Comprehensive immunophenotypic analysis reveals the pathological involvement of Th17 cells in Graves' disease.

Graves' disease (GD) is an organ-specific autoimmune disease, but there are a few studies that have evaluated how immunophenotypes are related to clinical symptoms and intractable pathology, or the effects of treatment on immunophenotypes. We performed peripheral blood immunophenotyping in GD. We assessed the proportion of functional subsets of T helper cells (such as Th1, Th17, Treg and Tfh cells), B cells (Naïve, IgM memory, Class-switched, IgD-CD27- double negative and Plasmablasts cells), Monocytes, Dendritic cells and NK cells, and evaluated the relationship of immunophenotypes with clinical indices, disease activity, risk of relapse, and changes in immunophenotypes after treatment with antithyroid drugs. The activated Th17 cells, activated T follicular helper (Tfh) cells, and IgD-CD27- double-negative B cells were higher in newly onset GD compared with healthy participants. Th17 cells were associated with thyroid autoantibodies, thyroid function, thyroid enlargement, and Graves' Recurrent Events After Therapy (GREAT) score; while double-negative B cells were associated with thyroid autoantibodies. Treatment with antithyroid drugs decreased the activated Tfh cells in parallel with the improvement in thyroid function. However, activated Th17 cells were not associated with clinical improvement and remained unchanged. Peripheral blood immunophenotyping identified the differential involvement of T and B cell subsets in the pathogenesis of GD. Abnormalities in the differentiation of Th17, Tfh, and double-negative B cells reflected the clinical pathology associated with autoantibody production and excess thyroid hormones. And Th17 cells are significantly associated with the marker for resistance to treatment. These results suggest the involvement of Th17 cell activation in the intractable pathology associated with potential immune abnormalities in GD. Clinical trial registration: #UMIN000017726 (Date: June 1st, 2015).

Safety monitoring of COVID-19 vaccines in Japan.

The assessment of the efficacy and safety of coronavirus disease 2019 (COVID-19) vaccines in actual practice is extremely important, and monitoring efforts are being implemented worldwide. In Japan, a joint council in the Ministry of Health, Labour and Welfare is held every two to three weeks to summarise information on the adverse events following COVID-19 vaccination, with careful assessment of individual case safety reports and comparison with background incidence rates. In 2021, the joint council mainly reviewed anaphylaxis, death, myocarditis/pericarditis, and thrombosis with thrombocytopenia syndrome. These activities resulted in several safety-related regulatory actions, including the revision of vaccine package inserts with warnings about myocarditis/pericarditis. International sharing of vaccine safety information, as well as details of the evaluation systems, is important for international discussion and decision-making on better safety monitoring of COVID-19 vaccines.

Hypoglycemia induces vascular endothelial dysfunction in subjects with normal glucose tolerance.

This prospective study determined the effects of hypoglycemic stimulation on vascular endothelial function in non-diabetic patients using reactive hyperemia peripheral arterial tonometry (RH-PAT). The study included non-diabetic patients who were hospitalized for an insulin tolerance test (ITT) for the diagnosis of hypoadrenocorticism or hypopituitarism. Vascular endothelial function was assessed using the reactive hyperemia index (RHI) measured by the RH-PAT. We also measured the levels of anterior pituitary hormone, adrenaline, noradrenaline, and dopamine at the time of hypoglycemia. The primary endpoint was a change in the RHI at 120 min after insulin administration. The study included 27 patients. ITT was associated with significant increases in systolic blood pressure, pulse rate, and the blood levels of adrenocorticotropic hormone, cortisol, growth hormone, adrenaline, noradrenaline, and dopamine. RHI significantly decreased after ITT from 2.24 ± 0.51 to 1.71 ± 0.42. A significant inverse correlation was observed between the change in RHI and change in adrenaline (r = - 0.670, p = 0.012). We concluded that hypoglycemic stimulation altered vascular endothelial function, as measured by RH-PAT, even in patients free of glucose intolerance. The observed deterioration in vascular endothelial function correlated with increases in catecholamine levels during hypoglycemia.Trial registration: UMIN000033244.

