Chronic urticaria is a very common clinical disease whose etiology and pathogenesis are not well understood, and treatment is mainly symptomatic, with the condition easily recurring and affecting the quality of life of patients. In recent years, with the deepening of research, the understanding of this disease has changed considerably, so that the concept of clinical treatment is constantly updated. However, sometimes clinical failure to correctly grasp the nature of the disease often brings unnecessary physical and mental burdens to patients. For this reason, this paper discusses the relevant issues as follows, taking into account the progress of foreign research in recent years.
1.Treatment is still based on symptom control, and the value of etiological treatment is limited
Etiological treatment is the basis for the treatment of many diseases, but in the case of chronic urticaria, there is a lack of sufficient theoretical and clinical research to support the development of etiological treatment. The central issue in the pathogenesis of chronic urticaria is mast cell activation, which is caused by complex causes [1]. Given that both immune and non-immune mechanisms are involved in mast cell activation, especially non-immune factors play an important role in the pathogenesis of urticaria, making the clinical analysis and interpretation of the etiology very difficult.
1.1 Classical type I allergic reactions are difficult to explain the pathogenesis of chronic urticaria
Type I allergic reactions can cause urticaria, but they have their own characteristics, mostly showing a clear etiology such as ingestion of certain foods, drugs or infections, and the onset of the disease is usually within 24 hours after exposure to these allergens, accompanied by systemic symptoms such as abdominal pain, respiratory distress or even shock, etc. The course of the disease is mostly acute, and can resolve on its own 2-3 weeks after removal of the etiology. In fact, chronic urticaria with the above-mentioned pathogenetic features is very rare in clinical practice, and it is clearly difficult to explain the pathogenesis of chronic urticaria with classical type I allergic reactions [1].
Allergen tests have been performed on patients by various means, however, their positive results are hardly compatible with the onset of the patient and support the limited role of allergens in the pathogenesis of chronic urticaria. Therefore, the status of classical type I allergic reactions in the pathogenesis of chronic urticaria is challenged, and it is clearly unreasonable to blindly carry out allergen testing or even desensitization therapy.
1.2 Diet and urticaria
Urticaria mediated by diet through immunoglobulin E (IgE) usually has the following characteristics: the onset of urticaria minutes or 1-2 hours after a meal, which lasts for several days and disappears, accompanied by aggravation of respiratory or gastrointestinal symptoms. As can be seen from the above characteristics, adults are rarely affected by food IgE-mediated urticaria, especially chronic urticaria.
Acute urticaria mediated by IgE from exposed food has an easily defined etiology, is often accompanied by orofacial manifestations, aggravated by repeated exposure, and is accompanied by angioedema and systemic symptoms. If the food is contaminated with mold, stored dust mites, food additives or condiments, it is difficult to be certain of the possible cause with certainty. In addition, other common causes of IgE-mediated urticaria may include the protease penicillin in insects, animal fur or saliva, biological decontaminants, and latex proteins.
Non-IgE-mediated food-associated urticaria plays a more important role in the development of urticaria than IgE-mediated urticaria. It has been suggested that natural salicylates in food or food additives, including artificial colorants (azo or non-azo dyes), preservatives (e.g., sulfites, nitrites), antioxidants (e.g., butylated hydroxyanisole, butyrate benzyl alcohol), and sweeteners (e.g., aspartame) can cause urticaria, especially in patients with a history of acute urticaria caused by oral NSAIDs, skin prick tests, and Serum-specific IgE tests can be negative. Some patients consume egg whites, shellfish, and strawberries, which can directly stimulate histamine release from mast cells after absorption through the digestive tract, among other things.
Another very rare type of food-mediated urticaria is histamine poisoning, which is mainly caused by the ingestion of foods that contain high levels of histamine components. The classic example is scombroid fish poisoning, especially when the improper storage of this fish leads to bacterial breakdown of histidine to produce histamine. The onset is usually 1 hour after consumption and is accompanied by systemic symptoms, including bronchospasm and hypotension in severe cases.
