Immunotherapy for type 1 diabetes.

INTRODUCTION: Despite advances in technology including the development of more sophisticated methods of monitoring blood glucose and delivering insulin, many individuals with type 1 diabetes continue to experience significant challenges in optimizing glycaemic control. Alternative treatment approaches to insulin are required. Increasing efforts have focused on developing treatments aimed at targeting the underlying disease process to modulate the immune system, maximize beta cell function and enhance endogenous insulin production and action. SOURCES OF DATA: Literature searches with keywords 'Type 1 diabetes and immunotherapy', publications relating to clinical trials of immunotherapy in type 1 diabetes. AREAS OF AGREEMENT: Insulin therapy is insufficient to achieve optimal glycaemic control in many individuals with type 1 diabetes, and new treatment approaches are required. Studies have showed promising results for the use of immunotherapy as a means of delaying disease onset and progression. AREAS OF CONTROVERSY: The optimal way of identifying individuals most likely to benefit from immunotherapies. GROWING POINTS: A better understanding of the natural history of type 1 diabetes has made it possible to identify individuals who have developed autoimmunity but have not yet progressed to clinical diabetes, offering opportunities not only to develop treatments that delay disease progression, but prevent its development in the first place. A consensus on how to identify individuals who may benefit from immunotherapy to prevent disease onset is needed. AREAS TIMELY FOR DEVELOPING RESEARCH: The development of optimal strategies for preventing and delaying progression of type 1 diabetes, and monitoring the response to immunointervention.

Asymmetry indicates more severe and active disease in Graves' orbitopathy: results from a prospective cross-sectional multicentre study.

PURPOSE: Patients with Graves' orbitopathy can present with asymmetric disease. The aim of this study was to identify clinical characteristics that distinguish asymmetric from unilateral and symmetric Graves' orbitopathy. METHODS: This was a multi-centre study of new referrals to 13 European Group on Graves' Orbitopathy (EUGOGO) tertiary centres. New patients presenting over a 4 month period with a diagnosis of Graves' orbitopathy were included. Patient demographics were collected and a clinical examination was performed based on a previously published protocol. Patients were categorized as having asymmetric, symmetric, and unilateral Graves' orbitopathy. The distribution of clinical characteristics among the three groups was documented. RESULTS: The asymmetric group (n = 83), was older than the symmetric (n = 157) group [mean age 50.9 years (SD 13.9) vs 45.8 (SD 13.5), p = 0.019], had a lower female to male ratio than the symmetric and unilateral (n = 29) groups (1.6 vs 5.0 vs 8.7, p < 0.001), had more active disease than the symmetric and unilateral groups [mean linical Activity Score 3.0 (SD 1.6) vs 1.7 (SD 1.7), p < 0.001 vs 1.3 (SD 1.4), p < 0.001] and significantly more severe disease than the symmetric and unilateral groups, as measured by the Total Eye Score [mean 8.8 (SD 6.6) vs 5.3 (SD 4.4), p < 0.001, vs 2.7 (SD 2.1), p < 0.001]. CONCLUSION: Older age, lower female to male ratio, more severe, and more active disease cluster around asymmetric Graves' orbitopathy. Asymmetry appears to be a marker of more severe and more active disease than other presentations. This simple clinical parameter present at first presentation to tertiary centres may be valuable to clinicians who manage such patients.

Is clinical experience important for obtaining the primary stability of dental implants with aggressive threads? An ex vivo study.

BACKGROUND: The aim of this study was to investigate the clinicians' experience on maintaining the primary stability of implants with aggressive threads belonging to a novel dental implant system. MATERIAL AND METHODS: Three hundred implants with aggressive threads were inserted in fresh bovine ribs mimicking Type IV bone by five clinicians which were classified according to their previous experience of total number of implant insertion. An independent examiner measured the primary stability of all implants after insertion by using resonance frequency analysis (RFA), electronic percussive testing (EPT) and removal torque methods. RESULTS: No significant differences were detected between the stability values measured by the clinicians (p> 0.05) except the Periotest values (PTVs) of the non-experienced clinician. PTVs of the non-experienced clinician were significantly higher than the PTVs of the expert and good clinicians (p<0.05). Significantly higher stability values were detected in the secondary insertion of the non-experienced clinician as compared to her initial insertion values (p<0.05). No significant differences were detected between the first and second measurements of the other clinicians (p> 0.05). CONCLUSIONS: Within the limitations of this ex-vivo study, it may be concluded that experience does not play an important role in maintaining the stability of implants with aggressive threads.

