Urticaria paradoxically aggraved by H1 antihistamines

BACKGROUND: H1 antihistamines (anti-H1) are the treatment of choice in chronic urticaria. We report five cases of urticaria, induced or aggravated by H1 antihistamines. METHODS: The immunoallergological investigations included prick-tests and intradermal tests with the antihistamine responsible for acute urticaria. RESULTS: The skin tests confirmed the non-IgE dependent nature of the urticarial eruptions and anti-leukotrienes (montelukast, Singulair) were effective in controlling chronic urticaria in 3/4 patients. DISCUSSION: Two hypotheses are discussed to explain the paradoxical aggravating effect of H1 antihistamines on the urticaria: 1) the patients are sensitive to the toxic, pro-inflammatory effect of the drug, which is the source of nonspecific activation of mast cells; 2) the fact that the urticaria is sensitive to anti-leukotrienes suggests that histamine is not the principal mediator of urticaria in these patients.     

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 H(1) 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.     

Effectiveness of combination treatment with H1-(Tavegyl) and H2-antagonists (Altramet) in chronic/chronically-recurrent urticaria

Histamine H1 receptor antagonists are a mainstay in the management of chronic/chronic recurrent urticaria (c./c.r.U.). Since experimental studies have confirmed the presence of cutaneous H2 receptors partially conflicting results have been reported on the use of H2 antagonists in c./c.r.U. 20 patients with c./c.r.U. of idiopathic type were treated with cimetidine plus clemastine or placebo plus clemastine in a double-blind crossover study. Before this treatment traditional H1 antagonists alone failed to show any satisfying therapeutic effect. The results reveal that combined therapy is statistically more effective than corresponding H1 antagonists alone (P = 0.001). The addition of cimetidine is proposed in patients with c./c.r.U. if conventional therapy has been tried and proven ineffective.     

Urticaria

Urticaria is often classified as acute, chronic, or physical based on duration of symptoms and the presence or absence of inducing stimuli. Urticarial vasculitis, contact urticaria, and special syndromes are also included under the broad heading of urticaria. Recent advances in our understanding of the pathogenesis of chronic urticaria include the finding of autoantibodies to mast cell receptors in nearly half of patients with chronic idiopathic urticaria. These patients may have more severe disease and require more aggressive therapies. Extensive laboratory evaluation for patients with chronic urticaria is typically unrevealing and there are no compelling data that associate urticaria with chronic infections or malignancy. Pharmacologic therapy consists primarily of the appropriate use of first- and second-generation histamine H1 receptor antihistamines. Additional therapy may include leukotriene receptor antagonists, corticosteroids, and immunomodulatory agents for severe, unremitting disease. Despite our greater understanding of the pathogenesis of urticaria, the condition remains a frustrating entity for many patients, particularly those with chronic urticaria.     

Management of idiopathic urticaria with H1 + H2 antagonists. A crossover double blind long-term study

A randomized crossover double-blind study in a selected group of patients with idiopathic urticaria (15 patients; 10 females, 5 males; 20-80 years old) has been performed in order to examine the clinical efficacy of H1 + H2-antagonists in this disease, as compared with the H1-antagonist alone and with placebo. Chlorpheniramine (4 X 4 mg/d) and cimetidine (4 X 400 mg/d) were administered, each of them over 4 weeks, after one week wash-out period. The number of wheals, the time of their persistance as well as the presence of itching were daily registered and then evaluated. The entire group showed no difference between antihistamines and placebo. Nevertheless, 4 patients have registered a definitely better response to the H1-antagonist, 4 other patients responded distinctly better to the combined H1 + H2-treatment and 5 patients showed no preference at all. In a long-term follow up period of 3 months the effect of chlorpheniramine became even better, whereas the response to the combined treatment remained unchanged. It seems that the clinical efficacy of H1 + H2-antagonists is rather moderate in idiopathic urticaria. Nevertheless, in individual cases non-responding to H1-antagonist the combined administration of H1 + H2-antagonists may be more beneficial for the patient.     

