Therapy of acute and chronic urticaria

Background The drug management of chronic urticaria can be divided into three approaches: (i) blockade of released histamine at the receptor sites; (ii) blockade of histamine release from mast cells; and (iii) blockade of other mediators and possible inflammatory and cellular components. The first approach is the most successful and widely used. It primarily involves the use of H₁-antihistamines, although tricyclic antidepressants and H₂-antihistamines also have a place. Treatments The usefulness of classic H₁-antihistamines, such as hydroxyzine, may be limited by side-effects (most notably, sedation). The four most widely used of the newer antihistamines are loratadine, terfenadine, astemizole and cetirizine. These antihistamines are significantly superior to placebo and have similar efficacies comparable with hydroxyzine. Novel agents and methods, including nifedipine, sulphasalazine and plasmapheresis have been tried with some success in refractory patients. Guidelines If acute cases are inadequately controlled, short-term oral corticosteroids may be added. Systemic corticosteroids are occasionally indicated for the management of severe acute urticaria, severe serum sickness, pressure urticaria or urticarial vasculitis, or to break the cycle of a resistant case, but have no place in regular therapy for chronic urticaria. For those with severe acute urticaria with signs of respiratory distress, possible treatments include subcutaneous epinephrine, systemic corticosteroids and intramuscular H₁-antihistamines. Patients with chronic urticaria inadequately controlled on H₁-antihistamines alone may benefit from the addition of a classic antihistamine, a tricyclic antidepressant or an H₂-antihistamine. A short course of systemic corticosteroids may help those with severe chronic refractory disease.     

The use of a responder analysis to identify clinically meaningful differences in chronic urticaria patients following placebo- controlled treatment with rupatadine 10 and 20 mg

Background  According to the EAACI/GA²LEN/EDF guidelines for urticaria management, modern non-sedating H1-antihistamines are the first-line symptomatic treatment for chronic urticaria. Two previous randomized clinical trials demonstrated rupatadine efficacy and safety in chronic urticaria treatment. However, a responder analysis to identify clinically meaningful differences in patients with chronic urticaria has not yet been performed.
Methods  This analysis includes the pooled data from two randomized, double-blind, placebo-controlled, multicentre studies in which chronic urticaria patients were treated with rupatadine at different doses. Responder rates were defined as the percentage of patients after 4 weeks of treatment who exhibited a reduction of symptoms by at least 50% or 75% as compared to baseline. The variables analysed were as follows: Mean Pruritus Score (MPS), Mean Number of Wheals (MNW), and Mean Urticaria Activity Score (UAS).
Results  A total of 538 patients were included. This responder analysis, using different response levels, shows that the efficacy of rupatadine 10 mg and 20 mg is significantly better as compared to placebo in the treatment of chronic urticaria patients. Notably, treatment with rupatadine 20 mg daily resulted in a higher percentage of patients with response of 75% symptom reduction or better than rupatadine 10 mg.
Conclusion  Our results support the use of higher than standard doses of non sedating antihistamines in chronic urticaria. We strongly recommend performing and reporting responder analyses for established and new drugs used by patients with chronic urticaria.     

In dermographic urticaria H2 receptor antagonists have a small but therapeutically irrelevant additional effect compared with H1 antagonists alone

Two studies of the additional effect of an H₂ receptor antagonist when given in combination with an H₁ antagonist were undertaken in dermographic urticaria. Using a randomized, double-blind, crossover design in 19 patients, a combination of cetirizine (10 mg at night) and ranitidine (150 mg twice daily) was compared with a combination of cetirizine (10 mg at night) and placebo. The addition of ranitidine did not produce any significant difference in linear analogue scores for weal, Itch or sleep disturbance. There was a significant depression of the frictional force/wealing response curve with an increase in wealing threshold (P<0.0001) following the addition of H₂ blockade. The wealing threshold was 54.7 ± 4.4 (mean ± SEM) g/mm² for the H₁ antagonist alone, and 73.2 ± 5.7 for the combination of H₁ and H₂ antagonists. In a second similar study involving nine different patients, comparing terfenadine (120 mg twice daily) with a combination of terfenadine and ranitidine (150 mg twice daily), the weal threshold was 59.8 ± 6.6 for the H₁ antagonist alone, and 73.0 ± 6.4 for the combination of H₁ and H₂ antagonists. Thus, in dermographic urticaria, adding an H₂ antagonist to treatment with a potent H₁ antagonist gives a small, significant reduction in wealing response, but no symptomatic benefit. We conclude that involvement of the H₂ receptor in this urticarial disease is minimal, and does not justify the use of H₂ receptor antagonists.     