ß-cell specific T-lymphocyte response has a distinct inflammatory phenotype in children with Type 1 diabetes compared with adults.

AIM: To examine the hypothesis that the quality, magnitude and breadth of helper T-lymphocyte responses to ß cells differ in Type 1 diabetes according to diagnosis in childhood or adulthood. METHODS: We studied helper T-lymphocyte reactivity against ß-cell autoantigens by measuring production of the pro-inflammatory cytokine interferon-γ and the anti-inflammatory cytokine interleukin-10, using enzyme-linked immunospot assays in 61 people with Type 1 diabetes (within 3 months of diagnosis, positive for HLA DRB1*0301 and/or *0401), of whom 33 were children/adolescents, and a further 91 were unaffected siblings. RESULTS: Interferon-γ responses were significantly more frequent in children with Type 1 diabetes compared with adults (85 vs 61%; P = 0.04). Insulin and proinsulin peptides were preferentially targeted in children (P = 0.0001 and P = 0.04, respectively) and the breadth of the interferon-γ response was also greater, with 70% of children having an interferon-γ response to three or more peptides compared with 14% of adults (P < 0.0001). Islet ß-cell antigen-specific interleukin-10 responses were similar in children and adults in terms of frequency, breadth and magnitude, with the exception of responses to glutamic acid decarboxylase 65, which were significantly less frequent in adults. CONCLUSIONS: At diagnosis of Type 1 diabetes, pro-inflammatory autoreactivity is significantly more prevalent, focuses on a wider range of targets, and is more focused on insulin/proinsulin in children than adults. We interpret this as indicating a more aggressive immunological response in the younger age group that is especially characterized by loss of tolerance to proinsulin. These findings highlight the existence of age-related heterogeneity in Type 1 diabetes pathogenesis that could have relevance to the development of immune-based therapies.

Management of thyroid eye disease in the United Kingdom: A multi-centre thyroid eye disease audit.

This article aims to provide baseline data and highlight any major deficiencies in the current level of care provided for adult patients with thyroid eye disease (TED). We undertook a prospective, nonrandomized cross-sectional multicenter observational study. During a 3-month period June-August 2014, consecutive adult patients with TED who presented to nominated specialist eye clinics in the United Kingdom, completed a standardized questionnaire. Main outcome measures were: demographics, time from diagnosis to referral to tertiary centre, time from referral to review in specialist eye clinic, management of thyroid dysfunction, radioiodine and provision of steroid prophylaxis, smoking, and TED classification. 91 patients (mean age 47.88 years) were included. Female-to-male ratio was 6:1. Mean time since first symptoms of TED = 27.92 (73.71) months; from first visit to any doctor with symptoms to diagnosis = 9.37 (26.03) months; from hyperthyroidism diagnosis to euthyroidism 12.45 (16.81) months. First, 13% had received radioiodine. All those with active TED received prophylactic steroids. Seven patients who received radioiodine and did not have TED at the time went on to develop it. Then, 60% patients were current or ex-smokers. 63% current smokers had been offered smoking cessation advice. 65% patients had active TED; 4% had sight-threatening TED. A large proportion of patients (54%) were unaware of their thyroid status. Not enough patients are being provided with smoking cessation advice and information on the impact of smoking on TED and control of thyroid function.

Stimulated urine C-peptide creatinine ratio vs serum C-peptide level for monitoring of ß-cell function in the first year after diagnosis of Type 1 diabetes.