Human dendritic cell-derived osteoclasts with high bone resorption capacity and T cell stimulation ability.

Osteoclasts are typically differentiated from monocytes (Mo-OC). A subset of osteoclasts (DC-OC) that are differentiated from dendritic cells (DC) has been reported in the arthritic mice model. However, little information is available on DC-OC in humans. The present study applied both in vitro and in vivo experiments to determine the function and pathological significance of DC-OC. DC-OC were differentiated from human monocyte-derived DC and their bone resorption and antigen-presenting functions were investigated. Synovial tissue samples from patients with rheumatoid arthritis were examined for the presence and characteristics of DC-OC. DC-OC differentiated from DC in the presence of M-CSF and RANKL in vitro were demonstrated to be cathepsin K-positive and TRAP-positive multinucleated giant cells. The DC-OC showed stronger bone resorption ability than monocyte-derived osteoclast (Mo-OC) as observed with the pit formation assay. The DC-OC retained CD11c positivity and expressed costimulatory molecules, unlike Mo-OC. T-cells proliferated when co-cultured with DC-OC, but not with Mo-OC. The addition of abatacept to the cocultures reduced T-cell stimulating activity of DC-OC. Abatacept inhibited the differentiation of monocytes into Mo-OC but did not suppress the differentiation of DC into DC-OC. TRAP-positive and CD86-positive DC-OC were detected in the synovial membranes of rheumatoid arthritis patients but not in patients with osteoarthritis. Human DC-OC demonstrated T-cell stimulating activity in addition to osteolytic activity. We further observed this subset of osteoclasts in the inflammatory synovial membrane of patients with rheumatoid arthritis. Such deviations from normal bone metabolism contribute to the inflammation and bone destruction in chronic inflammatory diseases such as rheumatoid arthritis.

Response of thyrotropin-secreting pituitary tumors to preoperative lanreotide therapy. Report of two cases.

Case 1 was a 51-year-old man diagnosed with thyrotropin (TSH)-secreting pituitary tumor. The octreotide loading test showed suppression of TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. Three months after treatment initiation, tumor shrinkage was observed, and pituitary tumor resection was performed through transsphenoidal surgery. Case 2 was a 47-year-old woman in whom the octreotide loading test showed suppressed TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. After six months of treatment, tumor reduction was observed, and transsphenoidal surgery was performed. In both cases, lanreotide administration before TSH-secreting pituitary tumor resection achieved normalization of thyroid function and tumor shrinkage. Treatment with lanreotide seems effective in patients who show TSH secretion suppression in the octreotide loading test.

Efficacy and Safety of Tofogliflozin on 24-h Glucose Profile Based on Continuous Glucose Monitoring: Crossover Study of Sodium-Glucose Cotransporter 2 Inhibitor.

Background: To compare the impact of two sodium-glucose cotransporter 2 (SGLT2) inhibitors, tofogliflozin and ipragliflozin, on hypoglycemia in patients with type 2 diabetes mellitus (T2DM), treated with sulfonylureas. Methods: Thirty patients with T2DM were allocated to treatment with either 20 mg/day tofogliflozin or 50 mg/day ipragliflozin and underwent continuous glucose monitoring (CGM) for 5 days at three times in a crossover manner. Results: The percent time spent at glucose <70 mg/dL per 24 h was 0.48, 2.77, and 0.06%, before treatment with SGLT2 inhibitors and treatment with ipragliflozin and tofogliflozin, respectively (P = 0.1135, difference between SGLT2 inhibitors). The addition of either ipragliflozin or tofogliflozin to sulfonylureas markedly and significantly improved other CGM-derived parameters, including average plasma glucose, standard deviation of glucose, mean postprandial glucose excursion, percent time with glucose >140, >180 mg/dL, and >200 mg/dL, area over the curve <70, area under the curve >140, >180, and >200, and maximum and minimum plasma glucose. However, there were no significant differences in these parameters between the two SGLT2 inhibitors. Conclusions: Based on the CGM, the addition of tofogliflozin to sulfonylureas tended to decrease the percent time spent in hypoglycemia in T2DM patients. The addition of SGLT2 inhibitors to sulfonylureas improved the average glucose level and reduced glucose fluctuations without increasing the time in hypoglycemia.

