M. Lorini

Chronic urticaria: novel clinical and serological aspects

Background Recently, distinct studies have shown that: (a) chronic idiopathic urticaria (CIU) is autoimmune in 30–50% of cases; (b) in patients with CIU the autologous serum skin test is inhibited by heparin; and (c) basophil histamine release induced in vitro by CIU sera maybe complement‐dependent.

Autoreactivity is highly prevalent in patients with multiple intolerances to NSAIDs

BACKGROUND A subset of drug-allergic patients show a marked propensity to react against several, chemically unrelated nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenesis of such multiple drug reactions is unclear. Approximately 30% of patients with chronic idiopathic urticaria, a condition frequently characterized by autoreactivity on autologous serum skin test (ASST), experience flares of hives after taking chemically unrelated NSAIDs. OBJECTIVE To detect whether a clinically unapparent autoreactivity may represent the nonspecific mechanism facilitating drug-induced histamine release in patients with a history of urticaria/angioedema induced by several, chemically unrelated NSAIDs. METHODS Thirty-six adults with a history of acute NSAID-induced urticaria (22 with multiple NSAID sensitivity [MNS]; 14 with single NSAID sensitivity [SNS]; and 20 atopic controls without a history of drug allergy) underwent ASST. Sera from 14 MNS and 4 SNS subjects (all ASST-positive) underwent histamine release assay with basophils from normal donors. Sera from five MNS patients were tested on autologous basophils as well. RESULTS Twenty of 22 (91%) MNS subjects versus 5 of 14 (36%) SNS subjects were positive on ASST (P < 0.01). No atopic control was ASST-positive. Sera from 4 of 14 (29%) MNS patients versus 0/4 SNS subjects (P = NS) induced significant histamine release from basophils of normal donors. The use of autologous basophils did not significantly change these results. CONCLUSION Most patients with multiple NSAID intolerance and approximately one-third of those with single NSAID hypersensitivity are characterized by the presence of circulating histamine-releasing factors. Their nature is still unclear, but the fact that only a minority of sera from ASST+ subjects were able to induce histamine release from normal basophils in vitro suggests that these factors might not differ from those involved in most patients with chronic urticaria. These factors might play a relevant pathogenic role in NSAID-induced urticaria reactions.

Plasma levels of matrix metalloproteinase-9 in chronic urticaria patients correlate with disease severity and C-reactive protein but not with circulating histamine-releasing factors

Background Matrix metalloproteinase‐9 (MMP‐9) is an endopeptidase produced by many inflammatory cells that has been found in increased amounts in plasma from patients with chronic urticaria (CU).

Plasma levels and skin-eosinophil-expression of vascular endothelial growth factor in patients with chronic urticaria.

Background:  Although chronic urticaria (CU) is often regarded as autoimmune in nature, only less than 50% of sera from CU patients contain histamine‐releasing autoantibodies. This suggests that other factors may contribute to its pathogenesis. We evaluated the possible involvement of vascular endothelial growth factor (VEGF), one of the major mediators of vascular permeability, in CU.

Inhibitory Effect of the H1 Antagonist Loratadine on Histamine Release from Human Basophils

Loratadine is a powerful H1 antagonist commonly employed in the treatment of allergic disorders. The present study was performed to investigate whether loratadine, in addition to anti-H1 activity, is able to modulate histamine release from human basophils. Leukocyte suspensions were prepared by dextran sedimentation of peripheral venous blood drawn from 10 normal subjects. Leukocytes were stimulated with anti-IgE (1/5,000), N-formyl-methionyl-leucyl-phenylalanine (FMLP; 10 microM) and the Ca2+ ionophore A23187 (1 microM), and histamine release in the cell supernatants was measured by an automated fluorometric method. Loratadine, at concentrations ranging from 1 to 50 microM, exerted a dose-dependent inhibitory effect on IgE-mediated and IgE-independent histamine release. The concentrations inhibiting 50% of histamine release were 30 microM (anti-IgE), 29 microM (FMLP) and 24 microM (Ca2+ ionophore A23187). The inhibitory activity of loratadine was optimal after incubation for 2 h at 37 degrees C and the effect of the drug was no longer evident when leukocytes were stimulated 2 h after cell washing. Increased extracellular Ca2+ concentrations reduced the inhibitory activity of loratadine, indicating that external Ca2+ and loratadine have antagonistic effects on basophil histamine release. These results indicate that loratadine, in addition to H1 receptor blocking activity, has the capacity to inhibit histamine release from human basophils.

Sera from Patients with Multiple Drug Allergy Syndrome Contain Circulating Histamine-Releasing Factors

Background: A subset of drug-intolerant patients show a marked propensity to react to several chemically unrelated antibacterial drugs. This condition is termed multiple drug allergy syndrome (MDAS). The pathogenesis of MDAS is still unclear. A possible mechanism is that a nonspecific patient-related factor leading to direct histamine release from mast cells and basophils is involved. We investigated whether a patient-related facilitating factor such as the clinically unapparent presence of circulating histamine-releasing factors may represent a nonspecific mechanism underlying drug-induced histamine release in patients with MDAS. Methods: 38 otherwise healthy adults with a history of acute urticaria following the ingestion of antibacterial drugs [18 subjects with MDAS (patients) and 20 monosensitive subjects (drug-allergic controls) on the basis of both clinical history and single-blind peroral challenges with alternative substances] and 20 subjects without a history of drug allergy (normal controls) underwent an autologous serum skin test (ASST). IgE specific for β-lactams was measured in sera from 25 subjects (11 patients and 14 drug-allergic controls) with a history of amoxicillin intolerance. Sera from 13 patients and 5 drug-allergic controls (all positive on ASST) were used in the in vitro histamine release assay using basophils from 3 normal donors. Results: 17 of 18 patients (94%) versus 8 of 20 drug-allergic controls (40%) showed an unequivocal wheal-and-flare reaction on ASST (p < 0.05). Skin reactions were generally more intense in the patient group. In one MDAS patient, the ASST was not assessable due to dermographism. No normal control was positive on ASST. Sera from 3 of 13 patients (23%) versus 0 of 6 drug-allergic controls (not significant) induced significant histamine release from basophils of normal donors. IgE specific for β-lactams was detected in sera from 1 of 11 patients (9%) versus 5 of 14 drug-allergic controls (36%) (not significant). Conclusion: Most patients with MDAS and more than one third of subjects with a history of hypersensitivity to a single antibacterial drug were characterized by the presence of circulating histamine-releasing factors. Such factors might play a role in drug-induced adverse reactions observed in these patients.