The role of dietary interventions in the treatment of urticaria is controversial. Food or food additives that induce or exacerbate urticaria have been of concern for a long time. One study found that food yeast or Candida albicans leachate could exacerbate urticaria, and also found a positive Candida skin prick test in up to 69% of such patients, most of whom responded well to a low yeast diet. Later, after more than 10 years of research, it was found that food or food additive IgE-mediated urticaria was rare, but pseudo-allergic reactions unrelated to IgE molecules were of interest. However, no close association between food and the development of urticaria has been found with food provocation tests or restrictive diets. Thus, the role of diet restriction in controlling the development of chronic urticaria has been questioned so far.
In patients with severe disease, combined angioedema, bronchospasm, induced or exacerbated by aspirin or NSAIDs, and especially those effectively treated with leukotriene receptor antagonists, low salicylate food restriction is warranted. Dietary restriction should be weighed against the pros and cons of not causing more damage to the patient than the urticaria itself by severely restricting the diet, while there is no need for continued strict dietary restriction if simple and regular drug-taking therapy is effective. A restricted low-salicylic acid diet in children with urticaria makes more sense than in adults, especially in patients whose onset or exacerbation is food-related.
In addition, although numerous studies have found that sensitivity to metals, chemicals, and food additives is an important part of the development of urticaria, the rate of positive patch tests in patients with urticaria is very similar compared to normal subjects. sharma et al [2] applied the standard patch test to 57 patients with chronic urticaria of unknown origin and found 11 cases with one or more positive patch test antigens, of which 9 patients had disappearance of symptoms within 2-3 weeks after avoidance of the appropriate allergen or dietary control, which lasted for 6 weeks. The other 2 cases had partial remission. Although avoidance of these factors including dietary control is known to result in remission in some patients, rigorous controlled studies are lacking and there is no evidence to suggest a strong association between symptom relief and avoidance of these substances.
1.3 Helicobacter pylori (Hp) infection and chronic urticaria
Hp infection may be the cause of some recurrent episodes of chronic urticaria. The reasons or evidence supporting the association of chronic urticaria development with Hp infection include.
(i) The presence of specific IgE-type anti-Hp antibodies in the patient and confirmation by Western blotting that IgE in the serum is an antibody against Hp44kD;
(ii) Histamine release from mast cells and basophils was regulated by Hp;
(iii) In vitro and in vivo studies revealed that Hp and its components can cause microvascular damage and dysfunction, which can induce or aggravate skin edema or wind mass formation;
④The local colonization of Hp and the resulting chronic inflammation can regulate the systemic immune process and amplify the process of skin inflammation by producing various mediators or cytokines;
⑤ A small number of patients improve after anti-Hp treatment;
(6) Hp can stimulate the body’s autoimmune response by molecular resemblance, and it is confirmed by treatment that patients with positive autologous serum skin lest (ASST) can have negative ASST after anti-Hp treatment as their condition improves. However, it was found that the rate of Hp infection in patients with chronic urticaria is not higher than that in the normal population, and there is no direct evidence of Hp-induced chronic urticaria in in vivo and ex vivo studies, so it is difficult to confirm that there is an inevitable link between Hp infection and chronic urticaria, and it may only play a facilitating role in the development of the disease in some patients.
It is currently believed that the gastrointestinal mucosal barrier is disrupted in the presence of Hp infection, resulting in easier absorption of antigens or other pro-inflammatory factors into the gut and exposure of the immune system to induce or exacerbate chronic urticaria. In addition, Hp toxins or components act as superantigens, or form antigen-antibody complexes in the body, or Hp-mimetic antigens including Lewis antigen, sialic acid glycosyl conjugates and laminin and its residues, which induce or exacerbate the inflammatory process of urticaria. In conclusion, Hp as a cause of urticaria or other diseases needs to be studied in depth, especially the phenomenon that Hp infections are extremely common in the population.
