Systemic Hypersensitivity Research Articles

The Incidence, Characteristics, Management, and Outcomes of Anaphylaxis in Pregnancy: A Population-based Descriptive Study

(BJOG. 2018;125:965–971) Anaphylaxis in pregnancy is characterized by life-threatening breathing, circulatory or airway problems stemming from a systemic hypersensitivity reaction, often caused by exposure to allergens including antibiotics or latex. The incidence of anaphylaxis in pregnancy is unknown but thought to be rising. There is a lack of guidelines for the management of anaphylaxis in pregnancy. This study aimed to describe the incidence, characteristics, management and outcomes of anaphylaxis in pregnancy in the United Kingdom.

Sudden hearing loss due to bee sting: A rare case

Sudden hearing loss (SHl); Define as, at least 30 dB sensorineural hearing loss in 3 consecutive frequencies. In general, idiopathic, viral and vascular causes are at the forefront. Local or systemic hypersensitivity reactions due to insect bites such as bee sting may occur. Sudden hearing loss is a more unknown finding in the literature due to bee sting. The first choice in treatment is systemic or local corticosteroid uses. In this case report, the patient who had bilateral sudden hearing loss following bee sting and treatment approaches have been presented.

Radiocontrast Media Hypersensitivity: Skin Testing Differentiates Allergy From Nonallergic Reactions and Identifies a Safe Alternative as Proven by Intravenous Provocation

Hypersensitivity reactions occurring within minutes after intravascular injection of iodinated radiocontrast media (RCM) are not rare and have been previously considered to be nonallergic. However, in the last decades, evidence is increasing that genuine RCM allergy may present as either full-blown anaphylaxis or delayed exanthematous skin reaction. We aimed to assess whether allergy diagnostics including skin and provocation testing can differentiate between nonallergic and allergic RCM hypersensitivity by identifying the causative RCM as well as tolerated alternative RCM. We retrospectively evaluated clinical and diagnostic data from 45 consecutive patients with RCM hypersensitivity. Immediate nonallergic RCM hypersensitivity was diagnosed in 21 patients, immediate-type RCM allergy in 11, delayed-type RCM allergy in 11, and delayed-type iodine allergy in 2. All patients with immediate-type RCM allergy had a history of moderate to severe anaphylaxis. Eleven of 13 patients with delayed-type allergic reactions including the 2 cases of iodine allergy suffered from maculopapular exanthem developing several hours to days after exposure, 1 was a systemic hypersensitivity syndrome, and 1 a fixed drug eruption. Of 18 RCM-allergic patients tested, all tolerated an alternative RCM in the intravenous provocation. The diagnostic sensitivity of intradermal RCM testing to identify allergic patients is high in both immediate-type and delayed-type RCM allergy. Intravenous provocation with a skin test-negative RCM is safe and enables identification of a tolerated alternative RCM. Additional skin testing of iodine solution is required to identify patients with iodine allergy.

Depletion of interfering IgG and IgM is critical to determine the role of IgE in pegvaliase-associated hypersensitivity