Chronic urticaria associated with intra-articular methylprednisolone

Reports of allergic reactions following treatment with systemic corticosteroids are rare, despite their widespread use. A 47-year-old man developed widespread urticaria, resistant to antihistamines, coinciding with injections of local anaesthetic and methylprednisolone for cervical spondylosis. He underwent immediate and delayed hypersensitivity tests. Intradermal tests showed immediate-type sensitivity to methylprednisolone and hydrocortisone. Patch tests were positive to 21 of 26 corticosteroids tested. A diagnosis of both an immediate and a delayed-type hypersensitivity to corticosteroids was made. With avoidance of all corticosteroids he has been free from urticarial rash for 9 months and has been able to stop all medication.     

The effect of H1 and H2 histamine antagonists on symptomatic dermographism

In ten patients suffering from symptomatic dermographism the combined administration of chlorpheniramine + cimetidine produced a greater reduction in the weal and flare response provoked by a standardized scratch than the administration of chlorpheniramine alone. There was a statistically significant improvement in the overall assessment of the patient's skin condition with the combined administration of chlorpheniramine + cimetidine. Chlorpheniramine given alone produced no significant benefit whilst cimetidine alone produced a marked exacerbation in itching in nearly half the patients who initially entered the study and was sufficient to require withdrawal.     

One-year treatment of chronic urticaria with mizolastine: efficacy and safety

AIM: To assess the long-term safety and efficacy of the H1-receptor antagonist mizolastine in the symptomatic treatment of chronic urticaria (CU). BACKGROUND: Mizolastine is a novel second generation antihistamine with additional anti-inflammatory properties which has been shown to be effective in this condition as well as in allergic rhinitis. As the drug is used for chronic treatment, a detailed study of its efficacy and safety over a prolonged period was warranted. METHODS: This open label multicentre trial recruited 211 patients suffering from CU (67% female; mean age 40+/-13 years), with > or = 1 episode/week if untreated. After a 7-day placebo run-in period, patients received mizolastine (10 or 15 mg) for 12 months. Efficacy was assessed by the patient using daily diary cards and overall condition evaluation at study visits. Clinicians also assessed the same parameters at each visit, and gave a global assessment at study termination. Safety was assessed by monitoring adverse events and laboratory parameters. Cardiac safety was monitored every 4 months using 12-lead ECGs, with particular attention to QT intervals. RESULTS: The trial was completed by 127 patients. Mizolastine reduced overall discomfort from the second week of therapy, and reduced itching and the number and size of wheals, as assessed by the patients. The clinician's assessment of the proportion of patients with > 10 wheals decreased from 42% to 28% after 2 months. Clinical assessment also indicated that itch intensity and angioedema were improved by mizolastine, and the improvement was sustained throughout the trial. The investigators estimated that 70% of patients benefited from therapy. There were no drug-related serious adverse events during the study. The cardiac repolarization assessed according to the QTc intervals was not modified during prolonged administration. CONCLUSION: Mizolastine improves CU symptoms, and these improvements are sustained over 12 months with no loss of drug sensitivity. No specific side-effects are associated with its long-term use in the current study.     

Suppression of alcohol-induced flushing by a combination of H1 and H2 histamine antagonists

Alcohol-induced flushing of the face and neck regions is a well recognized condition, probably genetically determined and due to individual differences in alcohol metabolism. We have shown that the flushing appears only after a threshold level of blood alcohol (20–35 mg per 100 ml) is exceeded. The rate of alcohol absorption and peak blood levels were reduced by a combination of H₁ and H₂ antagonists. This reduction was accompanied by abolition of flushing in sensitive individuals.     

Adverse skin reactions to vitamin K1: report of 2 cases

Vitamin K is essential to the biosynthesis of prothrombin and other clotting factors (VII, IX and X), and is mostly used for the prophylaxis of bleeding disorders, mainly in patients with hepatic disfunction (1). 4 different pharmacological forms exist: the natural form K1 (phytomenadione); K₂ (menaquinone), which is derived from intestinal bacterial action; K₃ (menadione); and K₄ (menadiol). The latter 2 are synthetic products. In Italy, only vitamin K1 is marketed (2).
Adverse cutaneous reactions to vitamin K are rare; 2 are mainly reported: an erythematous plaque (3, 4) or pseudo-scleroderma (5) at the injection site. Contact dermatitis and localized urticarial lesions have also been described (2).     

