Developing a Prediction Model for Determination of Peanut Allergy Status in the Learning Early About Peanut Allergy (LEAP) Studies.

BACKGROUND: The Learning Early About Peanut Allergy (LEAP) study team developed a protocol-specific algorithm using dietary history, peanut-specific IgE, and skin prick test (SPT) to determine peanut allergy status if the oral food challenge (OFC) could not be administered or did not provide a determinant result. OBJECTIVE: To investigate how well the algorithm determined allergy status in LEAP; to develop a new prediction model to determine peanut allergy status when OFC results are not available in LEAP Trio, a follow-up study of LEAP participants and their families; and to compare the new prediction model with the algorithm. METHODS: The algorithm was developed for the LEAP protocol before the analysis of the primary outcome. Subsequently, a prediction model was developed using logistic regression. RESULTS: Using the protocol-specified algorithm, 73% (453/617) of allergy determinations matched the OFC, 0.6% (4/617) were mismatched, and 26% (160/617) participants were nonevaluable. The prediction model included SPT, peanut-specific IgE, Ara h 1, Ara h 2, and Ara h 3. The model inaccurately predicted 1 of 266 participants as allergic who were not allergic by OFC and 8 of 57 participants as not allergic who were allergic by OFC. The overall error rate was 9 of 323 (2.8%) with an area under the curve of 0.99. The prediction model additionally performed well in an external validation cohort. CONCLUSION: The prediction model performed with high sensitivity and accuracy, eliminated the problem of nonevaluable outcomes, and can be used to estimate peanut allergy status in the LEAP Trio study when OFC is not available.

Effect of Costimulatory Blockade With Abatacept After Ustekinumab Withdrawal in Patients With Moderate to Severe Plaque Psoriasis: The PAUSE Randomized Clinical Trial.

IMPORTANCE: Psoriasis relapse may involve compensatory T-cell activation pathways in the presence of CD28-CD80/CD86 blockade with abatacept. OBJECTIVE: To determine whether costimulatory signaling blockade with abatacept prevents psoriasis relapse after ustekinumab withdrawal. DESIGN, SETTING, AND PARTICIPANTS: Psoriasis Treatment with Abatacept and Ustekinumab: a Study of Efficacy (PAUSE), a parallel-design, double-blind, placebo-controlled randomized clinical trial, was conducted at 10 sites in the US and Canada. Participant enrollment opened on March 19, 2014, and concluded on April 11, 2016. Participants were adults with moderate to severe plaque psoriasis and received ustekinumab in a lead-in phase. Those who responded to ustekinumab at week 12 were randomized 1:1 to either the continued with ustekinumab group (ustekinumab group) or the switched to abatacept group (abatacept group). Treatment was discontinued at week 39, and participants were followed up for psoriasis relapse until week 88. Statistical analyses were performed in the intention-to-treat (ITT) and safety samples from May 3, 2018, to July 6, 2021. INTERVENTIONS: Participants received subcutaneous ustekinumab at weeks 0 and 4 (45 mg per dose for those ≤100 kg; 90 mg per dose for those >100 kg). Participants randomized to the abatacept group at week 12 received subcutaneous abatacept, 125 mg weekly, from weeks 12 to 39 and ustekinumab placebo at weeks 16 and 28. Participants randomized to the ustekinumab group received ustekinumab at weeks 16 and 28 and abatacept placebo weekly from weeks 12 to 39. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of participants with psoriasis relapse (loss of ≥50% of the initial Psoriasis Area and Severity Index improvement) between weeks 12 and 88. Secondary end points included time to psoriasis relapse, proportion of participants with psoriasis relapse between weeks 12 and 40, and adverse events. The psoriasis transcriptome and serum cytokines were evaluated. RESULTS: A total of 108 participants (mean [SD] age, 46.1 [12.1] years; 73 [67.6%] men) were treated with open-label ustekinumab; 91 were randomized to blinded treatment. Similar proportions of participants in the abatacept group and the ustekinumab group relapsed between weeks 12 and 88 (41 of 45 [91.1%] vs 40 of 46 [87.0%]; P = .41). Median time to relapse from the last dose of ustekinumab was similar between groups as well: 36 weeks (95% CI, 36-48 weeks) in the abatacept group vs 32 weeks (95% CI, 28-40 weeks) in the ustekinumab group. Similar numbers and rates of adverse events occurred. Abatacept did not maintain suppression of the pathogenic IL-23-mediated psoriasis molecular signature in lesions after ustekinumab withdrawal, and serum IL-19 levels increased. CONCLUSIONS AND RELEVANCE: This parallel-design, double-blind randomized clinical trial found that abatacept did not prevent psoriasis relapse that occurred after ustekinumab withdrawal because it did not completely block the pathogenic psoriasis molecular pathways that led to relapse. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01999868.

Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis.

OBJECTIVE: To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN). METHODS: In a multicenter, randomized, open-label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group), or treated with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients' peripheral blood were analyzed by flow cytometry. RESULTS: Treatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/µl in the RCB group versus 11 cells/µl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with the observed impaired maturation of naive B cells and enhanced censoring of autoreactive B cells. CONCLUSION: The addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN.

ACCLAIM: A randomized trial of abatacept (CTLA4-Ig) for relapsing-remitting multiple sclerosis.

BACKGROUND: Costimulatory blockade of T lymphocytes with the CTLA4-Ig fusion protein abatacept could be an effective treatment for the immune-mediated neuroinflammatory disease relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate efficacy and safety of abatacept in RRMS. METHODS: ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) was a Phase II, randomized, double-blind, placebo-controlled, multi-center trial. In all, 65 of 123 planned participants with RRMS were randomized to monthly intravenous infusions of abatacept or placebo for 24 weeks in a 2:1 ratio, switched to the opposite treatment at 28 weeks, and received their final dose of study medication at 52 weeks. Enrollment was closed early due to slow accrual. The primary endpoint was the mean number of new gadolinium-enhancing (Gd+) lesions obtained on magnetic resonance imaging (MRI) scans performed every 4 weeks. RESULTS: No statistically significant differences were observed in mean number of new Gd+ MRI lesions between the abatacept and placebo groups. No statistically significant differences were observed in other MRI and clinical parameters of RRMS disease activity. Abatacept was well tolerated. CONCLUSION: The ACCLAIM study did not demonstrate efficacy of abatacept in reducing the number of new Gd+ MRI lesions, or clinical measures of disease activity in RRMS.

Response to cutaneous immunization with low-molecular-weight subunit keyhole limpet hemocyanin.

BACKGROUND: This study was carried out to determine whether humoral and cellular immune responses would be provoked by cutaneous administration of keyhole limpet hemocyanin (KLH) and in particular by scarification of the skin (SS). METHODS: This was an unblinded, single-center, 8-week pilot study in healthy young adults. Twenty-four subjects assigned to 4 groups completed the study. Each group was immunized twice, with a 3-week interval, either by SS or intradermally (ID), with an SS dose of 50 or 250 µg and an ID dose of 100 or 250 µg. Serum was collected for antibody assays at baseline and 3 weeks after both the first and second immunizations. Delayed-type hypersensitivity (DTH) testing was performed before the first immunization and 3 weeks after the second. RESULTS: In the 250-µg SS group, there was a significant increase from day 0 to day 47 in anti-KLH IgG (p = 0.02; day 0: 3.46 ± 5.49 mg/dl, day 47: 7.54 ± 8.87 mg/dl) and anti-KLH IgA (p = 0.04; day 0: 4.78 ± 9.15 mg/dl, day 47: 11.42 ± 13.62 mg/dl). One subject in each treatment group showed a positive DTH test result representing 20% (50-µg SS), 10% (250-µg SS), 25% (100-µg ID) and 20% (250-µg ID) of the subjects. CONCLUSIONS: It was possible to induce both humoral and cellular immune responses by SS administration despite the limited antigenic potency of the low-molecular-weight KLH preparation. This approach may be useful for studying the mechanisms of immune response in allergic skin diseases such as atopic dermatitis.

Pesticides on household surfaces may influence dietary intake of children.

The physical and chemical environment influences children's exposures to pesticides in and around the home. Children's activities, which increase their potential for exposure especially during eating, have been captured in the Children's Dietary Intake Model (CDIM). In addition to the chemical exposure associated with the food itself, this model incorporates excess dietary exposures due to handling of food during consumption. To stochastically evaluate CDIM, distributions of measured, and in some cases estimated, model factors were determined from measurements of permethrin, chlorpyrifos, and diazinon derived from assembled databases and laboratory experiments. Using the distributions of these factors, Monte Carlo simulations were performed to obtain distributions of total dietary intake of pesticides. To target the sources of pesticide contamination that were influencing total dietary intake, each factor was evaluated. We found pesticide surface concentration to be highly influential. By excluding surface concentration, we were also able to determine the influence of the other factors based on the F-statistic. Transfer efficiencies, followed by pesticide residue in consumed foods and amount of food consumed, were the next most influential factors within the model. With these distributions for model inputs, CDIM has the potential to more accurately predict total dietary intake of a contaminant by a child.