Pegvaliase is an enzyme substitution therapy developed to lower blood phenylalanine (Phe) in adults with phenylketonuria (PKU). In phase 3 clinical studies, pegvaliase substantially reduced mean blood Phe in adult subjects with PKU. The most common type of adverse event observed in the pegvaliase clinical program was hypersensitivity adverse events (HAEs), which included occurrences of arthralgia, rash, and pruritis. The most clinically relevant HAEs were acute systemic hypersensitivity reactions consistent with anaphylaxis observed in 4.6% of phase 3 patients. HAEs were more commonly observed around the time of high circulating immune complex (CIC) levels and complement activation, and the majority of subjects that experienced acute systemic hypersensitivity events were able to continue treatment, which is atypical for a classical IgE-mediated anaphylactic event, but common for type III hypersensitivity reactions.To investigate the alternative mechanism of type III hypersensitivity, serum samples collected shortly after hypersensitivity events (in phase 2 and 3 studies) were tested for anti-pegvaliase IgE using custom radioallergosorbent test and/or ImmunoCAP® (ThermoFisher Scientific, Waltham, MA) assay methods. All subjects with acute systemic hypersensitivity that were tested for anti-pegvaliase IgE at or near the time of event with one or both assays tested negative for IgE. As presented here, an investigation using selected study samples with high anti-drug antibody (ADA) titers demonstrated that presence of IgM and/or IgG ADA can interfere with measurement of a human anti-pegvaliase IgE surrogate positive control. A depletion method was therefore developed using protein A- and G-conjugated Sepharose to remove interfering IgG and IgM in serum samples to low levels (<45 mg/dL) before IgE testing. A final 2× concentration step brought the IgE concentration in the depleted sample to approximately the same level of the starting serum. Phase 3 study samples with sufficient volume remaining that previously tested negative for anti-pegvaliase IgE were re-tested after depletion of IgG and IgM. All samples again tested negative, confirming the original test results. Taken together, the clinical presentation, temporal association of HAEs with CIC levels and complement activation, and lack of anti-pegvaliase IgE suggest pegvaliase-associated acute systemic hypersensitivity events were not IgE-mediated. Furthermore, we describe a universal method that is broadly applicable to enzyme therapies for detection of low concentrations of drug-specific IgE in the presence of high titer anti-drug antibodies of different isotypes.

Allergy in total knee replacement surgery: Is it a real problem?

Total knee arthroplasty is a common procedure, with extremely good clinical results. Despite this success, it produces 20% unsatisfactory results. Among the causes of these failures is metal hypersensitivity. Metal sensitization is higher in patients with a knee arthroplasty than in the general population and is even higher in patients undergoing revision surgery. However, a clear correlation between metal sensitization and symptomatic knee after surgery has not been ascertained. Surely, patients with a clear history of metal allergy must be carefully examined through dermatological and laboratory testing before surgery. There is no globally accepted diagnostic algorithm or laboratory test to diagnose metal hypersensitivity or metal reactions. The patch test is the most common test to determine metal hypersensitivity, though presenting some limitations. Several laboratory assays have been developed, with a higher sensitivity compared to patch testing, yet their clinical availability is not widespread, due to high costs and technical complexity. Symptoms of a reaction to metal implants present across a wide spectrum, ranging from pain and cutaneous dermatitis to aseptic loosening of the arthroplasty. However, although cutaneous and systemic hypersensitivity reactions to metals have arisen, thereby increasing concern after joint arthroplasties, allergies against implant materials remain quite rare and not a well-known problem. The aim of the following paper is to provide an overview on diagnosis and management of metal hypersensitivity in patients who undergo a total knee arthroplasty in order clarify its real importance.

Vancomycin-associated drug-induced hypersensitivity syndrome

Although hypersensitivity reactions are well characterized for certain medications, vancomycin-associated drug-induced hypersensitivity syndrome (DIHS), or drug reaction with eosinophilia and systemic symptoms (DRESS), has yet to be defined. To better define the clinical phenotype of vancomycin-associated DIHS. A retrospective case series was conducted over an 8-year period at a single, academic institution. A total of 29 cases of DIHS/DRESS were identified, of which 4 were attributed to vancomycin. A literature review was performed; it identified 28 additional cases of vancomycin-induced DIHS. Vancomycin-associated acute interstitial nephritis was also reviewed to detect additional, previously uncharacterized cases of systemic hypersensitivity. The review yielded 11 additional cases. In this literature review and retrospective series, the incidence of renal dysfunction among vancomycin-induced cases (75% and 68% of cases in the series and literature, respectively) was notably higher than the overall reported incidence in DIHS (10%-40%). The degree of renal impairment was also significantly increased in the retrospective series (a median 4.98-fold change in baseline creatinine level vs a 2.25-fold increase in non-vancomycin-associated cases [P=.011]). The principal limitation of this study is the small sample size. Other notable limitations include the retrospective nature of the study and absence of confirmatory renal biopsies. Although the current understanding of DIHS/DRESS is imperfect, our findings suggest that vancomycin-induced cases present with a unique phenotype characterized by a higher burden of renal involvement.

