A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom.

BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.

Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK.

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

Surveillance study on the tolerability and safety of Flebogamma® DIF (10% and 5% intravenous immunoglobulin) in adult and pediatric patients.

Direct comparisons of tolerability and safety of concentrated intravenous immunoglobulin (IVIG) versus less concentrated products are scarce. In this postauthorization, prospective, observational, multicenter study, a systematic comparison of 10% and 5% concentrations of Flebogamma® DIF IVIG was performed in both adult and pediatric patients treated with the studied IVIG products according to the approved indications under routine conditions. Dose of product administered, adverse events (AEs), physical assessments, laboratory tests, and concomitant therapy were analyzed. Patient recruitment in the 10% and 5% product groups was, respectively, 34 (32 analyzed, 13 of them children, receiving 130 IVIG infusions) and 35 (34 analyzed, receiving 135 IVIG infusions). Twenty-four infusions (18.5%; 95% CI: 11.8, 25.1) with the 10% product and 3 (2.2%; 95% CI: -0.3, 4.7) with the 5% product were associated with potentially treatment-related AEs (P < 0.0001). Nine patients (28.1%) infused with the 10% product and 3 (8.8%) infused with the 5% product presented, respectively, 33 and 8 treatment-related AEs (of which 7 and 6, respectively, were serious AEs, experienced by only three hypersensitive patients). The profile of AEs occurring with the infusion of 10% and 5% products were comparable. The most frequent treatment-related AEs were headache (n = 17, 3 patients; 15 episodes, 1 patient) and pyrexia (n = 6, 4 patients). In conclusion, no unpredictable risk was detected for both Flebogamma DIF 10% and 5% concentrations, which were therefore deemed as safe and well-tolerated IVIG in the studied population. The frequency of infusions associated with treatment-related AEs was lower with the 5% concentration.

A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing.

TNF receptor associated periodic syndrome (TRAPS) is an autoinflammatory disease caused by mutations in TNF Receptor 1 (TNFR1). Current therapies for TRAPS are limited and do not target the pro-inflammatory signalling pathways that are central to the disease mechanism. Our aim was to identify drugs for repurposing as anti-inflammatories based on their ability to down-regulate molecules associated with inflammatory signalling pathways that are activated in TRAPS. This was achieved using rigorously optimized, high through-put cell culture and reverse phase protein microarray systems to screen compounds for their effects on the TRAPS-associated inflammatory signalome. 1360 approved, publically available, pharmacologically active substances were investigated for their effects on 40 signalling molecules associated with pro-inflammatory signalling pathways that are constitutively upregulated in TRAPS. The drugs were screened at four 10-fold concentrations on cell lines expressing both wild-type (WT) TNFR1 and TRAPS-associated C33Y mutant TNFR1, or WT TNFR1 alone; signalling molecule levels were then determined in cell lysates by the reverse-phase protein microarray. A novel mathematical methodology was developed to rank the compounds for their ability to reduce the expression of signalling molecules in the C33Y-TNFR1 transfectants towards the level seen in the WT-TNFR1 transfectants. Seven high-ranking drugs were selected and tested by RPPA for effects on the same 40 signalling molecules in lysates of peripheral blood mononuclear cells (PBMCs) from C33Y-TRAPS patients compared to PBMCs from normal controls. The fluoroquinolone antibiotic lomefloxacin, as well as others from this class of compounds, showed the most significant effects on multiple pro-inflammatory signalling pathways that are constitutively activated in TRAPS; lomefloxacin dose-dependently significantly reduced expression of 7/40 signalling molecules across the Jak/Stat, MAPK, NF-κB and PI3K/AKT pathways. This study demonstrates the power of signalome screening for identifying candidates for drug repurposing.

A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS).

