An essential role for the Zn2+ transporter ZIP7 in B cell development.

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial.

Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations. Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab). Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy. Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.

Emerging Paradigm of Primary Immunodeficiency Disease: Individualizing Immunoglobulin Dose and Delivery to Enhance Outcomes.

An emerging paradigm for the treatment of primary immunodeficiency disease (PIDD) with immunoglobulin (IgG) replacement therapy emphasizes the tailoring of treatments to each patient with the goal of preventing infections and minimizing side effects. Increasing evidence shows that the IgG dose needed to prevent infection varies with each patient, and both intravenous immunoglobulin (IGIV) and subcutaneous immunoglobulin (IGSC) have emerged as feasible modes of delivery. Although IGIV is currently the routine treatment, IGSC is increasingly being chosen as the preferred route of delivery due to greater flexibility and reduced side effects.

Facilitating home-based treatment of hereditary angioedema.

Hereditary angioedema (HAE) is a rare disorder causing periodic attacks of nonpruritic swelling, for which highly effective subcutaneous and intravenous therapies are available. The need to seek ongoing medical attention for HAE attacks at clinics and hospitals adds to the already considerable burden of the disease. Recent international consensus treatment guidelines have emphasized home-based therapy as a preferred managed strategy whenever possible. Here, we review various strategies for facilitating home-based treatment with injectable HAE medications (plasma-derived C1 esterase inhibitor [C1-INH], ecallantide, icatibant, and recombinant C1-INH). Medical literature relating to home-based treatment of HAE is reviewed and strategies for implementing home-based therapy are presented. Home-based treatment of HAE has been shown to reduce the time to initiation of treatment, reduce the duration and severity of attacks, and improve patients' quality of life. Several options are available to facilitate home treatment of HAE. Medical staff in a primary care setting can be educated in the care of HAE patients and can teach the technique of parenteral drug administration. Home care agencies and specialty pharmacies are present in most communities and specialize in patient education. Infusion centers are skilled at working with patients with chronic diseases who perform extensive self-care. HAE comprehensive care clinics provide expert diagnosis and disease management and may become the patient's primary source of HAE care. Home-based therapy of HAE has been shown to be safe and clinically advantageous. Various strategies are available for equipping HAE patients to administer their treatments outside of a medical facility.

Why I use subcutaneous immunoglobulin (SCIG).

Immunoglobulin (IgG) replacement is a life-saving treatment for individuals with primary immunodeficiency disease (PIDD). Today, there are many options for IgG replacement, and the choice is an individual one based on many factors. My preference for most patients is the subcutaneous (SCIG) route. It offers many advantages not offered by the intravenous (IVIG) route. These include: 1) independence from hospital-based infusion settings; 2) an alternative for patients with poor venous access; 3) better tolerability in those patients who are not able to tolerate IVIG; 4) flexibility of dosing; 5) ease of administration; 6) a very low side-effect profile; 7) a comparatively more even, almost physiological, IgG level; 8) less cost to administer than IVIG; and 9) improved quality of life in patients treated with SCIG compared with those treated with IVIG. For most patients with PIDD who require IgG replacement, SCIG offers advantages not available with IVIG.

Clinical ambiguities--ongoing questions.

Many factors need to be considered when choosing the mode of delivery of immunoglobulin (IgG) replacement therapy for a given patient with primary immunodeficiency disease (PIDD). Despite some general guidance as provided in the previous discussions, a number of ongoing questions remain. This article attempts to provide some answers and clarification for clinical situations in which the choice of intravenous IgG (IVIG) or subcutaneous IgG (SCIG) may be ambiguous.

Subcutaneous immunoglobulin: rapid push vs. infusion pump in pediatrics.

