A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition. (ClinicalTrials.gov number, NCT00279305.)
BACKGROUNDType 1 diabetes is a chronic autoimmune disease that leads to destruction of insulinproducing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODSWe conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTSA total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization -44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. TIGIT+KLRG1+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONSTeplizumab delayed progression to clinical type 1 diabetes in high-risk participants.
Background The immunopathogenesis of type 1 diabetes mellitus (T1DM) is associated with T-lymphocyte autoimmunity. To be fully active, immune T-lymphocytes require a co-stimulatory signal in addition to the main antigen driven signal. Abatacept modulates co-stimulation andprevents full T-lymphocyte activation. We evaluated the effect of abatacept in recent-onset T1DM. Methods In this multicentre, double-masked, randomised controlled trial, 112 subjects (ages 6–36) recently diagnosed with T1DM; 77 received abatacept (10 mg/kg, maximum 1000 mg/dose) and 35 received placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over two years. Primary outcome was baseline-adjusted geometric mean 2-hour area under the curve (AUC) serum C-peptide following a mixed meal tolerance test at two years. Secondary outcomes include difference between groups in incidence of loss of peak C-peptide to < 0·2 pmol/ml, slope of C-peptide over time, changes in HbA1c and insulin dose, and safety. This trial is registered in ClinicalTrials.gov (NCT00505375). Findings Adjusted C-peptide AUC was 59% (95% CI: 6·1%, 112%) higher at two years with abatacept (0·378 pmol/ml) versus placebo (0·238 pmol/ml) (p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months’ delay in decline with abatacept. There was lower HbA1c (p<0·002) but similar insulin use. There were few, clinically not significant infusion related adverse events and minimal overall adverse events. There was no increase in infections or neutropenia. Interpretation Co-stimulation modulation with abatacept slowed decline of beta cell function over two years. The beneficial effect suggests that T-lymphocyte activation still occurs around the time of clinical diagnosis of T1DM. Yet, despite continued administration of abatacept over 24 months, the decline in beta cell function with abatacept was parallel to that with placebo after six months of treatment, causing us to speculate that T-lymphocyte activation may lessen with time. Further observation will determine whether the beneficial effect continues after cessation of abatacept infusions. Funding National Institutes of Health.
Background Type 1 diabetes (T1DM) is an autoimmune disease leading to destruction of insulin producing beta cells and life-long requirement for insulin therapy. Glutamic acid decarboxylase (GAD) is a major target of this immune response. Studies in animal models of autoimmunity have shown that treatment with a target antigen can modulate aggressive autoimmunity. We evaluated immunization with GAD formulated in aluminum hydroxide (alum) as an adjuvant in recent onset T1DM. Methods In this multicentre, double-masked, randomised controlled trial, 145 subjects (ages 3-45) with T1DM for less than 3 months received 3 injections of 20 μg GAD-alum (48 subjects), 2 injections of GAD-alum and one of alum alone (49 subjects) or 3 injections of alum (48 subjects) subcutaneously at baseline, 4 weeks later and 8 weeks after the second injection. Primary outcome was baseline-adjusted geometric mean 2-hour area under the curve (AUC) serum C-peptide following a mixed meal tolerance test at one year. Secondary outcomes included changes in HbA1c and insulin dose, and safety. This trial is registered in ClinicalTrials.gov (NCT00529399). Findings The ratio (experimental to control) of the adjusted population mean of C-peptide for the GAD-alum ×3 and GAD-alum ×2/alum ×1 groups is 0.998 (95% CI: [0.779, 1.22], p = 0.98) and 0.926 (95% CI: [0.720, 1.13], p = 0.50), respectively. HbA1c and insulin use did not differ between groups. There was no difference in rate or severity of adverse events between groups. Interpretation Antigen-based immunotherapy therapy using GAD-alum given subcutaneously in two or three doses over 4 to 12 weeks does not alter the course of loss of insulin secretion over one year in subjects with recently diagnosed T1DM. While antigen-based therapy is a highly desireable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge. Funding National Institutes of Health.
Summary Background Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. Methods We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6–45 years and those in the anakinra trial were aged 18–35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. Findings Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI −0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (−0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. Interpretation Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. Funding National Institutes of Health and Juvenile Diabetes Research Foundation.
OBJECTIVEWe previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of β-cell function in recent-onset type 1 diabetes mellitus (T1DM) at 1 year. Subjects were followed further to determine whether there was persistence of effect.RESEARCH DESIGN AND METHODSEighty-seven subjects (aged 8–40 years) were randomly assigned to, and 81 received, infusions of rituximab or placebo on days 1, 8, 15, and 22. The primary outcome—baseline-adjusted mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 1 year—showed higher C-peptide AUC with rituximab versus placebo. Subjects were further followed with additional MMTTs every 6 months.RESULTSThe rate of decline of C-peptide was parallel between groups but shifted by 8.2 months in rituximab-treated subjects. Over 30 months, AUC, insulin dose, and HbA1c were similar for rituximab and placebo. However, in evaluating change in C-peptide over the entire follow-up period, the rituximab group means were significantly larger as compared within assessment times with the placebo group means using a global test (P = 0.03). Odds ratio for loss of C-peptide to <0.2 nmol/L following rituximab was 0.565 (P = 0.064). B-lymphocytes recovered to baseline values by 18 months. Serum IgG levels were maintained in the normal range but IgM levels were depressed.CONCLUSIONSLike several other immunotherapeutic approaches tested, in recent-onset T1DM, rituximab delays the fall in C-peptide but does not appear to fundamentally alter the underlying pathophysiology of the disease.
The term pedophilia denotes the erotic preference for prepubescent children. The term hebephilia has been proposed to denote the erotic preference for pubescent children (roughly, ages 11 or 12-14), but it has not become widely used. The present study sought to validate the concept of hebephilia by examining the agreement between self-reported sexual interests and objectively recorded penile responses in the laboratory. The participants were 881 men who were referred for clinical assessment because of paraphilic, criminal, or otherwise problematic sexual behavior. Within-group comparisons showed that men who verbally reported maximum sexual attraction to pubescent children had greater penile responses to depictions of pubescent children than to depictions of younger or older persons. Between-groups comparisons showed that penile responding distinguished such men from those who reported maximum attraction to prepubescent children and from those who reported maximum attraction to fully grown persons. These results indicated that hebephilia exists as a discriminable erotic age-preference. The authors recommend various ways in which the DSM might be altered to accommodate the present findings. One possibility would be to replace the diagnosis of Pedophilia with Pedohebephilia and allow the clinician to specify one of three subtypes: Sexually Attracted to Children Younger than 11 (Pedophilic Type), Sexually Attracted to Children Age 11-14 (Hebephilic Type), or Sexually Attracted to Both (Pedohebephilic Type). We further recommend that the DSM-V encourage users to record the typical age of children who most attract the patient sexually as well as the gender of children who most attract the patient sexually.
Juvenile Diabetes Research Foundation (JDRF), NIH, Diabetes UK.
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