A Study of the Vascular Endothelial Function in Patients with Type 2 Diabetes Mellitus and Rheumatoid Arthritis.

Objective Type 2 diabetes mellitus (T2DM) and rheumatoid arthritis (RA) are both complicated by arteriosclerosis, resulting in increased rates of cardiovascular events. No previous studies have compared the index between RA and T2DM. We assessed the vascular endothelial function in early-stage arteriosclerosis for each disease to determine the influential factors and compared the extent to which these two diseases cause vascular endothelial dysfunction. Methods This study is a retrospective study based on medical records. Differences in the reactive hyperemia index (RHI) among the groups and factors affecting the RHI in each group was analyzed. The vascular endothelial function was assessed by measuring the RHI using peripheral arterial tonometry. Patients The study subjects were 114 patients with non-functional thyroid tumors (healthy n=14), T2DM (T2DM n=64), and RA (RA n=36). Results The RHI was 2.29 in the control, 1.85 in the T2DM, and 1.83 in the RA group, with values lower in the T2DM and RA groups than in the control group (p=0.033) but not markedly different between the two disease groups. The RHI distribution (<1.68/1.68 to <2.10/≥2.1) was as follows: control group: 14.3%/28.6%/57.1%; T2DM group: 42.2%/39.1%/18.8%; and RA group: 36.1%/44.4%/19.4% (p=0.031), respectively. A multivariate analysis identified the triglyceride level and dyslipidemia in the control group and the Disease Activity Score in 28 joints with the erythrocyte sedimentation rate and fasting plasma glucose level in the RA group to influence the RHI. Conclusion The vascular endothelial function was impaired in approximately 80% of patients with T2DM and RA, with comparable degrees of impairment between the two diseases. No factors affecting the function were identified in the T2DM group, while the function was more impaired in patients with a higher disease activity in the RA group.

Hypoglycemia in blood glucose level in type 2 diabetic Japanese patients by continuous glucose monitoring.

BACKGROUND: Hypoglycemia is associated with cardiovascular diseases, increased risk of death. Therefore, it is important to avoid hypoglycemia. The aim of this study was to characterize hypoglycemia according to glycated hemoglobin (HbA1c) level and determine the contributing factors in type 2 diabetes mellitus (T2DM), using continuous glucose monitoring (CGM). METHODS: T2DM patients (n = 293) receiving inpatient care were divided into five groups according to HbA1c level on admission (Group 1: ≥ 6 to < 7%, Group 2: ≥ 7 to < 8%, Group 3: ≥ 8 to < 9%, Group 4: ≥ 9 to < 10%, and Group 5: ≥ 10%). The frequency of hypoglycemia and factors associated with hypoglycemia were analyzed. RESULTS: Hypoglycemia occurred in 15 patients (5.1%), including 4 (8%), 4 (6%), and 7 (10%) patients of Groups 1, 2, and 3, respectively, but in none of groups 4 and 5. Patients with hypoglycemia of Groups 1 had low insulin secretion and were high among insulin users, those of Groups 2 had low homeostasis model assessment of insulin resistance (HOMA-IR). Those of Group 2 and 3 had significantly lower mean blood glucose levels, those of Group 3 only had significantly lower maximum blood glucose level and percentage of AUC > 180 mg/dL. In any of the HbA1c groups, variations in blood glucose level were significantly larger in patients with hypoglycemia than without. CONCLUSIONS: Hypoglycemia occurred in patients with a wide range of HbA1c on admission (range 6-9%), suggesting that prediction of hypoglycemia based on HbA1c alone is inappropriate. Among patients with low HbA1c, strict control sometimes induce hypoglycemia. Among patients with high HbA1c, the possibility of hypoglycemia should be considered if there is a marked discrepancy between HbA1c and randomly measured blood glucose level. Larger variations in blood glucose level induce hypoglycemia in any of the HbA1c groups. The treatment to reduce variations in blood glucose level is important to prevent hypoglycemia.