咪唑斯汀抗组胺点刺试验及治疗荨麻疹临床疗效观察

目的：评价咪唑斯汀治疗荨麻疹的疗效及安全性。方法：①对93例急、慢性荨麻疹患者口服咪唑斯汀10mg,每日1次,急性荨麻疹患者首次服药后留观2h,慢陛荨麻疹患者连续用药2周。②选择10名健康志愿者作组胺点刺试验,观察咪唑斯汀对组胺诱导风团的抑制作用。结果：①61例急性荨麻疹患者首次服药后在1h内起效49例(80．3％);32例慢性荨麻疹治疗1周后有效率为90．6％,治疗2周后有效率为100．0％。3例患者出现短暂而轻度的嗜睡反应。②健康志愿者服用咪唑斯汀1、2h后,对组胺诱导风团的抑制率分别为40．19％和83．92％;红晕抑制率分别为49．90％和87．69％。结论：咪唑斯汀治疗急、慢性荨麻疹起效快,作用持久,不良反应少。     

Thyroid autoimmunity in chronic urticaria

BACKGROUND: Chronic urticaria (CU) is an autoimmune process in some patients. An association between CU and autoimmune thyroid disease has also previously been proposed. Our group has identified functionally significant histamine-releasing autoantibodies in one subset of CU patients (subset 1), predicted by positive autologous intradermal serum tests and positive histamine release from donor basophil leucocytes in vitro. Sera from a second subset of patients (subset 2), all of whom had positive autologous intradermal serum tests, failed to release histamine from donor basophils. A final disease subset (subset 3) has no identifiable skin reactivity (negative autologous serum skin test) or in vitro histamine releasing activity. OBJECTIVES: In order to examine further the possible relationships between thyroid autoimmunity, thyroid dysfunction and CU, we have examined thyroid autoantibodies and thyroid-stimulating hormone (TSH) levels (an indirect measure of thyroid dysfunction) in the three CU subsets. PATIENTS/METHODS: We studied 182 patients (69% female), of whom 90 had a positive autologous intradermal serum test. RESULTS: Eighteen skin test-positive and four skin test-negative patients had thyroid microsomal antibodies (TMA). TSH outside the normal range was found in 13 skin test-positive and one skin test-negative patient. These findings represent clustering of TMA positivity [risk ratio (RR) 4.06, 95% confidence interval (CI) 1.56-10.6] and of abnormal thyroid function (RR 15.5, CI 2.07-11.6) among the skin test-positive patients. However, in the overall study group an elevated TSH was present in seven patients (3.8%, CI 1.6-7.8) comparable to the 5% expected prevalence in the community. Thyroglobulin antibodies (TGA) were present in two of 182 patients. CONCLUSIONS: There were significant differences between skin test-positive and skin test-negative patients with regard to autoimmune thyroid disease. Evidence for autoimmune thyroid disease and abnormal thyroid function was largely found among the skin test-positive patients, supporting the theory of an autoimmune aetiology in this group.     

Pharmacological modulation of IL-6 and IL-8 secretion by the H1-antagonist decarboethoxy-loratadine and dexamethasone by human mast and basophilic cell lines

Abstract Mast cells and basophils are central effector cells of allergic reactions and are involved in inflammatory diseases. These cell types produce an array of mediators including a broad spectrum of cytokines. In order to examine whether antiallergic drugs modulate the release of these mediators, we have investigated the influence of dexamethasone and decarboethoxy-loratadine (DEL), the active metabolite of the H₁-blocking agent loratadine, on the release of IL-6 and IL-8 by the human mast cell line HMC-1 and the human basophilic cell line KU812 by ELISA. Dexamethasone (10^?6-10^?11 M) or Del (10^?5-10^?14 M) were added to the cells either 1 h prior to or simultaneously with PMA and Ca-ionophore A23187. When preincubated with the cells, DEL dose-dependently suppressed IL-6 release by up to 40% and IL-8 release by up to 50%. Dexamethasone potently suppressed secretion of both cytokines if simultaneously added to the cells with the stimuli by up to 60% and after preincubalion by up to 80%. Since both antihistamines and glucocorticoids are used for treatment of allergic diseases, the findings reported here indicate that these drugs may modulate allergic reactions via inhibition of cytokine release from mast cells and basophils.     

H2 Blockers in Chronic Urticaria

Two hundred unselected patients with chronic idiopathic urticaria were treated with adequate doses of conventional antihistamines given at frequent intervals; 98.5% were completely freed of disease while on therapy. In three cases, the lesions subsided but did not clear completely. The addition of 800 mg of cimetidine in divided doses cleared the lesions in two cases, and in the third case the dose of H1 blocker was increased, which resulted in complete clearance of wheals and symptoms. Addition of H2 blockers play a role, but only in a very small percentage of patients with chronic idiopathic urticaria who do not completely respond to adequate doses of H1 blockers.     