Therefore, treatment to remove Hp in patients with chronic urticaria is not advocated as a routine or unprincipled practice. For patients who are clinically resistant to antihistamine therapy, a course of 1 to 2 courses of anti-Hp therapy can be tried when other predisposing factors are excluded and evidence of Hp infection is found. The medication consists of the following 3 components, i.e. proton pump inhibitor (PPI) + bismuth + antibiotic (including any 1 of amoxicillin, tetracycline, furazolidone).
1.4 Treatment issues in thyroid disease and urticaria
It was found that 18.1% of patients with chronic urticaria had a combination of their own thyroid disease. Effective relief and reduction of recurrence can be achieved by oral thyroxine [3].
In conclusion, as far as the current state of research is concerned, the value of conducting etiological treatment studies in controlling the development of chronic urticaria is very limited, and more work needs to be done in depth.
2. Antihistamines are still the basic drugs used in the treatment of chronic urticaria, but it is important to pay attention to the changes in antihistamines treatment strategies
2.1 Second-generation non-sedating antihistamines are the first choice for the treatment of chronic urticaria
The principle of preference for increasing the dose is advocated in case of ineffectiveness or poor response to treatment [4-6]. Meta-analysis found that second-generation antihistamines are very similar to the first generation in the treatment of chronic urticaria, but with significantly less side effects, and most of them are effective in controlling symptoms with a single daily dose, thus becoming the basic means of treatment for chronic urticaria. Again, there are some differences in the second generation antihistamines. Cetirizine and levocetirizine still have varying degrees of sedation, especially at increasing doses. Some antihistamines such as Avastin require 3 daily doses due to their short half-life, which affects patient compliance.
Some antihistamines such as imipramine and loratadine still need to be metabolized by hepatic drug metabolizing enzymes (CYP450), so potential drug interactions, cardiotoxicity (mainly Q-T interval prolongation) need to be noted, as well as caution in patients with severe hepatic abnormalities. Cetirizine, imipramine, levocetirizine and loratadine have anti-inflammatory effects at therapeutic doses. Imipristine has a clear anti-5 lipoxygenase effect and a unique anti-inflammatory property by antagonizing leukotriene metabolism, which should theoretically be more relevant in diet-related urticaria.
When antihistamine therapy is ineffective, the priority of changing drug species or combination, or increasing the dose of a single drug is of great clinical concern. The change of species is based on the fact that the pharmacokinetics of different antihistamines differ between individuals or that their pharmacological effects are somewhat different. Differences in pharmacokinetics, affinity for H1 receptors, and drug concentrations reaching the skin can be reflected in histamine-mediated windrow inhibition assays, although this is not a determinant of clinical response to treatment. The therapeutic effects of either first- or second-generation antihistamines are very similar for a single drug.
Most multicenter clinical studies suggest that there is no significant difference in the effectiveness of second-generation histamines in the treatment of urticaria, especially chronic idiopathic urticaria, and it has been found that switching drugs is often not effective, reflecting the limited value of switching to improve the therapeutic effect of an antihistamine if it is ineffective.
The basis for the ineffectiveness of antihistamine therapy is the inability of antihistamines to fully block the three events that follow mast cell activation, including degranulation, inflammatory factor synthesis and release, and prostaglandin metabolism. A comparative study found that cases in which antihistamines were ineffective were dominated by polymorphonuclear cell infiltration in the tissues and exhibited elevated levels of various inflammatory mediators such as leukotrienes, prostaglandins, and cytokines to varying degrees in the blood in addition to the presence of histamine. Thus the need for antihistamines to improve their efficacy is closely related to the broader anti-inflammatory properties of antihistamines. The European Society for Allergic Reactions and the British Society for Allergy and Clinical Immunology (BSACI) jointly advocate that advocating increased doses of drugs in treatment-naïve cases is the preferred treatment strategy. Increasing the dose of antihistamines is to improve the ability of antihistamines to exert a broader anti-inflammatory effect while antagonizing histamine receptors.