BACKGROUND: Subcutaneous immunoglobulin (SCIG) therapy is gaining favor for the management of primary immunodeficiency disease (PIDD) in adults and children. METHODS: A retrospective chart review captured data on 96 pediatric patients with PIDD using SCIG (16% or 20%) delivered by infusion pump or SC rapid push over 620 clinic visits. Patients previously using intravenous immunoglobulin (IVIG) were converted to SCIG dosing on a 1:1 basis. Patients/caregivers voluntarily chose an administration technique. RESULTS: Although mean SCIG dosing was lower on a g/kg/month basis compared with prior IVIG dosing, mean steady-state serum IgG levels during SCIG administration were about 100-200 mg/dl higher than IVIG trough values. On average, much more rapid infusion was achieved with the SC rapid push method, with 49% of patients reporting infusion times of 9 min or less; median duration of infusion pump administration was 45 min. The use of 20% SCIG increased dosing efficiency compared with 16% SCIG, allowing for a smaller weekly mean SCIG volume and fewer dosing days per week. Adverse event (AE) rates were lower in the pediatric subgroup compared with adults (15.8% vs. 18.8% of visits), and the majority of AEs were local. SC rapid push was reported most frequently for patients under age 2; its use decreased between ages 2 and <10 yr and then increased in adolescence and into adulthood. Only one of the pediatric patients returned to IVIG use. CONCLUSIONS: Administration of replacement Ig via SC rapid push is a safe and viable option in pediatric patients with PIDD.

Subcutaneous immunoglobulin therapy given by subcutaneous rapid push vs infusion pump: a retrospective analysis.

BACKGROUND: Administration of subcutaneous immunoglobulin (SCIG) via rapid push, an alternative to infusion pump delivery, can offer heightened simplicity and convenience for patients with primary immunodeficiency disease (PIDD). OBJECTIVE: To assess dosing and administration patterns, serum IgG responses, safety, and tolerability of the subcutaneous (SC) rapid push technique. METHODS: A retrospective medical record review captured data on 173 patients with PIDD (1,140 follow-up visits) who self-administered SCIG (16% or 20%) via infusion pump or SC rapid push. RESULTS: Serum IgG levels increased from a mean (SD) trough of 903.8 (285.4) mg/dL during intravenous immunoglobulin use to a steady-state mean (SD) of 1,121.6 (257.6) mg/dL on SCIG. Mean frequency of weekly SCIG administration was 2.3 days per week with pump and 2.8 days per week with SC rapid push. Mean serum IgG levels were higher among push vs pump users (1,164 vs 1,048 mg/dL). Mean (SD) SCIG volume administered per infusion site with SC rapid push was 15.0 (7.3) mL (maximum, 60.0 mL). Most patients using SC rapid push infused in 9 minutes or less; median pump infusion duration was 49 minutes. Use of 20% SCIG was associated with smaller mean weekly product volumes vs 16% SCIG (41.7 vs 51.0 mL) and fewer mean dosing days per week (2.0 vs 2.8 days). Adverse events, primarily local, were reported on fewer visits with SC rapid push (15.6%) than with infusion pump (20.7%). CONCLUSION: The SC rapid push technique is a safe, viable alternative to an infusion pump, seemingly preferred by patients and offering more rapid administration.

Payor issues: barriers to optimal management of patients with primary immunodeficiency.

Since 2005, when changes in Medicare reimbursement for IgG replacement therapy went into effect, physicians and patients with primary immunodeficiency disease (PIDD) have encountered a number of challenges to administering and receiving appropriate immunoglobulin therapy. A 2006 membership survey conducted by the American Academy of Allergy, Asthma & Immunology found that 95 % of responders thought that the health of their patients was at risk due to Medicare changes; many patient surveys also found a significant number adversely affected by these changes. Decisions critical for optimal care being made by third-party payors are often in conflict with guidelines on recommended standard of care. Many payors, for example, are dictating where infusions can occur despite evidence clearly demonstrating that choice of the site of care needs to be determined by the particular patient's circumstance and experience. Another critical issue is the lack of product availability due to the determination by payors of which IgG products appear on formularies. Patients, physicians, and payors all bring their own perspective to these issues, and finding a solution to these challenges requires balancing the needs of all three groups.

Local and national advocacy support.

Decisions by third-party payors that are restricting delivery of appropriate IgG treatment for primary immunodeficiency disease (PIDD) are summoning action from patients, physicians, and their organizations to ensure that high quality treatment remains accessible. Some of the strongest advocacy to date is from patient organizations, such as the Immune Deficiency Foundation (IDF), which strive to educate stakeholders on key issues that determine patient access to appropriate IgG treatment. These issues include the ability to choose the appropriate site of care based on a patient's experience and circumstance and greater awareness of product choice. Advocacy by physicians on these issues at the local level is needed, as are national efforts by organizations such as the American Academy of Allergy, Asthma & Immunology and their regional societies.

