Hypersensitivity to monoclonal antibodies used for cancer and inflammatory or connective tissue diseases.

OBJECTIVE: To review the medical literature on hypersensitivity reactions to therapeutic monoclonal antibodies for patients with malignant tumors and chronic inflammatory or connective tissues diseases. DATA SOURCES: We searched the PubMed database using the terms monoclonal antibody, hypersensitivity, and allergy. STUDY SELECTIONS: We selected case reports and cohort studies of patients with hypersensitivity reactions to monoclonal antibodies. We included selected review articles to glean expert opinion on issues for which high-quality data are available. We sought specific information on the incidence, clinical description, pathobiology, and treatment of reactions. RESULTS: Hypersensitivity reactions to therapeutic monoclonal antibodies can be classic type I (mast cell mediated, perhaps IgE dependent) reactions, cytokine release reactions, or type IV cell-mediated reactions. There are limited data on the frequency of such reactions, and because new agents are added to the set at a relatively high rate, it is difficult to determine precisely the incidence of reactions to this class of drugs as a whole. The classification of a specific hypersensitivity reaction depends mainly on the medical history. Skin testing may be available but often is not validated and may be prohibitively expensive. Avoidance of the culpable agent is ideal, but if treatment with the responsible drug is necessary, rapid drug desensitization is an option for type I reactions. Desensitization is less likely to be effective for cytokine release reactions and is contraindicated for type IV reactions. CONCLUSION: Hypersensitivity reactions to therapeutic monoclonal antibodies are heterogeneous. Management depends on accurate identification and thoughtful consideration of the pathobiologic features of the reaction.

Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment.

BACKGROUND: Rapid desensitization, a procedure for graded drug administration, allows for the safe readministration of a medication after certain types of hypersensitivity reactions (HSRs) and is indicated in cases in which there are no reasonable therapeutic alternatives. The use of rapid desensitization for HSRs to mAbs has not been validated. OBJECTIVE: We sought to describe our experience with rapid desensitization to mAbs, including rituximab, infliximab, and trastuzumab. METHODS: One hundred five rapid desensitizations were performed in 23 patients with a standardized 12-step, 6-hour protocol. Our approach to patient evaluation before desensitization is described. The severity, characteristics, and timing of both initial HSRs and HSRs during desensitization were determined by means of retrospective review of medical records. After a reaction during desensitization, patient-specific protocol modifications were made before each subsequent desensitization. RESULTS: 104 of 105 desensitizations undertaken were successfully completed. We observed HSRs during 29% of desensitizations, including 27 mild reactions, 1 moderate reaction, and 2 severe reactions. Overall, reactions during desensitization were markedly less severe than initial HSRs, but reactions did recur in a minority of successive desensitizations. CONCLUSIONS: Rapid desensitization is a promising method for the delivery of monoclonal therapeutics after an HSR, but the possibility of a reaction remains with each desensitization.

Endophenotyping Oxaliplatin Hypersensitivity: Personalizing Desensitization to the Atypical Platin.

BACKGROUND: Oxaliplatin causes a wider variety of immediate hypersensitivity reactions than do other platin-based chemotherapeutics. Some resemble type 1 reactions that respond to desensitization. Others are atypical, possibly mast cell-independent cytokine release reactions refractory to desensitization. Given this variability, clinicians need an evidence-based strategy to personalize therapy for oxaliplatin-hypersensitive patients. OBJECTIVE: To develop a data-driven algorithm to optimize treatment of oxaliplatin-hypersensitive patients. METHODS: We retrospectively analyzed the baseline clinical characteristics, biomarkers, and reactions of 48 oxaliplatin-hypersensitive patients who received a total of 266 oxaliplatin desensitizations. RESULTS: We characterized 4 endophenotypes: type 1, cytokine release, mixed, and either. A mean 40-fold increase in serum concentration of IL-6 helped define the cytokine release endophenotype. Younger patients were more likely to have a cytokine release endophenotype, whereas older patients were more likely to have a type 1 reaction. Skin testing was not informative for determining endophenotype or risk of reaction during desensitization, and did not associate with initial or desensitization grade of reaction. Patients with a history of atopy and an initial type 1 reaction responded to desensitization with antihistamine premedications, whereas nonatopic patients with the same initial reaction phenotype were more likely to convert to a cytokine release or mixed reaction during desensitization. We combined these reaction patterns with biomarker data and desensitization outcomes to construct an algorithm that helps tailor desensitization protocol design to meet individual patient needs. CONCLUSIONS: Endophenotyping oxaliplatin hypersensitivity reactions may help forecast desensitization outcomes and personalize treatment plans.

Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.

BACKGROUND: Hypersensitivity reactions (HSRs) to chemotherapeutic drugs, including mAbs, often require that the provoking medication be discontinued, thus raising a dilemma for the caregiver: further use could precipitate a severe, even fatal, allergic reaction on re-exposure, but alternative drugs might be poorly tolerated or much less effective compared with the preferred agent. OBJECTIVE: We have developed a standardized rapid desensitization protocol for achieving temporary tolerization to drug allergens. In this study we evaluate the safety and efficacy of this protocol. METHODS: Ninety-eight patients who had HSRs in response to treatment with carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomal doxorubicin, doxorubicin, or rituximab received rapid desensitization to these agents. A standardized 12-step protocol was used, with treatment given intravenously or intraperitoneally. Initial desensitizations occurred in the medical intensive care unit, whereas most subsequent infusions took place in an outpatient setting. Safety and efficacy of the protocol were assessed by review of treatment records. RESULTS: Of the 413 desensitizations performed, 94% induced mild or no reactions. No life-threatening HSRs or deaths occurred during the procedure, and all patients received their full target dose. Most reactions occurred during the first desensitization. Reactions were most commonly reported at the last step of the protocol. Desensitizations through the intravenous and intraperitoneal routes were equally effective. CONCLUSIONS: Our standardized 12-step protocol for rapid drug desensitization is safe and effective and has been adopted as the standard of care at our institutions in treating patients with HSRs to chemotherapeutic drugs, including mAbs.

Surgery Clerkship Evaluations Are Insufficient for Clinical Skills Appraisal: The Value of a Medical Student Surgical Objective Structured Clinical Examination.

OBJECTIVE: Optimal methods for medical student assessment in surgery remain elusive. Faculty- and housestaff-written evaluations constitute the chief means of student assessment in medical education. However, numerous studies show that this approach has poor specificity and a high degree of subjectivity. We hypothesized that an objective structured clinical examination (OSCE) in the surgery clerkship would provide additional data on student performance that would confirm or augment other measures of assessment. DESIGN: We retrospectively reviewed data from OSCEs, National Board of Medical Examiners shelf examinations, oral presentations, and written evaluations for 51 third-year Harvard Medical School students rotating in surgery at Massachusetts General Hospital from 2014 to 2015. We expressed correlations between numeric variables in Pearson coefficients, stratified differences between rater groups by one-way analysis of variance, and compared percentages with 2-sample t-tests. We examined commentary from both OSCE and clinical written evaluations through textual analysis and summarized these results in percentages. RESULTS: OSCE scores and clinical evaluation scores correlated poorly with each other, as well as with shelf examination scores and oral presentation grades. Textual analysis of clinical evaluation comments revealed a heavy emphasis on motivational factors and praise, whereas OSCE written comments focused on cognitive processes, patient management, and methods to improve performance. CONCLUSIONS: In this single-center study, an OSCE provided clinical skills data that were not captured elsewhere in the surgery clerkship. Textual analysis of faculty evaluations reflected an emphasis on interpersonal skills, rather than appraisal of clinical acumen. These findings suggest complementary roles of faculty evaluations and OSCEs in medical student assessment.

Autoimmune progesterone dermatitis: clinical presentation and management with progesterone desensitization for successful in vitro fertilization.

OBJECTIVE: To report clinical cases of autoimmune progesterone (P) dermatitis, its relationship to IVF, and the potential for P desensitization to treat these cases to achieve viable pregnancies. DESIGN: Clinical description. SETTING: Institutional hospitalary practice. Allergy Division. PATIENT(S): Six patients from the Allergy Clinic consulting for cyclic rashes or anaphylaxis related to the luteal phase of the menstrual cycle. Three of the conditions were related to IVF. INTERVENTION(S): Skin tests were performed with P. For IVF, rapid 8- and 10-step P desensitization protocols were performed, with increasing doses administered every 20 minutes via intravaginal suppositories. A rapid oral desensitization protocol was performed in one patient who required an oral contraceptive for uterine bleeding. MAIN OUTCOME MEASURE(S): Progesterone skin test results. Tolerance to P desensitization. Achievement of viable pregnancies. RESULT(S): Skin tests were positive in all patients and negative in 10 controls. Desensitization was successful in four patients: three patients for IVF, resulting in viable pregnancies. Another patient achieved tolerance to oral contraceptives. CONCLUSION(S): Women with autoimmune P dermatitis can be desensitized successfully to P. We provide the first evidence of successful P desensitization in patients requiring IVF culminating in successful pregnancies.

Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema.

OBJECTIVE: To provide a summary of the literature regarding the use of attenuated androgens during the past 40 to 50 years for the treatment of hereditary angioedema (HAE). DATA SOURCES: MEDLINE and PubMed were searched to identify studies involving the treatment of HAE with androgens. STUDY SELECTION: Studies were selected based on their relevance to the use of androgens for the treatment of HAE. RESULTS: Attenuated androgens have proven successful for the short- and long-term treatment of HAE. Adverse effects are still concerning, and their use in children and pregnant women must be undertaken with great caution. Scheduled monitoring of liver function tests and lipid profiles in patients treated with these medications is critical. CONCLUSIONS: Attenuated androgens have been successful in the short- and long-term treatment of HAE, and they are still the most frequently used medications in the United States for the treatment of this disease. There is a lack of readily available options for the treatment of acute HAE attacks apart from the administration of fresh frozen plasma or safe prophylactic therapies; however, several appropriate agents currently in clinical trials in the United States appear promising.

Induced loss of Syk in human basophils by non-IgE-dependent stimuli.

In the general population, Syk expression in human basophils is highly variable and correlates well with the IgE-mediated responsiveness of these cells. Previous studies established that IgE-mediated stimulation results in loss of Syk expression. The current studies investigated whether stimulation through other receptors results in loss of Syk. Two classes of stimulation were examined, those that operate through the kinase Syk and those that operate through a GTP-binding protein. These studies demonstrated that aggregation of leukocyte Ig-like receptor LILRA-2 resulted in phosphorylation of Syk and c-Cbl, was inhibited by a third generation Syk inhibitor with an expected IC(50), and induced histamine release in strict proportion to release induced by anti-IgE Ab. Stimulation of LILRA-2 for 18 h resulted in modest loss of Syk that correlated with the more profound loss of Syk induced by anti-IgE Ab. Human recombinant histamine-releasing factor has also recently been shown to induce Syk phosphorylation and in the current studies has also been shown to induce loss of Syk in 18-h cultures. fMLP stimulation for 18 h was also found to induce modest loss of Syk. fMLP induced phosphorylation of c-Cbl that was sustained for at least 45 min. Phosphorylation of c-Cbl was inhibited by a Syk kinase inhibitor but with an IC(50) that was not consistent with Syk activity, suggesting another kinase was responsible for Cbl phosphorylation following fMLP. These studies demonstrate that it is possible to induce the loss of Syk expression in human basophils by a non-IgE-dependent mechanism and even by a mechanism that does directly involve Syk in the reaction complex.

Purification from human milk of matriptase complexes with secreted serpins: mechanism for inhibition of matriptase other than HAI-1.

Matriptase, a type 2 transmembrane serine protease, is predominately expressed by epithelial and carcinoma cells in which hepatocyte growth factor activator inhibitor 1 (HAI-1), a membrane-bound, Kunitz-type serine protease inhibitor, is also expressed. HAI-1 plays dual roles in the regulation of matriptase, as a conventional protease inhibitor and as a factor required for zymogen activation of matriptase. As a consequence, activation of matriptase is immediately followed by HAI-1-mediated inhibition, with the activated matriptase being sequestered into HAI-1 complexes. Matriptase is also expressed by peripheral blood leukocytes, such as monocytes and macrophages; however, in contrast to epithelial cells, monocytes and macrophages were reported not to express HAI-1, suggesting that these leukocytes possess alternate, HAI-1-independent mechanisms regulating the zymogen activation and protease inhibition of matriptase. In the present study, we characterized matriptase complexes of 110 kDa in human milk, which contained no HAI-1 and resisted dissociation in boiling SDS in the absence of reducing agents. These complexes were further purified and dissociated into 80-kDa and 45-kDa fragments by treatment with reducing agents. Proteomic and immunological methods identified the 45-kDa fragment as the noncatalytic domains of matriptase and the 80-kDa fragment as the matriptase serine protease domain covalently linked to one of three different secreted serpin inhibitors: antithrombin III, alpha1-antitrypsin, and alpha2-antiplasmin. Identification of matriptase-serpin inhibitor complexes provides evidence for the first time that the proteolytic activity of matriptase, from those cells that express no or low levels of HAI-1, may be controlled by secreted serpins.

Hereditary angioedema: Safety of long-term stanozolol therapy.

