Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including ...an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy.
This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed.
Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 90% of 50 participants) and the withdrawal group (46 88% of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 64%) compared with the withdrawal group (24 46%).
Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE.
The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
BackgroundIL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody ...tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.MethodsWe conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6-17 years).ResultsThere was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.ConclusionTocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial RegistrationClinicalTrials.gov NCT02293837.FundingNIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.
Abstract Objective To examine the effectiveness of an intervention that combined continuing medical education with process improvement methods to implement “office systems” to improve the delivery of ...preventive care to children. Design Randomised trial in primary care practices. Setting Private paediatric and family practices in two areas of North Carolina. Participants Random sample of 44 practices allocated to intervention and control groups. Intervention Practice based continuing medical education in which project staff coached practice staff in reviewing performance and identifying, testing, and implementing new care processes (such as chart screening) to improve delivery of preventive care. Main outcome measure Change over time in the proportion of children aged 24-30 months who received age appropriate care for four preventive services (immunisations, and screening for tuberculosis, anaemia, and lead). Results The proportion of children per practice with age appropriate delivery of all four preventive services changed, after a one year period of implementation, from 7% to 34% in intervention practices and from 9% to 10% in control practices. After adjustment for baseline differences in the groups, the change in the prevalence of all four services between the beginning and the end of the study was 4.6-fold greater (95% confidence interval 1.6 to 13.2) in intervention practices. Thirty months after baseline, the proportion of children who were up to date with preventive services was higher in intervention than in control practices; results for screening for tuberculosis (54% v 32%), lead (68% v 30%), and anaemia (79% v 71%) were statistically significant (P < 0.05). Conclusion Continuing education combined with process improvement methods is effective in increasing rates of delivery of preventive care to children.
To improve health outcomes of children, the US Maternal and Child Health Bureau has recommended more effective organization of preventive services within primary care practices and more coordination ...between practices and community-based agencies. However, applying these recommendations in communities is challenging because they require both more complex systems of care delivery within organizations and more complex interactions between them. To improve the way that preventive health care services are organized and delivered in 1 community, we designed, implemented, and assessed the impact of a health care system-level approach, which involved addressing multiple care delivery processes, at multiple levels in the community, the practice, and the family. Our objective was to improve the processes of preventive services delivery to all children in a defined geographic community, with particular attention to health outcomes for low-income mothers and infants.
Observational intervention study in 1 North Carolina county (population 182 000) involving low- income pregnant mothers and their infants, primary care practices, and departments of health and mental health. An interrupted time-series design was used to assess rates of preventive services in office practices before and after the intervention, and a historical cohort design was used to compare maternal and child health outcomes for women enrolled in an intensive home visiting program with women who sought prenatal care during the 9 months before the program's initiation. Outcomes were assessed when the infants reached 12 months of age.
Our primary objective was to achieve changes in the process of care delivery at the level of the clinical interaction between care providers and patients that would lead to improved health and developmental outcomes for families. We selected interventions that were directed toward major risk factors (eg, poverty, ineffective care systems for preventive care in office practices) and for which there was existing evidence of efficacy. The interventions involved community-, practice-, and family-level strategies to improve processes of care delivery to families and children. The objectives of the community-level intervention were: 1) to achieve policy level changes that would result in changes in resources available at the level of clinical care, 2) to engage multiple practice organizations in the intervention to achieve an effect on most, if not all, families in the community, and 3) to enhance communication between, among, and within public and private practice organizations to improve coordination and avoid duplication of services. The objective of the practice-level interventions was to overcome specific barriers in the process of care delivery so that preventive services could be effectively delivered. To assist the health department in implementing the family-level intervention, we provided assistance in hiring and training staff and ongoing consultation on staff supervision, including the use of structured protocols for care delivery, and regular feedback data about implementation of the program. Interventions with primary care practices focused on the design of the delivery system within the office and the use of teamwork and data in an "office systems" approach to improving clinical preventive care. All practices (N = 8) that enrolled at least 5 infants/month received help in assessing performance and developing systems (eg, preventive services flow sheets) for preventive services delivery. Family-level interventions addressed the process of care delivery to high-risk pregnant women (<100% poverty) and their infants. Mothers were recruited for the home visiting intervention when they first sought prenatal care at the community health center, the county's largest provider of prenatal care to underserved women. The home visiting intervention involved teams of nurses and educators and involved 2 to 4 visits per month through the infant's first year of life to provide parental education on fetal and infant health and development, enhance parents' informal support systems, and link parents with needed health and human services. We included training in injury prevention and discipline, and home visitors assisted mothers in obtaining care from one of the primary care offices.