Future doctors and anaphylaxis: What do they know? what should we do?

Aim: Anaphylaxis is a severe, potentially life-threatening systemic hypersensitivity reaction. Previous studies reveal that there are many potential deficiencies in the knowledge of doctors regarding the diagnosis and management of anaphylaxis in different health-care settings.The main purpose of this study was to assess the knowledge of 4th-6th-year medical students regarding the diagnosis and management of anaphylaxis. Material and Methods: The study was designed as a cross-sectional survey. The total number of 4th-, 5th-, and 6th-grade medical students at Trakya University Medical School was 651, and 172 (26%) agreed to participate in the study. The participants were asked to answer the questionnaire forms were including the questions assessing students’ knowledge about the diagnosis and management of anaphylaxis, before and after a training session about anaphylaxis. Results:Awareness of students about symptoms indicating anaphylaxis other than cutaneous and respiratory symptoms was between 40% and 77% in the initial test. Although the majority of participants (94%) chose epinephrine as the first-line drug for the treatment of anaphylaxis, correct answers about dosage, concentration, and the route for administration of epinephrine were low when compared with the final test (p < 0.001 for each item). While 14% stated they felt they could diagnose and treat anaphylaxis in the initial test, this increased 83% after the training (p < 0.001). Conclusion: The study revealed that, knowledge of medical students relating diagnosis and treatment of anaphylaxis is unsatisfactory. Much more attention is needed in medical-school education concerning anaphylaxis management to prevent anaphylaxis-related mortalities in the future.

Hypersensitivity Reaction to Perioperative Drug Mistaken for Local Anesthetic Systemic Toxicity in a Patient under Brachial Plexus Block

Perioperative anaphylaxis, although rare, is a severe, life-threatening unexpected systemic hypersensitivity reaction. Simultaneous administration of various drugs during anesthesia, the difficulty of communicate with patients in sedation and anesthesia, and coverage of the patient with surgical drapes are considered to be factors that impede early recognition of anaphylactic reactions. It is very important to perform an intradermal skin test because antibiotics are the most common cause of perioperative anaphylaxis. We report a case of negative-intradermal skin test antibiotic anaphylaxis mistaken for local aesthetic systemic toxicity without increase of serum tryptase for confirmative diagnostic biomaker during surgery under brachial plexus block. It is not possible to exclude the danger of anaphylaxis completely, even if it is negative-intradermal skin test and normal tryptase level. Therefore, anesthesiologists should be closely monitored and treated early for antibiotics related hypersensitive reaction, like other medicines during anesthesia.

Every 2 Weeks or Every 4 Weeks Subcutaneous Injection of Emicizumab in Pediatric Patients with Severe Hemophilia A without Inhibitors: A Multi-Center, Open-Label Study in Japan (HOHOEMI Study)