Mutations in TNFRSF1A encoding TNF receptor 1 (TNFR1) cause the autosomal dominant TNF receptor-associated periodic syndrome (TRAPS): a systemic autoinflammatory disorder. Misfolding, intracellular aggregation, and ligand-independent signaling by mutant TNFR1 are central to disease pathophysiology. Our aim was to understand the extent of signaling pathway perturbation in TRAPS. A prototypic mutant TNFR1 (C33Y), and wild-type TNFR1 (WT), were expressed at near physiological levels in an SK-Hep-1 cell model. TNFR1-associated signaling pathway intermediates were examined in this model, and in PBMCs from C33Y TRAPS patients and healthy controls. In C33Y-TNFR1-expressing SK-Hep-1 cells and TRAPS patients' PBMCs, a subtle, constitutive upregulation of a wide spectrum of signaling intermediates and their phosphorylated forms was observed; these were associated with a proinflammatory/antiapoptotic phenotype. In TRAPS patients' PBMCs, this upregulation of proinflammatory signaling pathways was observed irrespective of concurrent treatment with glucocorticoids, anakinra or etanercept, and the absence of overt clinical symptoms at the time that the blood samples were taken. This study reveals the pleiotropic effect of a TRAPS-associated mutant form of TNFR1 on inflammatory signaling pathways (a proinflammatory signalome), which is consistent with the variable and limited efficacy of cytokine-blocking therapies in TRAPS. It highlights new potential target pathways for therapeutic intervention.

Identifying the culprit allergen in seasonal allergic rhinitis.

Seasonal allergic rhinitis (SAR) is the main form of rhinitis in children whereas in adults it accounts for about a third of cases of rhinitis. It is a risk factor for the development of asthma and chronic rhinosinusitis. The most common allergic triggers are grass and tree pollens, allergy to moulds and weeds is less common. Identifying the months of the year when an individual is symptomatic will help define the culprit allergen. If there is a clear recurring seasonal history the diagnosis may be made on the strength of the history. Skin prick tests are available in specialist clinics and are a useful tool in differentiating SAR from non-allergic rhinitis and defining the culprit allergen(s). Specific IgE tests for suspected allergens can be performed if skin tests are not available. A positive specific IgE test to an allergen does not necessarily mean that clinical allergy is present, it may reflect sensitisation of the immune system. Although, in general, specific IgE tests have a high negative predictive value they are less sensitive than skin prick tests for grass pollen and moulds. Allergen avoidance is the first step in the management of any allergic rhinitis. Oral non-sedating antihistamines are recommended as first-line treatment for mild SAR, higher doses may be necessary in moderate to severe SAR. Intranasal corticosteroids should be used in moderate to severe forms of SAR and also in mild forms where treatment with antihistamines has failed. There are no major differences in terms of efficacy between different corticosteroid preparations. Long-term growth studies in children using fluticasone, mometasone and budesonide (but not beclometasone) have been reassuring.

Internal standard-based analysis of microarray data2--analysis of functional associations between HVE-genes.

In this work we apply the Internal Standard-based analytical approach that we described in an earlier communication and here we demonstrate experimental results on functional associations among the hypervariably-expressed genes (HVE-genes). Our working assumption was that those genetic components, which initiate the disease, involve HVE-genes for which the level of expression is undistinguishable among healthy individuals and individuals with pathology. We show that analysis of the functional associations of the HVE-genes is indeed suitable to revealing disease-specific differences. We show also that another possible exploit of HVE-genes for characterization of pathological alterations is by using multivariate classification methods. This in turn offers important clues on naturally occurring dynamic processes in the organism and is further used for dynamic discrimination of groups of compared samples. We conclude that our approach can uncover principally new collective differences that cannot be discerned by individual gene analysis.

Role of interleukin-6 in a patient with tumor necrosis factor receptor-associated periodic syndrome: assessment of outcomes following treatment with the anti-interleukin-6 receptor monoclonal antibody tocilizumab.

