Infusion of Pituitary Adenylate Cyclase-Activating Polypeptide-38 in Patients with Rosacea Induces Flushing and Facial Edema that Can Be Attenuated by Sumatriptan.

BACKGROUND: The pathogenesis of rosacea is incompletely understood. Signaling neuropeptides, including PACAP, a regulator of vasodilation and edema, are upregulated in rosacea skin. Here, we evaluated PACAP38-induced rosacea features and examined whether a 5-HT1B/1D receptor agonist could reduce these features. METHODS: A total of 35 patients with erythematotelangiectatic rosacea received an intravenous infusion of 10 pmol/kg/minute of PACAP38 followed by an intravenous infusion of 4 mg sumatriptan or placebo (saline) on two study days in a double-blind, randomized, placebo-controlled, and cross-over trial. RESULTS: PACAP38 increased facial skin blood flow by 90%, dilated the superficial temporal artery by 56%, and induced prolonged flushing and facial edema. Compared with placebo, sumatriptan reduced PACAP38-induced facial skin blood flow for 50 minutes (P = 0.023), constricted the superficial temporal artery for 80 minutes (P = 0.010), and reduced duration of flushing (P = 0.001) and facial edema (P < 0.001). CONCLUSIONS: We established a clinical experimental model of rosacea features and showed that sumatriptan was able to attenuate PACAP38-induced rosacea flushing and edema. Findings support a key role of PACAP38 in rosacea flushing pathogenesis. It remains unknown whether PACAP38 inhibition can improve rosacea. TRIAL REGISTER: The trial was registered at ClinicalTrials.govNCT03878784 in March 2019.

Treatment with pembrolizumab after hypersensitivity reaction to nivolumab in a patient with hepatocellular carcinoma.

PURPOSE: The options for immunotherapy treatment are limited for treatment of hepatocellular carcinoma. In this case study, we report a case of successful alternation of one PD-1 inhibitor for another after a hypersensitivity reaction. SUMMARY: Nivolumab (Opdivo, Bristol-Myers Squibb) has been Food and Drug Administration (FDA) approved for a variety of malignancies, including a recent approval for hepatocellular carcinoma (HCC). Infusion-related reactions occur in less than 1% of patients, and although such reactions are rare, recognition of infusion-related reactions induced by nivolumab is an important aspect of its usage. The PD-1 checkpoint inhibitor pembrolizumab is also FDA approved for subsequent-line therapy in treatment of HCC. Thus far, approximately 0.2% of patients experienced severe infusion-related reaction in studies using pembrolizumab. A 70-year-old male with HCC had an infusion reaction to nivolumab that presented as facial flushing, dyspnea, and back pain. The patient received prompt administration of diphenhydramine and hydrocortisone, which led to the amelioration of symptoms and allowed the patient to complete his immunotherapy treatment. For the third dose of nivolumab, the patient received premedications prior to treatment, including diphenhydramine, hydrocortisone, and famotidine. During his infusion, the patient experienced facial flushing, coughing, chest tightness, and an itchy throat. The patient again received diphenhydramine and hydrocortisone to treat infusion-related symptoms and his therapy was discontinued. Because of the nivolumab infusion-related reaction, nivolumab was discontinued, and the patient was started on pembrolizumab. The patient tolerated pembrolizumab without any subsequent infusion-related reactions. Prompt recognition and attention to immunotherapy infusion-related reactions could potentially prevent the fatal complication of anaphylaxis with immune checkpoint inhibitors. In this report, we describe the successful transition from one anti-PD-1 therapy to another for continued immunotherapy treatment without any subsequent infusion reactions. CONCLUSION: A patient with HCC was successfully treated with pembrolizumab after experiencing adverse effects with nivolumab.

Infusion reactions during infliximab treatment are not associated with IgE anti-infliximab antibodies.