Glycemic Profiling in Patients with Drug-Naïve Type 2 Diabetes by Continuous Glucose Monitoring.

The purpose of this study was to determine the glycemic profiles of drug-naïve type 2 diabetes patients according to hemoglobin A1c (HbA1c) level using continuous glucose monitoring. We aimed to clarify factors associated with HbA1c and average blood glucose level. Patients were divided into three groups according to their HbA1c level (< 7.0% n=23, 7.0% ≤ HbA1c < 8.0% n=17 and ≥ 8.0% n=31), and the factors associated with HbA1c and average glucose of each group were evaluated. Pre-meal glucose levels were the highest before lunch, and the 2 hour postprandial blood glucose level was the lowest after lunch. The pre-meal and postprandial blood glucose levels increased after each meal with increases in HbA1c. Average glucose level was the most significant determinant of HbA1c, whereas pre-meal glucose level at dinner was the most significant determinant of average glucose level, and the range of increase in glucose from pre-meal at dinner was the most significant determinant of standard deviation (SD) of 24 hour glucose levels. HbA1c subgroup analysis indicated that pre-meal glucose level at lunch significantly correlated with average glucose level in the HbA1c < 8.0% group, while pre-meal glucose level at dinner significantly correlated with average glucose level in the HbA1c ≥ 8.0% group. The range of increase in glucose from pre-meal in the morning significantly correlated with SD of 24 hour glucose levels in the HbA1c < 8.0% group, and the postprandial peak glucose level at lunch significantly correlated with SD of 24 hour glucose levels in the HbA1c ≥ 8.0% group. The results suggest that improvement of the average glucose level is necessary to improve the HbA1c levels. For patients with HbA1c < 7.0%, it is important to improve blood glucose level after breakfast and before lunch to decrease the average glucose level. For patients with 7.0% ≤ HbA1c < 8.0%, it is important to improve blood glucose level before lunch and after dinner to decrease the average glucose level. For patients with HbA1c ≥ 8.0%, it is important to improve blood glucose levels after lunch and before dinner to decrease the average glucose level.

Association Between Diabetic Microangiopathies and Glycemic Variability Assessed by Continuous Glucose Monitoring.

The aim of this retrospective study was to elucidate the association between glucose profile using the continuous glucose monitoring system (CGMS) and microvascular complications in patients with type 2 diabetes mellitus (T2DM). The subjects were 160 inpatients with T2DM. The mean blood glucose (MBG) level, percentage of time in a 24-hour period spent with blood glucose level higher than 180 mg/dl (time at >180 mg/dl), standard deviation (SD), and mean amplitude of glycemic excursions (MAGE) were measured continuously over 48 hours using the CGMS. The primary outcome was the association between microvascular complications and glycemic variability. The secondary outcome was the association between microangiopathies and MBG. The SD and MAGE were not associated with presence of microangiopathies or number of complications. There were also no associations between abnormal vibratory sensation in the bilateral lower extremities, coefficient of variation of the R-R interval (CVRR), retinopathy stage, nephropathy stage, or microalbuminuria. MBG was associated, however, with retinopathy, retinopathy stage, and number of complications. Time at >180 mg/dl correlated with abnormal vibratory sensation in the bilateral lower extremities and presence or stage of retinopathy. MBG and time at >180 mg/dl were not associated with presence or stage of nephropathy. Our findings suggest that broad glycemic variability was not associated with microvascular complications, the number of which increased in patients with a high mean glucose level and long time spent with hyperglycemia. It is important, therefore, to reduce the mean glucose level and time spent with hyperglycemia to prevent future microangiopathies.

