Search

Claes-Göran Östenson,1 Stephan Matthaei,2 Matthew Reaney,3 Thure Krarup,4 Bruno Guerci,5 Jacek Kiljanski,6 Carole Salaun-Martin,7 Hélène Sapin,7 David Bruhn,8 Chantal Mathieu,9 Michael Theodorakis10 1Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; 2Diabetes-Center Quakenbrück, Quakenbrück, Germany; 3Eli Lilly, Windlesham, Surrey, UK; 4Department of Endocrinology I, Bispebjerg Hospital, Copenhagen, Denmark; 5Diabetology, Metabolic Diseases and Nutrition, Brabois Hospital, CHU Nancy, and INSERM CIC, ILCV, Vandoeuvre Lès Nancy, France; 6Eli Lilly, Warsaw, Poland; 7Eli Lilly, Neuilly Cedex, France; 8Eli Lilly, San Diego, California, USA; 9Department of Endocrinology, UZ Gasthuisberg, Leuven, Belgium; 10Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece* *Michael Theodorakis was affiliated with the institution shown at the time of the study, but has since left this institution Objective: The CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy (CHOICE) study assessed time to, and reasons for, significant treatment change after patients with type 2 diabetes (T2DM) initiated their first injectable glucose-lowering therapy (exenatide twice daily [BID] or insulin) in routine clinical practice, and these patients’ clinical outcomes, in six European countries. This paper reports interim data from the first 12 months of the study. Research design and methods: CHOICE (NCT00635492) is a prospective, noninterventional, observational study. Clinical data were collected at initiation of first injectable therapy and after approximately 3, 6, and 12 months. Results: Of 2497 patients enrolled in CHOICE, 1096 in the exenatide BID and 1239 in the insulin cohorts had ≥1 post-baseline assessment and were included in this analysis. Overall, 32.2% of the exenatide BID cohort and 29.1% of the insulin cohort (Kaplan–Meier estimates) had significant treatment change during the first 12 months, most commonly discontinuing injectable therapy or adding new T2DM therapy, respectively. Glycemic control improved in both cohorts, but weight loss occurred only in the exenatide BID cohort (mean change –3.3 kg). Hypoglycemia occurred in 13.2% of the exenatide BID cohort and 28.6% of the insulin cohort (82.8% and 55.6% of these patients, respectively, received sulfonylureas). The post hoc endpoint of glycated hemoglobin < 7%, no weight gain, and no hypoglycemia was attained at 12 months by 24.3% and 10.3% of patients who had data at 12 months and who were receiving exenatide BID and insulin, respectively. Conclusion: About 30% of patients in CHOICE changed treatment in the first 12 months after initiation of first injectable therapy (exenatide BID or insulin). Overall, both cohorts achieved improved glycemic control, which was accompanied by a mean weight loss in the exenatide BID cohort. Keywords: type 2 diabetes mellitus, exenatide, insulin, injectable therapy

Urpo Kiiskinen,1 Stephan Matthaei,2 Matthew Reaney,3 Chantal Mathieu,4 Claes-Göran Östenson,5 Thure Krarup,6 Michael Theodorakis,7,* Jacek Kiljanski,8 Carole Salaun-Martin,9 Hélène Sapin,9 Bruno Guerci10 1Eli Lilly, Helsinki, Finland; 2Quakenbrück Diabetes Center, Quakenbrück, Germany; 3Eli Lilly, Windlesham, Surrey, UK; 4Department of Endocrinology, UZ Gasthuisberg, Leuven, Belgium; 5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 6Department of Endocrinology, Bispebjerg Hospital, Copenhagen, Denmark; 7Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; 8Eli Lilly, Warsaw, Poland; 9Eli Lilly, Neuilly Cedex, France; 10Department of Diabetes, Metabolic Diseases, and Nutrition, Hôpital Brabois, Vandoeuvre-Lès-Nancy, France *Michael Theodorakis was affiliated with the institution shown above at the time of the study, but has since left this institution Purpose: CHOICE (CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy) assessed patterns of exenatide bid and initial insulin therapy usage in clinical practice in six European countries and evaluated outcomes during the study. Methods: CHOICE was a 24-month, prospective, noninterventional observational study. Clinical and resource use data were collected at initiation of first injectable therapy (exenatide bid or insulin) and at regular intervals for 24 months. Costs were evaluated from the national health care system perspective