Efficacy of H, antihistamine, corticosteroids and cyclophosphamide in the treatment of chronic dermographic urticaria

H, antihistamines relieve urticaria by blocking the action of histamine on the target tissue, while demonstration of autoantibodies in the sera of a proportion of the patients having chronic idiopathic urticaria, use of immunosuppressive drugs for the treatment of these patients has acquired the greater rationality. We evaluated the role of corticosteroids and cyclophosphamide in the treatment of chronic dermographic urticaria. Twenty-five patients, 13 males and 12 females, between 18-53 years in age, having chronic dermographic urticaria were taken up for this study. The patients were divided into three groups. Group I patients (n=9) were treated with cetirizine hydrochloride 10 mg per day orally, group II patients (n=7) were treated with betamethasone 2 mg along with cyclophosphamide 50 mg along with cetirizine 10 mg per day for a total period of 4 weeks. The patients were evaluated every week to record the therapeutic response and side effects, and then followed up without treatment for a period of 6 months to look for recurrence of the urticaria, if any. Six patients in group I and all the patients in group II and group III had complete remission while the remaining patients in group I had partial relief. The side effects included drowsiness in 4 patients. All the patients in group II had weight gain, 4 patients had acne and 2 patients developed cushingoid features. Majority of the patients relapsed within 3 days after stopping the treatment. Supplementation of the treatment with oral corticosteroids or cyclophosphamide was more effective in controlling the symptoms as compared to cetirizine alone. But a four weeks supplementation was not adequate for preventing the relapses when the drugs were withdrawn.     

Treatment of acquired cold urticaria with cetirizine and zafirlukast in combination

Acquired cold urticaria is an infrequent physical urticaria that can provoke severe systemic reactions. Histamine is the primary mediator, but leukotrienes are also involved in the pathogenesis. H(1) antihistamines are recommended as first-choice treatment, but their efficacy is sometimes unsatisfactory. On the basis of pathogenic knowledge, it can be hypothesized that a combination therapy with antihistamines and leukotriene receptor antagonists is more effective than each drug given alone. We tested this hypothesis in 2 patients with severe systemic cold urticaria poorly responsive to conventional therapy. The patients underwent 3 consecutive treatment regimens (each of 2 weeks): cetirizine (10 mg once a day); zafirlukast (20 mg twice a day); and their combination. They were clinically evaluated, after each regimen, by means of a visual analog scale and ice-cube test. The combination therapy was superior to the 2 drugs given alone, as testified by subjective and objective evaluations.     

苦参素联合抗组胺药治疗慢性荨麻疹疗效的Meta分析

目的:评价苦参素联合抗组胺药治疗慢性荨麻疹的疗效及不良反应。方法:检索中国知网、万方、维普、Pubmed、EMbase及Cochrane library等数据库,筛选符合标准的文献,采用RevM an 4.2进行Meta分析。结果:共纳入14篇文献,入选文献发表偏倚较小,无明显异质性(P=0.34)。Meta分析结果显示,苦参素联合抗组胺药组与单用抗组胺药组比较,有效率高[P0.00001,RR=1.40,95%CI(1.30~1.51)],复发率低[P0.00001,RR=0.19,95%CI(0.10-0.37)]。结论:苦参素联合抗组胺药治疗慢性荨麻疹疗效优于单用抗组胺药。     

组胺和抗组胺药的研究进展

组胺与H1受体结合可增强抗原提呈细胞的能力,促进肥大细胞和嗜碱性粒细胞中组胺和其他介质的释放,在荨麻疹等过敏性疾病的发病中起着作用。第一代川抗组胺药由于相对分子质量小,嗜脂性,易通过血脑屏障,临床应用可产生较多不良反应,尤其是对警觉性、认知等的影响。第二代H1抗组胺药相对分子质量大,受体专一性强、亲和力高,抗组胺活性更强,安全性更好,国外指南均推荐作为荨麻疹的一线治疗药物,治疗剂量可增至标准剂量的4倍以提高疗效,仍具有很好的安全性。H3、H4抗组胺药也已进入临床试验,有望治疗过敏性疾病及瘙痒症。     

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.     

Therapeutische Alternativen bei Antihistamintherapie-refraktärer Urtikaria

Patients with chronic spontaneous urticaria, the most frequent non-acute form of urticaria, generally exhibit a clinical picture of persistent disease, a high degree of disease activity, considerable impairment of quality of life, and poor response to treatment. More than half of the patients continue to develop symptoms despite standard therapy with non-sedating antihistamines. In these cases, the antihistamine dose should be increased (up to four times the daily dose). If this approach also does not result in symptom control, the high-dose antihistamine should be combined with a leukotriene antagonist and if necessary an H2 blocker. If the patient does not respond to this combination therapy, cyclosporin A, dapsone, or omalizumab should be administered.     