Twenty-four-hour variations in blood glucose level in Japanese type 2 diabetes patients based on continuous glucose monitoring.

AIMS/INTRODUCTION: High fluctuations in blood glucose are associated with various complications. The correlation between glycated hemoglobin (HbA1c) level and fluctuations in blood glucose level has not been studied in Japanese patients with type 2 diabetes. In the present study, blood glucose profile stratified by HbA1c level was evaluated by continuous glucose monitoring (CGM) in Japanese type 2 diabetes patients. MATERIALS AND METHODS: Our retrospective study included 294 patients with type 2 diabetes who were divided by HbA1c level into five groups (≥6.0 to <7.0%, ≥7.0 to <8.0%, ≥8.0 to <9.0%, ≥9.0 to <10.0% and ≥10%). The correlation between HbA1c level and CGM data was analyzed. The primary end-point was the difference in blood glucose fluctuations among the HbA1c groups. RESULTS: The mean blood glucose level increased significantly with increasing HbA1c (Ptrend  < 0.01). The standard deviation increased with increases in HbA1c (Ptrend  < 0.01). The mean amplitude of glycemic excursions did not vary significantly with HbA1c. The levels of maximum blood glucose, minimum blood glucose, each preprandial blood glucose, each postprandial maximum blood glucose, range of increase in postprandial glucose from pre-meal to after breakfast, the area under the blood concentration-time curve >180 mg/dL and percentage of the area under the blood concentration-time curve >180 mg/dL were higher with higher HbA1c. Mean glucose level and pre-breakfast blood glucose level were significant and independent determinants of HbA1c. CONCLUSIONS: In Japanese patients treated for type 2 diabetes, the mean amplitude of glycemic excursions did not correlate with HbA1c, making it difficult to assess blood glucose fluctuations using HbA1c. Parameters other than HbA1c are required to evaluate fluctuations in blood glucose level in patients receiving treatment for type 2 diabetes.

Metabolic Reprogramming Commits Differentiation of Human CD27+IgD+ B Cells to Plasmablasts or CD27-IgD- Cells.

B cells play a crucial role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the relevance of the metabolic pathway in the differentiation of human B cell subsets remains unknown. In this article, we show that the combination of CpG/TLR9 and IFN-α markedly induced the differentiation of CD27+IgD+ unswitched memory B cells into CD27hiCD38hi plasmablasts. The response was accompanied by mammalian target of rapamycin complex 1 (mTORC1) activation and increased lactate production, indicating a shift to glycolysis. However, CpG alone induced the differentiation of unswitched memory B cells into CD27-IgD- memory B cells with high cytokine production, but such differentiation was suppressed by IFN-α. AMP-activated protein kinase activation enhanced the differentiation to CD27-IgD- B cells, but it attenuated mTORC1 activation and differentiation into plasmablasts. High mTORC1 activation was noted in CD19+ B cells of patients with SLE and correlated with plasmablast differentiation and disease activity. Taken together, differential metabolic reprogramming commits the differentiation of human unswitched memory B cells into plasmablasts (the combination of CpG and IFN-α amplifies mTORC1-glycolysis pathways) or CD27-IgD- memory B cells (CpG alone amplifies the AMP-activated protein kinase pathway). The former metabolic pathway may play a pivotal role in SLE.

Clinical Features of Patients with Basedow's Disease and High Serum IgG4 Levels.