Introduction: Emicizumab is a novel, subcutaneously injectable, recombinant humanized bispecific monoclonal antibody which mimics the function of activated coagulation factor VIII. Due to its mechanism of action and lack of sequence homology, emicizumab is not expected to induce or be affected by anti-factor VIII (FVIII) antibodies (inhibitors). Emicizumab once-weekly dosing has been approved for hemophilia A patients with inhibitors of all ages in several countries. A clinically meaningful prophylactic effect and favorable safety of emicizumab given every 2 weeks (Q2W) and every 4 weeks (Q4W) in adult/adolescent patients has been demonstrate in HAVEN3 study (NCT02847637) and HAVEN4 study (NCT03020160). This is the first report to assess emicizumab prophylaxis in pediatric patients without inhibitors including a patient previously untreated with FVIII.Methods: The present study (JapicCTI-173710) enrolled Japanese patients aged <12 years with hemophilia A without inhibitors. Patients received a loading dose of 3 mg/kg weekly for the first 4 doses, followed by a maintenance dose of 3 mg/kg Q2W or 6 mg/kg Q4W. This interim analysis was performed after at least 6 patients in each dosing cohort had completed at least 12 weeks of treatment with emicizumab prophylaxis.Results: A total of 13 male patients were enrolled in 2 cohorts. The numbers of patients aged 0 - < 2, 2 - < 6, and 6 - < 12 years were 1, 2, and 3 in the Q2W cohort and 2, 2, and 3 in the Q4W cohort. All patients had been previously treated with FVIII prophylaxis except for 1 patient aged 4 months in the Q4W cohort who was previously untreated. As of the data cutoff date of March 14, 2018, the medians (range) of treatment duration were 21 (18.3 - 22.1) and 16 (4.3 - 16.6) weeks in the Q2W and Q4W cohorts, respectively.The interim analysis results showed a clinically meaningful effect of emicizumab prophylaxis with the Q2W and Q4W regimens. As of the data cutoff date, 3/6 patients in the Q2W cohort and 5/7 patients including 1 patient previously untreated with FVIII in the Q4W cohort experienced no treated bleeds. There were no treated spontaneous bleeds and a total of 6 treated bleeds were traumatic. Two out of them were treated joint bleeds. Model-based annualized bleeding rates for treated bleeds with FVIII products under emicizumab prophylaxis were 1.6 (95% CI, 0.60 to 4.25) and 1.0 (95% CI, 0.25 to 4.06) in the Q2W and Q4W cohorts, respectively.All 13 patients experienced at least 1 adverse event (AE) and a total of 78 AEs were reported. There were no AEs that were grade 3 or higher, serious, led to withdrawal from treatment, or resulted in dose modification or interruption. None of the AEs were considered related to emicizumab. Neither thromboembolic events, thrombotic microangiopathy, systemic hypersensitivity reactions, nor local injection site reactions were reported. The most frequent AEs were contusion in 10 (76.9%) patients, excoriation and nasopharyngitis in 4 (30.8%) patients each, and ligament sprain and influenza in 3 (23.1%) patients each.The emicizumab exposures observed in this study were within the observed variability in preceding studies. No effects of age or body weight on emicizumab exposure were evident.Conclusions: This interim analysis results suggested clinically meaningful efficacy and favorable safety of the emicizumab Q2W and Q4W regimens in patients aged <12 years with severe hemophilia A without inhibitors. This suggests that it should be appropriate to apply the same dosing regimens of emicizumab for pediatric patients without inhibitors and other patient populations of hemophilia A. The updated results of primary analysis after completing at least 24 weeks on emicizumab treatment will be presented at the meeting. DisclosuresShima:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Nogami:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Nagami:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership. Yoshida:Chugai Pharmaceutical Co., Ltd: Employment. Yoneyama:Chugai Pharmaceutical Co., Ltd: Employment, Patents & Royalties: Anti-FIXa/X bispecific antibodies . Ishiguro:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Suzuki:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Taki:Chugai Pharmaceutical Co., Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

936. Body Fat Redistribution/Accumulation, Pancreatic Disorders, Musculoskeletal Disorders, IRIS, Severe Systemic Rash and Hypersensitivity Reactions Following Initiation of Commonly Prescribed Antiretrovirals