Antihistamines do not just block H1 receptor activity, but can also exert a variety of anti-inflammatory effects. In the case of desloratadine, the anti-inflammatory effect can be achieved in several ways. Firstly, desloratadine stabilizes mast cell and basophil membranes and affects the release of mediators in a dose-dependent manner through IgE-dependent or non-dependent mechanisms. It has also been found that desloratadine inhibits the release of inflammatory mediators from leukocytes. Eosinophils are important effector cells in the formation of the late phase of allergic inflammation, and desloratadine can reduce local infiltration of eosinophils in inflammation by inhibiting the secretion of adhesion molecules and chemokines.
In a study of allergic rhinitis treated with 20 mg of oral desloratadine daily and crossed over with placebo, it was found that desloratadine effectively reduced the magnitude of the decline in blood eosinophils and basophils, and the level of eosinophil chemotactic factor (Eotaxin) in nasal secretions was significantly lower than that in the placebo group, indicating that oral high-dose desloratadine can effectively prevent eosinophil localization in the lesion. It is believed that this effect is not produced by blocking H1 receptors. Similarly, numerous studies have demonstrated that desloratadine can inhibit the production of adhesion molecules and modulate the Th1/Th2 balance, thus acting as an anti-inflammatory agent in several ways. Thus, dexloratadine can fully block the allergic inflammatory process, and this pharmacological effect is achieved at low concentrations (10-9 to 10-7 M). Newer studies have further revealed that desloratadine can achieve anti-inflammatory effects by controlling key aspects of cellular inflammatory factor expression through inhibition of NF-κB gene expression [7].
There is a lack of additional clinical studies to support whether increasing the drug dose can improve the efficacy. Recently Siebenhaar et al [8] conducted a placebo-controlled crossover trial using high doses of desloratadine for the treatment of acquired cold urticaria. The study was based on the background of the European Society for Allergic Reactions and Clinical Immunology on the recommendation of higher doses of antihistamines in cases of cold urticaria where conventional dose therapy is ineffective. The authors selected 30 cases of acquired cold urticaria treated with placebo, 5 mg daily, and 20 mg daily, each for 7 days followed by a 14-day washout period, and observed for cold provocation test tolerance, wind group volume changes, and side effects after treatment. The results showed that a 5 mg daily dose was effective in improving cold tolerance and reducing wind pooling, while the treatment effect was significantly higher with 20 mg daily than with 5 mg daily.
Therefore, this study found that increasing the dose of antihistamines can improve the efficacy of urticaria without a corresponding increase in side effects, supporting the guidelines proposed by the European Society for Allergic Reactions and Clinical Immunity that the regular dose of antihistamines is not effective by increasing the dose of the drug. It has also been argued that since skin scratching is primarily histamine-mediated, the recommended increase in dose of antihistamines may improve efficacy and be more valuable for application in this patient population. Increasing the drug dose needs to ensure the safety of the drug as a prerequisite, advocating that loratadine, desloratadine, and cetirizine are options, but the side effect of drowsiness may be aggravated by increasing the dose of cetirizine. Evidence for the clinical application of increased doses of other drugs is lacking relative to the above recommended drugs.
2.2 First-generation antihistamines should be the first choice for combination therapy when second-generation antihistamines are ineffective
The side effects of the first generation, especially drowsiness and sedation, are significantly stronger than those of the second generation and are important factors affecting patients’ quality of life, unless their sedative and drowsy effects are beneficial in reducing pruritus and promoting sleep. However, objectively speaking, first-generation antihistamines are not inferior to second-generation in the control of urticaria, especially in terms of efficacy.
Kaplan [9], through a summary of clinical experience and etiological analysis of 10 000 cases, found that the effects and side effects of antihistamines have to be analyzed objectively. In fact, patients with urticaria who are unable to sleep because of itching,, can be more productive with oral administration of first generation antihistamines. The side effects such as sedation of any antihistamine are mild compared to corticosteroids, cyclosporine A, etc. and can be accepted by the patient.