The apparent volumes of distribution of H1 receptor antagonists

ABSTRACT: The apparent volume of distribution (V_D) of a drug estimates its distribution into the body. Referring to the volume of exchangeable water (0.6 L/kg body weight), it indicates if tissue distribution is extensive when V_D is greater than 0.6 L/kg or poor if V_D is less than 0.6 L/kg. Its interest in the selection of an appropriate drug is found after comparing the map of selected targets (mainly receptors) to be reached by the drug, the accessibility of these targets by the drug, and the V_D necessary and sufficient to reach them. This analysis is here applied to H₁ receptor antagonists, a pharmacologic class, where target cells, endothelial cells such as eosinophils, mastocytes, basophils, and smooth fibers have receptors on the external side of cell membranes and thus are more readily accessible from blood than toxic sites located inside cells (heart, brain, liver). Of the H₁ receptor antagonists marketed today, cetirizine has the lowest V_D, 0.4 L/kg, enough to reach selected targets without extensive distribution in organs where it would be useless. These characteristics are related to its chemical amphoteric structure.     

Comparative evaluation of Type 1 latex hypersensitivity in patients with chronic urticaria,rubber factory workers and healthy control subjects

Latex hypersensitivity manifests itself most commonly with contact urticaria. In this study, we investigated the frequency of latex hypersensitivity as a possible aetiological factor in patients with chronic urticaria (CU) and compared latex hypersensitivity of CU patients (n = 50) with that of rubber factory workers (n = 50) and healthy controls (n = 50). Prick test with latex and fruit extracts and determination of latex-specific immunoglobulin E (IgE) were performed. As a risk factor, contact dermatitis due to rubber additives was tested by patch test. Latex hypersensitivity was detected in 14% of CU patients, 12% of rubber factory workers and 12% of healthy controls (P > 0.05). Positive patch test with rubber additives was detected in 6% of CU and 4% of rubber factory workers. 3 of 7 CU patients had sensitivity to fruits in addition to latex hypersensitivity. In 1 patient with CU, the clinical complaints were found to be related to latex hypersensitivity. These findings suggest that the frequency of latex hypersensitivity in CU patients is no higher than that in healthy individuals. However, CU patients should be carefully asked about latex allergy, as we demonstrated that 1 of the CU patients had undiagnosed symptomatic latex allergy.     

Clinical and aetiological aspects in urticaria and angio-oedema

BACKGROUND: Urticaria is a common disorder that affects as many as 20% of all people at some time during their lifetime. OBJECTIVES: To analyse the prevalence of various forms of urticaria according to an aetiological and clinical classification, we carried out a 4-year study in an outpatient clinic. METHODS: The study was carried out on 562 consecutive patients (178 males and 384 females; mean age 35.4 +/- 16), who had been referred to our unit for the study of urticaria and angio-oedema. Baseline investigations included: the patient's family and personal history of allergy; duration of symptoms, presence of associated symptoms and objective signs of the current episode; clinical, laboratory and instrumental investigations; assessment of response to antihistamine treatment. RESULTS: A family history of atopy was present in 35% of patients and a personal history of allergy in 24%. We subdivided urticaria and angio-oedema into several groups on the basis of their clinical and aetiological aspects. Of the 562 patients, 424 (76%) presented with ordinary urticaria (43 acute urticaria, 311 chronic urticaria, 70 episodic urticaria), 80 (14%) physical urticaria, 49 (9%) angio-oedema without weals, six (1%) IgE-mediated contact urticaria and three (0.5%) urticarial vasculitis. In 64 cases (11%) urticaria/angio-oedema was associated with one or more symptoms. We identified 394 cases (82%) of idiopathic urticaria, 42 (9%) of immunological urticaria, 29 (6%) of non-immunological urticaria and 17 (3%) of urticaria secondary to infections. Of the treated subjects, 54% showed a good response to treatment with antihistamines. CONCLUSIONS: Our data provide an overview of urticaria/angio-oedema in a large series of patients, based on clinical-aetiological aspects, and related to recent diagnostic guidelines.     

Dermatitis and urticaria from rubber and plastic gloves

The number and nature of allergic occupational glove dermatoses were analysed. 542 cases of allergic contact dermatosis were diagnosed during 1974-1983. Amongst these, 68 (12.5%) were caused by rubber or plastic gloves. 2 patients had contact urticaria due to rubber gloves. Gloves were the main cause of occupational allergic rubber eczema, inducing 63 (58.3%) of 108 rubber eczema cases. 38 of them had positive reactions to rubber chemicals and glove material, 14 to glove material only, and 11 to rubber chemicals. 5 cases of allergic eczema from plastic gloves were diagnosed, all due to polyvinyl chloride (PVC). 2 cases of contact urticaria from natural rubber gloves were diagnosed by a provocation test. Epicutaneous testing with material of natural rubber gloves and rubber chemicals was negative. The present study shows that allergy to rubber gloves is usual, while allergy to plastic gloves is rare. Thus, plastic gloves should be used, when possible. Patch testing with protective gloves should always be used when patients develop prolonged hand dermatitis and where the possibility of glove eczema exists.