OBJECTIVES: Controversy exists on the role of IgE antidrug antibodies (IgE-ADA) in infusion reactions (IR) on infliximab treatment, partly due to the lack of a positive control used for assay validation. We sought to (1) develop a robust assay to measure IgE-ADA, including a positive control, (2) determine the association between IgE-ADA and IR and (3) determine the incidence of IgE-ADA in infliximab treated patients. METHODS: A recombinant human IgE anti-infliximab monoclonal antibody was developed as standard and positive control. With this antibody, we set up a novel robust assay to measure IgE-ADA. IgE-ADA was determined in three retrospective cohorts (n=159) containing IR+ (n=37) and IR- (n=39), and longitudinal sera of 83 spondyloarthritis. RESULTS: IgE-ADA was found in 0/39 IR-, whereas 4/37 (11%) IR+ showed low levels (0.1-0.3 IU/mL, below the 0.35 IU/mL threshold associated with elevated risk of allergic symptoms). All patients who were IgE-ADA positive also had (very) high IgG-ADA levels. The incidence of IgE-ADA in patients with infliximab-treated spondyloarthritis was estimated at less than approximately 1%. CONCLUSIONS: IgE-ADA is rarely detected in infliximab-treated patients. Moreover, the absence of IgE-ADA in the majority of IR+ patients suggests that IgE-ADA is not associated with infusion reactions.

Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations.

BACKGROUND: Diagnostic criteria for mast cell (MC) activation syndrome have been recently proposed, but clinical studies to validate these criteria are lacking. OBJECTIVE: We sought to determine the clinical manifestations of this newly recognized syndrome in a cohort of patients. METHODS: We prospectively evaluated 18 patients seen at our institution with MC activation syndrome from 2006 to 2009. Patients enrolled had at least 4 of the signs and symptoms of abdominal pain, diarrhea, flushing, dermatographism, memory and concentration difficulties, or headache. Response to treatment with anti-MC mediator medications was assessed based on established criteria. Laboratory tests indicating MC mediator release and histopathology and immunohistochemical studies on gastrointestinal biopsy samples were performed. RESULTS: Ninety-four percent of the patients had abdominal pain, 89% had dermatographism, 89% had flushing, and 72% had the constellation of all 3 symptoms. Patients additionally had headache, diarrhea, and memory and concentration difficulties. All patients had at least 1 positive laboratory test result for an increased MC mediator level. On the basis of the response to treatment criteria, 67% of the patients in the cohort had either a complete or major regression in symptoms while taking medications targeting MC mediators. There was no significant difference in the numbers of intestinal mucosal MCs between our patients and healthy control subjects. CONCLUSION: MC activation syndrome might be the underlying cause of unexplained symptoms when several organ systems are involved, such as the gastrointestinal tract and the skin. It is especially important to be able to recognize the constellation of clinical features because response to anti-MC mediator medications is often excellent.

Nitrate anaphylaxis.

BACKGROUND: Nitrate and nitrite salts are commonly used to preserve and sustain color in a number of processed meats. To date there have been no described cases of anaphylaxis to either nitrates or nitrites in the literature. OBJECTIVE: We report a patient with anaphylaxis to nitrates and nitrites documented by double-blind, placebo-controlled capsule challenge. METHODS: A 22-year-old previously well male, presented to a tertiary referral center with a 4-year history of recurrent anaphylaxis after eating take-out food. No further episodes occurred while adhering to a strict elimination diet. We performed a double-blind, placebo-controlled capsule challenge both with food substances and starch placebo. These occurred in a hospital setting with full resuscitative procedures available. RESULTS: An acute anaphylactic reaction occurred following a challenge to nitrates and nitrites. Generalized allergic reactions were observed on separate occasions following administration of artificial colorings and metabisulfite. There was a mild urticarial reaction following salicylates. He was placed on a diet free of sulfites, nitrates, nitrites, and low in salicylates and he has had no further reactions. A computer based search of the Medline, Current Contents and EMBASE databases found no previously reported cases of urticaria, angioedema, or anaphylaxis to either nitrates or nitrites. CONCLUSION: The ingestion of processed meats containing nitrate or nitrite salts may be associated with angioedema and anaphylaxis and should be considered when investigating patients with suspected food allergy.