The effect of sedation on work, study and life should be observed for more than 2 weeks rather than evaluated by a few hours or 1 to 2 days. While the first generation antihistamines are considered for their side effects, their broader pharmacological effects including anti-adrenergic effects, anti-5hydroxytryptamine effects, anti-basophil degranulation and targeting of H4 receptors (which are closely related to pruritus, etc.) are an important basis for exerting control of urticaria symptom onset and are therefore clinically advocated as the first choice for combination therapy.
Combination therapy with H1 and H2 receptor antagonists is ineffective in most cases. It has been found that H2 receptor antagonists alone apparently have no definite effect on reducing pruritus and improving the wind mass. It is now believed that the combination of the two classes of drugs improves efficacy primarily by competitively relying on the hepatic drug metabolizing enzyme CYP3A4, thereby increasing the blood levels of antihistamines, and not synergistically by antagonizing both H1 and H2 receptors, as is well established. Therefore, those second-generation antihistamines that do not depend on hepatic metabolism, such as cetirizine, levocetirizine, desloratadine, and fexofradine, combined with H2 receptor antagonists are clearly unreasonable and cannot effectively improve the clinical treatment outcome.
2.3 Theoretical basis of maintenance therapy
The theoretical basis for maintenance therapy after symptom control is that antihistamines can act as counter agonists to affect the activation state of histamine receptors in a lasting manner. Histamine stabilizes the activated receptors, while antihistamines stabilize the non-activated receptors.
Antihistamines do not exert their pharmacological effects through antagonist histamine binding to receptors, but are counter agonists that can implement inhibition of histamine receptor activation in the presence of histamine deficiency. The introduction of agonist and counter agonist theories into the interpretation of the pharmacological effects of antihistamines has some relevance, especially since the use of antihistamines for the treatment of chronic urticaria to control complete symptoms still requires a further period of maintenance therapy to further reduce the histamine receptor activation state and prevent recurrence of the disease due to immediate discontinuation of the drug [10]. The duration of maintenance therapy is not supported by a large body of clinical evidence, suggesting that patients with urticaria in general need to be maintained for 3-4 months, with special cases such as physical urticaria and, patients with positive ASST needing to be extended to 6 months or longer, as clearly recommended in the BSACI guidelines.
2.4 The use of antihistamines in special populations should be justified by their rationality
2.4.1 Medication use in pregnancy and lactation In principle, antihistamines should be avoided during pregnancy as much as possible. Clinical observation shows that most patients with chronic urticaria have reduced or disappeared their symptoms during pregnancy. However, if symptoms flare up and seriously affect work and life, treatment must be taken. When choosing antihistamines, patients should be informed that there is no absolutely safe and reliable drug available and choose a relatively safe and reliable drug on balance.
It has been found that most antihistamines can be secreted into breast milk, but relatively speaking, cetirizine, loratadine, and desloratadine are secreted at low levels in breast milk. Therefore, when oral medications must be taken for urticaria attacks in breastfeeding female patients, the above-mentioned drugs can be recommended, and lower doses should be used whenever possible. Chlorpheniramine has been reported to have side effects such as reducing appetite and causing drowsiness in infants and should be avoided.
2.4.2 Problems with medication use in children Non-sedating H1 receptor antagonist drugs remain the first-line choice for the treatment of urticaria in children, but most antihistamines are prescribed for use at an age of 12 years or older. The age limits and doses used vary significantly among drugs. Cetirizine, desloratadine, levocetirizine, and loratadine are all available in syrup formulations for pediatric use, but desloratadine has the lowest approved age of use, 1 to 5 years.
Only chlorpheniramine and hydroxyzine can be used in children under 1 year of age. In treatment-naïve patients, treatment with increased doses, combined sedative (nighttime use) and non-sedative (daytime use) antihistamines is possible. On this basis, H2 receptor antagonists and leukotriene receptor antagonists can be tried, the latter of which can be used in children over 6 months of age. Severe and treatment-resistant patients can use corticosteroids for a short period of time, but use with caution and prevent side effects of the drugs.