BackgroundDolutegravir (DTG), elvitegravir (EVG), raltegravir (RAL), and darunavir (DRV) are commonly used for the treatment of HIV. We assessed the frequency of 6 select disorders after prescription of DTG-, EVG-, RAL-, or DRV-based regimens.MethodsHIV-positive patients in the OPERA® Observational Database initiating DTG-, EVG-, RAL-, or DRV-containing regimens were included. Disorders of interest were body fat redistribution/accumulation, pancreatic disorders, and musculoskeletal disorders, as defined in Figures 2–3, as well as immune reconstitution inflammatory syndrome (IRIS), severe systemic rash and hypersensitivity reaction (HSR). Baseline patient characteristics and disorder history were described. The proportion of patients with disorders of interest during follow-up were compared between core agents for each disorder. All events occurring during follow-up were considered prevalent, while incident disorders excluded patients with any history of disorder. To account for multiple comparisons, the Sidak Correction was applied (adjusted α level: 0.017).ResultsOut of 22,674 patients, 7,860 (35%) initiated DTG, 9,738 (43%) EVG, 1,600 (7%) RAL, and 3,477 (15%) DRV. Baseline demographic and clinical characteristics varied by core agent initiated (Figure 1). Compared with DTG, history of body fat redistribution/accumulation was less frequent in patients initiating EVG, and more frequent in patients initiating RAL (Figure 2). EVG users also had a lower prevalence during follow-up than DTG users (Figure 3). However, there was no difference in new onset of body fat redistribution/accumulation between groups (Figure 3). No difference in prevalent or incident pancreatic or musculoskeletal disorders was detected between core agents (Figure 3). IRIS, severe systemic rash, and HSR occurred in no more than 2 patients per core agent group, with no difference detected between groups.ConclusionIncident body fat redistribution/accumulation, pancreatic disorders, musculoskeletal disorders, IRIS, severe systemic rash, and HSR were rare in this large cohort of patients initiating DTG, EVG, RAL, or DRV. Despite some channeling of patients with a disorder history towards DTG and RAL use, the likelihood of new events did not differ by core agent. Disclosures L. Brunet, Epividian, Inc.: Employee, Salary. ViiV Healthcare: ViiV Healthcare has contracted research with my employer, Epividian, Inc., Employer received funding for research. Merck: Merck has contracted research with my employer, Epividian, Inc., Employer received funding for other research. J. Fusco, Epividian, Inc.: Employee, Salary. ViiV Healthcare: Viiv Healthcare contracted research with my employer, Epividian, Inc., Employer received funding for research. Merck & Co.: Merck contracted research with my employer, Epividian, Inc., Employer received funding for research. V. Vannappagari, ViiV HealthCare: Employee, GlaxoSmithKline Company Stock and Salary. L. Ragone, ViiV Healthcare: Employee and Shareholder, restricted shares and Salary. G. Fusco, Epividian, Inc.: Employee, Salary. ViiV Healthcare: Viiv Healthcare contracted research with my employer, Epividian, Inc., Employer received funding for research. Merck & Co.: Merck contracted research with my employer, Epividian, Inc., Employer received funding for research.

SUCCESSFUL DESENSITIZATION FOR SEVERE LOCAL REACTIONS TO ANAKINRA

Introduction Anakinra is a recombinant human IL-1R antagonist that is used as a treatment option in various autoimmune disorders. Systemic reactions to anakinra are rare, but significant local reactions are common. We present a case of a patient with severe local reactions to anakinra, successfully treated with outpatient subcutaneous desensitization. Case Description A 9-year-old female with systemic juvenile idiopathic arthritis (JIA) was evaluated for local reactions to anakinra. She developed erythema, edema and pruritus at anakinra sites within an hour, lasting two to three days. Cetirizine and topical steroids gave minimal improvement. She spaced anakinra injections to every other day, but had loss of control of her JIA, necessitating systemic corticosteroids. She failed alternative monoclonal antibody therapies, developing eosinophilic dermatitis on canakinumab and treatment failure with tocilizumab. She had negative skin prick test to full-strength anakinra, but positive 1:10 intradermal dilution. A two-day, 12-step outpatient anakinra desensitization was administered subcutaneously. The desensitization protocol was completed without reaction and patient went on to tolerate future anakinra injections successfully. Discussion Desensitization with anakinra has been described in at least five other published reports. Three cases were desensitized for delayed hypersensitivity, and two cases were desensitized for systemic immediate hypersensitivity to anakinra. However, large local reactions continued to occur in one of two desensitizations administered for immediate hypersensitivity. This desensitization is the first describing success for treating local reactions to anakinra, which are a common complication of this biologic. Skin testing and subsequent desensitization may be considered for patients with treatment-limiting local reactions.

