Management of Chronic Urticaria

The management of urticaria, although complex, relies on two postulates: 
• Recognition and eradication of the triggering factor(s) 
• Provision of symptomatic relief

Recognition and eradication of the triggering factors(s)
Factors known are drugs, food, infections, and physical stimuli.
Drugs: Analgesics and NSAIDs can exacerbate already present urticaria and are also recognized triggers of new-onset urticaria.2 When suspected, they should be withdrawn entirely or can be replaced. ACE inhibitors can cause angioedema.
Eradication of infectious agents 
Infections and infestations should be treated where suspected, including infections of the GI tract e.g., H Pylori associated gastritis3, nasopharyngeal bacterial infections, and intestinal worms.8
Management of diet
The allergens in food need to be avoided if a patient has type I hypersensitivity to any one of these allergens. Pseudo-allergic reactions5 which are not IgE mediated have been described for organic foods and food additives.9-13
Physical stimuli
They are usually recognized and controlled, e.g., in chronic pressure urticaria patients are advised to use bags with a wide handle and similarly, in symptomatic dermographism, simple avoidance of friction can give relief from symptoms.15 
Symptomatic therapy
One of the objectives of symptomatic therapy is to mask the effects of histamine, platelet-activating factor, and other mast cell mediators. Histamine plays a primary role in inducing the symptoms associated with urticaria. The activation of receptors on endothelial cells by histamine results in wheals whereas this histamine receptor activation on sensory nerves results in itching. Different guidelines have been proposed for managing chronic urticaria including the EACCI [5] and BSACI [4].


Introduction
The management of urticaria, although complex, relies on two postulates:  Recognition and eradication of the triggering factor(s)  Provision of symptomatic relief Recognition and eradication of the triggering factors(s) Factors known are drugs, food, infections, and physical stimuli. Drugs: Analgesics and NSAIDs can exacerbate already present urticaria and are also recognized triggers of new-onset urticaria. 2 When suspected, they should be withdrawn entirely or can be replaced. ACE inhibitors can cause angioedema. Eradication of infectious agents Infections and infestations should be treated where suspected, including infections of the GI tract e.g., H Pylori associated gastritis 3 , nasopharyngeal bacterial infections and intestinal worms. 8 Management of diet The allergens in food need to be avoided if a patient has type I hypersensitivity to any one of these allergens. Pseudo-allergic reactions 5 which are not IgE mediated have been described for organic foods and food additives. [9][10][11][12][13] Physical stimuli They are usually recognized and controlled, e.g., in chronic pressure urticaria patients are advised to use bags with a wide handle and similarly, in symptomatic dermographism, simple avoidance of friction can give relief from symptoms. 15 Symptomatic therapy One of the objectives of symptomatic therapy is to mask the effects of histamine, platelet-activating factor, and other mast cell mediators. Histamine plays a primary role in inducing the symptoms associated with urticaria. The activation of receptors on endothelial cells by histamine results in wheals whereas this histamine receptor activation on sensory nerves results in itching. Different guidelines have been proposed for managing chronic urticaria including the EACCI [5] and BSACI [4]. According to EACCI guidelines, the first choice in treating chronic urticaria is second-generation histamine type I receptor blockers. 17 However, continuous treatment is recommended 14 because of their non-sedating or minimally sedating properties free of anticholinergic side effects. More than four-fold higher doses can be used in the majority. Table 1 enlists the commonly used H1 antihistamines in Pakistan. Non-sedating antihistamine Safety data of H1 antihistamines are available regarding prolonged use. 14 In the recent GA2LEN position paper 15 first-generation antihistamines are no longer recommended. This view is shared by the World Allergy Organization guideline for Allergic Rhinitis and its Impact on Asthma. 16 Modern second-generation antihistamines 17 (loratadine, and fexofenadine) are non-sedating metabolites of earlier sedative antihistamines. Astemizole and terfenadine are disregarded because of cardiotoxic effects. 15 Seven of second-generation antihistamines (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, rupatadine, and bilastine) have been tested in detail.
Studies show the benefit of dose more than four-fold of the recommended dose. 18,19 It has been verified using bilastine, cetirizine, desloratadine, levocetirizine, fexofenadine, and rupatadine. 18,20 H2-Antihistamines There is little evidence for their use. 29 A combination of cimetidine with hydroxyzine results in increased hydroxyzine levels hence recommended only in hydroxyzine unresponsiveness. Cimetidine is not recommended in combination with cetirizine. 30 The combination of ranitidine with terfenadine was superior to terfenadine alone in terms of itch, but not in wheals or swellings. 31 Treatment of refractory symptoms Repeated courses of glucocorticoids may be used 33 , but it may cause severe side effects without inducing remission or altering the course. So they are only advisable for short periods at the minimal effective dose while considering other options.

Goal of Therapy
There is no standardized approach. 34 Options include omalizumab, and anti-inflammatory or immunosuppressants.
Therapy must be individualized, considering concomitant medical conditions and patient preferences.

Treatment strategies
Any ineffective standard therapies should be discontinued. A baseline complete blood count and chemistry panel with liver function tests should be obtained prior to initiation. Drugs for refractory urticaria can be divided into three groups: 1. Anti-inflammatory group Predominantly anti-inflammatory, with low toxicity and less proven efficacy e.g., dapsone, sulfasalazine, and hydroxychloroquine. 2. Immunosuppressant group Potent immune suppression with greater toxicity and efficiency e.g; calcineurin inhibitors, sirolimus, and mycophenolate mofetil.  Same as cyclosporine. 1mg twice daily for 1 week; increased to 2mg twice daily.

OMALIZUMAB:
This recombinant humanized monoclonal IgG antibody binds free IgE, down-regulates mast cell function and induces eosinophil apoptosis 25 through the reduction of FcεRI in basophils and mast cells. 47 It has proven efficacy in refractory CU. Add-on therapy with subcutaneous omalizumab 300 mg every 4 weeks for 12 or 24 weeks, reduced itching severity, hives, and angioedema. It is the second choice in the EAACI guidelines 6 and officially approved by the European Regulatory Agency. 25 Efficacy is proven in symptomatic dermographism, cold urticaria, heat urticaria, delayed pressure, solar and cholinergic urticaria. 48 Dosing -Two doses approved by the FDA are 150 mg or 300 mg every four weeks. If the response is adequate, taper to a lower dose (e.g., 150 mg every four or six weeks). An algorithm for dose individualization has been proposed. Treated patients, who, after stopping therapy, had a recurrence, have been reported to respond to omalizumab again, suggesting that resistance does not develop readily. Monitoring -No specific laboratory monitoring is required for patients receiving omalizumab.
Side Effects There appears to be no reported side effect. However, transient hair loss was reported in three subjects who continued therapy despite it. 49 Therapies with Significant Limitations Some additional agents that can be useful, albeit with limitations. Glucocorticoids remain the standard comparator. Immunoglobulin Used where immunomodulation is preferable to immunosuppression, e.g., history of malignancy. It alters cell adhesion, immunoregulatory molecules, complement function, cytokine levels, and autoantibody production. 50 It can be administered intravenously [IVIG]) or subcutaneously [SCIG]. Adverse effects are generally predictable and manageable. It may be dosed individually, the optimal dose, number of infusions and schedule are unknown. TNF-inhibitors Tumor necrosis factor (TNF)-alpha is upregulated in the epidermis in lesional and nonlesional skin. Etanercept, adalimumab, and infliximab have been studied. 51 However, the effectiveness is limited. Colchicine It acts by suppressing leukotriene generation or leukocyte adhesiveness and migration. 2 It is safe at recommended doses, with a rapid onset of action. Androgens These are effective in hereditary angioedema and have been studied in chronic idiopathic urticaria and angioedema. 52 Methotrexate It reduces neutrophil accumulation 2 , diminishes leukocyte adhesiveness, leukotriene synthesis, and alters cytokine activity. 53 Efficacy is limited. 54 Doses ranged from 5-25 mg/week and effects observed after four weeks. Cyclophosphamide Reserved where multiple alternative agents have failed. 22 It is believed to act on plasma cells to reduce autoantibody production in autoimmune CU. Antifibrinolytics These 55 are useful because coagulation and inflammatory pathways in urticaria are interconnected. 22 Serine protease inhibitors decrease proteases including tryptase, kallikrein, complement, factor XII, and plasmin e.g., tranexamic acid Methylxanthines Theophylline. 56 I/M or aerosolized epinephrine (BASCI): Intramuscular epinephrine not routinely prescribed except for self-administration in angioedema affecting the upper airway.
Nondrug therapies Nondrug treatments that have been studied in CU include phototherapy, autohemotherapy, and plasmapheresis. Phototherapy It is useful in solar and physical urticarias, suitable for patients who visit frequently or intolerant to systemic treatment. 57 Narrowband UVB is effective, safe and affordable for steroid-dependent CRU. Autohemotherapy It 58 involves the parenteral injection of autologous blood to desensitize patients to pro-urticarial factors in his serum 2 and improved quality of life. 3 Plasmapheresis It removes proteins and other substances and may be immunomodulatory. 59 However, it is not easily available and not recommended for routine use. Inducing Tolerance It can be useful in physical, cholinergic, solar and cold urticarias. However, it lasts only a few days. A consistent exposure is required, which is often not acceptable. 15 Corticosteroids are recommended in the resistance of the maximal dose of H1 antihistamines with the addition of H2 blockers and leukotrienes. More effective in delayed-pressure urticarias, but sideeffects should be monitored. Pregnancy: Most of the antihistamines are not contraindicated in pregnancy and can be used safely. Loratadine & hydroxyzine have shown teratogenicity at high doses in animals. Chlorpheniramine, loratadine & cetirizine have been recommended as Class B drugs in pregnancy. However, the lowest possible doses should be used. Breastfeeding: Antihistamines are only recommended for breast-feeding if potential benefits outweigh the risk as the majority of the drugs are excreted in the human breast milk. Chlorpheniramine can cause drowsiness and poor feeding.

Conclusion
Urticaria significantly affects the quality of life and therefore its early and effective treatment is imperative. Sound cooperation between the patient and the treating physician is required for successful therapy. The objective is to make the patient asymptomatic and hence elevate his quality of life. An individualized approach is required and the treatment of chronic urticaria needs to be tailored differently for each patient because of the highly variable disease presentation.