BACKGROUND: Attenuated androgens control attacks of hereditary angioedema. Short-term studies of such patients treated at our institution with attenuated androgens demonstrated no adverse effects. However, the side-effect frequencies in patients receiving long-term treatment are relatively less well characterized. OBJECTIVE: To assess the frequencies of various side effects of the attenuated androgen stanozolol in a population of patients with hereditary angioedema treated for 20 to 40 years. METHODS: Data on side effects in patients who continued stanozolol therapy since 1987 were obtained by means of questionnaire. Patients were evaluated by physical examination; biochemical assays of hepatic function, serum lipids, and prostate specific antigen; and liver ultrasound. RESULTS: The minimal initial effective dosage of stanozolol was 0.5 to 2.0 mg daily, although most patients achieved symptomatic control and decreased the dose and frequency as the frequency of attacks decreased. Treatment-related symptoms developed in 10 of 21 patients. No interruption in stanozolol therapy was required because symptoms subsided with a reduction in the stanozolol dosage. Adverse side effects included hirsutism, weight gain, menstrual irregularities or postmenopausal bleeding, acne, and mood changes. Liver enzyme assays revealed no persistent abnormalities. Liver ultrasounds in 8 patients revealed 3 abnormalities deemed unrelated to therapy. Five patients had a reduced high-density lipoprotein, and 2 patients had elevated triglycerides. CONCLUSION: Stanozolol is a safe and effective drug for the long-term management of hereditary angioedema. CLINICAL IMPLICATIONS: Stanozolol may be used in the long-term treatment of patients with hereditary angioedema provided such patients are closely supervised with routine clinical, biochemical, and radiologic assessments.

An 80-year-old woman with chronic nasal congestion.

Nasal congestion is a common problem in outpatient allergy and immunology. Here, we present the case of an 80-year-old woman with long-standing nasal congestion of uncommon cause and discuss its diagnosis, treatment, and prognosis. Although most patients with chronic nasal congestion do not have a life-threatening condition, it is important to remain vigilant for warning signs that a rare disease is at work behind this common complaint.

Leukocyte immunoglobulin-like receptors: novel innate receptors for human basophil activation and inhibition.

Basophils, recruited from the blood to tissues, have been implicated by their presence in diverse allergic disorders including bronchial asthma, allergic rhinitis, and cutaneous contact hypersensitivity. We hypothesized that like other leukocytes involved in inflammatory responses, basophils would express members of the leukocyte immunoglobulin-like receptor (LIR) family of immuno-regulatory molecules on their cell surface. We identified LIR7, an activating member coupled to the common Fc receptor gamma chain, and LIR3, an inhibitory member containing cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, on these cells from human peripheral blood. Cross-linking of LIR7 resulted in the concentration-dependent net release of histamine (29.8 +/- 10.8%) and cysteinyl leukotrienes (cysLTs) (31.4 +/- 8.7 ng/10(6) basophils) that were maximal at 30 minutes, and of interleukin-4 (IL-4) (410.2 +/- 61.6 pg/10(6) basophils) that was maximal at 4 hours and comparable with the response initiated by cross-linking of the high-affinity receptor for immunoglobulin E (FcepsilonRI). Coligation of LIR3 to LIR7 or to FcepsilonRI by means of a second monoclonal antibody significantly inhibited net histamine release, cysLT production, and IL-4 generation. That LIR3 is profoundly counter-regulatory for both adaptive and innate receptors suggests a broad role in containment of the inflammatory response.

Activation of human eosinophils through leukocyte immunoglobulin-like receptor 7.

Eosinophils are implicated prominently in allergic diseases and the host response to parasitic infections. Eosinophils may be activated in vitro by diverse classes of agonists such as immunoglobulins, lipid mediators, and cytokines. The leukocyte Ig-like receptors (LIRs) comprise a family of inhibitory and activating cell-surface receptors. Inhibitory LIRs down-regulate cellular responses through cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. There are limited data on the action of the activating LIRs, which are thought to signal through the Fc receptor gamma chain, which contains an immunoreceptor tyrosine-based activation motif. We now demonstrate the expression of LIR1 (inhibitory), LIR2 (inhibitory), LIR3 (inhibitory), and LIR7 (activating) on eosinophils from 4, 4, 12, and 11, respectively, of 12 healthy donors. Cross-linking of LIR7 with plate-bound antibody elicited the dose- and time-dependent release of eosinophil-derived neurotoxin and leukotriene C(4). Eosinophils activated with antibodies to LIR7 embedded in gel-phase EliCell preparations showed leukotriene C(4) generation at the nuclear envelope and the release of IL-12 but not IL-4 by vesicular transport. Thus, LIR7 is an activating receptor for eosinophils that elicited the release of cytotoxic granule proteins, de novo lipid mediator generation, and cytokine release through vesicular transport.