ASSESSMENT OF RESIDENT KNOWLEDGE REGARDING ANAPHYLAXIS USING AN ELECTRONIC EDUCATIONAL MODULE AND PRE/POST QUESTIONNAIRE

Introduction Anaphylaxis is an acute, life-threatening systemic hypersensitivity reaction that is frequently underdiagnosed, underreported, and undertreated by medical professionals. There is limited graduate medical education (GME) curriculum dedicated to allergy/immunology (A/I) topics, including anaphylaxis. We hypothesized that providing an electronic educational learning module would improve resident knowledge regarding anaphylaxis diagnosis and treatment. Methods Participants included pediatric, internal medicine, family medicine, and emergency medicine residents of all training levels. Participants watched a pre-recorded 15-minute video module reviewing high yield topics regarding the diagnosis and management of anaphylaxis. General knowledge regarding the diagnosis and management of anaphylaxis was evaluated by a 10-point questionnaire before and 5 weeks following completion of the module. Results The pre-test questionnaire and educational module was completed by 78 residents, whose training level was either PGY-1, PGY-2, PGY-3 or higher. Over half of the participants (60%) had prior clinical experience diagnosing and treating anaphylaxis, yet only 15% had completed a rotation in A/I. Overall, the number of questions answered correctly in the post-test questionnaire (88%) was higher than the pre-test questionnaire (80%) (p-value Conclusions Residents from various levels of training and specialties improved their knowledge in diagnosis and treatment of anaphylaxis after participation in an electronic educational module.

TRIGGERS AND SEVERITY OF ANAPHYLAXIS IN INFANTS

Introduction Anaphylaxis is a severe, life-threatening, systemic hypersensitivity reaction, which can occur at any age. Lately, there is special interest in severity of anaphylaxis in early age. We examined causes, clinical features and severity of infant anaphylaxis. Methods We performed a retrospective case-note review between January-December 2016 for infants presenting with anaphylaxis at our children's hospital. Results Among a total of 275 children presenting with anaphylaxisover a 1-year period, 15 (5%) were infants between 4-11 months of age (median: 8 months). Food was the most common cause of anaphylaxis (11/15; 73%); specifically, egg (8/15;53%), followed by milk (1/15;7%), peanut (1/15;7%) and banana (1/15;7%). Other causes of anaphylaxis included drug (3/15;20%) and unknown (1/15;7%). Cutaneous symptoms were reported in all cases (15/15;100%), followed by respiratory (9/15;60%), gastrointestinal (8/15;53%), and other (1/15;7%). In the majority (10/15;67%), symptoms developed within 15 minutes, whereas symptoms developed after 30 minutes in 7% (1/15) of patients, and time of symptom onset was unrecorded in 27% (4/15). Almost all infants (13/15, 87%) received epinephrine as rescue treatment, with 3/15 (20%) requiring 2 or more doses. Conclusions Infant anaphylaxis is most commonly the result of a severe allergic reaction to food, especially egg. In the majority, symptoms occur soon after ingestion, with skin symptoms predominating. Infant anaphylaxis can be severe and may require multiple doses of epinephrine administration. Parents must be educated appropriately on use of emergency medication and management of allergic reactions.

