Biologicals in Treatment of Chronic Urticaria: A Narrative Review : Indian Dermatology Online Journal

Secondary Logo

Journal Logo

Review Article

Biologicals in Treatment of Chronic Urticaria: A Narrative Review

Mustari, Akash P.; Bishnoi, Anuradha; Kumaran, Muthu Sendhil

Author Information
Indian Dermatology Online Journal 14(1):p 9-20, Jan–Feb 2023. | DOI: 10.4103/idoj.idoj_145_22
  • Open

Abstract

Introduction

Urticaria is a common skin disease affecting up to 20% of world’s population during lifetime, presents as itchy transient wheals lasting for minutes to hours.[1] In contrast, angioedema presents as painful swelling of lips, eyelids, tongue, pharynx, larynx, hands, feet, and genitals due to edema in dermis, submucosa, and subcutis lasting for 2–3 days. Acute urticaria is defined as urticaria episodes lasting for less than 6 weeks, episodic urticaria as urticaria episodes lasting for more than 6 weeks, but less than 2 episodes/week, and chronic urticaria as occurrence of at least 2 episodes of urticaria per week and lasting more than 6 weeks.[2] Chronic urticaria is further divided into chronic spontaneous urticaria (without specific stimulus, CSU) and chronic inducible urticaria (with specific stimulus, CIU). It significantly affects the quality of life, leading to sleep disturbances, decreased work efficiency, and social withdrawal. The 1-year, 3-year, and 5-year remission rates in CSU are 21%, 38%, and 45%, respectively.[34]

Pathogenesis

The key step in urticaria is complex immunological display after mast cell–basophil degranulation which can occur immunologically or nonimmunologically. Immunological activation can occur by type-I or type-IIa autoimmunity. Type-I autoimmunity is auto-allergen triggered, immunoglobulin E (IgE)-mediated mast cell degranulation involving cross-linking of IgE on mast cells and basophils. Type-IIa autoimmunity involves binding of IgG or IgM autoantibodies against IgE or FceRI receptor on mast cell leading to degranulation.[5] Apart from FceRI receptor, mast cell has many other surface receptors including C3a, C5a, toll-like receptor, cytokine, and chemokine receptors, and further activation of these receptors by their ligands can also lead to mast cell degranulation. In nonimmunological activation, drugs like codeine, food molecule, and neuropeptides such as substance P cause direct toxicity on the mast cells leading to degranulation.[4] Mast cell degranulation by above two mechanisms lead to cascade of immunological milieu starting with release of histamine which acts on H1 receptor on blood vessels leading to vasodilation and increases vascular permeability resulting in wheals and itching. Apart from histamine, mast cells also releases interleukin 5 (IL-5) and TNF-a, which also have a role to play in urticaria pathogenesis.[6]

Management

The first line of treatment for chronic urticaria is second-generation nonsedating antihistamines (AHs). The European Academy of Allergy and Clinical Immunology (EAACI/2021) recommends to increase the dose of AHs up to 4 times if there is unsatisfactory response after 2–4 weeks of standard doses of second-generation AHs. If there is no further improvement after 2–4 weeks of increasing the dose, omalizumab (up to 600 mg q2w) or ciclosporin (up to 5 mg/kg/day) can be added.[7]

Biologicals are large complex glycoproteins derived from living organisms such as microorganisms, humans, plants, or animals. Monoclonal antibodies (mAbs) are biologicals that target the specific antigen or epitope. The use of biologicals has revolutionized the management of chronic resistant urticaria (CRU) and are often preferred in CSU resistant to other treatment options. Omalizumab and ligelizumab are commonly used biologicals in urticaria because of their better efficacy and safety profile.

Biologicals in the Treatment of Chronic Urticaria

Anti-IgE therapy

Omalizumab

Omalizumab is a recombinant humanized IgG mAb that binds to C epsilon 3 (Ce3) domain of IgE.[89] It is the first US Food and Drug Administration (FDA)-approved biological in treatment of CSU. Autoantibodies in CSU patients bind to alpha-chain of high-affinity receptor FceRI or to IgE leading to mast cell degranulation.[1011] Omalizumab binds to free IgE, leading to decrease in free IgE and block the binding of IgE to FceRI receptors on mast cells, dendritic cells, and basophils.[1213] It also reduces mast cell degranulation by increasing the threshold of degranulation, reverses the basopenia, and improves basophil IgE receptor function.[14-16] It reduces IgG autoantibody activity against FceRI and IgE and reduces IgE autoantibody activity against auto-allergen. The mechanism of omalizumab is summarized in Figure 1.

F1
Figure 1:
Mechanism of omalizumab in urticaria. FcεRI, high-affinity IgE receptor; IgE, immunoglobulin E; IgG, immunoglobulin G

Efficacy

Phase II–IV clinical trials have demonstrated the efficacy of omalizumab among CSU patients who failed to respond to AHs. The complete response rate ranged from 34% to 70%.[17-21] The initial report on omalizumab efficacy in CSU came as early as in 2002.[22] The first prospective trial included 12 patients with chronic autoimmune urticaria resistant to AHs for at least 6 weeks. At week 16, there was a significant reduction in urticaria activity score (UAS) (7.5 ± 1.8 to 2.7 ± 3.3, −4.8 ± 2.9, P = 0.0002) and seven (58.3%) patients achieved complete remission.[23] The efficacy was confirmed in subsequent studies.[24-26] A meta-analysis of 67 studies on omalizumab with AHs has shown complete and partial response rates of 72.2% and 17.8%, respectively.[27] The summary of the important RCTs on omalizumab in CSU is given in Table 1. The relapse rates are high, seen in up to 61% of the patients.[28] Most of the adverse effects are benign which include upper respiratory tract infection, headache, injection-site inflammation, and rarely anaphylaxis.[29] Based on three good-quality RCTs on 733 patients, FDA has approved omalizumab at doses of 150 mg or 300 mg every 4 weeks.[181930] A systematic review has shown promising results of omalizumab in cold urticaria, symptomatic dermographism, and solar urticaria.[18] In an open-label study by Chen et al.[31] in 23 normocomplementemic urticarial vasculitis patients, 17.3% and 56.5% had a complete and partial response, respectively. Apart from the CSU, inducible urticaria, and urticarial vasculitis, omalizumab is also effective in angioedema.[3233]