AIMS: To determine if urine C-peptide/creatinine ratio is a useful tool for monitoring ß-cell function in new-onset Type 1 diabetes. METHODS: Data were obtained from a prospective immunomodulation study in people with Type 1 diabetes ≤ 3 months from diagnosis, with a standard mixed-meal tolerance test and measurement of urine C-peptide/creatinine ratio carried out at 0, 3, 6, 9 and 12 months. The change in the insulin-dose-adjusted HbA1c level was also correlated with the change in serum/urine C-peptide level during the 12-month follow-up period. RESULTS: A significant reduction in urine C-peptide/creatinine ratio, measured after a mixed-meal, was reached at 9 months (-45.4%), whilst the reduction in stimulated serum C-peptide level reached significance after 3 months (-54.7%) in placebo-treated participants. Neither change in stimulated serum C-peptide nor change in urine C-peptide level correlated with each other, and nor did change in insulin-dose-adjusted HbA1c level in the first 6 months, but all measures correlated significantly in the second half of the 12-month follow-up period. CONCLUSION: Mixed-meal-stimulated urine C-peptide/creatinine ratio was similar to, although less sensitive than, stimulated serum C-peptide level in monitoring ß-cell function during the first year after diagnosis. Because the former is significantly less invasive, it warrants inclusion in further studies in Type 1 diabetes and may represent an attractive alternative outcome measure in cohort studies and in children.

Performance of statistical methods to correct food intake distribution: comparison between observed and estimated usual intake.

There are statistical methods that remove the within-person random error and estimate the usual intake when there is a second 24-h recall (24HR) for at least a subsample of the study population. We aimed to compare the distribution of usual food intake estimated by statistical models with the distribution of observed usual intake. A total of 302 individuals from Rio de Janeiro (Brazil) answered twenty, non-consecutive 24HR; the average length of follow-up was 3 months. The usual food intake was considered as the average of the 20 collection days of food intake. Using data sets with a pair of 2 collection days, usual percentiles of intake of the selected foods using two methods were estimated (National Cancer Institute (NCI) method and Multiple Source Method (MSM)). These estimates were compared with the percentiles of the observed usual intake. Selected foods comprised a range of parameter distributions: skewness, percentage of zero intakes and within- and between-person intakes. Both methods performed well but failed in some situations. In most cases, NCI and MSM produced similar percentiles between each other and values very close to the true intake, and they better represented the usual intake compared with 2-d mean. The smallest precision was observed in the upper tail of the distribution. In spite of the underestimation and overestimation of percentiles of intake, from a public health standpoint, these biases appear not to be of major concern.

The sodium iodide symporter is unlikely to be a thyroid/breast shared antigen.

PURPOSE: Anti-thyroid peroxidase (TPO) autoantibodies (TPOAb) seem to be protective for patients with breast cancer (BC). Thyroid and breast tissues both express the sodium iodide symporter (NIS), similarly both have a peroxidase activity, TPO and lactoperoxidase (LPO) respectively. We hypothesize a common immune response to a thyroid/breast shared antigen suggesting three putative mechanisms: (1) TPOAb react to both TPO and LPO, (2) TPO could be expressed in BC and (3) patients with TPOAb could have autoantibodies to NIS (NISAb). Previous studies excluded NISAb that block NIS activity in sera of patients with thyroid autoimmunity (TA) and/or BC. This study investigates neutral NISAb (binding without affecting function). METHODS: Clones of CHO cells stably expressing human NIS (hNIS; CHO-NIS) were isolated following transfection of hNIS in pcDNA3 vector. Expression of hNIS mRNA and surface protein was confirmed by PCR and flow cytometry respectively using a hNIS-mouse-monoclonal-antibody. CHO-NIS and controls transfected with the empty pcDNA3 vector (CHO-Empty) were incubated with 42 heat-inactivated human sera followed by an anti-human-IgG-AlexaFluor488-conjugate: 12 with BC, 11 with TA, 10 with both BC and TA and 9 with non-autoimmune thyroid diseases. The Kolmogorov-Smirnov Test was used to compare the fluorescence intensity obtained with CHO-NIS and CHO-Empty, using sera from six young males as a negative control population. RESULTS: None of the 42 sera were positive for NISAb. CONCLUSIONS: NISAb are rare and NIS is unlikely to be a common thyroid/BC shared antigen. We have recently demonstrated TPO expression in BC tissue and are currently investigating TPOAb cross-reactivity with TPO/LPO.

Does thyroid peroxidase provide an antigenic link between thyroid autoimmunity and breast cancer?