Malignancies in the setting of primary immunodeficiency: Implications for hematologists/oncologists.

Many primary immunodeficiency disorders (PIDD) are associated with elevated risks for different types of cancer. Defective immunosurveillance mechanisms in PIDD and infection with oncogenic viruses (eg, Epstein Barr, herpesvirus 8) seem to have significant contributory roles in many cases. Non-Hodgkin lymphoma and Hodgkin disease are two of the most common PIDD-associated malignancies. The impact of PIDD-associated malignancy has increased in recent years in parallel with improved patient with PIDD survival and longevity, due largely to effective immunoglobulin replacement therapy. Epidemiologic data, clinical patterns, and management considerations of the common PIDD-associated cancers are reviewed.

Efficacy, Safety and Tolerability of a New 10% Intravenous Immunoglobulin for the Treatment of Primary Immunodeficiencies.

We report here the results of a phase 3 study to assess the efficacy, safety, and tolerability of GC5107, a new 10% liquid intravenous immunoglobulin (IVIG) in preventing serious bacterial infections in patients with primary immunodeficiency (ClinicalTrials.gov: NCT02783482). Over a 12-month study period, 49 patients aged 3 to 70 years with a confirmed diagnosis of primary immunodeficiency received GC5107 at doses ranging from 319 to 881 mg/kg body weight every 21 or 28 days, according to their previous IVIG maintenance therapy. A total of 667 infusions of GC5107 were administered comprising a total of 45.86 patient-years of treatment. A single acute serious bacterial infection occurred during the study, resulting in an incidence of 0.02 events per patient-year (upper 99% one-sided confidence interval limit: 0.21), meeting the prespecified primary efficacy endpoint. The mean incidence of infections other than acute serious bacterial infections was 2.9 infections per patient-year. Efficacy was also demonstrated by the low mean annualized rate of hospitalizations due to infection (0.1 day) and the mean annualized duration of hospitalizations (0.1 day). The mean rate of intravenous and oral antibiotic use was 0.1 day and 13.2 days, respectively. There was a mean of 7.1 days of missed work, school, or daycare days. The proportion of infusions with temporally associated adverse events (TAAEs) occurring during or within 72 hours after GC5107 infusion was 0.24 (upper 95% one-sided confidence interval limit: 0.31), meeting the pre-specified primary safety endpoint. Overall, 149 of 667 infusions (22%) were associated with TAAEs. The most common TAAE was headache, reported by 49% of patients. More than 98% (731/743) of all adverse events that occurred throughout the 12-month study period were mild or moderate. More than 98% of infusions were completed without discontinuation, interruption or rate reduction. There were no treatment-emergent serious adverse events related to GC5107 or study discontinuations due to an adverse event. Overall, pharmacokinetic parameters for GC5107 were within the range of those reported in studies of other marketed IVIG products. Results of the present study demonstrate that GC5107 is an effective, safe and well-tolerated treatment for patients with primary immunodeficiency.

A custom 148 gene-based resequencing chip and the SNP explorer software: new tools to study antibody deficiency.

Hyper-IgM syndrome and Common Variable Immunodeficiency are heterogeneous disorders characterized by a predisposition to serious infection and impaired or absent neutralizing antibody responses. Although a number of single gene defects have been associated with these immune deficiency disorders, the genetic basis of many cases is not known. To facilitate mutation screening in patients with these syndromes, we have developed a custom 300-kb resequencing array, the Hyper-IgM/CVID chip, which interrogates 1,576 coding exons and intron-exon junction regions from 148 genes implicated in B-cell development and immunoglobulin isotype switching. Genomic DNAs extracted from patients were hybridized to the array using a high-throughput protocol for target sequence amplification, pooling, and hybridization. A Web-based application, SNP Explorer, was developed to directly analyze and visualize the single nucleotide polymorphism (SNP) annotation and for quality filtering. Several mutations in known disease-susceptibility genes such as CD40LG, TNFRSF13B, IKBKG, AICDA, as well as rare nucleotide changes in other genes such as TRAF3IP2, were identified in patient DNA samples and validated by direct sequencing. We conclude that the Hyper-IgM/CVID chip combined with SNP Explorer may provide a cost-effective tool for high-throughput discovery of novel mutations among hundreds of disease-relevant genes in patients with inherited antibody deficiency.