Objective IgG4-related disease is a recently characterized condition presenting with high blood IgG4 levels, swelling of organs, and hypertrophic lesions. This disease is associated with thyroid disease, Hashimoto's disease, and Riedel's thyroiditis. However, there is little information on the association between IgG4-related disease and Basedow's disease. We herein defined the clinical features of patients with Basedow's disease and high IgG4 levels. Methods We compared two groups of patients with Basedow's disease (n=72) who had either normal IgG4 levels (<135 mg/dL; n=67) or high IgG4 levels (≥135 mg/dL; n=5 [6.9%], mean IgG4: 206±116 mg/dL, IgG4/IgG ratio: 10.6%±3.3%). Patients Seventy-two newly diagnosed, untreated patients with Basedow's disease. Results Compared to the normal IgG4 group, patients in the high IgG4 group were predominantly male and showed a significantly higher thyroid low-echo score (1.8±0.4 vs. 1.2±0.5) and eosinophil count (363±354/mm2 vs. 136±122/mm2). Five patients had high IgG4 levels: one had a pancreatic lesion, and four had thyroid lesions. Conclusion Patients with Basedow's disease and high IgG4 levels may represent a new subtype of Basedow's disease. Further studies with larger sample sizes are needed.

Factors influencing inter-day glycemic variability in diabetic outpatients receiving insulin therapy.

INTRODUCTION: The aim of the present study was to determine the actual state of inter-day glycemic variability and identify the factors that affect glycemic variability in diabetic outpatients on insulin therapy. MATERIALS AND METHODS: The participants were 45 outpatients with diabetes mellitus receiving insulin therapy. The mean plasma glucose (MPG) levels, intra-day glycemic variability (expressed by standard deviation and mean amplitude of glucose excursion) and inter-day glycemic variability (expressed by mean of daily differences [MODD] in blood glucose levels) were measured continuously over 7 days with iPro2® . The primary outcome was the relationship between MODD and the life variability index. RESULTS: MODD values were high in 93.3% of the participants, and significantly higher in patients with lifestyle changes than in those without (higher in patients with high life variability index). MODD values were not associated with age, but significantly higher in women. MODD values correlated significantly with glycated hemoglobin and glycoalbumin levels, and negatively with 1,5-anhydroglucitol levels. MODD values were significantly higher in type 1 diabetes patients and not associated with duration of disease. MODD values correlated significantly with insulin dose. Multivariate analysis identified the life variability index as a significant determinant of MODD. CONCLUSIONS: iPro2® provided detailed information on glycemic profile in diabetic outpatients receiving insulin therapy. The results suggest that patients with large inter-day glycemic variability are unlikely to achieve an improvement in their glycated hemoglobin level. Treatment and instructions based on a patient's characteristics, day-to-day glycemic variability and lifestyle are important to achieve good glycemic control.

Comparative analysis of the effects of alogliptin and vildagliptin on glucose metabolism in type 2 diabetes mellitus.

The aim of this 24-week, prospective randomized open-label study was to compare the effects of alogliptin and vildagliptin on glucose control, renal function, and lipid metabolism. In Study 1, DPP-4 inhibitor-naive type 2 diabetes (T2DM) were randomly assigned to alogliptin 25 mg/day or vildagliptin 50 mg twice daily. In Study 2, T2DM on treatment with 50 mg/day sitagliptin were switched to either 25 mg/day alogliptin or 50 mg twice daily vildagliptin. The primary endpoint was change in glycosylated hemoglobin (HbA1c) level at 24 weeks, while the secondary endpoints were changes in urinary albumin excretion and low-density lipoprotein cholesterol (LDL-C) levels at 24 weeks. In Study 1, HbA1c levels changed at 24-week by -0.5±0.7% in the alogliptin group (p=0.002, relative to baseline) and -0.7±0.9% in the vildagliptin group (p=0.001, relative to baseline), and the extent of these changes were comparable between the two groups (p=0.219). The decrease in log urinary albumin excretion was more significant in the vildagliptin group (p=0.008). In Study 2, HbA1c levels at 24-week changed by 0.2±0.7% in the switch-to-alogliptin group (p=0.007) and 0.0±0.6% in the switch-to-vildagliptin group (p=0.188), indicating a significant difference between the groups (p=0.003). In both studies, the changes in LDL-C levels were comparable between the two groups. The two drugs had comparable glucose-lowering effects in DPP-4 inhibitor-naive patients but the effect was more pronounced for vildagliptin in patients switched from sitagliptin. The results may point to subtle yet important differences between the two DPP-4 inhibitors. This trial was registered with UMIN (no. #000019022).