Women with breast cancer (BC) and antithyroid peroxidase (TPO) autoantibodies (TPOAb) have a better prognosis than women lacking TPOAb. Sera from women with TPOAb displayed immunoreactivity to BC tissue by immunofluorescence that was not apparent in women without TPOAb. We hypothesize a BC/thyroid shared antigen that provides a target for humoral or cell-mediated immune activity; candidates include the sodium/iodide symporter (expressed in thyroid and BC), cross-reacting epitopes in TPO and lactoperoxidase (LPO) or TPO itself. As the association is with TPOAb, we investigated TPO expression in BC, breast peritumoral tissue (PT), other tissues (tumoral and not) and thyroid as positive control. Transcripts for known and novel TPO isoforms were detected in BC (n = 8) and PT (n = 8) but at approximately 10(4) -fold lower than in thyroid while in non-BC tumors (n = 5) they were at the limit of detection. TPO was expressed also in adipose tissue (n = 17), 10(3) -fold lower than in thyroid. Full length TPO (Mr 105-110 kDa) was detected in Western blots in the majority of examined tissues; preabsorption of the TPO antibody with recombinant TPO (but not LPO) reduced the signal, indicating specificity. The same occurred with some lower molecular weight bands, which could correspond to smaller TPO transcript isoforms, present in all samples. In conclusion, TPO is weakly expressed in BC and other tissues; this could partly explain the high frequency and protective role of TPOAb in BC patients. Further studies will investigate tissue specificity, function and immunogenicity of the novel TPO variants (some BC-specific) identified.

Efficacy and safety of low-dose otelixizumab anti-CD3 monoclonal antibody in preserving C-peptide secretion in adolescent type 1 diabetes: DEFEND-2, a randomized, placebo-controlled, double-blind, multi-centre study.

AIMS: Phase III DEFEND-2 investigated whether otelixizumab (3.1 mg over 8 days) preserved C-peptide secretion in patients with new-onset Type 1 diabetes, focusing on adolescents (12-17 years). METHODS: One hundred and seventy-nine patients (54 adolescents) were randomized to otelixizumab or placebo. The primary endpoint was change in 2-h mixed-meal-stimulated C-peptide area under the curve at month 12. Enrolment was suspended in April 2011 following negative efficacy results from DEFEND-1. DEFEND-2 terminated early after 12 months' efficacy and safety follow-up. RESULTS: Change from baseline C-peptide was not significantly different [∆ = -0.09 nmol/l (95% CI -0.17 to 0; P = 0.051)]. No differential C-peptide effect was seen for otelixizumab in adolescents and more adverse events were reported. CONCLUSIONS: Efficacy and tolerability of otelixizumab was similar to DEFEND-1. The 3.1-mg dose was non-efficacious in adults and adolescents. Further investigation of the mechanism of action seen at higher doses and therapeutic window is required. Clinical Trials Registry No: NCT 00763451.

Sedentary time and markers of inflammation in people with newly diagnosed type 2 diabetes.

BACKGROUND AND AIMS: We investigated whether objectively measured sedentary time was associated with markers of inflammation in adults with newly diagnosed type 2 diabetes. METHODS AND RESULTS: We studied 285 adults (184 men, 101 women, mean age 59.0 ± 9.7) who had been recruited to the Early ACTivity in Diabetes (Early ACTID) randomised controlled trial. C-reactive protein (CRP), adiponectin, soluble intracellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), and accelerometer-determined sedentary time and moderate-vigorous physical activity (MVPA) were measured at baseline and after six-months. Linear regression analysis was used to investigate the independent cross-sectional and longitudinal associations of sedentary time with markers of inflammation. At baseline, associations between sedentary time and IL-6 were observed in men and women, an association that was attenuated following adjustment for waist circumference. After 6 months of follow-up, sedentary time was reduced by 0.4 ± 1.2 h per day in women, with the change in sedentary time predicting CRP at follow-up. Every hour decrease in sedentary time between baseline and six-months was associated with 24% (1, 48) lower CRP. No changes in sedentary time between baseline and 6 months were seen in men. CONCLUSIONS: Higher sedentary time is associated with IL-6 in men and women with type 2 diabetes, and reducing sedentary time is associated with improved levels of CRP in women. Interventions to reduce sedentary time may help to reduce inflammation in women with type 2 diabetes.

Islet cells in human type 1 diabetes: from recent advances to novel therapies - a symposium-based roadmap for future research.