3. Choice of antihistamines for treatment-resistant patients
3.1 Definitely effective treatments
(1) Corticosteroids: In severe acute urticaria, which may be combined with angioedema, or systemic symptoms, a short course of oral corticosteroids is necessary. In the treatment of chronic urticaria, try to avoid long-term use of corticosteroids. When they must be used, they should be strictly indicated, the daily dose should be controlled (consider using a low dose, prednisone: 10 mg/d or 20-25 mg every other day), with regular follow-up and attention to the prevention and treatment of side effects, especially osteoporosis.
One study reported that treatment of cutaneous scrofula with corticosteroids was found to be more effective than cetirizine in controlling the symptoms, but the side effects were also very pronounced and the same relapse existed after discontinuation of the drug [16]. Thus, it appears that corticosteroid therapy does not reduce relapses and can induce the formation of corticosteroid-dependent urticaria.
(2) Cyclosporine A: Cyclosporine A is also confirmed in clinical studies to treat persistent and treatment-resistant chronic urticaria with positive efficacy. Considering the side effects of the drug and the relatively expensive price of the drug, it is only used as an alternative therapy in cases where corticosteroid therapy is ineffective, a larger dose is needed to control symptoms, or corticosteroid side effects are intolerable and contraindicated.
3.2 Studies suggest that effective therapies are lacking in multicenter double-blind controlled studies
3.2.1 Therapeutic value of antihistamines in combination with anticoagulants in patients with chronic urticaria with positive ASST Studies have found that skin tests with autologous plasma are positive in up to 95% of patients with chronic urticaria, whereas tests with serum are only 25% to 50%, suggesting that the blood coagulation system may be involved in the development of urticaria. Dipyridamole is a platelet adhesion inhibitor. In one study, 64 patients with autologous plasma skin test (APST) positive chronic urticaria were randomly divided into a combination group of 34 patients and a control group of 30 patients. The efficiency rates of the combined group and the control group were 85.20% and 70%, respectively, with significant differences (P < 0.05), suggesting that abnormal activation of the coagulation and fibrinolytic system in the pathogenesis of chronic urticaria has a role in the development of chronic urticaria and that corresponding therapeutic measures can be carried out. It has also been found that the application of anticoagulants such as warfarin and heparin sodium can yield positive results, suggesting that anticoagulation therapy has a role in the treatment of urticaria and is more relevant in patients with negative ASST [11].
3.2.2 Anti-leukotriene and prostaglandin therapy The release of histamine from mast cells is an important part of the pathogenesis of chronic urticaria, but prostaglandins and leukotrienes also play an important role in the pathogenesis. Mast cells in the skin can produce prostaglandin D2 (PGD2), synthesized primarily by cyclooxygenase 2 (COX-2), and also leukotriene C4 (LTC4) via the 5-lipoxygenase pathway. Both can induce or exacerbate the formation of wind masses.
In addition, COX1 can produce prostaglandin E2 (PGE2), which can downregulate the synthesis of LTC4. Classical NSAIDs can block both COX1 and COX2 and, therefore, affect the production of PGD2 and PGE2 and are therefore considered to induce or exacerbate urticaria. The use of COX2 inhibitors, which selectively inhibit PGD2 synthesis without affecting PGE2 synthesis, could theoretically be used in the treatment of urticaria.Goel et al [12] used rofecoxib to control intractable urticaria, resulting in complete resolution of treatment and successful withdrawal of corticosteroids in five of eight patients. Effective cases were seen within 5 to 7 days.
Tumor cells can also produce PGD2, which has been associated with the development of urticaria in a small number of cases. Also COX2 inhibitors can be effective against colon, rectal, breast and oral tumors, therefore, the use of COX2 in such patients can both prevent tumors and control urticaria. It has been found that corticosteroids can selectively inhibit COX2 gene expression without affecting COX1 or the number of local mast cells in the skin, which has a similar mechanism of action to that of COX2 inhibitors for urticaria. Therefore, in terms of mechanism of action, COX2 inhibitors can replace corticosteroids in the treatment of urticaria. Other COX2 inhibitors vadexib, celecoxib and meloxicam all inhibit COX1 to varying degrees, but there is no evidence whether the treatment is effective. Also the drugs in this area lack validation in multicenter clinical trials [12].
