Purpose of reviewThe purpose of this literature review was to review the latest use of biologics in the management of anaphylaxis. The methodology was to highlight both the nonbiologic management of anaphylaxis and the biologic management and how they can be used in conjunction with each other.Recent findingsAs the phenotypes and endotypes of anaphylaxis are better portrayed, it furthers our understanding of the mechanisms of anaphylaxis. New applications of existing biologics to the prevention of anaphylaxis are described.SummaryAnaphylaxis is a potentially life-threatening acute hypersensitivity reaction affecting up to 16.8% of the U.S. population. Acute management entails swift identification, removal of the causative agent, and the prevention of cardiovascular collapse, firstly with epinephrine. Adjunctive treatments such as antihistamines work to prevent anaphylaxis from recurring. Biologic management of anaphylaxis involves the use of large-molecule drugs such as monoclonal antibodies. Omalizumab, an IgG1 monoclonal antibody targeting unbound IgE, is the most prevalent and widely studied biologic in the prevention of anaphylaxis. Other monoclonal antibodies in development or approved for other indications, such as ligelizumab, quilizumab, MEDI4212, and dupilumab, may also have potential for preventing anaphylaxis through various mechanisms.

Hypersensitivity reactions to drugs have increased in the past 25 years due to increased exposures and availability of efficient, targeted, and personalized medications. Rapid drug desensitization is a clinical procedure that allows for the safe administration of a drug in patients with a history of such hypersensitivity reactions. Desensitization allows the continued use of first-line therapies, leading to higher efficacy of treatment, fewer side effects, cost-effectiveness, and increased quality of life and life expectancy of patients when compared with the use of second-line therapy. In this review, we discuss the who, what, where, when, why, and how of drug desensitization.

The purpose of this literature review was to review the latest advancements with biologics in rapid drug desensitization. Our methodology was to highlight both desensitization to biologics themselves and the use of biologics in desensitization to both biologic and nonbiologic drugs. Biologics are a vast category of drugs that include monoclonal antibodies, nanobodies, modern vaccinations, and even hormones. Desensitization to biologics can be safely performed through standardized procedure. Biomarkers are used both in vitro and in vivo to help identify and classify hypersensitivity reactions. Hypersensitivity reactions to the mRNA vaccinations against SARS-CoV-2 present their own unique challenges to management. There are specific excipients in monoclonal antibodies that are thought to be responsible for many of their hypersensitivity reactions. Certain biologics can even be used to assist in desensitization to other drugs. Rapid drug desensitization is a standardized procedure that may be able to help many patients who have experienced hypersensitivity reactions to biologics and would best be treated with them to continue to receive them. Biologic drugs have opened a new era in medicine for the prevention and treatment of infectious diseases, cancer, and inflammatory diseases. Hypersensitivity reactions to biologics are quite common. This literature review presents the latest advancements in our understanding of hypersensitivity reactions to biologics, how rapid drug desensitization can be used to continue therapy despite history of hypersensitivity, and how biologics themselves can be used to aid in desensitization itself.

Rituximab is a chimeric monoclonal anti-CD20 antibody with wide use in cancer (lymphoma) and connective tissue diseases (rheumatoid arthritis and vasculitis). 1 Ataca P. Atilla E. Kendir R. Bavbek S. Ozcan M. Successful desensitization of a patient with rituximab hypersensitivity. Case Reports Immunol. 2015; 2015: 524507 Crossref PubMed Google Scholar Hypersensitivity reactions to rituximab can range from type I immunoglobulin E (IgE)-mediated reaction (urticaria, shortness of breath, hypotension, or anaphylaxis) to cytokine-mediated reaction (fevers, chills, rigors) or a mix of both, thus limiting the use of rituximab as first-line therapy for many cases. Desensitization is a new therapeutic approach that can be performed with rituximab to offset these reactions. Drug allergy: Veni, vidi, vici—come, understand, and delabel, avoid, or desensitizeAnnals of Allergy, Asthma & ImmunologyVol. 123Issue 1Preview“Veni, vidi, vici” [I came, I saw, I conquered], said Julius Caesar in 47 bc in a letter to the Roman Senate after achieving a swift, conclusive victory against Pharnaces of Pontus in the battle of Zela in northern Turkey.1 A modern version of the determined words of Julius Caesar can be applied to drug allergy: first, come and spend time learning about the reaction, observe the signs and symptoms, or look at the pictures sent by the patient; second, observe the phenotype, understand the endotype, and get help from the biomarkers (tryptase, skin test, challenge, genotype); and third, provide an appropriate treatment option, recommend avoidance or desensitization if possible and/or indicated, and delabel all nonallergic patients. Full-Text PDF