法莫替丁与H_1受体拮抗剂联合治疗慢性荨麻疹临床观察

３０例单用Ｈ１受体拮抗剂治疗疗效差的慢性荨麻疹患者,联合应用法莫替丁治疗４周。结果显示临床痊愈率和显效率分别为８３．３％和１０％,表明法莫替丁与Ｈ１受体拮抗剂联合用于这类单用Ｈ１受体拮抗剂不能奏效的慢性荨麻疹患者是一种有效的治疗方法。     

Therapy of urticaria with H1 and H2 antihistaminics. Results of clinical and experimental studies

The antipruritic effect of modern H1- and H2-receptor blockers in chronic urticaria, that had been clinically proved, was experimentally studied by means of the histamine weal test. The H2-antihistamine preparation ranidine alone did not clearly reduce weals or erythemas induced by histamine when compared with a placebo. As expected, both parameters were markedly reduced by the H1-antihistamine preparation terfenadine. After combined administration of both drugs, the effect of the H1-blocker proved to be significantly increased. We discuss the possible mode of action and the consequences for anti-allergic therapy.     

Omalizumab bei therapierefraktärer chronischer Urtikaria mit Angioödem

A 29-old man presented with severe chronic urticaria and angioedema. Routine evaluation including history, laboratory parameters and imaging procedures did not reveal any pathologic findings. We tried combined therapy regimes including high-dose systemic corticosteroids and antihistamines, leukotriene antagonist, cyclosporine and antibiotics. Because of a poor response and dramatic escalation of symptoms, we initiated therapy with omalizumab resulting in the complete remission of the chronic urticaria after two weeks.     

Evaluation of the efficacy of antihistamines using human monocyte-derived dendritic cells stimulated with histamine

BACKGROUND: It has been reported that histamine induces CD86 expression and chemokine production in human immature monocyte-derived dendritic cells (MoDCs), which can be blocked by both H(1)- and H(2)-receptor antagonists. OBJECTIVE: We sought to examine whether the efficacy of H(1)-type antihistamines can be assessed by using MoDCs. METHODS: We examined the suppressive effects of 1 H(2)-type antihistamine (cimetidine) and 5 different H(1)-type antihistamines (cetirizine, diphenhydramine, ketotifen, olopatadine, and emedastine) on the induction of CD86 and IL-8 production by MoDCs from 23 healthy individuals stimulated with histamine. We also examined the responses of MoDCs from 13 patients with chronic urticaria to these antihistamines, and compared the in vitro efficacy with the actual clinical response to antihistamines evaluated by patient and physician assessments. RESULTS: All the antihistamines we examined suppressed the increase of CD86(+) cells after histamine stimulation in a dose-dependent fashion, and all H(1)-type antihistamines were more efficacious than cimetidine. IL-8 production stimulated with histamine was also suppressed by cetirizine, ketotifen, and olopatadine. Unexpectedly, the suppressive effect of these antihistamines on the CD86 augmentation was highly variable among different healthy control participants. Interestingly, in 10 of 13 cases of chronic urticaria, this in vitro analysis of antihistamines correlated with the clinical response to antihistamines. CONCLUSION: This study suggests that the evaluation of antihistamines using MoDCs can be a useful method for the screening of effective antihistamines, for the comparison of the efficacy of antihistamines, and for predicting the efficacy of antihistamines on an individual basis.     

Desloratidine for the treatment of chronic urticaria

Chronic urticaria is a common dermatologic condition that is idiopathic in most cases. Antihistamines are the mainstays of treatment for this condition. The newer, second and third generation antihistamines are the preferred agents because of their improved safety profile and comparable efficacy to the first generation antihistamines. Desloratadine is a new non-sedating H1-receptor agonist. Based on clinical studies, desloratadine is a valuable new addition to the available treatment options and should be considered as a first-line therapy for patients with chronic urticaria.     