The application of leukotriene receptor antagonists has been shown in most multicenter double-blind clinical studies to have an unclear therapeutic effect. There are a few reports of their use in NSAIDs or food-related urticaria with positive efficacy.
3.2.3 Desloratadine in combination with thalidomide for chronic urticaria Engin et al [13] used thalidomide in combination with antihistamines in a non-double-blind randomized controlled study in which 65 patients with chronic idiopathic urticaria were selected and randomized to the thalidomide and desloratadine combination group and the desloratadine alone group for a course of 3 months, with a change to maintenance treatment with desloratadine alone after 3 months. The indicators observed included the number of wind clusters per day and the pruritic urticarial activity score.
After 3 months of treatment, the results showed that the mean decrease in the urticarial activity score was 7 points in the combination group compared to 5.77 in the control group, a highly significant difference (P < 0.000 1). the mean decrease in the VAS score was 2.58 and 2.55 in the combination and control groups, respectively, a statistically significant difference (P < 0.001). after 3 months, a decrease in the UAS value of 1.16 was observed in the combination group, while control group increased by 4.8 instead.
The results suggest that thalidomide can consistently reduce UAS and VAS values and can lead to complete remission in some patients. This study also further suggests that the inflammatory response plays a more important role in the formation of wind clumps and itching in urticaria and in the recurrence of the disease, and that selective anti-inflammatory therapy has a definite benefit in improving the symptoms of urticaria and prolonging the remission period. However, this study has the drawbacks of non-double-blind method, short observation period, and no placebo control.
3.2.4 Successful treatment of severe chronic urticaria with hydroxychloroquine sulfate One author applied hydroxychloroquine sulfate to treat 12 patients with severe recalcitrant urticaria, all of whom were treated with oral skin hormones and did not respond to treatment with multiple antihistamines. In 11 cases, the oral administration of hydroxychloroquine (200 mg, 2/d) in combination with antihistamines or doxepin reduced or disappeared the symptoms and the corticosteroids were gradually discontinued. 7 patients were able to completely discontinue all medications after an average of 12 months or were treated with only one antihistamine. 2 of the 7 patients relapsed at 8 and 18 months after discontinuation, and the same results were obtained with the addition of hydroxychloroquine. The same effect was achieved with the addition of hydroxychloroquine.
3.2.5 Mirtazapine for severe urticaria Mirtazapine is an antidepressant that has been used successfully for the treatment of intractable pruritus caused by cholestasis, malignancy and lymphoma. Mirtazapine was applied to treat a patient (70 years old, female) with severe chronic urticaria who had failed conventional treatment, excluding various systemic diseases such as urticarial vasculitis and thyroid, and whose symptoms could be temporarily slightly reduced by using high-dose antihistamines or combined with a short course of low-dose hormones. After 7 days of oral administration of 15 mg/kg mirtazapine, the symptoms were completely relieved with concomitant administration of epalrestine, fexofenadine and hydroxyzine. 10 days later, the antihistamines were gradually discontinued and the patient’s symptoms did not recur. After 1 month of discontinuation of Mirtazapine, the symptoms returned after 6 days.
The combination treatment was again effective and the other combination drugs were discontinued after 5 days and continued for 5 months to obtain stable control. It was well tolerated by patients in use, with no significant adverse effects. Like doxepin, it also has an antagonistic effect on H1 receptors, but has fewer side effects and no significant drug interactions, so it shows better prospects for clinical application.
3.2.6 Salazosulfapyridine for intractable urticaria Mcgirt et al [16] observed 19 patients between 2002 and 2005 in whom antihistamines had failed, and after adding salazosulfapyridine at a starting dose of 500 mg/d and increasing it by 500 mg/d weekly according to the response to treatment, with an average dose of 2-4 g/d, 14 patients (74%) showed significant improvement and 4 patients (21%) had a slight reduction in symptoms, 1 case (5%) was ineffective, and all 13 patients who had relied on corticosteroid therapy were able to reduce or discontinue corticosteroids during treatment.