A Conspectus: Hepatotoxicity Caused by Drug’s

Liver is the principle organ for metabolism of various drugs, endotoxins. Hepatotoxicity is one of the reversible conditions. Drugs are an vital cause of liver injury. Drug-induced injury to the liver can mimic any form of acute or chronic liver disease. The action of cytochrome P450 can induce acute injury to liver, through which drug will break down into electrophiles or free radicals. These spontaneous metabolites can covalently bind to protein and unsaturated fatty acids or induce lipid peroxidation, respectively. The clinical presentation of liver damage may be either cytolytic or cholestatic. Systemic hypersensitivity reaction against the applied agent may be one of the major causes of liver damage. Drug- or toxin-induced liver damage includes vascular damage, induction of liver tumours and development of liver cirrhosis. The most important pre-emptive measure is judicious drug used by the prescribing physician. Early recognition of hepatotoxicity and termination of the offending agent is essential for treatment. The diagnosis may be confirmed by additional diagnostic measures (e. g. liver biopsy) or the clinical course after exposure to the causing agent has been stopped. Therefore, the main aim is to prevent chronic liver damage through early and correct diagnosis. Due to the extensive variety of possibly liver toxic drugs and chemical agents this aspect is a major challenge to physicians. Taking into account the significance of drug-induced hepatotoxicity as a key cause of liver damage, this review pitch light on various drugs which induce hepatotoxicity, with their mechanism of liver damage and clinical scenario.

Anaphylaxis and anaesthesia

No abstract available.

Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria

BackgroundPhenylketonuria (PKU) is caused by a deficiency in phenylalanine hydroxylase enzyme activity that leads to phenylalanine (Phe) accumulation in the blood and brain. Elevated blood Phe levels are associated with complications in adults, including neurological, psychiatric, and cognitive issues. Even with nutrition and pharmacological management, the majority of adults with PKU do not maintain blood Phe levels at or below guideline recommended levels. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is an investigational enzyme substitution therapy to lower blood Phe in adults with PKU. MethodsPegvaliase was administered using an induction, titration, and maintenance dosing regimen in adults with PKU naïve to pegvaliase treatment. Doses were gradually increased until blood Phe ≤ 600 μmol/L was achieved. The maintenance dose was the dose at which participants achieved and sustained blood Phe ≤ 600 μmol/L for at least 4 weeks without dose modification. Analyses were performed for participants who achieved (Group A, n = 11) and did not achieve (Group B, n = 13) maintenance dose during the first 24 weeks of study treatment. ResultsBaseline mean blood Phe for Group A and Group B were 1135 μmol/L and 1198 μmol/L, respectively. Mean blood Phe ≤ 600 μmol/L was achieved for Group A by Week 11 (mean blood Phe of 508 ± 483 μmol/L) and for Group B by Week 48 (mean blood Phe of 557 ± 389 μmol/L). The most common adverse events involved hypersensitivity reactions, which were mostly mild to moderate in severity and decreased over time. One participant in Group B had four acute systemic hypersensitivity events of anaphylaxis consistent with clinical National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria; all events were non-IgE mediated and resolved without sequelae, with pegvaliase dosing discontinued after the fourth event. The incidence and titers of anti-drug antibodies were generally lower in Group A compared to Group B. ConclusionsPegvaliase administered with an induction, titration, and maintenance dosing regimen demonstrated substantial efficacy at reducing blood Phe in both Group A and Group B by Week 48, with a manageable safety profile in most participants. Blood Phe reduction due to pegvaliase appears to be related to dose, treatment duration, and individual immune response; given additional time on treatment and dose titration, later Phe responders (Group B) achieved benefit similar to early Phe responders (Group A), with similar long-term safety profiles.