Background: Patch testing is the "gold standard" to identify culprit allergen(s) causing allergic contact dermatitis (ACD), but there are limited studies of patch testing from allergy practice settings. Objective: We sought to explore patch test findings in a large academic allergy practice, including patch testing results, history of atopy, location of dermatitis, and referral source. We also wanted to determine whether patch testing using an extended panel, such as the North American screening series, compared with a limited series, such as the Thin-Layer Rapid-Use Epicutaneous (T.R.U.E.) Test, increased the sensitivity. Methods: A retrospective chart review was conducted of patients referred for patch testing over a 6-year period. Results: A total of 585 patients (mean age 48.7 years, 71.6 % female) underwent patch testing over the 6-year period, of which 369 (63%) had a positive test. Of those who tested positive, 202 (55%) reported a history of atopy. The extremities were the most commonly involved site, followed by the head/neck and trunk. The 5 most common positive allergens were nickel sulfate, gold sodium thiosulfate, methylchloroisothiazolinone, thimerosal, and bacitracin. Three hundred fourteen (53.6%) patients were positive to at least 1 allergen on TRUE testing. Extended screening series identified an additional 10.8% of patients with positive tests who were negative to T.R.U.E. test allergens. Conclusion: Patch testing is a valuable diagnostic tool for the practicing allergist and provides early identification of culprit allergens in ACD. Performing an extended screening series such as the North American Contact Dermatitis Group (NACDG) or supplemental panel of allergens increased sensitivity when compared with a limited series. (C) 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Gold Is Precious—But a Potent Sensitizer?The Journal of Allergy and Clinical Immunology: In PracticeVol. 7Issue 1PreviewMetallic gold, carat jewelry alloys, and dental gold alloys are widely accepted as nonsensitizing materials. These substances are considered safe and inert when in contact with the skin or oral mucosa,1 and this is attributed to the inertness of gold. In contrast, gold salts appear to be strong sensitizers, as shown by Kligman2 in a human maximization test with gold chloride. But when gold sodium thiosulfate was added to a standard series for patch testing in Sweden, positive reactions were noted in 8.6% of 823 consecutive patients with a suspected contact allergy. Full-Text PDF

Background Patch testing is the “gold standard” to identify culprit allergen(s) causing allergic contact dermatitis (ACD), but there are limited studies of patch testing from allergy practice settings. Objective We sought to explore patch test findings in a large academic allergy practice, including patch testing results, history of atopy, location of dermatitis, and referral source. We also wanted to determine whether patch testing using an extended panel, such as the North American screening series, compared with a limited series, such as the Thin-Layer Rapid-Use Epicutaneous (T.R.U.E.) Test, increased the sensitivity. Methods A retrospective chart review was conducted of patients referred for patch testing over a 6-year period. Results A total of 585 patients (mean age 48.7 years, 71.6 % female) underwent patch testing over the 6-year period, of which 369 (63%) had a positive test. Of those who tested positive, 202 (55%) reported a history of atopy. The extremities were the most commonly involved site, followed by the head/neck and trunk. The 5 most common positive allergens were nickel sulfate, gold sodium thiosulfate, methylchloroisothiazolinone, thimerosal, and bacitracin. Three hundred fourteen (53.6%) patients were positive to at least 1 allergen on TRUE testing. Extended screening series identified an additional 10.8% of patients with positive tests who were negative to T.R.U.E. test allergens. Conclusion Patch testing is a valuable diagnostic tool for the practicing allergist and provides early identification of culprit allergens in ACD. Performing an extended screening series such as the North American Contact Dermatitis Group (NACDG) or supplemental panel of allergens increased sensitivity when compared with a limited series.

Elaine F. Remmers1, Fulya Cosan2, Yohei Kirino1, Michael J. Ombrello1, Neslihan Abaci3, Colleen Satorius1, Julie M. Le1, Barbara Yang4, Benjamin D. Korman1, Aris Cakiris3, Oznur Aglar3, Zeliha Emrence3, Hulya Azakli3, Duran Ustek3, Ilknur Tugal-Tutkun5, Gulsen Akman-Demir6, Wei Chen7, Christopher I. Amos7, Michael B. Dizon4, Afet Akdag Kose8, Gulsevim Azizlerli8, Burak Erer2, Oliver J. Brand9, Virginia G. Kaklamani10, Phaedon Kaklamanis11, Eldad Ben-Chetrit12, Miles Stanford13, Farida Fortune14, Marwen Ghabra15, William E. R. Ollier16, Young-Hun Cho17, Dongsik Bang18, John O'Shea19, Graham R. Wallace20, Massimo Gadina4, Daniel L. Kastner1, and Ahmet Gül2,3 1 Laboratory of Clinical Investigation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA

OBJECTIVE:Monogenic autoinflammatory diseases are disorders of Mendelian inheritance that are characterized by mutations in genes that regulate innate immunity and whose typical features are systemic inflammation without high-titer autoantibodies or antigen-specific T cells. Skin and bone inflammation in the newborn period have been described in 3 of these autoinflammatory disorders: neonatal-onset multisystem inflammatory disease, Majeed syndrome, and deficiency of interleukin-1 (IL-1) receptor antagonist (DIRA) syndrome. This study was undertaken to present the characteristics of the DIRA syndrome in 2 cases from Brazil, and describe a novel mutation in IL1RN. METHODS:Two unrelated Brazilian patients were evaluated for the clinical signs and symptoms of these 3 disorders, and peripheral blood samples were assessed for mutations in NLRP3, LPIN2, and IL1RN by DNA resequencing analysis. A mutation in IL1RN that encodes a mutant protein was identified, and the expression and function of this mutant protein were compared to those of the wild-type protein. RESULTS:Both patients presented with pustular dermatitis resembling generalized pustular psoriasis, recurrent multifocal aseptic osteomyelitis, and elevation in the levels of acute-phase reactants, all of which are features most consistent with the DIRA syndrome. Chronic lung disease was observed in 1 of the patients, and jugular venous thrombosis was observed in the other patient. Both patients showed a partial response to corticosteroid therapy, and 1 patient experienced an initial improvement of dermatitis with the use of acitretin. Both patients were homozygous for a novel 15-bp (in-frame) deletion on the IL1RN gene. The mutated protein expressed in vitro had no affinity with the IL-1 receptor, and stimulation of the patients' cells with recombinant human IL-1α or IL-1β led to oversecretion of proinflammatory cytokines, similar to the findings obtained in previously reported patients. CONCLUSION:The presence of the same homozygous novel mutation in IL1RN in 2 unrelated Brazilian patients suggests that this genetic variant may be a founder mutation that has been introduced in the Brazilian population.

Inflammatory processes resulting from the secretion of soluble mediators by immune cells, lead to various manifestations in skin, joints and other tissues as well as altered cytokine homeostasis. The innate immune system plays a crucial role in recognizing pathogens and other endogenous danger stimuli. One of the major cytokines released by innate immune cells is Interleukin (IL)-1. Therefore, we utilize a whole blood stimulation assay in order to measure the secretion of inflammatory cytokines and specifically of the pro-inflammatory cytokine IL-1β 1, 2, 3. Patients with genetic dysfunctions of the innate immune system causing autoinflammatory syndromes show an exaggerated release of mature IL-1β upon stimulation with LPS alone. In order to evaluate the innate immune component of patients who present with inflammatory-associated pathologies, we use a specific immunoassay to detect cellular immune responses to pathogen-associated molecular patterns (PAMPs), such as the gram-negative bacterial endotoxin, lipopolysaccharide (LPS). These PAMPs are recognized by pathogen recognition receptors (PRRs), which are found on the cells of the innate immune system 4, 5, 6, 7. A primary signal, LPS, in conjunction with a secondary signal, ATP, is necessary for the activation of the inflammasome, a multiprotein complex that processes pro-IL-1β to its mature, bioactive form 4, 5, 6, 8, 9, 10. The whole blood assay requires minimal sample manipulation to assess cytokine production when compared to other methods that require labor intensive isolation and culturing of specific cell populations. This method differs from other whole blood stimulation assays; rather than diluting samples with a ratio of RPMI media, we perform a white blood cell count directly from diluted whole blood and therefore, stimulate a known number of white blood cells in culture 2. The results of this particular whole blood assay demonstrate a novel technique useful in elucidating patient cohorts presenting with autoinflammatory pathophysiologies.

Elaine Remmers and colleagues report a genome-wide association study for Behçet's Disease in a Turkish population. They identify associations in the Class I region of the MHC, IL10 and IL23R-IL12RB2. Behçet's disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçet's disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçet's disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 × 10−8). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 × 10−18, odds ratio = 1.45, 95% CI 1.34–1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 × 10−9, OR = 1.28, 95% CI 1.18–1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.

BACKGROUNDAutoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone.METHODSWe studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN.RESULTSWe identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1 beta stimulation. Patients treated with anakinra responded rapidly.CONCLUSIONSWe propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)

CD28 is recognized as the primary costimulatory molecule involved in the activation of naïve T cells. However, the biochemical signaling pathways that are activated by CD28 and how these pathways are integrated with TCR signaling are still not understood. We have recently shown that there are at least two independent activation pathways induced by CD28 costimulation. One is integrated with TCR signaling in the context of the immunological synapse and is mediated through transcriptional enhancement and the second is mediated through the induction of mRNA stability. Here, we review the immunological consequences and biochemical mechanisms associated with CD28 costimulation and discuss the major questions that need to be resolved to understand the molecular mechanisms that transduce CD28 costimulation.