There is a growing understanding that the early phases of type 1 diabetes (T1D) are characterised by a deleterious dialogue between the pancreatic beta cells and the immune system. This, combined with the urgent need to better translate this growing knowledge into novel therapies, provided the background for the JDRF-DiabetesUK-INNODIA-nPOD symposium entitled 'Islet cells in human T1D: from recent advances to novel therapies', which took place in Stockholm, Sweden, in September 2022. We provide in this article an overview of the main themes addressed in the symposium, pointing to both promising conclusions and key unmet needs that remain to be addressed in order to achieve better approaches to prevent or reverse T1D.

Sedentary time, breaks in sedentary time and metabolic variables in people with newly diagnosed type 2 diabetes.

AIMS/HYPOTHESIS: We investigated whether objectively measured sedentary time and interruptions in sedentary time are associated with metabolic factors in people with type 2 diabetes. METHODS: We studied 528 adults (30-80 years) with newly diagnosed type 2 diabetes, who were participants in a diet and physical activity intervention. Waist circumference (WC), fasting HDL-cholesterol, insulin and glucose levels, HOMA of insulin resistance (HOMA-IR) and physical activity (accelerometer) were measured at baseline and at 6 months follow-up. Linear regression models were used to investigate cross-sectional and longitudinal associations of accelerometer-derived sedentary time and breaks in sedentary time (BST) with metabolic variables. RESULTS: In cross-sectional analyses each hour of sedentary time was associated with larger WC (unstandardised regression coefficient [B] [95% CI] 1.89 cm [0.94, 2.83]; p < 0.001), higher insulin (B = 8.22 pmol/l [2.80, 13.65]; p = 0.003) and HOMA-IR (B = 0.42 [0.14, 0.70]; p = 0.004), and lower HDL-cholesterol (B = -0.04 mmol/l [-0.06, -0.01]; p = 0.005). Adjustment for WC attenuated all associations. Each BST was associated with lower WC (B = -0.15 cm [- 0.24, -0.05]; p = 0.003) and there was evidence of a weak linear association with HDL-cholesterol, but no association with insulin levels or HOMA-IR. Volume of sedentary time at baseline predicted HDL-cholesterol (B = -0.05 mmol/l [-0.08, -0.01]; p = 0.007), insulin levels (B = 8.14 pmol/l [0.1.51, 14.78]; p = 0.016) and HOMA-IR (B = 0.49 [0.08, 0.90]; p = 0.020) at 6 months, though not WC. Baseline BST did not substantially predict any metabolic variables at follow-up. No change was seen in sedentary time or BST between baseline and 6 months follow-up. CONCLUSIONS/INTERPRETATION: Higher sedentary time is associated with a poorer metabolic profile in people with type 2 diabetes.

Diet or diet plus physical activity versus usual care in patients with newly diagnosed type 2 diabetes: the Early ACTID randomised controlled trial.

BACKGROUND: Lifestyle changes soon after diagnosis might improve outcomes in patients with type 2 diabetes mellitus, but no large trials have compared interventions. We investigated the effects of diet and physical activity on blood pressure and glucose concentrations. METHODS: We did a randomised, controlled trial in southwest England in adults aged 30-80 years in whom type 2 diabetes had been diagnosed 5-8 months previously. Participants were assigned usual care (initial dietary consultation and follow-up every 6 months; control group), an intensive diet intervention (dietary consultation every 3 months with monthly nurse support), or the latter plus a pedometer-based activity programme, in a 2:5:5 ratio. The primary endpoint was improvement in glycated haemoglobin A(1c)(HbA(1c)) concentration and blood pressure at 6 months. Analysis was done by intention to treat. This study is registered, number ISRCTN92162869. FINDINGS: Of 593 eligible individuals, 99 were assigned usual care, 248 the diet regimen, and 246 diet plus activity. Outcome data were available for 587 (99%) and 579 (98%) participants at 6 and 12 months, respectively. At 6 months, glycaemic control had worsened in the control group (mean baseline HbA(1c) percentage 6·72, SD 1·02, and at 6 months 6·86, 1·02) but improved in the diet group (baseline-adjusted difference in percentage of HbA(1c) -0·28%, 95% CI -0·46 to -0·10; p=0·005) and diet plus activity group (-0·33%, -0·51 to -0·14; p<0·001). These differences persisted to 12 months, despite less use of diabetes drugs. Improvements were also seen in bodyweight and insulin resistance between the intervention and control groups. Blood pressure was similar in all groups. INTERPRETATION: An intensive diet intervention soon after diagnosis can improve glycaemic control. The addition of an activity intervention conferred no additional benefit. FUNDING: Diabetes UK and the UK Department of Health.

