroidal Disease: An Update.

Authors:
George J Kahaly

J Clin Endocrinol Metab 2020 12;105(12)

Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany.

Context: Invited update on the management of systemic autoimmune Graves disease (GD) and associated Graves orbitopathy (GO).

Evidence Acquisition: Guidelines, pertinent original articles, systemic reviews, and meta-analyses.

Evidence Synthesis: Thyrotropin receptor antibodies (TSH-R-Abs), foremost the stimulatory TSH-R-Abs, are a specific biomarker for GD. Their measurement assists in the differential diagnosis of hyperthyroidism and offers accurate and rapid diagnosis of GD. Thyroid ultrasound is a sensitive imaging tool for GD. Worldwide, thionamides are the favored treatment (12-18 months) of newly diagnosed GD, with methimazole (MMI) as the preferred drug. Patients with persistently high TSH-R-Abs and/or persistent hyperthyroidism at 18 months, or with a relapse after completing a course of MMI, can opt for a definitive therapy with radioactive iodine (RAI) or total thyroidectomy (TX). Continued long-term, low-dose MMI administration is a valuable and safe alternative. Patient choice, both at initial presentation of GD and at recurrence, should be emphasized. Propylthiouracil is preferred to MMI during the first trimester of pregnancy. TX is best performed by a high-volume thyroid surgeon. RAI should be avoided in GD patients with active GO, especially in smokers. Recently, a promising therapy with an anti-insulin-like growth factor-1 monoclonal antibody for patients with active/severe GO was approved by the Food and Drug Administration. COVID-19 infection is a risk factor for poorly controlled hyperthyroidism, which contributes to the infection-related mortality risk. If GO is not severe, systemic steroid treatment should be postponed during COVID-19 while local treatment and preventive measures are offered.

Conclusions: A clear trend towards serological diagnosis and medical treatment of GD has emerged.
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http://dx.doi.org/10.1210/clinem/dgaa646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543578PMC
December 2020

Graves' disease.

Nat Rev Dis Primers 2020 07 2;6(1):52. Epub 2020 Jul 2.

Department of Medicine I, Johannes Gutenberg University Medical Centre, Mainz, Germany.

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.
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http://dx.doi.org/10.1038/s41572-020-0184-yDOI Listing
July 2020

Chromogranin Serves as Novel Biomarker of Endocrine and Gastric Autoimmunity.

J Clin Endocrinol Metab 2020 08;105(8)

Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany.

Context: The glycoprotein chromogranin A (CgA) is expressed by endocrine and neuroendocrine cells. High levels of serum CgA serve as markers of neuroendocrine tumors (NET), but its role in autoimmunity has not been assessed.

Objective: To investigate CgA utility as a marker of endocrine autoimmunity.

Methods: CgA serum levels were evaluated in 807 consecutive unselected participants (cross-sectional study) with the time-resolved amplified cryptate emission technology.

Results: Serum CgA concentrations were increased in 66%, 39%, 38%, and 24% of patients with NET, type 1 diabetes (T1D), autoimmune gastritis (AG) and autoimmune polyendocrinopathy (AP), respectively. Compared with healthy participant controls (C), the odds of positive CgA measurement were up to 28 times higher in the disease groups. In detail, the odds ratios (ORs) for positive CgA levels were 27.98, 15.22, 7.32 (all P < 0.0001) and 3.89 (P = 0.0073) in patients with NET, T1D, AG, and AP, respectively. In AG, CgA and serum gastrin correlated positively (r = 0.55; P < 0.0001). The area under the receiver operating characteristic curve to predict AG was higher for parietal cell antibody (PCA) positivity than for CgA (0.84 vs 0.67; P < 0.0001). However, in combination with PCA and intrinsic factor autoantibodies, CgA independently improved prediction of AG (OR 6.5; P = 0.031). An impact of age on CgA positivity and on CgA value was detected (P < 0.0001) while current smoking significantly increased CgA serum levels by 25% (P = 0.0080).

Conclusion: CgA qualifies as a novel biomarker for T1D, AP, and AG.
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http://dx.doi.org/10.1210/clinem/dgaa288DOI Listing
August 2020

Teprotumumab for Active Thyroid Eye Disease. Reply.

N Engl J Med 2020 05;382(20):1959-1960

Johannes Gutenberg University Medical Center, Mainz, Germany.

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http://dx.doi.org/10.1056/NEJMc2002754DOI Listing
May 2020

Comparison of a Novel Homogeneous Cyclic Amp Assay and a Luciferase Assay for Measuring Stimulating Thyrotropin-Receptor Autoantibodies.

Eur Thyroid J 2020 Feb 27;9(2):67-72. Epub 2019 Nov 27.

Molecular Thyroid Research Laboratory, Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany.