Prednisolone Dosing Regimen for Treatment of Subacute Thyroiditis.

The rate of recurrence of subacute thyroiditis (SAT) during prednisolone (PSL) therapy is approximately 10 to 20%. However, there is little or no information on the time period to relapse following administration of a tapered dose of PSL and the factors associated with such relapse. The aim of this study was to determine the correlation between SAT recurrence and PSL tapering regimen used in the treatment of SAT. This study was a medical record-based retrospective study and involved 26 patients (3 men, 23 women) who received PSL therapy for SAT. The primary endpoint was the association between recurrence and number of days required to taper daily PSL dose to 5 mg. The secondary endpoint was the relationship between recurrence and several variables including age, clinical score, free thyroxine, inflammatory reaction, thyroglobulin, total treatment time, total dose of PSL and presence or absence of creeping thyroiditis. The SAT recurrence rate was 15.3%. There was no significant difference in the initial PSL dose between the non-recurrence and recurrence groups (27.5 mg vs 24.5 mg, P = 0.302). However, for the primary endpoint, significant differences were found between the two groups in time required for tapering PSL to 5 mg/day (non-recurrence: 44.3 ± 15.3 days, recurrence: 19.0 ± 11.9 days, P = 0.012). None of the clinical variables evaluated correlated significantly with SAT relapse. In conclusion, to prevent recurrence of SAT, consideration should be given to the period required for PSL tapering to 5 mg/day.

Induction of thyroid remission using rituximab in a patient with type 3 autoimmune polyglandular syndrome including Graves' disease and type 1 diabetes mellitus: a case report.

Rituximab (RTX) is a monoclonal antibody that targets the B-cell-specific CD20 antigen. Recent reports indicate that RTX is effective against type 1 diabetes mellitus (T1DM) and hematologic as well as autoimmune diseases. Other studies have indicated that RTX therapy leads to the remission of recurrent or active Graves' disease (GD). However, the efficacy of RTX in Japanese patients with autoimmune polyglandular syndrome (APS) has not been reported to date. Herein, we report the case of a patient with GD and T1DM with sustained endogenous insulin secretion capacity. To protect pancreatic ß cells, we administered RTX at a dose of 500 mg (approximately 300 mg/m2) on 2 occasions 1 week apart. After treatment, no adverse effects were observed, and thyroid stimulating hormone receptor antibody (TRAb) was no longer detectable 4 months after RTX administration. In addition, the reduction in TRAb level improved thyroid function. Notably, the treatment induced remission over a period of 1 year after the diagnosis of GD.

[Apathetic hyperthyroidism with heart failure in an elderly patient with Plummer's disease].

We report a case of apathetic hyperthyroidism associated with unrecognized slowly growing functional thyroid adenoma (Plummer's disease), atrial fibrillation and heart failure. An 81-year-old woman with worsening thyroid dysfunction was admitted to our hospital for the treatment of heart failure. The patient had developed heart failure associated with chronic atrial fibrillation at 76 years of age, and one year later was found to have asymptomatic hyperthyroidism. Anti-thyroid autoantibodies were negative, but thyroid echography showed a 32-mm tumor devoid of internal blood flow in the left lower lobe. Free thyroxine 4 (FT4) decreased from 3.30 to 2.60 ng/dl without treatment. The patient was diagnosed with transient thyroiditis and was followed-up without treatment. However, a repeat thyroid echography showed growth of the tumor to 41 mm in 4 years. Thyroid scintigraphy showed uptake that matched the thyroid mass. Based on these findings, the established diagnosis was Plummer's disease complicated with heart failure. The patient was treated with anti-thyroid drugs, which resulted in improvement of FT4 and reduced the severity of heart failure. In this rare case of an elderly patient, Plummer's disease was associated with a slowly-growing functional thyroid adenoma, apathetic hyperthyroidism, repeated episodes of atrial fibrillation and heart failure. Since symptoms of thyrotoxicosis are likely to be missed in the elderly, it is necessary to include hyperthyroidism in the pathoetiology of heart failure and atrial fibrillation in this population.