There were high levels of participation, changes in the organization of the delivery system, and improvements in preventive health outcomes. Agencies cooperated in joint contracting, staff training, and defining program eligibility. All 8 eligible practices agreed to participate and 7/8 implemented at least 1 new office system element. Of eligible women, 89% agreed to participate, and outcome data were available on 80% (180/225). After adjusting for differences in baseline characteristics, intervention group women were significantly more likely than comparison group women to use contraceptives (69% vs 47%), not smoke tobacco (27% vs 54%) and have a safe and stimulating home environment for their children. Intervention group children were more likely to have had an appropriate number of well-child care visits (57% vs 37%) and less likely to be injured (2% vs 7%). Intervention mothers also received Aid to Families with Dependent Children for fewer months after the birth of their child (7.7 months vs 11.3 months).
We observed a number of positive effects at all 3 levels of intervention. Policy-level changes at the state and community led to lasting changes in the organization and financing of care, which enabled changes in clinical services to take place. These changes have now been expanded beyond this community to other communities in the state. We were also able to engage multiple practice organizations, reduce duplication, and improve the coordination of care. Changes in the process of preventive services delivery were noted in participating practices. Finally, the outcomes of the family-level intervention were comparable in direction and magnitude to the outcomes of previous randomized trials of the intervention. All the changes were achieved over a relatively brief 3-year study period, and many have been sustained since the project was completed. Tiered, interrelated interventions directed at an entire population of mothers and children hold promise to improve the effectiveness and outcomes of health care for families and children.
Trials of immune therapies in new-onset type 1 diabetes (T1D) have shown success, but not all subjects respond, and the duration of response is limited. Our aim was to determine whether two courses ...of teplizumab, an Fc receptor–nonbinding anti-CD3 monoclonal antibody, reduces the decline in C-peptide levels in patients with T1D 2 years after disease onset. We also set out to identify characteristics of responders. We treated 52 subjects with new-onset T1D with teplizumab for 2 weeks at diagnosis and after 1 year in an open-label, randomized, controlled trial. In the intent to treat analysis of the primary end point, patients treated with teplizumab had a reduced decline in C-peptide at 2 years (mean −0.28 nmol/L 95% CI −0.36 to −0.20) versus control (mean −0.46 nmol/L 95% CI −0.57 to −0.35; P = 0.002), a 75% improvement. The most common adverse events were rash, transient upper respiratory infections, headache, and nausea. In a post hoc analysis we characterized clinical responders and found that metabolic (HbA1c and insulin use) and immunologic features distinguished this group from those who did not respond to teplizumab. We conclude that teplizumab treatment preserves insulin production and reduces the use of exogenous insulin in some patients with new-onset T1D. Metabolic and immunologic features at baseline can identify a subgroup with robust responses to immune therapy.
Trials of immune therapies in new-onset type 1 diabetes (T1D) have shown success, but not all subjects respond, and the duration of response is limited. Our aim was to determine whether two courses ...of teplizumab, an Fc receptor-nonbinding anti-CD3 monoclonal antibody, reduces the decline in C-peptide levels in patients with T1D 2 years after disease onset. We also set out to identify characteristics of responders. We treated 52 subjects with new-onset T1D with teplizumab for 2 weeks at diagnosis and after 1 year in an open-label, randomized, controlled trial. In the intent to treat analysis of the primary end point, patients treated with teplizumab had a reduced decline in C-peptide at 2 years (mean -0.28 nmol/L 95% CI -0.36 to -0.20) versus control (mean -0.46 nmol/L 95% CI -0.57 to -0.35; P = 0.002), a 75% improvement. The most common adverse events were rash, transient upper respiratory infections, headache, and nausea. In a post hoc analysis we characterized clinical responders and found that metabolic (HbA1c and insulin use) and immunologic features distinguished this group from those who did not respond to teplizumab. We conclude that teplizumab treatment preserves insulin production and reduces the use of exogenous insulin in some patients with new-onset T1D. Metabolic and immunologic features at baseline can identify a subgroup with robust responses to immune therapy.
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