Objective: Stimulating thyrotropin-receptor antibodies (TSAb) cause Graves' disease (GD). We tested a novel homogeneous fluorescent 3',5' cyclic adenine monophosphate (cAMP) assay for the detection of TSAb in a bioassay.

Methods: Chinese hamster ovary (CHO) cell lines expressing either a chimeric (MC4) or wild-type (WT) TSH-R were incubated with the adenyl cyclase activator forskolin, a human TSAb monoclonal antibody (M22), and with sera from GD patients. Intracellular cAMP levels were measured using a Bridge-It® cAMP assay, and the results were compared with a luciferase-based bioassay.

Results: Both cell lines were stimulated with forskolin concentrations (0.006-200 µM) in a dose-dependent manner. The linear range in the MC4 and WT cells was 0.8-25 and 3.1-50 µM, respectively. Levels of cAMP and luciferase in forskolin-treated MC4 and WT cells were positively correlated ( = 0.91 and 0.84, both < 0.001). The 50% maximum stimulatory concentration of forskolin was more than 16-fold higher for the CHO-WT cells than the CHO-MC4 cells in the cAMP assay and 4-fold higher in the luciferase assay. Incubation of both cell lines with M22 (0.006-50 ng/mL) resulted in a dose-dependent increase in cAMP levels with linear ranges for the MC4 and WT cells of 0.8-12.5 and 0.2-3.125 ng/mL, respectively. Comparison of cAMP and luciferase levels in M22-treated MC4 and WT cells also showed a positive correlation ( = 0.88, < 0.001 and 0.75, = 0.002). A positive correlation was also noted when using patient samples ( = 0.96, < 0.001) that were all TSH-R-Ab binding assay positive.

Conclusion: The novel, rapid, simple-to-perform cAMP assay provides TSAb-mediated stimulatory results comparable to a luciferase-based bioassay.
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http://dx.doi.org/10.1159/000504509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109431PMC
February 2020

Graves Disease With Thyroid-Stimulating Hormone Receptor-Blocking Autoantibodies During Pregnancy.

Ann Intern Med 2020 06 24;172(11):767-769. Epub 2020 Mar 24.

Johannes Gutenberg University Medical Center, Mainz, Germany (G.J.K.).

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http://dx.doi.org/10.7326/L19-0818DOI Listing
June 2020

Reply to Drs. Kiaei and Molinaro Regarding the Publication "Comparison of a Bridge Immunoassay with Two Bioassays for Thyrotropin Receptor Antibody Detection and Differentiation".

Horm Metab Res 2020 Feb 13;52(2):126-127. Epub 2020 Feb 13.

Department of Medicine I, Molecular Thyroid Research Laboratory, Johannes Gutenberg University (JGU) Medical Center, Mainz , Germany.

Dear Editor,Drs. Kiaei and Molinaro 1 put forth two criticisms of the manuscript published by us 2. They state that the experimental design of this study is flawed and that the authors falsely claim that negative Thyretain™ TSI Reporter BioAssay results for two Graves' diseases patients undergoing drug treatments means the absence of stimulating antibodies. To substantiate this claim Drs. Kiaei and Molinaro point out that the manufacturer of the Thyretain TSI Reporter BioAssay clearly states in the package insert that "[t]he effects of various drug therapies on the performance of this Kit have not been established" 1. Second, the package insert explicitly states that "[a] negative result does not exclude the possibility of the presence of TSI" and results of the test should be interpreted in conjunction with information available from other clinical information, such as physical symptoms and thyroid hormone testing, as recommended by the American Thyroid Association (ATA)". Furthermore they state that the "authors of the manuscript did not consider the manufacturer's warning regarding the intended patient population and the ATA guidelines regarding the interpretation of the test results in conjunction with other clinical information. Instead, the authors based their conclusions on the negative Thyretain TSI Reporter BioAssay results and ignored the patients' clinical history of Graves' disease."
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http://dx.doi.org/10.1055/a-1089-8026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746516PMC
February 2020

[Healthcare relevant data from an interdisciplinary consultation for endocrine orbitopathy].

Ophthalmologe 2020 Nov;117(11):1105-1111

I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland.

Background: Endocrine orbitopathy (EO) encompasses functional and cosmetic limitations. The aim of this study was to assess the health services situation of patients with EO treated at a multidisciplinary specialized center.

Methods: The medical records pertaining to the clinical spectrum, access route, and medical specialty of the referring physician of patients who were treated within a period of 5 years at a tertiary referral orbit center were systematically assessed.