at 2009 prices. Results: A total of 2515 patients were recruited. At the 24-month analysis, significant treatment change had occurred during the study in 42.2% of 1114 eligible patients in the exenatide bid cohort and 36.0% of 1274 eligible patients in the insulin cohort. Improvements in glycemic control were observed over the course of the study in both cohorts (P < 0.001 for both), but mean weight was reduced in the exenatide bid cohort (P < 0.001) and increased in the insulin cohort (P < 0.001) by 24 months. Across all countries, total per patient health care costs for the 24 months post baseline were €3997.9 in the exenatide bid cohort and €3265.5 in the insulin cohort (€1791.9 versus €2465.5 due to costs other than those of injectable therapy). When baseline direct cost and patients' and disease characteristics were controlled for, mean direct costs differed by country (P < 0.0001), irrespective of treatment initiated, and the mean cost difference between treatments varied by country (P < 0.0001). Conclusion: Much of the higher mean cost of exenatide bid, compared with insulin, therapy was compensated for by lower mean costs of other health service utilization. Costs associated with exenatide bid or insulin initiation varied across countries, highlighting the need to avoid generalization of resource use and cost implications of a particular therapy when estimated in specific country settings. Keywords: exenatide, health care costs, injectable therapy, insulin, resource use, type 2 diabetes mellitus

Aim: To assess the relationship between HbA1c and body weight reductions with tirzepatide treatment (5, 10 or 15 mg)., Materials and Methods: HbA1c and body weight data at 40 weeks (SURPASS-1, -2 and -5) and 52 weeks (SURPASS-3 and -4) were analysed by trial., Results: Across the SURPASS clinical trials, HbA1c reductions from baseline were observed in 96%-99%, 98%-99% and 94%-99% of participants treated with tirzepatide 5, 10 and 15 mg, respectively. Moreover, 87%-94%, 88%-95% and 88%-97% of participants, respectively, experienced weight loss associated with HbA1c reductions. Statistically significant associations (correlation coefficients ranging from 0.1438 to 0.3130 across studies; P ≤ .038) between HbA1c and body weight changes were observed with tirzepatide in SURPASS-2, -3, -4 (all doses) and -5 (tirzepatide 5 mg only)., Conclusions: In this post hoc analysis, consistent reductions in both HbA1c and body weight were observed in most participants treated with tirzepatide at doses of 5, 10 or 15 mg. A statistically significant but modest association between HbA1c and body weight change was observed in SURPASS-2, SURPASS-3 and SURPASS-4, suggesting that both weight-independent and weight-dependent mechanisms are responsible for the tirzepatide-induced improvement in glycaemic control., (© 2023 Eli Lilly and Company and The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: We evaluated risk factors for clinically relevant hypoglycaemia (blood glucose <3 mmol/L) in patients with type 2 diabetes during insulin glargine self-titration. Data were from two clinical trials in which patients were able to improve glycaemic control by self-titration of insulin glargine using a simple algorithm., Materials and Methods: We performed post hoc analyses of pooled treatment groups from each of two Phase 3 studies comparing LY2963016 with LANTUS: ELEMENT-2 (double-blind) and ELEMENT-5 (open label). Clinically relevant hypoglycaemia was analysed by category of HbA1c (<7%, 7%-8.5%, >8.5%) at Week 12 (titration period) and at Week 24 (overall study), and by subgroups of age (<65, ≥65 years) and previous insulin use (naïve or not)., Results: In the ELEMENT-2 study (N = 756), there were no overall differences in rate or incidence of hypoglycaemia among HbA1c categories. In the ELEMENT-5 study (N = 493), patients with HbA1c greater than 8.5% had a lower rate and incidence of hypoglycaemia throughout the study compared to those in the lower HbA1c categories. In both studies, patients 65 years of age or older, compared to those less than 65 years, had a higher rate and incidence of hypoglycaemia during the titration phase, had lower baseline HbA1c, and experienced smaller increases in dose, with no differences in HbA1c post baseline. The