TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cellspecific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n ‫؍‬ 39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferationinducing ligand (APRIL). However, the majority (n ‫؍‬ 41; 82%) of the patients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P <.001 , relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P < .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD ؊ CD27 ؉ B cells (P ‫؍‬ .019), benign lymphoproliferation (P < .001), and autoimmune complications (P ‫؍‬ .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation. (Blood.

Patients with primary immunodeficiency disease (PIDD) typically require life-long intravenous (IV) or subcutaneous (SC) immunoglobulin (Ig) replacement therapy to prevent recurrent infections. The efficacy, safety, and pharmacokinetics of a highly concentrated (20 %) Ig preparation for SC administration (IGSC 20 %) were evaluated in a prospective trial in patients with PIDD. A total of 74 patients (aged 3–83 years) received 4327 IGSC 20 % infusions over a median of 380.5 days. The rate of validated serious bacterial infections was 0.012 event/patient-year (p < 0.0001 compared with the historical control), and the annualized rate of infection was 2.41 events/patient. Median IgG trough levels were >14.5 g/l. The median maximum infusion rate was 60 ml/h/site (range 4.4–180), resulting in a median infusion duration of 0.95 h. A volume ≥30 ml was infused per site in 74.8 % of IGSC 20 % infusions. Most (84.9 %) infusions were administered using ≤2 infusion sites; for 99.8 % of infusions, there was no need to interrupt/stop administration or reduce the infusion rate. No related serious adverse event (AE) occurred during IGSC 20 % treatment; related non-serious AEs occurred at a rate of 0.036 event/infusion. The incidence of related local AEs was 0.015 event/infusion and of related systemic AEs was 0.021 event/infusion; most were mild in severity, none severe. Increased infusion rates or volumes were not associated with higher AE rates. The investigated IGSC 20 % treatment was shown to be effective and safe, enabling higher infusion rates and volumes per site compared to conventional SC treatments, resulting in fewer infusion sites and shorter infusion durations.Electronic supplementary materialThe online version of this article (doi:10.1007/s10875-016-0327-9) contains supplementary material, which is available to authorized users.

In a phase 2 study of patients with symptomatic celiac disease and histologic evidence of significant duodenal mucosal injury, latiglutenase did not improve histologic and symptom scores when compared with placebo. There were no significant differences in change from baseline between groups. ClinicalTrials.gov no: NCT01917630.

IntroductionAn investigational 10% liquid intravenous immunoglobulin (IVIG) was studied in 63 patients with primary immunodeficiency (PID) at 15 study sites.MethodsPatients were treated every 3 or 4 weeks with 254–1029 mg/kg/infusion of IVIG.ResultsOverall, Biotest-IVIG infusions were well tolerated. The proportion of infusions that were associated with adverse events during infusion, and up to 72 h after infusion, including those unrelated to study product, was 27.7% with an upper 95% confidence limit ≤30.6%. Two serious bacterial infections (SBIs) were observed resulting in a serious bacterial infection rate of 0.035 per person per year and an upper one-sided 99% confidence limit of ≤0.136 SBI/patient/year. The number of days of work or school missed due to infection were relatively low at 2.28 days/patient/year. Two patients were hospitalized for infection producing a rate of 0.21 hospitalization days/patient/year. The IgG half-life was approximately 30 days with variation among individuals.ConclusionsPharmacokinetic parameters of specific antibody activities were essentially the same as those of total IgG. Biotest-IVIG is safe and effective in the treatment of PID.

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Background: Hereditary angioedema (HAE) is often caused by low serum levels or functional deficiency in C1 inhibitor (C1-INH); however, in some cases, C1-INH serum level and function are measured as normal (HAE-nl-C1INH). Management of HAE-nl-C1INH is similar to management of HAE with C1-INH deficiency, including on-demand therapy for angioedema attacks and, potentially, prophylaxis. Recombinant human C1 esterase inhibitor (rhC1-INH) is indicated for treatment of acute HAE attacks. This study assessed the clinical profile and treatment outcomes in an HAE-nl-C1INH population with a history of rhC1-INH treatment.Methods: Medical records containing patient-reported outcomes from ten US treatment centers were analyzed retrospectively for medical history, angioedema attack characteristics, attack treatments, and clinical outcomes.Results: Twenty-three patients were included, with wide US geographic representation. Most patients (87.0%) were female; median age was 36.0 years (range, 19-67 years). Of 20 patients with available data, 4 had their first angioedema attack during childhood (aged <12 years), 3 during adolescence (aged 12-17 years), and 13 during adulthood (aged 18-29 years, n ¼ 7; aged 30 years, n ¼ 6). Median age at HAE-nl-C1INH diagnosis was 31.5 years (range, 9-59 years). Previous failed treatments included high-dose antihistamines (n ¼ 20) and corticosteroids (n ¼ 20). Use of US Food and Drug Administration (FDA)-approved HAE therapy positively impacted patientreported assessments of angioedema attacks. Most patients were taking rhC1-INH or lanadelumab as prophylaxis and icatibant or rhC1-INH for acute management. Most patients reported improved disease control with these therapies, including reductions in angioedema attack frequency and severity. Although most patients were receiving prophylactic therapy, availability of treatment for breakthrough attacks was important. Conclusion:Findings from this retrospective study support use of FDA-approved HAE medications for prophylaxis and acute treatment of HAE attacks in patients with HAE-nl-C1INH. Individualized HAE treatment regimens were needed to optimize therapeutic outcomes.

SummaryThis open-label multi-centre study evaluated a new intravenous immunoglobulin, Gammaplex®, in the treatment of 50 patients with primary immunodeficiency and significant hypogammglobulinaemia. Patients treated previously with other intravenous immunoglobulins received Gammaplex® on their same infusion schedule for 1 year; 22 were on a 21-day and 28 on a 28-day regimen (300-800 mg/kg/infusion). There were no serious, acute bacterial infections, whereas six subjects (12·0%) had at least one such infection in the 6 months before enrolment. Forty subjects (80·0%) had at least one non-serious infection; the median number of infective episodes per subject per year was 3·07. Antibiotics were taken by 38 subjects therapeutically and prophylactically by 16 at some time. Fewer than half (46·0%) missed any time off work or school because of infection or other illness. Trough immunoglobulin (Ig)G levels were above 6·00 g/l in all subjects at all assessments after 15 weeks with two exceptions. Overall, 21·2% of infusions were associated with an adverse event up to 72 h after infusion. The frequency of adverse events increased with infusion rate. Headache was the most common product-related adverse event (7·5% of 703 infusions). In conclusion, Gammaplex® is effective in primary immunodeficiency and is well tolerated.

Aim: This pooled analysis evaluated the safety and tolerability of the subcutaneous immunoglobulin 20% product, Ig20Gly, in primary immunodeficiency diseases using data from two Phase II/III studies conducted in North America and Europe. Patients & materials/methods: Patients received Ig20Gly (volumes, ≤60 ml/site; rates, ≤60 ml/h/site). Adverse events (AEs), tolerability and infusion parameters were assessed. Results: Patients (2–83 years; N = 122) received 6676 Ig20Gly infusions. No causally related serious or severe AEs were reported. Thirty-five patients (28.7%) reported 232 causally related local AEs. Twenty-seven patients (22.1%) reported 165 causally related systemic AEs. There was no association between the infusion volume or rate and causally related local AEs. Conclusion: Ig20Gly was well tolerated in a broad population of patients with primary immunodeficiency diseases.