Results: A total of 431 subjects with EO (female n =354, 82%; median age 40 years, range 5-79 years) were included in the study. Of the patients 148 (35%) and 123 (29%) were referred by family physicians and ophthalmologists, respectively. A sight-threatening optic nerve neuropathy was present in 11 (14.3%) men and 21 (5.9%) women (p =0.011). At least 2 other autoimmune diseases were found in 8 (10.4%) men and in 15 (4.3%) women (p =0.079). Psychotherapeutic support was utilized by 2 (2.6%) men and 92 (26%) women (p <0.001). An access route of 50 km or more was accepted by 14 (28%) men and 83 (43%) women (p =0.054). There was also an association between an access route ≥100 km and a prior medical treatment (odds ratio 3.78, 95% confidence interval 1.18-12.05, p =0.025).

Conclusion: Men were more severely affected by EO than women and often had complex autoimmune diseases; however, male patients were less frequently willing to accept long access routes and barely used psychosocial support. Especially patients with further autoimmune diseases travelled long distances to be treated at a specialized center.
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http://dx.doi.org/10.1007/s00347-020-01050-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644527PMC
November 2020

TSH RECEPTOR ANTIBODIES: RELEVANCE & UTILITY.

Endocr Pract 2020 Jan;26(1):97-106

Antibodies (Abs) to the thyrotropin (TSH) receptor (TSH-R) play an important role in the pathogenesis of autoimmune thyroid disease (AITD). We define the complex terminology that has arisen to describe TSH-R-Abs, review the mechanisms of action of the various types of TSH-R-Abs, and discuss significant advances that have been made in the development of clinically useful TSH-RAb assays. Literature review and discussion. TSH-R-Abs may mimic or block the action of TSH or be functionally neutral. Stimulating TSH-R-Abs are specific biomarkers for Graves disease (GD) and responsible for many of its clinical manifestations. TSH-R-Abs may also be found in patients with Hashimoto thyroiditis in whom they may contribute to the hypothyroidism of the disease. Measurement of TSH-R-Abs in general, and functional Abs in particular, is recommended for the rapid diagnosis of GD, differential diagnosis and management of patients with AITD, especially during pregnancy, and in AITD patients with extrathyroidal manifestations such as orbitopathy. Measurement of TSH-R-Abs can be done with either immunoassays that detect specific binding of Abs to the TSH-R or cell-based bioassays that also provide information on their functional activity and potency. Application of molecular cloning techniques has led to significant advances in methodology that have enabled the development of clinically useful bioassays. When ordering TSH-R-Ab, clinicians should be aware of the different tests available and how to interpret results based on which assay is performed. The availability of an international standard and continued improvement in bioassays will help promote their routine performance by clinical laboratories and provide the most clinically useful TSH-R-Ab results. Measurement of TSH-R-Abs in general, and functional (especially stimulating) Abs in particular, is recommended for the rapid diagnosis, differential diagnosis, and management of patients with Graves hyperthyroidism, related thyroid eye disease, during pregnancy, as well as in Hashimoto thyroiditis patients with extra-thyroidal manifestations and/or thyroid-binding inhibiting immunoglobulin positivity. = antibody; = autoimmune thyroid disease; = antithyroid drug; = cyclic adenosine 3',5'-monophosphate; = enzyme-linked immunosorbent assay; = Graves disease; = Graves orbitopathy; = Hashimoto thyroiditis; = monoclonal antibody; = thyrotropin receptor blocking antibody; = thyroid-binding inhibiting immunoglobulin; = thyrotropin receptor-stimulating antibody; = thyrotropin receptor-stimulating blocking antibody; = thyrotropin; = thyrotropin receptor.
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http://dx.doi.org/10.4158/EP-2019-0363DOI Listing
January 2020

Teprotumumab for the Treatment of Active Thyroid Eye Disease.

N Engl J Med 2020 01;382(4):341-352

From Cedars-Sinai Medical Center, Los Angeles (R.S.D., A.P.); Johannes Gutenberg University Medical Center, Mainz (G.J.K.), and University Hospital Essen, Essen (A.E.) - both in Germany; Horizon Therapeutics, Lake Forest, IL (S.S., E.H.Z.T., R.P., J.W.S., T.V., R.J.H.); University of Tennessee Health Science Center, Memphis (J.C.F., B.T.F.); University of Pisa, Pisa (C.M., M.M., A.A.), and Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (M.S.) - both in Italy; Oregon Health and Sciences University, Portland (R.D.); Medical College of Wisconsin Eye Institute, Milwaukee (G.J.H.); Eye Wellness Center-Neuro-Eye Clinical Trials, Houston (J.S., R.T.); Kellogg Eye Center-Michigan Medicine (C.N., T.J.S.) and University of Michigan Medical School (T.J.S.) - both in Ann Arbor; and Bascom Palmer Eye Institute, Miami (S.W.).

Background: Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease.

Methods: In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful).

Results: A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation.

Conclusions: Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).
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http://dx.doi.org/10.1056/NEJMoa1910434DOI Listing
January 2020
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