Assessment of histamine‐releasing activity of sera from patients with chronic urticaria showing positive autologous skin test on human basophils and mast cells

Background All previous studies agree that only a proportion of sera from patients with chronic urticaria (CU) positive on the autologous serum skin test (ASST) are able to induce histamine release in vitro. A non‐specific release of bradykinins during clotting of blood samples has been suggested; however, ASST seems rather specific and some data point to the existence of a mast cell‐specific histamine‐releasing factor.

Chronic urticaria: a role for newer immunomodulatory drugs?

Chronic urticaria is now recognized as an autoreactive disorder in a substantial fraction of patients. A serologic mediator of whealing has been demonstrated in 50–60% of patients with chronic urticaria, and autoantibodies against the high affinity IgE receptor or IgE have been detected in about half of these patients. The demonstration that chronic urticaria is frequently autoimmune has encouraged a more aggressive therapeutic approach, with the use of immunomodulatory drugs.A step-by-step approach to the management of chronic urticaria is proposed, based on our personal experience and review of current medical literature, identified through Medline research and hand searching in medical journals.The non- or low-sedating H1 receptor antagonists (antihistamines), such as cetirizine, fexofenadine, loratadine, mizolastine and, more recently, levocetirizine, desloratadine and ebastine, represent the basic therapy for all chronic urticaria patients. Older sedating antihistamines, such as hydroxyzine and diphenhydramine, may be indicated if symptoms are severe, are associated with angioedema, and if the patient is anxious and disturbed at night.Corticosteroid therapy with prednisone or methylprednisolone can be administered for a few days (7–14) if urticarial symptoms are not controlled by antihistamines and a rapid clinical response is needed. In cases of relapse after corticosteroid suspension, leukotriene receptor antagonists, such as montelukast and zafirlukast, should be tried. In our experience, remission of urticarial symptoms can be achieved in 20–50% of chronic urticaria patients unresponsive to antihistamines alone. When urticaria is unremitting and is not controlled by combined therapy with antihistamines and leukotriene receptor antagonists, prolonged corticosteroid therapy may be needed. Long-term corticosteroid therapy should be administered at the lowest dose able to control urticarial symptoms, in order to minimize adverse effects. In a few patients, however, high-dose corticosteroid therapy may have to be administered for long periods. In these patients, immunosuppressive treatment with low-dose cyclosporine can be started. This type of treatment has a corticosteroid-sparing effect and is also generally effective in patients with severe, unremitting urticaria, but requires careful monitoring of cyclosporine plasma concentration and possible adverse effects.Other immunomodulating drugs that have been tried in chronic urticaria patients include hydroxychloroquine, dapsone, sulfasalazine and methotrexate, but their efficacy has not been proven in large controlled studies. Warfarin therapy may also be considered in some patients with chronic urticaria and angioedema unresponsive to antihistamines.

Autologous serum skin test reactivity in patients with non-allergic asthma

Background Inflammatory alterations of respiratory airways have been found in patients with non‐allergic asthma, but the triggering event has not been defined. An autoimmune activation of inflammatory cells has been hypothesized.

Regulation of histamine release from human basophil leucocytes: role of H1, H2 and H3 receptors

A novel class of histamine receptors (H3, controlling histamine synthesis and release, was described in rat and human brain and peripheral nerve endings. The present study was undertaken to evaluate whether H3, receptors contribute to the regulation of histamine release from human basophils. Basophil leucocytes were incubated with a H., antagonist (thioperamide; concentrations ranging from 1 nM to 10 μM) or with a H3 agonist ((R)αmethyl‐histamine; concentrations ranging from I to 100 μM), and subsequently were stimulated with optimal doses of anti‐IgE and formyl‐methionyl‐leueyl‐phenyl‐alanine (f‐met peptide). No significant modifications of histamine release were observed after incubation either with the H3 agonist or with the H3 antagonist. By contrast, a H3 antagonist (cimetidine; concentrations ranging from 1 to 100 μM) exerted a dose‐dependent enhancing effect on anti‐IgE‐ and, to a lesser extent, on f‐met peptide‐induced histamine release. A H, antihistamine (chlorpheniramine; concentrations ranging from 100 nM to 1μM), at the highest concentration employed, displayed an inhibitory activity on IgE‐dependent and IgE‐independent histamine release. Exogenous histamine was shown to exert a dose‐dependent inhibitory effect on two‐staged anti‐IgE‐induced histamine release. Taken as a whole, these results suggest that H3 receptors are not involved in the regulation of histamine release from human basophils; by contrast, H2 receptors participate in controlling histamine release from human basophils, as previously demonstrated by other authors.