In this report, we describe treatment outcomes in the first case of a patient with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) treated with the anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody tocilizumab. Since IL-6 levels are elevated in TRAPS, we hypothesized that tocilizumab might be effective. The patient, a 52-year-old man with lifelong TRAPS in whom treatment with etanercept and anakinra had failed, was administered tocilizumab for 6 months, and the therapeutic response was assessed by measurement of monocyte CD16 expression and cytokine levels. Following treatment, the evolving acute attack was aborted and further attacks of TRAPS were prevented. The patient did not require corticosteroids and showed significant clinical improvement in scores for pain, stiffness, and well-being. Moreover, the acute-phase response diminished significantly with treatment. Monocyte CD16 expression was reduced and the numbers of circulating CD14+CD16+ and CD14++CD16- monocytes were transiently decreased. However, cytokine levels were not reduced. This case supports the notion of a prominent role for IL-6 in mediating the inflammatory attacks in TRAPS, but blockade of IL-6 did not affect the underlying pathogenesis. These preliminary findings require confirmation.

Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome.

Hyperimmunoglobulinemia D (hyper-IgD) and periodic fever syndrome, a hereditary autoinflammatory syndrome, is characterized by lifelong recurrent episodes of fever and inflammation. No effective treatment is known. It is caused by a defect of mevalonate kinase, an enzyme that follows 3'-hydroxy-3'-methylglutaryl-coenzyme A (HMG-CoA) reductase in the isoprenoid pathway. We wanted to test the hypothesis that inhibition of HMG-CoA reductase would ameliorate the inflammatory attacks. Six patients with hyper-IgD syndrome and proven mevalonate kinase deficiency were followed up for 2 treatment periods with either simvastatin, 80 mg/d, or placebo for 24 weeks, separated by a 4-week washout period in a double-blind fashion. Simvastatin resulted in a drop in urinary mevalonic acid concentration in all patients and decreased the number of febrile days in 5 of 6 patients. No side effects were observed. These data offer preliminary evidence for the hypothesis that simvastatin may improve inflammatory attacks in the hyper-IgD syndrome. This highlights the anti-inflammatory properties of HMG-CoA reductase inhibition.

The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder.

The present report describes and expands the clinical and genetic spectrum of the autoinflammatory disorder, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). A total of 20 mutations have been identified since our initial discovery of 6 missense mutations in TNF receptor super family 1A (TNFRSF1A) in 1999. Eighteen of the mutations result in amino acid substitutions within the first 2 cysteine-rich domains (CRDs) of the extracellular portion of the receptor. A single splicing mutation also affects the first CRD by causing the insertion of 4 amino acids. Haplotype analysis of the most commonly occurring and ethnically heterogeneous mutation, R92Q, demonstrates an ancient founder; however, analysis of the T50M mutation, another commonly occurring mutation in Irish and Scottish families, does not, suggesting that T50M is a recurring mutation. Mutations that result in cysteine substitutions demonstrate a higher penetrance of the clinical phenotype (93% versus 82% for noncysteine residue substitutions), and also increase the probability of developing life-threatening amyloidosis (24% versus 2% for noncysteine residue substitutions). Retrospective and prospective evaluation of more than 50 patients, representing 10 of the 20 known mutations, allows us to expand and better define the clinical spectrum of TRAPS. Recurrent episodes of fever, myalgia, rash, abdominal pain, and conjunctivitis that often last longer than 5 days are the most characteristic clinical features of TRAPS. Defective shedding of TNFRSF1A can only partially explain the pathophysiologic mechanism of TRAPS, since some mutations have normal shedding. Consequently, other mechanisms may be mediating the observed phenotype. We are currently investigating other possible mechanisms using stable and transiently transfected cell systems in vitro, as well as developing a knockin mouse model. Preliminary data suggest that etanercept may be effective in decreasing the severity, duration, and frequency of symptoms in TRAPS patients. Additionally, it provides a viable therapeutic alternative to glucocorticoid therapy, which has numerous serious, long-term adverse effects. Two clinical trials are being conducted to evaluate the efficacy of etanercept in decreasing the frequency and severity of symptoms in TRAPS. Lastly, we have summarized data that R92Q and P46L, and probably as yet undiscovered substitutions, represent very low penetrance mutations that may play a much larger role in more broadly defined inflammatory diseases such as rheumatoid arthritis. Our laboratories are currently undertaking both clinical and basic research studies to define the role of these mutations in more common inflammatory diseases.