Glucose variability before and after treatment of a patient with Graves' disease complicated by diabetes mellitus: assessment by continuous glucose monitoring.

A 48-year-old woman was diagnosed and treated for Graves' disease (GD) in 1999 but she discontinued treatment at her own discretion. In 2011, she was admitted to a local hospital for management of thyrotoxic crisis. Treatment with propylthiouracil, iodide potassium (KI), and prednisolone (PSL) was started, which resulted in improvement of the general condition. PSL and KI were discontinued before she was transferred to our hospital. At the local hospital, fasting plasma glucose (FPG) was 212 mg/dL and hemoglobin A1c concentration was 11.2%; intensive insulin therapy had been instituted. Upon admission to our hospital, FPG level was 122 mg/dL, but insulin secretion was compromised, suggesting aggravation of thyroid function and deterioration of glycemic control. The FPG level increased to 173 mg/dL; continuous glucose monitoring (CGM) identified dawn phenomenon at approximately 0400 h. Resumption of KI resulted in improvement of FPG and disappearance of the dawn phenomenon, as assessed by CGM. These results indicate that in patients with compromised insulin secretion, hyperthyroidism can induce elevation of not only postprandial blood glucose, but also FPG level due to the dawn phenomenon and that the dawn phenomenon can be alleviated with improvement in thyroid function. To our knowledge, no studies have assessed glucose variability by CGM before and after treatment of Graves' disease. The observations made in this case shed light on the understanding of abnormal glucose metabolism associated with Graves' disease.

Efficacy of combination of Ezetimibe 10 mg and rosuvastatin 2.5 mg versus rosuvastatin 5 mg monotherapy for hypercholesterolemia in patients with type 2 diabetes.

BACKGROUND: Statins are used to treat hypercholesterolemia in patients with type 2 diabetes mellitus, but many of these patients fail to achieve the target LDL-C level. Recent reports have suggested that a synergistic effect can be obtained by concomitant administration of the cholesterol absorption inhibitor ezetimibe and a statin. However, in patients with type 2 diabetes who are already being treated with satins, it remains unclear whether it is more effective to add ezetimibe or to increase the statin dose. Therefore, this study was performed to examine the effects of these two regimens on LDL-C and lipoproteins. METHODS: The subjects were type 2 diabetic patients under treatment with rosuvastatin (2.5 mg daily), who had LDL-C levels ≥80 mg/dL. They were randomly allocated to a group that received add-on therapy with ezetimibe at 10 mg/day (combination group, n = 40) or an increase of the rosuvastatin dose to 5 mg/day (dose escalation group, n = 39). These two groups were compared at baseline and after 12 weeks of treatment. RESULTS: The percent change of LDL-C was -31% in the combination group and -12% in the dose escalation group. Both groups showed a significant decrease, but the decrease was greater in the combination group. In both groups, there was a significant decrease in the levels of small dense LDL-C, oxidized LDL and remnant-like lipoprotein cholesterol. For all of these parameters, the percent changes were greater in the combination group. Only the combination group showed a significant decrease of triglycerides. Multivariate analysis was performed to identify factors associated with reaching an LDL-C level <80 mg/dL. As a result, add-on therapy with ezetimibe was extracted as a factor related to improvement of LDL-C. CONCLUSIONS: Compared with increasing the dose of rosuvastatin, the combination of rosuvastatin and ezetimibe not only achieves quantitative but also qualitative improvement of serum lipid levels in type 2 diabetic patients, suggesting that this combination could suppress the progression of atherosclerosis. TRIAL REGISTRATION: UMIN000011005.