窄谱中波紫外线联合抗组胺药治疗慢性自发性荨麻疹的疗效观察

目的观察窄谱中波紫外线(NB-UVB)联合抗组胺药治疗慢性自发性荨麻疹的疗效。方法 80例慢性荨麻疹患者,随机分为试验组和对照组,每组各40例。试验组采用NB-UVB光疗,每周2次,共24次,同时口服抗组胺药;对照组仅口服抗组胺药。比较两组治疗后的临床疗效以及随访12周内的复发情况。结果两组患者的症状和体征评分明显下降,且试验组下降更为明显(t=46.37,P0.05)。试验组的临床疗效明显优于对照组(χ~2=6.76,P0.05);且复发率明显低于对照组(χ~2=9.83,P0.01)。结论 NB-UVB安全有效,可作为慢性自发性荨麻疹的辅助治疗手段。     

Omalizumab markedly improves urticaria activity scores and quality of life scores in chronic spontaneous urticaria patients: a real life survey

Treatment of chronic urticaria consists of antihistamines as the first-line treatment. For more severe symptoms, combinations can be necessary as well as dose augmentations. The recent guidelines suggest the possibility of using omalizumab in resistant cases, but this therapy is still investigational. We treated two patients with idiopathic recurrent angioedema and 12 patients with chronic spontaneous urticaria (CSU) with omalizumab, who had not benefited from the recommended first-line, second-line and third-line treatments. To evaluate the efficacy of the omalizumab treatment, urticaria activity scores (UAS) and chronic urticaria quality of life (CU-Q2oL) scores were measured at baseline, and at the end of the first and sixth month of the therapy. The dosage and intervals of omalizumab therapy were determined according to the rules suggested for severe asthma treatment. CU-Q2oL scores and UAS displayed significant improvements in all 14 patients. None of the patients reported any adverse effect during the treatment until the submission of this data. Our results show that omalizumab apparently improves CU-Q2oL as well as UAS in treatment-resistant CSU in a real life setting.     

玉屏风散加味联合抗组胺药治疗慢性荨麻疹疗效与安全性Meta分析

目的： 评价玉屏风散联合抗组胺药治疗慢性荨麻疹的临床疗效及 安全性。方法： 检索中国知网、万方、维普、PubMed、EMbase 及 Cochrane library 等数据库建库至2017年11月期间发表的使用玉屏风散加味联合抗组胺药治疗慢性荨麻疹的随机对照试验（RCTs）。由两名研究者独立筛选文献并提取数据,根据Cochrane 偏倚风险评估工具对纳入研究进行方法学质量评估,用Rev Man 5.3软件进行Meta分析。结果：共纳入15篇文献, 133 6例患者。Meta分析结果显示,玉屏风散联合抗组胺药组与单用抗组胺药组比较,有效率高（P<0.00001）,复发率低（P<0.00001）,不良反应发生率低（P=0.003）。结论：玉屏风散加味联合抗组胺药治疗慢性荨麻疹疗效优于单用抗组胺药,且更安全。     

Druckurtikaria – Dapson auf dem Weg zur First‐Line‐Therapie?

Background: Pressure urticaria as a subform of physical urticaria is rare and treatment is often difficult. Established therapeutic regimes include antihistamines (generally exceeding approved dosages in order to achieve a therapeutic benefit) or antihistamines combined with montelukast. Complete relief of symptoms is difficult. Patients and methods: We used dapsone as an early therapeutic alternative in the event of treatment failure and established a standardized therapeutic regime at our clinic. We surveyed 31 patients retrospectively who had received dapsone between 2003–2009. Results: In 74 % of patients in whom symptoms persisted despite established therapies, the results of treatment with dapsone were good or very good. Longer‐term pressure urticaria and the co‐existence of a chronic spontaneous urticaria were associated with a smaller benefit (p<0.05). No significant effects were found related to age, gender, duration of therapy, side‐effects, or Met‐Hb elevation (a tendency toward a decreased benefit was associated with middle‐age, male sex, shorter duration of therapy, observed side‐effects, and Met‐Hb elevation). Conclusions: Therapy is well tolerated and results in a good therapeutic benefit which lasts after termination of therapy. With adequate monitoring, the use of dapsone in patients with pressure urticaria has such a good risk‐benefit ratio that we support early treatment initiation.