Metal ion release barrier function and biotribological evaluation of a zirconium nitride multilayer coated knee implant under highly demanding activities wear simulation

Total knee arthroplasty is a well established treatment for degenerative joint disease, which is also performed as a treatment in younger and middle-aged patients who have a significant physical activity and high life expectancy. However, complications may occur due to biological responses to wear particles, as well as local and systemic hypersensitivity reactions triggered by metal ions and particles such as cobalt, chromium and molybdenum. The purpose of the study was to perform a highly demanding activities (HDA) knee wear simulation in order to compare the wear characteristics and metal ion release barrier function of a zirconium nitride (ZrN) coated knee implant, designed for patients with suspected metal ion hypersensitivity, against an uncoated knee implant made out of CoCrMo. The load profiles were applied for 5 million HDA cycles, which represent 15–30 years of in vivo service depending on the activity level of the patient. Results showed a significant wear rate reduction for the coated group (1.01 ± 0.29 mg/million cycles) in comparison with the uncoated group (2.89 ± 1.04 mg/million cycles). The zirconium nitride coating showed no sign of scratches nor delamination during the wear simulation, whereas the uncoated femurs showed characteristic wear scratches in the articulation areas. Furthermore, the metal ion release from the coated implants was reduced up to three orders of magnitude in comparison with the uncoated implants. These results demonstrate the efficiency of zirconium nitride coated knee implants to reduce wear as well as to substantially reduce metal ion release in the knee joint.

Systemic IgE-mediated hypersensitivity reaction to topical polymyxin B

Systemic IgE-mediated hypersensitivity reaction to topical polymyxin B

Immediate local and systemic hypersensitivity due to etanercept and adalimumab

Immediate local and systemic hypersensitivity due to etanercept and adalimumab

The MultiPepT1De Study—Examining the Safety of Peptide Immunotherapy Using Multiple Islet Antigens in Recent-Onset Type 1 Diabetes

Background: Peptide immunotherapy (PIT) aims to modulate immune responses to specific antigens in order to restore immune tolerance. Recently, we reported outcomes of a phase 1b study of PIT at type 1 diabetes onset, showing safety, tolerability and changes in immune regulation pathways, following up to 12 doses of 10μg of a single proinsulin peptide that is naturally processed and presented by HLA-DR4 (DRB1*0401). Preclinical PIT studies show that multiple peptides in combination enhance tolerance induction. Aims: To evaluate the safety and clinical effects of PIT using a mix of multiple islet autoantigen peptides in adults with recent-onset type 1 diabetes. Methods: The MultiPepT1De study was a single centre, double-blind placebo-controlled, ascending dose, randomized trial recruiting adults aged 18-45 years within 4 years of diagnosis with HLA-DRB1*0401 genotype, positive islet autoantibodies and stimulated C-peptide &amp;gt;0.2pmol/mL. Study drug comprised of 6 naturally processed and presented, islet-derived peptides (MultiPepT1De). Participants were enrolled into 3 cohorts for monthly intradermal injections for 6 months. In each cohort, subjects were randomized to receive placebo (n=2) or MultiPepT1De (n=6) at 10µg (Cohort 1), 100µg (Cohort 2) or 500µg (Cohort 3) doses. Results: Twenty-seven participants were randomized; 3 participants withdrew for non-clinical reasons and were replaced. There were no episodes of systemic hypersensitivity, anaphylaxis or serious adverse reactions linked to MultiPepT1De administration. Analysis of changes in stimulated C-peptide, HbA1c and insulin dose per kg showed no evidence of disease acceleration following dosing compared with placebo. Mild transient injection site erythema was observed in all cohorts, with no increase on repeated dosing. Conclusions: Intradermal administration of multiple islet-derived peptides up to a cumulative dose of 3000µg, is well tolerated with no safety concerns. Disclosure Y. Liu: Other Relationship; Self; Novo Nordisk Limited. Research Support; Self; Bristol-Myers Squibb Company. J.K. Powrie: None. S. Arif: None. N. Fountoulakis: None. M. Joshi: None. E.L. Smith: Employee; Self; UCB, Inc. F. Strimenopoulou: Employee; Self; UCB, Inc. M. Thomson: Employee; Self; UCB, Inc. M. Peakman: Research Support; Self; Bristol-Myers Squibb Company. Advisory Panel; Self; Bristol-Myers Squibb Company. Consultant; Self; UCB, Inc.. Research Support; Self; UCB, Inc.. Advisory Panel; Self; T1D Exchange.