rate and incidence of hypoglycaemia was similar between naïve patients and patients previously using basal insulin, across all levels of glycaemic control. With the exception of the older subgroup, hypoglycaemia rates were similar during titration and maintenance periods., Conclusion: Our results support broader use of self-titration algorithms for patients with type 2 diabetes., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Introduction: This research compares costs, resource utilization, and complications between adherent and nonadherent patients over the 3-year period post initiation on basal insulin therapy., Methods: The study utilized the US-based Truven Health MarketScan ® Research Databases from 2011 through 2015. Adults aged 18 years or older and identified with type 2 diabetes (T2D) who initiated therapy on basal insulin in 2012 were included. Patients were excluded if they were pregnant, filled their index basal insulin prescription via mail order, or were not continuously insured from 1 year before through 3 years following initiation of treatment with basal insulin. Instrumental variables were used to control for selection bias, and multivariable analyses were used to examine the associations between adherence to basal insulin therapy and costs, resource utilization, and acute complications., Results: A total of 21,363 individuals were included in the study. Three years after initiating therapy on basal insulin, patients who were adherent over time to basal insulin treatment therapy (33.8% of patients) had significantly higher diabetes-related drug costs. However, patients' adherence was associated with significantly lower diabetes-related outpatient, acute care, and total costs. Results for all-cause costs were similar. Adherent patients also had significantly fewer all-cause and diabetes-related hospitalizations and emergency room visits and were significantly less likely to be diagnosed with an acute complication., Conclusions: Results of this study illustrate that despite higher drug costs, there are disease-specific and all-cause cost offsets and improved patient outcomes associated with adherence to basal insulin therapy for people with T2D., Funding: Eli Lilly and Company.

Objective: We compared two strategies initiating and intensifying insulin treatment and tested for noninferiority of premixed insulin to basal ± mealtime insulin analog in patients eating light breakfasts., Research Design and Methods: This randomized, open-label, 48-week study compared two algorithms. Up to three injections of insulin lispro mix 25 and/or insulin lispro mix 50 (premix; premixed insulin lispro) or basal insulin glargine plus up to three injections of insulin lispro (basal+; glargine + insulin lispro) were used in type 2 diabetic patients uncontrolled with oral antihyperglycemic medication and consuming <15% daily calories at breakfast. The hypothesis was to test noninferiority of premix to basal+ for glycemic control measured by HbA1c after 48 weeks, assessed using ANCOVA with a 0.4% margin., Results: Patients (n = 344; 176 [51%] females; mean [SD] age 54.3 [8.8] years; BMI 29.4 [4.6] kg/m(2); baseline HbA1c 9.02 [0.97]%) were randomized to premix (n = 171) or basal+ (n = 173). In the per-protocol analysis (n = 230), least squares means (95% CI) end point HbA1c were 7.40% (7.15-7.65) and 7.55% (7.27-7.82) in respective arms. Between-treatment difference was -0.14% (-0.42 to 0.13), with noninferiority met. Significantly more patients in premix achieved HbA1c targets of <7.0% compared with basal+ (48.2 vs. 36.2%; P = 0.024). Self-monitored blood glucose profiles, body weight changes, total insulin doses, and overall hypoglycemia (65 vs. 60%) were similar in premix and basal+ (P = 0.494), except nocturnal episodes (34.3 vs. 23.7%; P = 0.018) were more common in premix., Conclusions: Both intensive insulin strategies improved glycemic control; however, final HbA1c levels were seen above those achieved in previous treat-to-target trials, likely due to the inadequate insulin titrations and probably due to the complexity of tested insulin regimens. A higher percentage of patients achieved target HbA1c <7% with multiple premixed insulins, but this treatment resulted in more nocturnal hypoglycemia than a basal-bolus regimen.

Introduction: Changes to Treatment and Outcomes in Patients with Type 2 Diabetes Initiating Injectable Therapy (CHOICE) is a European prospective, observational cohort study assessing time to, and factors associated with, a significant change in therapy after type 2 diabetes patients initiate their first injectable glucose-lowering therapy, and these patients' clinical outcomes over 24 months. The authors report baseline data and factors associated with the injectable treatment regimen., Methods: Demographic, clinical, and healthcare resource-use data were collected at initiation of injectable therapy and analyzed using univariate tests between cohorts and multivariate logistic regression analysis for treatment., Results: Overall, 1,177 patients initiated exenatide twice daily (b.i.d.) and 1,315 initiated insulin. Most patients were recruited by secondary-care physicians. Univariate analyses revealed statistically significant differences between the characteristics of patients who initiated exenatide b.i.d. and patients who initiated insulin. On multivariate analysis, higher body mass index [BMI; 5 kg/m(2) higher: odds ratio (OR) 2.10, 95% confidence intervals (CI) 1.84-2.40], lower glycated hemoglobin (HbA(1c); 1% higher: OR 0.77, 95% CI 0.69-0.86), and lower age (5 years older: OR 0.82, 95% CI 0.76-0.88) were the variables most strongly associated with increased probability of receiving exenatide b.i.d. (P < 0.0001). Patients initiating exenatide b.i.d. had a mean BMI of 35.3 ± 6.5 kg/m(2), HbA(1c) of 8.4 ± 1.4%, and age of 58 ± 10 years, compared with 29.7 ± 5.4 kg/m(2), 9.2 ± 1.9%, and 64 ± 11 years, respectively, in patients initiating insulin (P < 0.0001). Other characteristics significantly associated with exenatide b.i.d. initiation were "disinhibited eating" (Diabetes Health Profile-18), lower random blood glucose, less blood glucose self-monitoring, lower low-density lipoprotein cholesterol, and receipt of diet/exercise advice., Conclusions: Patients who initiated exenatide b.i.d. were on average younger and more obese with lower HbA(1c) than those initiating insulin.

Background: Studies of the glucagon-like peptide-1 receptor agonists (GLP-1RAs) are needed to determine the durability of metabolic response and tolerability associated with long-term treatment., Objective: The present study was conducted to provide long-term data on glycemic control, weight changes, and tolerability of exenatide 10 μg BID treatment in patients with type 2 diabetes mellitus who have failed to achieve glycemic targets with oral antihyperglycemic medication., Methods: In this uncontrolled, open-label trial with treatment up to 156 weeks, patients received exenatide 10 μg BID while continuing treatment with metformin and/or a sulfonylurea (SFU). Intent-to-treat (ITT), 52-, 100-, and 132-week completer populations were defined. Metabolic changes were analyzed in the completer and ITT populations; adverse events (AEs) were summarized in the ITT population. Descriptive statistics were used for absolute and change-from-baseline data. Within-treatment comparisons were conducted using the paired t test., Results: Of 155 patients in the ITT population (mean [SD]: age, 59 [9] years; 56% female; duration of diabetes, 9.1 [5.9] years; weight, 88.8 [16.5] kg; body mass index, 31.9 [4.7] kg/m(2); hemoglobin [Hb] A(1c), 8.7% [1.2%]), 133, 111, and 103 patients completed 52, 100, and 132 weeks of treatment, respectively. In the ITT population, the mean (SE) change in HbA(1c) from baseline to week 132 was -1.0% (0.10%) (P < 0.0001). In patients completing 52, 100, and 132 weeks, HbA(1c) changes from baseline to end point were -1.3% (0.10%), -1.0% (0.12%), and -1.0 (0.13%) (P < 0.0001), with 40% of patients achieving HbA(1c) <7% at 132 weeks. Patients in the ITT and completer populations experienced mean (SE) weight changes of -3.7 (0.39) kg and -3.9 (0.51) kg (P < 0.0001) at week 132. Improved glycemic control and weight loss occurred in 63% of patients in the completer population at week 132. In addition, 38% of completers at week 132 achieved HbA(1c) <7% without weight gain. No relationship was found between the development of antiexenatide antibodies and change in HbA(1c). The most common AEs were gastrointestinal in nature, reported in 46% of patients and leading to discontinuation in 7 cases. Serious AEs were reported in 26% of patients, and 18% withdrew due to a treatment-emergent AE. Of 24% of patients in whom hypoglycemia was reported, 22% were on SFU or metformin + SFU combination, and 2% were on metformin., Conclusions: The findings from this open-label, single-arm study characterized the response to exenatide 10 μg BID for up to 132 weeks. Significant, persistent improvements in HbA(1c) and weight were observed in patients receiving exenatide BID, with reported AEs consistent with those from studies of shorter duration. ClinicalTrials.gov identifier: NCT00044668., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Background: Prandial premixed therapy 3 times daily has been proposed recently for type 2 diabetes mellitus (T2DM) patients who fail to achieve glycemic control with commonly used premixed insulin analogs, insulin lispro mix 75/25 (LM75/25) and biphasic insulin aspart 70/30 (BIAsp70/30) BID., Objective: The aim of this work was to compare the efficacy and safety of 3-times daily insulin lispro mix 50/50 (TID group) with progressive titration of twice-daily LM75/25 or BIAsp70/30 (BID group) administered along with metformin in T2DM patients., Methods: This was an open-label, 16-week, multicenter, randomized, parallel trial. End point glycosylated hemoglobin (HbA(1c)) was the primary efficacy measure; HbA(1c) reduction from baseline to end point, percentage of patients reaching target HbA(1c) (<7.0% and ≤6.5%), postprandial blood glucose (BG), and BG excursions after lunch were secondary measures. Safety was evaluated by collecting adverse events., Results: A total of 302 patients with mean (SD) age 57.7 (9.27) years, diabetes duration 11.2 (6.47) years, HbA(1c) 8.5% (1.23), fasting BG 184.0 (53.04) mg/dL, body weight 86.8 (14.79) kg, body mass index 31.7 (4.23) kg/m(2), and daily insulin dose ∼48 IU were randomized. No significant difference was observed in end point HbA(1c) between the 2 groups. Seven-point BG profiles showed lower fasting and postbreakfast BG in the BID group but lower postlunch BG in the TID group. Daily insulin dose change was similar in both groups, with more weight gain in the TID group (P = 0.0009). Overall hypoglycemic rates were similar in both groups, but nocturnal hypoglycemia was more frequent in the BID group (P = 0.0063)., Conclusions: In patients with T2DM who have not achieved adequate glycemic control with LM75/25 and BiAsp70/30 BID plus metformin and who are not candidates for basal bolus therapy, switching either to treatment with LM50/50 TID or to progressive titration of premix insulin analogs BID did not produce sufficient evidence of a difference of overall glycemic control between the 2 treatment groups. Short study duration and less intensive dose adjustments might have contributed to these results., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)

Thyroid-associated ophthalmopathy (TAO) is a progressive orbital disorder associated with Graves' hyperthyroidism and, less often, Hashimoto's thyroiditis in which autoantibodies react with orbital antigens and lead to exophthalmos and eye muscle inflammation. Eye muscle (EM) membrane proteins initially reported as 55 and 64 kd are the best markers of ophthalmopathy. The "64-kd protein" is now shown to be the flavoprotein subunit of mitochondrial succinate dehydrogenase and to have a correct molecular weight of 67 kd. We have cloned a fragment of a novel eye muscle protein, which we call G2s, and sequenced 1.4 kb of the full length cDNA. G2s does not share any significant homologies with other reported proteins. The 5.9 kb G2s mRNA, that corresponds to a protein of approximately 220 kd, is expressed in EM, other skeletal muscle and thyroid, but not in other tissues tested. We have also cloned and sequenced a 63-kd eye muscle protein identified as the calcium binding protein calsequestrin. Antibodies against calsequestrin were found in 40% of patients with active ophthalmopathy, but in 0% of normal subjects. Finally, we have sequenced a 19 amino acid fragment of a 55-kd porcine eye muscle membrane protein that exactly matched porcine and human sarcalumenin, a 160-kd glycoprotein localized in the lumen of the longitudinal sarcoplasmic reticulum of the skeletal muscle fiber where it binds calcium. A 53-kd glycoprotein fragment of the molecule corresponds to the 55-kd protein. In a preliminary study, serum antibodies against purified sarcalumenin were detected in 40% of patients with active TAO of less than 1 year duration, but in no controls tested. We porpose that the primary autoantigen in TAO is G2s, which would also explain the association of ophthalmopathy with thyroid autoimmunity, and that antibodies against the intracellular proteins flavoprotein, calsequestrin, and sarcalumenin are secondary markers of an immune-mediated reaction in eye muscle in patients with thyroid autoimmunity.