3.2.7 Biologic agents for chronic urticaria Omalizumab for chronic urticaria: Omalizumab is a recombinant human-derived monoclonal antibody that binds IgE molecules, blocks the high affinity between IgE molecules and the surface of mast cells and basophils, binds to Ig receptors, and reduces the expression of IgE receptors on the surface of basophils. Spector et al. selected three patients with chronic urticaria resistant to conventional therapy and treated with higher doses of antihistamines, anti-leukotrienes and H2 receptor blockers with no improvement. Systemic treatment with hormones provided only temporary relief.
One patient had a low serum IgE level with an elevated anti-IgE receptor level, one had an elevated serum IgE level with a normal anti-IgE receptor level, and the other had a significantly elevated serum IgE level with an elevated anti-IgE receptor level. 3 patients were given omalizumab every 2 weeks. The results were that the symptoms disappeared within 1 week in two patients and after 6 weeks of treatment in the other patient. 1 patient with elevated anti-IgE receptor level decreased to normal after treatment. The study suggests that omalizumab is definitely effective in improving the symptoms of urticaria, and its therapeutic mechanism needs to be further investigated. Other investigators suggest that omadzumab could be an effective option for patients with autoimmune urticaria who are not responding to antihistamine therapy. There have also been studies with successful treatment of cholinergic urticaria with omadzumab.
② Intravenous immunoglobulin for chronic urticaria: studies based on the fact that about 1/3 of patients with chronic urticaria have autoimmune pathology, the use of intravenous immunoglobulin could theoretically be used as an immunomodulatory agent in such patients.Pereira et al [18] selected bed diagnostic and therapeutic levels. Current clinical concerns.
(1) How to increase the dose and how long to maintain it when clinical conventional treatment is ineffective still needs evidence from multicenter large sample studies.
(2) Investigation of factors that influence patient prognosis and response to antihistamine therapy.
(3) To investigate possible factors that trigger or exacerbate urticaria, 29 patients with evidence of autoimmune urticaria (ineffective to multiple conventional treatments or relapsing after discontinuation) were selected for intravenous immunoglobulin, 0.15 g/kg, once every 4 weeks for 6 to 51 months. After treatment, 26 patients showed significant improvement in symptoms and reduced dependence on antihistamines, with reduced histamine-releasing activity, and 20 patients were followed up for 20 months without relapse after treatment. Thus, intravenous immunoglobulin is a better therapy for the treatment of patients with intractable urticaria with autoimmunity.
(iii) Autologous serum therapy Bajaj et al. applied autologous serum therapy to treat patients with ASST-positive chronic urticaria and obtained positive results. In the ASST-positive group, 35.5% of patients had complete remission and another 24.2% had significant improvement, while in the ASST-negative group, 23% had complete remission and 23% had significant improvement, with complete remission and significant improvement in each group. There was a significant difference between the two rates.
The degree of pruritus reduction and the dosage of antihistamines were also significantly reduced in both groups. The results suggest that autologous serum therapy has positive efficacy in ASST-positive urticaria and is equally effective in ASST-negative patients, but with slightly less efficacy. Similarly a randomized placebo-controlled study conducted by Staubach et al [20] found that this therapy was definitely effective in ASST-positive urticaria, but not in ASST-negative patients.
4. Recommended procedures for systemic medications for chronic urticaria
5.Summary
Our dermatologists should make full use of the large number of case resources and actively carry out various tasks to improve the clinical to provide stronger evidence for etiological studies, especially focusing on factors such as food, drugs and infections. Second-line therapeutic drugs (including H2 receptor antagonists, leukotriene receptor antagonists and corticosteroids, etc.) clinical standardization studies to reasonably evaluate the status of these drugs in the treatment of urticaria.