In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis.

UNLABELLED: Steroids improve the outcome in alcoholic hepatitis (AH), but up to 40% of patients fail to respond adequately. Interleukin-2 (IL-2) exacerbates steroid resistance in vitro. We performed a prospective study to determine if intrinsic steroid sensitivity correlates with response to steroids in individuals with severe AH and if IL-2 receptor blockade can reverse this. Peripheral blood mononuclear cells (PBMCs) were isolated from 20 patients with AH and a Maddrey's score >32. Patients were treated with oral prednisolone plus full supportive measures. Clinical resistance to oral steroid treatment was defined as a drop in serum bilirubin of <25% within 7 days or death within 6 months. In vitro steroid resistance was measured in PBMC using the dexamethasone suppression of lymphocyte proliferation assay and repeated after the addition of the anti-IL-2 receptor (anti-CD25) monoclonal antibody, basiliximab. Suppression of lymphocyte proliferation <60% was considered to indicate steroid resistance. In all, 82% (9/11) of in vitro steroid-resistant patients were dead at 6 months as compared to 21% (2/9) of steroid-sensitive patients (P = 0.03). Similarly, 91% (10/11) of in vitro steroid-resistant patients failed to show a significant fall in bilirubin at day 7 as compared to 44% (4/9) of steroid-sensitive patients (P < 0.05). Basiliximab improved the maximal proliferation count in 91% (10/11) of in vitro steroid-resistant patients (P = 0.003). CONCLUSION: Clinical outcome of steroid therapy in this patient cohort correlated with in vitro steroid resistance. IL-2 blockade improved in vitro steroid sensitivity. This suggests that intrinsic lack of steroid sensitivity may contribute to poor clinical response to steroids in severe AH. IL-2 receptor blockade represents a possible mechanism to overcome this.

Investigation of thyroid dysfunction is more likely in patients with high psychological morbidity.

BACKGROUND: Mild or subclinical hypothyroidism [raised thyroid-stimulating hormone (TSH) but normal free thyroxine (T4)] affects 5-10% of adults. Symptoms are non-specific and TSH levels are needed for diagnosis. OBJECTIVES: We explore the relationship between thyroid function and psychological distress and investigate the usefulness of an expert-designed Thyroid Symptom Questionnaire (TSQ) in identifying hypothyroidism. METHODS: DEPTH (DEPression and THyroid) is a cross-sectional study of 325 patients recruited from general practices in Bristol, for whom thyroid function tests were requested by the GP. Subjects completed the TSQ, General Health Questionnaire (GHQ-12) and Patient Health Questionnaire (PHQ) and had blood tests for TSH and free T4. RESULTS: The mean age was 45.7 years; 252 subjects (78%) were female; median TSH was 1.6. Psychological morbidity in this population is high: 54.2% have a GHQ-12 score >3, indicating psychological distress. We found no relationship between TSH and psychological distress [adjusted odds ratio 1.02 (95% confidence interval 0.91-1.13), P = 0.78]. The prevalence of hypothyroidism was 6.2% (95% confidence interval 3.8-9.5%). We found no evidence of an unadjusted association between TSQ score and subclinical hypothyroidism [adjusted odds ratio of 1.09 (95% confidence interval 0.95-1.24), P = 0.23]. CONCLUSIONS: Those referred for thyroid function tests, although no more likely than others to have hypothyroidism, have high rates of psychological distress. When mild (subclinical) hypothyroidism is detected in patients with psychological distress, it is important that GPs are aware that this is likely to be coincidental rather than causal and offer appropriate treatment.

Safety of the use of gold nanoparticles conjugated with proinsulin peptide and administered by hollow microneedles as an immunotherapy in type 1 diabetes.

Antigen-specific immunotherapy is an immunomodulatory strategy for autoimmune diseases, such as type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune ß-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNPs), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well tolerated in participants with type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal administration offers a number of possibilities to enhance its tolerogenic potential, which should be explored in future studies.