Although thyroid-associated ophthalmopathy (TAO) is now generally accepted as an autoimmune inflammatory disorder of the extraocular muscles and the orbital connective tissue, its aetiopathogenesis remains poorly understood. Recent data indicate that impaired interactions between T cells and extracellular matrix (ECM) proteins may play an important role in development and maintaining of an inflammatory process. We report here results of the study focusing on interactions between T lymphocytes and collagen-I (Coll-I), collagen-IV (Coll-IV), fibronectin (FN), laminin (LM) in patients with TAO. Using a standard peripheral blood mononuclear cells (PBMC) proliferation assay, we observed a markedly enhanced T cell response to Coll-I in patients with active TAO (mean SI=4.5). The proliferatory response to Coll-I was significantly greater (Wilcoxon test; p < 0.001) than in normal subjects (mean SI=1.88), patients with stable TAO (mean SI=2.05) and patients with thyroid autoimmune diseases (AITD) without ophthalmopathy (mean SI=2.49). PBMC stimulation by Coll-I is likely to be antigen-dependent requiring engagement of the T cell receptor with collagen peptides, rather than mediated via integrins. The percentage of circulating CD29+ (beta1 integrin chain) T cells was not increased in patients with active TAO. Additionally in the assay of costimulation of CD3-mediated proliferation, we found that peripheral blood T cells from patients with TAO and AITD were costimulated only by FN. On the other hand a markedly enhanced costimulation of CD3-mediated proliferative responses by Coll-I, Coll-IV, FN and LM were observed in a retrobulbar T cell line. We conclude that abnormalities in T cell interactions with ECM proteins, especially Coll-I may play a role in the pathogenesis of TAO.

The relationship between the many immunologic abnormalities demonstrated in the peripheral blood of patients with Graves' disease (GD) and the broad spectrum of clinical features with which patients may present has not yet been addressed in detail. In this review we examine the evidence to support the notion that GD could be considered a multi-system autoimmune disorder in which tissue damage is restricted to the thyroid gland, connective tissue of the skin and orbit, extra-ocular and other skeletal muscles and, possibly, the lacrimal glands. Apart from the well recognized reactions of autoantibodies and sensitized T lymphocytes with epitopes on the thyroid specific TSH receptor, thyroid peroxidase and thyroglobulin, in patients with hyperthyroidism, there is also good evidence for autoantibody and, to a lesser extent, T lymphocyte reactivity with several eye muscle, other skeletal muscle and connective tissue, antigens in patients with ophthalmopathy, systemic myopathy, dermopathy and acropachy. There is also some evidence for immunoreactivity against lacrimal gland antigens in patients with ophthalmopathy associated with other features of GD. There are, in addition, a variety of organ non-specific reactions in GD; antinuclear antibodies are detected in serum from about one-third of patients with hyperthyroidism and ophthalmopathy, while from 5% to 10% have antibodies reactive with several other ubiquitous tissue proteins. Cloned proteins which are autoantigenic in some patients with hyperthyroidism or Hashimoto's thyroiditis and ophthalmopathy include collagen XIII, nebulin, the calcium binding protein calmitine, and the Mac-II antigen. All antibodies reactive with eye muscle antigens, except the 64 kDa protein which is also expressed in the thyroid, cross react with the same, or a related, protein in other skeletal muscle. Future research should focus on the underlying mechanisms for this broad loss of tolerance to self antigens and the effect of environmental factors such as stress, radioiodine and viral infection of the thyroid gland and other target tissues, in precipitating disease.

The exact pathogenic mechanism of thyroid-associated ophthalmopathy (TAO) remains unclear, and extensive studies on this disorder have resulted in often conflicting data. Well-known technical difficulties including the limited access to orbital tissues from patients with active and early disease, lack of an animal model and poor reproducibility of some of the immunological techniques used are in part responsible for this confusing situation. Despite this there is considerable evidence for eye muscle (EM) tissue involvement in the autoimmune reactions of TAO. Although the primary EM antigen(s) recognized by immunocompetent cells and autoantibodies has not been definitely identified, some good candidates, among them a membrane antigen of 64 kD which is also expressed in the thyroid, have been partially characterized. While it is unclear which component of the autoimmune reaction against EM-humoral or cell mediated-plays the more important role, autoantibodies seem to be responsible at least in part for the clinical features of the eye disorder. On the other hand, the orbital connective tissue (OCT) cells, especially the fibroblasts surrounding the EM fibers, seem to be extremely sensitive to stimulation by cytokines and other soluble proteins and immunoglobulins released in the course of an immune reaction in the muscle cells. Fibroblasts secrete large amounts of glycosaminoglycans and also participate in maintaining the autoimmune reaction. It seems likely that the EM is the main and primary target of the orbital autoimmune process whereas inflammation of the OCT is probably secondary.