Subcutaneous immunoglobulin therapy by rapid push is preferred to infusion by pump: a retrospective analysis.

BACKGROUND: Subcutaneous immunoglobulin (SCIg) replacement therapy for primary immune deficiency disease (PIDD) is a safe, effective, and convenient alternative to intravenous Ig (IVIg) therapy. Although SCIg is typically administered weekly by infusion pump, administration by a rapid push technique may provide a greater degree of convenience. Rapid push administration has been an option at the author's clinic for several years. We report experience with a cohort of patients given a choice between rapid push and standard pump administration. METHODS: This was a retrospective chart review of PIDD patients at a single site who initiated treatment with SCIg (16% solution) therapy between January 1, 2006 and April 1, 2008. Patients selected either infusion pump or rapid push administration after receiving a description and demonstration of each method and training for home self-administration. Demographics, dose, adverse events (AEs), serum immunoglobulin G (IgG) levels, and therapy disposition (discontinued, switched technique) were recorded on a standardized data collection form. RESULTS: Charts for 104 patients (45 male, 59 female; mean age, 21.1 years; range, 0.5-67.6 years; SD = 17.9 years) were reviewed. Seventy-four patients (71%) chose rapid push. Mean SCIg dose was 32.11 g/month (range, 1.92-89.6 g/month; SD = 8.3 g/month) split into an average of 3.11 times per week. Volume per site ranged from 3 to 20 mL, typically administered over 5-20 min and at one site. Mean serum IgG levels did not differ significantly by administration method: pump, 1,153.06 mg/dL (SD = 240.8); rapid push, 1,225.8 mg/dL (SD = 299.8). Local infusion-site reactions were the most common AEs and were experienced by one third of patients in each group. Only two patients discontinued therapy because of an AE. CONCLUSION: The results suggest that PIDD patients prefer SCIg administered as a rapid push rather than as conventional pump infusion. Serum IgG levels were comparable between methods, and safety was similar, if not slightly better, with rapid push. Rapid push offers the potential for even greater convenience than the pump infusion technique, although these results should be confirmed in prospective studies.

Efficacy and safety of an intravenous C1-inhibitor concentrate for long-term prophylaxis in hereditary angioedema.

BACKGROUND: The plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) is approved in the United States as an intravenous (IV) on-demand treatment for hereditary angioedema (HAE) attacks, and, in Europe, as on demand and short-term prophylaxis. OBJECTIVE: This analysis evaluated Berinert Patient Registry data regarding IV pnfC1-INH used as long-term prophylaxis (LTP). METHODS: The international registry (2010-2014) collected prospective and retrospective usage, dosing, and safety data on individuals who used pnfC1-INH for any reason. RESULTS: The registry included data on 47 subjects (80.9% female subjects; mean age, 44.8 years), which reflected 4082 infusions categorized as LTP and a total of 430.2 months of LTP administration. The median absolute dose of pnfC1-INH given for LTP was 1000 IU (range, 500-3000 IU), with a median time interval between infusion and a subsequent pnfC1-INH-treated attack of 72.0 hours (range, 0.0-166.4 hours). Fifteen subjects (31.9%) had no pnfC1-INH-treated HAE attacks within 7 days after pnfC1-INH infusion for LTP; 32 subjects (68.1%) experienced 246 attacks, with rates of 0.06 attacks per infusion and 0.57 attacks per month. A total of 81 adverse events were reported in 16 subjects (34.0%) (0.02 events per infusion; 0.19 events per month); only 3 adverse events were considered related to pnfC1-INH (noncardiac chest pain, postinfusion headache, deep vein thrombosis in a subject with an IV port). CONCLUSION: In this international registry, IV pnf-C1-INH given as LTP for HAE was safe and efficacious, with a low rate of attacks that required pnfC1-INH treatment, particularly within the first several days after LTP administration.