Immunology of Diabetes Society T-Cell Workshop: HLA class I tetramer-directed epitope validation initiative T-Cell Workshop Report-HLA Class I Tetramer Validation Initiative.

BACKGROUND: Identification of T-cell reactivity to ß-cell antigen epitopes is an important goal for studying pathogenesis and for designing and monitoring of immunotherapeutic interventions in type 1 diabetes (T1D). METHODS: We performed a multicentre validation of known human leukocyte antigen (HLA) class I CD8+ T-cell epitopes. To this end, peripheral blood T-cell responses were measured in 35 recently (<2 years) diagnosed HLA-A*02:01+ T1D patients using blind-coded HLA-A2 tetramers (TMrs) and pentamers (PMrs), encompassing two epitopes of preproinsulin (PPI; PPIA12-20 and PPIB10-18) and two epitopes of glutamic acid decarboxylase (GAD; GAD114-122 and GAD536-545). We also compared the readout of TMrs and PMrs with a CD8+ T-cell interferon-γ enzyme-linked immunospot assay. RESULTS: Despite the minute frequencies of autoreactive cells detected by TMrs/PMrs, most (73-77%) T1D patients had responses to one or more of the epitopes used. All four epitopes were recognized by T1D patients, with a prevalence ranging from 5 to 25%. TMrs and PMrs detected more positive responses to the ß-cell epitopes than CD8+ T-cell interferon-γ enzyme-linked immunospot. However, concordance between positive responses to TMrs and PMrs was limited. CONCLUSIONS: Using a multicentre blind-coded setup and three different T-cell assays, we have validated PPI and GAD epitopes as commonly recognized CD8+ T-cell targets in recently diagnosed T1D patients. Both TMrs and PMrs showed higher detection sensitivity than the CD8+ T-cell interferon-γ enzyme-linked immunospot assay. However, there are some important methodological issues that need to be addressed in using these sensitive techniques for detecting low frequency responses.

Sensor-augmented pump therapy lowers HbA(1c) in suboptimally controlled Type 1 diabetes; a randomized controlled trial.

AIMS: To investigate the efficacy of sensor-augmented pump therapy vs. multiple daily injection therapy in patients with suboptimally controlled Type 1 diabetes. METHODS: In this investigator-initiated multi-centre trial (the Eurythmics Trial) in eight outpatient centres in Europe, we randomized 83 patients with Type 1 diabetes (40 women) currently treated with multiple daily injections, age 18-65 years and HbA(1c) ≥ 8.2% (≥ 66 mmol/mol) to 26 weeks of treatment with either a sensor-augmented insulin pump (n = 44) (Paradigm(®) REAL-Time) or continued with multiple daily injections (n = 39). Change in HbA(1c) between baseline and 26 weeks, sensor-derived endpoints and patient-reported outcomes were assessed. RESULTS: The trial was completed by 43/44 (98%) patients in the sensor-augmented insulin pump group and 35/39 (90%) patients in the multiple daily injections group. Mean HbA(1c) at baseline and at 26 weeks changed from 8.46% (SD 0.95) (69 mmol/mol) to 7.23% (SD 0.65) (56 mmol/mol) in the sensor-augmented insulin pump group and from 8.59% (SD 0.82) (70 mmol/mol) to 8.46% (SD 1.04) (69 mmol/mol) in the multiple daily injections group. Mean difference in change in HbA(1c) after 26 weeks was -1.21% (95% confidence interval -1.52 to -0.90, P < 0.001) in favour of the sensor-augmented insulin pump group. This was achieved without an increase in percentage of time spent in hypoglycaemia: between-group difference 0.0% (95% confidence interval -1.6 to 1.7, P = 0.96). There were four episodes of severe hypoglycaemia in the sensor-augmented insulin pump group and one episode in the multiple daily injections group (P = 0.21). Problem Areas in Diabetes and Diabetes Treatment Satisfaction Questionnaire scores improved in the sensor-augmented insulin pump group. CONCLUSIONS: Sensor augmented pump therapy effectively lowers HbA(1c) in patients with Type 1 diabetes suboptimally controlled with multiple daily injections.

The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy.

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves' hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations.