Chronic Urticaria: An Overview of Treatment and Recent Patents

Abstract

Background:

Up to 1% of the general population in the USA and Europe suffer from chronic urticaria (CU) at some point in their lifetime. CU has an adverse effect on the quality of life.

Objective:

This study aims to provide an update on the epidemiology, pathogenesis, clinical manifesta-tions, diagnosis, aggravating factors, complications, treatment and prognosis of CU.

Methods:

The search strategy included meta-analyses, randomized controlled trials, clinical trials, reviews and pertinent references. Patents were searched using the key term “chronic urticaria” at the following links: www.google.com/patents, www.uspto.gov, and www.freepatentsonline.com.

Results:

CU is a clinical diagnosis, based on the episodic appearance of characteristic urticarial lesions that wax and wane rapidly, with or without angioedema, on most days of the week, for a period of six weeks or longer. Triggers such as medications, physical stimuli, and stress can be identified in 10 to 20% of cases. C-reactive protein/erythrocyte sedimentation rate, and complete blood cell count with differential are the screening tests that may be used to rule out an underlying disorder. The mainstay of therapy is reassurance, patient education, avoidance of known triggers, and pharmacotherapy. Second-generation H1 antihistamines are the drugs of choice for initial therapy because of their safety and efficacy profile. If satisfactory improvement does not occur after 2 to 4 weeks or earlier if the symptoms are intolerable, the dose of second-generation H1 antihistamines can be increased up to fourfold the manufacturer’s recom-mended dose (all be it off license). If satisfactory improvement does not occur after 2 to 4 weeks or earlier if the symptoms are intolerable after the fourfold increase in the dosage of second-generation H1 antihis-tamines, omalizumab should be added. If satisfactory improvement does not occur after 6 months or earli-er if the symptoms are intolerable after omalizumab has been added, treatment with cyclosporine and sec-ond-generation H1 antihistamines is recommended. Short-term use of systemic corticosteroids may be considered for acute exacerbation of CU and in refractory cases. Recent patents for the management of chronic urticaria are also discussed. Complications of CU may include skin excoriations, adverse effect on quality of life, anxiety, depression, and considerable humanistic and economic impacts. On average, the duration of CU is around two to five years. Disease severity has an association with disease duration.

Conclusion:

CU is idiopathic in the majority of cases. On average, the duration of CU is around two to five years. Treatment is primarily symptomatic with second generation antihistamines being the first line. Omalizumab has been a remarkable advancement in the management of CU and improves the quality of life beyond symptom control.

1. INTRODUCTION

Urticaria (also called hives, wheals, or nettle rash) is characterized by pruritic, erythematous, and edematous wheals [1-10]. The hallmark of urticaria is that individual lesions wax and wane rapidly, usually lasting less than 4 hours [8, 9]. In clinical practice, it is important to ascertain whether lesions last less or more than 24 hours as this increases the likelihood of urticarial vasculitis. Urticaria can be classified as acute or chronic. Chronic Urticaria (CU) conventionally refers to recurrent wheals, on most days of the week, which occur for a period of ≥ six weeks. CU can be further divided into two different subtypes, namely, chronic idiopathic urticaria (also called chronic spontaneous urticaria) and chronic inducible urticaria (also called physical urticaria) [10, 11]. In most patients, CU is a sporadic and self-limited disorder [12]. Treatment is mainly symptomatic. Other than second-generation H1 antihistamines which form the first line of treatment, many other medications for the treatment of CU have been described [1]. This paper reviews the epidemiology, pathogenesis, aggravating factors, clinical manifestations, treatment, and prognosis of CU. Recent patents related to the management of CU are also discussed.

2. EPIDEMIOLOGY

CU affects up to 1% of the general population in the USA and Europe at some point in their lifetime [2, 13-15]. Both children and adults can develop CU though the condition is more common in adults [1]. A population-based study in Korea reported that the crude prevalence of CU was 2,256.5 per 100,000 person-years and the prevalence increased every year between 2010 and 2014 [16]. A hospital-based study in Korea showed that the prevalence of CU in children is approximately 1.8%, which appears to be similar to that in adults [17]. However, a lower prevalence of angioedema is observed among the pediatric populations [17, 18]. Atopy is, however, more prevalent in children (58%) than in adults (23%) (p < 0.05) [1]. There is evidence that CU is strongly associated with autoimmunity with a similar prevalence in adults and children [1, 19-21].

CU typically begins in the third to fifth decade of life [12, 13, 22]. The female to male ratio is approximately 2:1 [1-3, 12-14, 22, 23]. In a multicenter epidemiologic survey conducted in China, female preponderance was not observed in patients < 20 years of age [24]. Data from Korea showed an age peak at 0 to 9 years in addition to the usual age peak at an older age range [17, 25]. In most studies, the peak age of CU occurrence is between 20 and 40 years [26].

3. PATHOGENESIS

CU can be idiopathic or inducible. Chronic idiopathic urticaria accounts for as many as 80 to 90% of adults and children with CU. Lesions in patients with chronic idiopathic urticaria occur spontaneously, without physical or environmental stimuli [1, 19, 27]. Chronic inducible urticaria is less common and requires specific triggers which can be medications, physical stimuli or stress for the urticaria to occur [28].

It is not uncommon for chronic idiopathic urticaria and chronic inducible urticaria to coexist in the same patient [11, 28].

CU can also be a manifestation of an auto-immune or an auto-inflammatory disease and be distinguished from urticarial vasculitis [1, 19, 20, 21, 29].

4. AGGRAVATING FACTORS AND ASSOCIATED DISORDERS

Triggering factors for chronic inducible urticaria include physical stimuli, stress, and anti-inflammatory medications [8, 9, 30]. Physical stimuli such as heat (heat urticaria), cold (cold urticaria), extreme humidity, pressure (pressure urticaria, also called delayed pressure urticaria), exercise (exercise-induced urticaria), sweating (cholinergic urticaria), vibration (vibratory urticaria), water (aquagenic urticaria), and sunlight (solar urticaria) are common triggering factors [31]. Stress is another common aggravating factor. Patients often report more severe symptoms during times of psychological stress [32-34]. Drugs such as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and beta-lactams are well-known triggers [35]. NSAIDs may aggravate the skin lesions in up to 25 to 50% of patients with CU [36]. Ingestion of food (notably peanuts, eggs, chocolate), hot and spicy food, alcoholic beverages etc. may aggravate the skin lesions in some patients [8, 9, 37].

Autoimmune disorders such as hypothyroidism, hyperthyroidism, celiac disease, Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes mellitus are more commonly seen in patients with CU [14, 22, 38]. In a recent cross-sectional study of 11,271 patients with CU, CU was significantly associated with irritable colon syndrome (odds ratio: 1.86; 95% confidence interval:1.47 to 2.19; p < .001) [39]. The authors speculated that mast cells may have a role in the coexistence of these two conditions. The association of CU with malignancy is less clear as data have been conflicting [40].

Urticaria can be a manifestation in auto-inflammatory syndromes such as Cryopyrin-Associated Periodic Syndrome (CAPS) [41, 42]. CAPS is a rare hereditary inflammatory disorder encompassing a continuum of three phenotypes: Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and Neonatal-Onset Multisystem Inflammatory Disease [NOMID, also known as Chronic Infantile Neurologic Cutaneous and Articular syndrome (CINCA)]. FCAS is the mildest phenotype, characterized by recurrent urticaria, arthralgia, and fever after a general exposure to cold [43-45]. MWS is the intermediate phenotype caused by genetic mutations on the NLRP3 (CIAS1) gene that encodes the cryopyrin protein [46]. The NLRP3 mutation is autosomal dominant. Chronic, recurrent, generally non-pruritic (not itchy) urticaria is usually present during early infancy but occasionally starts in early childhood. Inflammation can occur spontaneously without an apparent provocation or result from triggers such as cold, stress, or exercise. MWS is characterized by renal amyloidosis, sensorineural hearing loss, and conjunctivitis [46]. The most severe is NOMID [Syndrome for diagnosis: dwarfing, persistently open fontanelle; recurrent meningitis; recurrent subdural effusions with temporary alternate-sided hemiplegia; high-tone deafness; visual defect with pseudo papilledema; slowing intellectual development; recurrent acute polyarthritis; erythema marginatum, splenomegaly and iron-resistant hypochromic anemia]. The hallmark of NOMID is the neonatal onset of cutaneous symptoms along with an end-organ damage. These include the “triad” of arthropathy, chronic urticaria, and Central Nervous System (CNS) involvement [47, 48]. NOMID more commonly results from de novo mutations. Schnitzler syndrome is a late-onset acquired autoinflammatory syndrome, in which, the cytokine IL-1 plays a crucial role. IL-1 blocking therapies are efficient for the inflammation-linked symptoms but not for the monoclonal component [49, 50].

5. PATHOPHYSIOLOGY

The wheal and angioedema associated with CU are caused by active and degranulating mast cells with the release of histamine, bradykinin, prostaglandins, leukotrienes, eosinophil and neutrophilic chemotactic factors, platelet-activating factor, and cytokines. The mast cell mediators lead to vasodilation and an increase in vascular permeability with the resultant formation of urticaria. Autoimmunity plays a major role and is the main underlying mechanism. Chronic idiopathic urticaria can be caused either by IgE autoantibodies against auto-allergens or IgG autoantibodies directed against the mast cells high-affinity receptor Fc-epsilon-RI and/or IgE [11, 28]. The concept of autoimmunity originated from the observation that thyroid disorders and thyroid autoantibodies are more prevalent in CU patients [4, 5, 14, 20, 51-53]. It has been shown that approximately 50% of patients with CU have autoantibodies directed against the subunit of the receptor of IgE or IgE itself, leading to the degranulation of mast cells [31]. Autoantibodies, especially mast cell-activating autoantibodies, can be found in a significant number of patients with CU [54].

Interleukin 3 (IL-3) is also relevant to the pathogenesis of urticaria. There is evidence suggesting the upregulation of IL-3 and TNF-alpha expression in lesional and uninvolved skin in different types of urticaria [55, 56]. Cytokines are involved in the pathology of urticaria, possibly by inducing subthreshold inflammation in endothelial cells of uninvolved skin. Activated status of basophils in chronic urticaria leads to the IL-3 hyper-responsiveness and the enhancement of histamine release induced by anti-IgE stimulus [56].

6. CLINICAL MANIFESTATIONS

CU typically presents with edematous wheals that are raised and circumscribed [1, 10]. Lesions range from a few millimeters to several centimeters in diameters [1]. They are usually round or annular but may be serpiginous. Larger plaques may occur if the lesions coalesce together. Lesions may appear flattened rather than raised if the patient is currently taking H1 antihistamines [1]. Although any part of the body may be affected, those areas subjected to pressure and rubbing (e.g., axillae) are more commonly affected.

Wheals of CU usually last 30 minutes to 24 hours and resolve without residual marks [1]. Pruritus is the most predominant symptom and lesions can be intensely pruritic [57]. Many patients report worsening of the itch at nighttime [1]. Lesions of urticaria may also be pricking or burning in nature.

Approximately 40 to 50% of CU patients have accompanied angioedema [58]. Wheals and angioedema commonly occur together, but may also occur at different times [37]. Angioedema refers to transient, episodic submucosal or subcutaneous, nonpitting and less well-defined edema which normally lasts less than 24 hours [8, 9]. Rather than being pruritic, the affected sites are more likely to have a numb or tingling sensation and, at times, pain. They are usually asymmetric in distribution and commonly affected areas include lips, periorbital areas, cheeks, extremities, and genitals [1, 9].

Wheals in patients with physical urticaria (not including delayed pressure urticaria) usually occur within 15 minutes after the stimulus and last for less than 2 hours [1]. The lesions are edematous and erythematous. Some patients may exhibit dermographism (also called dermatographia) which is a phenomenon whereby stroking the skin with a firm object results in a linear wheal-and-flare response following the site of the pressure [59].

A subset of CU patients might have systemic symptoms such as fatigue, headache, arthralgias/arthritis, flushing, wheezing, palpitations, nausea, and abdominal pain [33, 60]. In a survey of 155 patients with concomitant hives, joint pain or swelling (55.3%), headache/fatigue (47.6%), flushing (42.7%), wheezing (30.1%), gastrointestinal complaints (26.2%), and palpitations (9.7%) were reported [3]. This subgroup of patients tend to have a more severe and long-lasting disease [1, 22].

7. DIAGNOSIS

Most cases of CU can be diagnosed clinically following a detailed history (duration of episodic and transient wheals for a period of six weeks or longer, use of medications, physical stimuli) and careful physical examination (characteristic erythematous, edematous wheals that wax and wane rapidly, with or without accompanying angioedema) [19, 38, 61]. Usually, no cause can be identified in 80 to 90% of patients with CU [15, 21, 62, 63]. Inducible physical CU can be confirmed by tests (e.g. cold ice cube test for cold urticaria) [64]. The differential diagnoses of urticarial vasculitis, as well as auto-immune and auto-inflammatory associated urticaria need careful consideration in clinical and laboratory investigations [65].

8. LABORATORY INVESTIGATIONS

C- Reactive protein/erythrocyte sedimentation rate, and complete blood cell count with differential are screening tests that may be used to rule out an underlying disorder [10, 11, 66, 67]. CU patients usually have normal complete blood cell count result. A high eosinophil count suggests atopy or parasitic infestation. Significant elevations in C- reactive protein/erythrocyte sedimentation rate suggest an underlying systemic disease such as autoimmune, rheumatologic, infectious, or neoplastic disease [68, 69]. An abnormal serum thyroid stimulating hormone (TSH) level is suggestive of a thyroid disease. Serum complement levels should be ordered if urticarial vasculitis is suspected as affected patients often have decreased C1, C1q, C2, C3, and/or C4 levels.

Further investigational laboratory tests include the autologous serum skin test, tests of basophil activation, and tests for autoantibodies to the IgE receptor or the Fc region of IgE [70].

Blood levels of IgG-anti-FceRI, IgG anti-IGE, total IgE, IgE anti-self and other autoantibodies, and autologous serum skin testing are important [71-74]. There are recent data linking low basophil counts with more rapid resolution in children [75]. The clinical history should guide the need for additional tests, given the link to coeliac disease, rheumatoid arthritis and diabetes [76]. However, results of these tests usually do not affect the management of CU [1, 27].

Skin biopsy is not routinely needed for the diagnosis of CU. Nevertheless, a lesional skin biopsy of a newly formed wheal (preferably < 24hours) should be performed and submitted for Hematoxylin and Eosin (H & E) staining and immunofluorescence if urticarial vasculitis is suspected. Histological findings in early lesions show a perivascular neutrophilic infiltrate involving postcapillary venules with fibrin deposition and extravasation of red blood cells. Eosinophils may be noted early. Immunofluorescence may show deposition of complement and fibrin in the blood vessels and, occasionally, immunoglobulin M, immunoglobulin G, and immunoglobulin A along the basement membrane zone of the skin [1].

9. COMPLICATIONS

Excoriations of the skin may result from vigorous scratching. CU has an adverse effect on the quality of life such as disruptions of sleep and daily activities [1, 10, 18, 26, 77]. The condition is often associated with anxiety and depression disorders [28]. In addition, CU has considerable humanistic and economic impacts [1, 10, 18, 26, 77].

10. PROGNOSIS

On average, the duration of CU is around two to five years [6, 7, 32, 78, 79]. Studies have shown that spontaneous remission occurs in 17%, 39%, and 67% of children with CU after 1, 3, and 5 years, respectively [30, 80]. While remission rate at one year in children might be higher [81], it is about 30 to 50% for adult CU patients who do not have an identified triggering factor or underlying disorder [21]. Prospective studies have shown that disease severity has an association with disease duration; that is, the more severe disease tends to last longer [78]. A recent study showed that children with CU who had basophil-activating serum activity and low blood basophil counts had earlier disease resolution than their counterparts [82].

Disease management for CU may affect its prognosis. In a retrospective study, it was found that the remission rate was considerably longer in those affected patients who were not taking a standard dose of oral antihistamine for disease control [82]. The co-existing disease may also have an effect on prognosis. A prospective study of 228 patients with moderate to severe CU showed that those with systemic hypertension tended to have more persistent symptoms and a significantly lower resolution rate [83]. Moreover, the comorbidity of inducible urticaria and concomitant recurrent angio-edema may also be linked to longer CU duration [84]. All the patients should have a blood pressure measurement as this can affect prognosis, and also undergo an assessment of the QoL. Urticaria is a common disease with marked effects on the QoL [85, 86]. Hence, the use of disease-modifying and costly medications such as omalizumab may be justified [87, 88].

11. TREATMENT

Urticaria is alarming for patients as it is often acute at the time of onset and can affect large areas of the skin. Patients need reassurance and education. The mainstay of therapy is the avoidance of known triggers and pharmacotherapy [6, 7, 32, 37, 38, 88]. The majority of individuals with CU have no identifiable triggers, thereby making avoidance impractical [58]. Its treatment is mainly symptomatic [19, 59, 89]. According to the 2014 American practice parameters, the pharmacological treatment involves a stepwise approach [59].

Based on the consensus between American, UK and European guidelines published between 2014 and 2018, principles on the management of CU are essentially similar with patient education, trigger avoidance, first and second-generation antihistamines, immunomodulating drugs and biologics [10, 37, 70, 80, 89]. The up-titration of anti-histamines is a guideline recommendation, however, not a licensed use [10, 37, 80, 89]. The age at which each medication is licensed in the USA, UK and Europe varies [6, 90]. One report specifically mentions the cut-off age of 12 years to differentiate children from adults [91].

Omalizumab, a monoclonal antibody against IgE, has been proven to be an effective and safe agent for the treatment of patients ≥ 12 years whose CU is refractory to higher dose H1 receptor blocking antihistamines [92, 93].

11.1. Stepwise Approach

Step 1 consists of monotherapy with a second-generation H1 receptor blocking antihistamine [10, 59]. Second-generation H1 receptor blocking antihistamines selectively antagonize the peripheral H1 receptors and are less sedating and less anticholinergic [80]. They are preferred over the first-generation antihistamines which have adverse effects of sedation and anticholinergic effects [10]. Second-generation H1 antihistamines are the drugs of choice for initial therapy because of their safety and efficacy profile [94-96]. Examples of second-generation H1 antihistamines are loratadine (Claritin, Claratyne), desloratadine (Aerius, Clarinex, Dasselta, Deslordis) cetirizine (Zyrtec), levocetirizine (Xyzal), azelastine (Allergodil, Astelin, Optivar), bilastine (Bilaxten), and fexofenadine (Allegra) [94-96].

The EAACI/GA²LEN/EDF/WAO guidelines strongly support the use of second-generation H1-antihistamines for CU [89]. In children, several studies regarding the safety and efficacy of cetirizine, levocetirizine, loratadine, fexofenadine, desloratadine, and rupatadine have been performed [90]. The regular dosage of second-generation H1-antihistamines could be increased up to 2-4 times if symptoms are not resolved or improved within the first 2-4 weeks of treatment; if there is still no improvement, another H1-antihistamine could be tried [97, 98]. A few studies performed in children with CU have shown that around 35-38% of these patients required double doses of second-generation H1-antihistamines, while only 6% and 5% needed triple or quadruple dosage, respectively. Interestingly, younger children seemed to respond better to regular doses, while older children required higher doses to achieve resolution of their symptoms [97, 99]. Some authors recommended adding an H2-antihistamine (cimetidine, ranitidine) for patients who still have not been able to achieve complete remission of their symptoms [100].

Step 2. For those patients whose symptoms are not adequately controlled within one to two weeks, step 2 may have to be initiated. Step 2 consists of one or more of the following treatment options: Increasing the dose of the current second-generation H1 antihistamine (up to four times the manufacturer’s recommended dose), adding another second-generation H1 antihistamine, adding an H2 receptor blocking antihistamine such as ranitidine (Zantac) or famotidine (Pepcid), adding a leukotriene receptor antagonist such as montelukast (Singulair) or zafirlukast (Accolate), and/or adding a first-generation H1 antihistamines such as doxepin (Sinequan), hydroxyzine (Atarax, Vistaril), chlorpheniramine (Piriton, Chlor-Trimeton), or diphenhydramine (Benadryl, Unisom, Sominex) [59, 80]. Montelukast and zafirlukast block leukotriene receptors and can be used in isolation or as an add on treatment for patients with CU. These medications may be more efficacious for patients with NSAID-induced CU [7, 101, 102].

LTRAs have been used successfully in children with asthma or other allergic diseases but not pediatric CU. A recent systematic review on adult patients showed most trials indicating that leukotriene antagonists are not superior to placebo or antihistamine therapy, while combination therapy of leukotriene antagonist and antihistamines appeared to be more efficacious compared to antihistamine alone. The side effect profile and tolerability of leukotriene antagonist are acceptable. The use of leukotriene antagonist as a monotherapy cannot be recommended [103].

Step 3. For patients whose symptoms are not adequately controlled in spite of the measures taken in step 2, step 3 may need to be followed. Step 3 consists of increasing the dose of potent first-generation H1 antihistamines such as doxepin and hydroxyzine and titrating the dose as tolerated.

First-generation H1 antihistamines block both central and peripheral H1 receptors. They have similar efficacy as second-generation H1 antihistamines but adverse effects associated with their use such as drowsiness, sedation, daytime somnolence, and impaired concentration which make them less favorable [11]. Any medications used in step 2 that did not seem to work should be discontinued.

These are no longer recommended in children due to undesired side effects of sedation, impairment of alertness and cognition [104]. However, some authors have reported the efficacy and safety of ketotifen (a non-competitive H1-antih- istamine and mast-cell stabilizer) in patients with CU [105].

Step 4. For patients whose symptoms are not adequately controlled in spite of the measures taken in step 3 (refractory CU), step 4 may need to be followed. Medications used in step 4 include anti-inflammatory medications such as dapsone (Aczone), hydroxychloroquine (Plaquenil), or sulfasalazine (Salazopyrin, Sulazine, Azulfidine), leukotriene receptor antagonists such as montelukast or zafirlukast, systemic glucocorticoids, immunosuppressants such as cyclosporine (Neoral, Sandimmune), tacrolimus (Prograf, Advagraf), mycophenolate (cellCept, Myfortic), or sirolimus (Rapamune) and a biologic agent such as omalizumab (Xolair) [7, 95, 106] (Table 1).

A meta-analysis of randomized clinical trials in 2016 provides high-quality evidence for the efficacy and safety of omalizumab in patients with CSU and for treating these patients with 300mg of omalizumab every 4 weeks [107]. Overall, omalizumab seems to be safe with few side effects reported (mainly mild skin reactions at the injection site and, in rare cases, anaphylaxis), but its high cost has limited its use [90, 91, 108, 109].

The 2018 version of the evidence- and consensus-based guideline developed by the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO), with the participation of 48 delegates of 42 national and international societies, recommends second-generation H1 antihistamines to be the drug of choice for the management of CU and are preferred over first-generation H1 antihistamines [10].

If sufficient improvement does not occur after 2 to 4 weeks or earlier if the symptoms are intolerable, the dose of second-generation H1 antihistamines can be increased up to fourfold the manufacturer’s recommended dose [10]. If sufficient improvement does not occur after 2 to 4 weeks or earlier if the symptoms are intolerable after the fourfold increase in the dosage of second-generation H1 antihistamines, omalizumab should be added [10]. If sufficient improvement does not occur after 6 months or earlier if the symptoms are intolerable after omalizumab has been added, treatment with cyclosporine and second-generation H1 antihistamines are recommended. Short-term (maximum, 10 days) use of systemic corticosteroids may be considered for acute exacerbation of CU and in refractory cases [58] but the long-term use of systemic corticosteroids is not justified.

Omalizumab is a recombinant DNA-derived humanized monoclonal antibody that binds to the constant region of the IgE molecule, avoiding the interaction between free IgE with high and low-affinity IgE receptors [92, 93]. This leads to a downregulation of high-affinity IgE receptor expression on inflammatory cells [110]. Lately, the interest in omalizumab as a second-line therapy for patients with CU has increased significantly following several studies demonstrating its effectiveness and safety in both adults and children [87]. In children, omalizumab is currently approved for moderate-to-severe uncontrolled allergic asthma and CSU (≥12 years) [91-93]. At least 5 doses are necessary to prevent recurrence and obtain complete remission of CU [87]. In phase 3, multicenter, randomized, double-blind study with omalizumab for the treatment of chronic idiopathic or spontaneous urticaria, omalizumab diminished clinical symptoms and signs of chronic idiopathic urticaria in patients who had remained symptomatic despite the use of approved doses of H-antihistamines [70, 111].

Calcineurin inhibitors, such as cyclosporine and tacrolimus are preferred by some authors to treat severe symptoms [112-113]. Cyclosporine has also been used as an adjuvant therapy in the treatment of difficult to control CU [70]. In children, few studies have shown its effectiveness [114]. Doshi and colleagues reported seven patients treated with cyclosporine [115]. All the patients reached cessation of the symptoms within the first 8 weeks of treatment, with no evidence of side effects [115]. Uncommon side effects such as hypertension, nephrotoxicity, headache, nausea, abdominal pain and infections have been reported. A close monitoring of blood pressure, renal function, and cyclosporine levels is recommended [116].

Oral corticosteroids are highly effective in controlling symptoms of CU. However, they have an extensive list of adverse effects [117]. Because of the potential adverse effects, oral corticosteroids should only be used short-term for refractory cases and the lowest effective dose should be used [80]. When a high dose of corticosteroids needs to be given for a prolonged period of time, other immunosuppressants should be considered. Current guidelines advocate that the use of corticosteroids in CU is restricted only for exacerbations and for short periods of time (3-7 days) due to their side effects [89, 90, 104, 118, 119].

There is less evidence to justify the use of sirolimus, mycophenolate mofetil and dapsone; while hydroxychloroquine or sulphasalazine is rarely used [120, 121].

Treatment of the rare auto-inflammatory urticarial syndromes is challenging. Several reports have demonstrated the efficacy of anakinra for urticaria associated with these diseases [122, 123].

Once CU is controlled, a “step-down” in treatment is recommended. When CU can be controlled with second-generation H1 antihistamines alone, it is recommended that the medication be withdrawn periodically in order to identify spontaneous remission of the disease [28]. CU should be treated until spontaneous remission occurs.

CONCLUSION

CU is a clinical diagnosis, based on the episodic appearance of characteristic urticarial lesions, with or without angioedema, on most days of the week, or for a period of six weeks or longer. No specific cause could be identified in the majority of cases. CU is a sporadic and self-limited disorder. Approximately two-thirds of CU patients resolve within 5 years. However, some may persist for many years, impairing patients' quality of life. Its treatment is primarily symptomatic and involves mainly the use of second-generation H1 antihistamines at diagnosis. If satisfactory improvement does not occur, other treatment options should be considered. Recent patents including newer antihistamine and immunomodulating medications have been reviewed. The efficacy of these medications needs to be subjected to rigorous randomized trials. Omalizumab has been a remarkable advancement in the management of CU which improves the QoL beyond symptom control.

CURRENT & FUTURE DEVELOPMENTS

CU is idiopathic in the majority of cases, and some resolve spontaneously. Treatment is primarily symptomatic. Second-generation non-impairing non-sedating H1-antihistamines are recommended as first-line medications for initial treatment. New effective and safe therapeutic options have emerged for the treatment of patients with CU refractory to the standard dosage of a second-generation non-impairing non-sedating H1-antihistamine. Up-dosing with a second-generation non-impairing non-sedating H1-antihistamine higher than the licensed dosage may be recommended as the second-line treatment. Omalizumab often effectively and safely induces remission in H1-antihistamine-resistant CU and is used as a third-line treatment for this indication. Subcutaneous omalizumab injections at monthly intervals are recommended as a novel effective and safe therapeutic option for CU refractory to the above. Research in progress will help to define some specific aspects of these new approaches and further establish their significance in the treatment algorithm.

There have been no recent patents on newer antihistamines beyond the first and second generation antihistamines [70]. Most of the patents are for Dexpramipexole and its enantiomer, pramipexole which are cell depleters. Dexpramipexole has already been in phase II trials. Toxicity and adverse effect profile of CU is not yet available. The targeted eosinophil-lowering effects of dexpramipexole in clinical studies for amyotrophic lateral sclerosis are significant [124]. All doses tested were well tolerated. The overall adverse event rate was similar for dexpramipexole and placebo, and notably with no increase in infection-related adverse events.

Patents for the use of anti-IL-1beta compound Il-3 inhibitors and an NLRP3 inhibitor are discussed. Both the anti-IL-1beta compounds and the NLRP3 are likely to have a role in auto-inflammatory syndromes rather than CU [42, 65, 125-127].

Pertinent European and US patents are described in the following paragraphs.

European Patents

Gram and colleagues disclosed an invention related to the novel use of IL-1β-ligand/IL-1 receptor disrupting compounds (herein referred to as “IL-1beta Compounds”); such as small molecular compounds disrupting IL-1β ligand - IL-1 receptor interaction, IL-1β antibodies or IL-1 receptor antibodies, e.g. IL-1β binding molecules described herein, antibodies disclosed herein, IL-1β binding compounds or IL-1 receptor binding compounds, and/or RNA compounds decreasing either IL-1β ligands or IL-1 receptor protein levels, in the treatment and/or prevention of auto-inflammatory syndromes, and the use of methods of treating and/or preventing auto-inflammatory syndromes in mammals, particularly humans [EP2468302 (2012)] [128].

United States Patents

There have only been few patents contributed for chronic urticarial in recent years.

Vairo et al. disclosed a method for the treatment of a chronic inflammatory condition in a patient which comprises administering an agent to the patient of which blocks or inhibits IL-3 signalling events in the patient [US20150017180] [129]. There is no information as to whether further clinical trials are underway. The treatment modality is for a chronic inflammatory condition and not specific for CU.

Bozik et al. disclosed methods of treating CU and related conditions in a subject by administering a therapeutically effective amount of dexpramipexole or a pharmaceutically acceptable salt in the subject to treat the condition [US20160193186 (2016)] [130]. In some cases, the levels of mast cells, basophils, eosinophils, or a combination thereof reduced following administration of a therapeutically effective amount of dexpramipexole or a pharmaceutically acceptable salt thereof. Some patients were directed to treatment for a condition characterized by elevated levels of mast cells, basophils, eosinophils, or a combination thereof, comprising administering of a therapeutically effective amount of dexpramipexole or a pharmaceutically acceptable salt thereof, wherein the levels of mast cells, basophils, eosinophils, or a combination thereof reduced. In some cases, the condition was characterized by elevated levels of mast cells, basophils, eosinophils, or a combination thereof in the bone marrow, peripheral blood, tissue, or a combination thereof. In some cases, patients were directed to treatment of a condition characterized by the increased levels of activation of mast cells, basophils, eosinophils, or a combination thereof, comprising the administration of a therapeutically effective amount of dexpramipexole or a pharmaceutically acceptable salt, wherein the levels of activation of mast cells, basophils, eosinophils reduced. In some patients, the condition was characterized by elevated levels of mast cells, basophils, eosinophils, or a combination thereof in the bone marrow, peripheral blood, tissue, or a combination thereof.

In 2018, Bozik et al. further disclosed methods of treating conditions, which may be associated with elevated levels of mast cells, basophils, eosinophils, or a combination thereof, with a therapeutically effective amount of dexpramipexole or pharmaceutical acceptable salt thereof. [US20180015073 (2018)] [131].

Alpan et al. disclosed methods for treating or relieving at least one symptom of urticarial disorders including chronic idiopathic urticaria, angioedema, and anaphylaxis, or a combination of these disorders in a mammal, including humans. The method comprises administering the mammal with a therapeutically effective amount of pramipexole, dexpramipexole or pharmaceutically acceptable salts thereof [US20160271112 (2016)] [132].

Chen et al. described methods and compositions for inhibiting the expression of an apoptosis-related speck-like protein containing a caspase recruitment domain (ASC), the expression of NLRP3, and/or the formation of the NLRP3 inflammasome complex by using diacerein or its analogs. Also provided are methods and compositions for the treatment and/or prevention of a disorder mediated by ASC and/or NLRP3, and/or by the formation of the NLRP3 inflammasome complex by using diacerein or its analogs [US20170049733 (2017)] [133].

WIPO Patents

Alpan et al. disclosed methods for treating or relieving at least one symptom of urticarial disorders including chronic idiopathic urticaria, angioedema, and anaphylaxis, or a combination of these disorders in a mammal, including humans. The method comprises administering to the mammal a therapeutically effective amount of pramipexole, dexpramipexole or pharmaceutically acceptable salts thereof [WIPO WO2015061777] [134]. This patent is not specific to urticaria.

Patents for Test Kits

Harbeck et al. disclosed a rapid, non-invasive and highly specific and sensitive diagnostic assay for the identification of individuals with autoimmune chronic urticaria, which makes use of CD203c, and additional proteins, as markers for the disease. Test kits for the diagnosis of an individual suspected of having autoimmune chronic urticaria were also disclosed. Also disclosed are a method of identifying compounds useful for treating autoimmune chronic urticaria and a method of treating autoimmune chronic urticaria [USP20130183248 (2013)] [135]. This is a patent of the diagnostic assay and not a treatment.

Table 1. Treatments for Chronic Urticaria [89, 97, 98].

Step 1	➢ Establish a diagnosis. Reassurance, patient education, avoidance of known triggers	[10, 89, 97, 98]
	➢ Second-generation H1 antihistamines
Step 2	➢ Optimize dosages of second-generation H1 antihistamines ➢ Adding another second-generation H1 antihistamine, or a leukotriene receptor antagonist such as montelukast	[10, 11, 89, 97, 98]
Step 3	➢ Increase the dose of potent first-generation H1 antihistamines such as or doxepin and hydroxyzine and titrating the dose as tolerated ➢ Any medications that did not seem to work should be discontinued	[10, 11, 89, 97]
Step 4	➢ Omalizumab, cyclosporin, corticosteroid, etc.	[10, 28, 89, 97, 98]
	➢ Once CU is controlled, “step-down” in treatment is recommended ➢ Second-generation H1 antihistamines may be withdrawn periodically to identify spontaneous remission of the disease ➢ CU should be treated until spontaneous remission occurs

Current and future potential treatments for chronic urticaria.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

HUMAN AND ANIMAL RIGHTS

No Animals/Humans were used for studies that are the basis of this research.

CONSENT FOR PUBLICATION

Not applicable.

AVAILABILITY OF DATA AND MATERIALS

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

Professor Hon, and Professor Leung, disclose no relevant financial relationship. Prof. Kam L. Hon, Prof. Alexander K.C. Leung, Ms Ng and Dr. Loo confirm that this article has no conflict of interest.