T1
Table 1:
Summary of the major RCTs on omalizumab

Types of Responders

The onset of response to omalizumab in CSU patients varies, based on the onset of response, patients are divided into early responders (<1 week), late responders (>12 weeks), and nonresponders.[34] Patients with negative autoimmune serum skin test (ASST), normal-to-high IgE, and high expression of FceRI respond early (<1 week) and patients with positive ASST, positive basophil histamine release assay, low IgE, and lower expression of FceRI respond late (>12 weeks).

Dose and Frequency in Nonresponders

Factors predicting the response to omalizumab are summarized in Table 2. Patients with low IgE, positive ASST, basopenia, eosinopenia, low expression of FceRI on basophils, IgG autoantibodies against FceRI, and positive basophil activation test are associated with poor prognosis. Around 30% of patients fail to respond to standard regimen requiring a higher dose or increasing the frequency of administration. The dose can be increased from 450[35-37] to 600[3839] mg every 4 weeks or the frequency can be increased to 300 mg to 600[40] mg every 2 weeks. Curto-Barredo et al.[39] used 300-mg omalizumab every 4 weeks; if insufficient response after five doses, updosing was done to either 450 mg or 600 mg q4w. If insufficient response after three doses of 600 mg, frequency was increased to every 2 weeks for two consecutive doses. A total of 286 patients on 300 mg were included, 27.6% required updosing (UAS >7). Among these, 65% had successful updosing (55% in 450 mg q4w and 25% in 600 mg q4w) and 25% had no improvement even at higher doses. Predictors of the poor responses were obesity, age >57, past treatment with cyclosporine. Changing from 300 mg q4w to 150 mg q2w is also effective.[28] If no improvement is seen even after 6 months of omalizumab, it can be stopped.

T2
Table 2:
Prognostic markers for response to omalizumab in urticaria

Duration of Treatment and Tapering

There is no standard duration of therapy or standard method of weaning recommended by EAACI, it can be done as soon as remission is achieved. Possible methods are decreasing the frequency of administration or reducing the doses. Injection interval can be increased by 1 week (q5w) to 4 weeks (q8w) if urticaria is controlled. It can be stopped if it is controlled by q8w for 8 weeks and tapering [Figure 2].[5051] After post-withdrawal relapse, retreatment with omalizumab can be done and is not associated with reduced efficacy but requires more number of doses (4–6) in some patients. During entire course of omalizumab, AHs will be continued.

F2
Figure 2:
Tapering of omalizumab. *Treatment options include cyclosporine, methotrexate, and cyclophosphamide. A short course (less than 1 week) of oral steroids can be considered for severe exacerbation

Omalizumab in Children

There is paucity of controlled studies among children, but it is safe and effective.[52] Omalizumab dose in children ranges from 150 mg q4w to 300 mg q2w. RCTs are needed in children and adolescents.

Omalizumab in Pregnancy

Omalizumab crosses the placenta, but only a small amount (0.001–0.0001%) of omalizumab in the maternal serum is secreted into breast milk.[53] But no significant adverse effects are noted and FDA has categorized it as pregnancy category B. European Medicines Agency (EMA) has stated that omalizumab might be considered for use in pregnancy.[54]

Omalizumab and Risk of Malignancy

Allergies and serum IgE are associated with a reduced risk of malignancy.[55] Long-term omalizumab and other anti-IgE treatment may disrupt this protective antitumor mechanism and increase the risk of malignancy. But systematic review and meta-analysis found no increased risk of cancer on long-term use.[56]

Omalizumab in Elderly

Not much data is available in the elderly >65 years, the dose is similar to young adults.[57]

Ligelizumab

It is recombinant humanized anti-IgE mAb which has similar mechanism of action to omalizumab and has 40–50 times higher affinity to IgE receptor than the omalizumab. The complete response rate range from 30% to 50%.[5859] Maurer et al.[58] in a phase IIb RCT on 382 patients demonstrated ligelizumab to have rapid onset of action, better efficacy, and longer relapse time after discontinuation than omalizumab with similar safety profile. The complete control of symptoms in ligelizumab 24 mg, 72 mg, and 240 mg group were 30%, 44%, and 40%, respectively, as compared to 26% in omalizumab. Recently, FDA has approved ligelizumab in the management of CSU who have an inadequate response to H1 AHs, but ligelizumab in angioedema has shown inconsistent results.[58] Currently, phase III studies are under trial in patients with CSU, once cleared can be a boon for CRU.

Quilizumab

It is an afucosylated humanized IgG mAb against M1-prime segment of membrane-bound IgE on B cells. In contrast to omalizumab, it only binds to bound IgE but not free IgE. Harris et al.[60] in RCT has found no improvement in weekly severity itch score or UAS at the end of 20 weeks, but there was a decrease in serum IgE level by 30%. There is no evidence of quilizumab role in angioedema.

UB-221

It is a humanized IgG mAb with similar mechanism of action to omalizumab, has eightfold higher affinity to FceRI than omalizumab, and also binds to CD23-bound IgE. In preclinical studies, UB-221 was better than omalizumab and phase-I trials are currently under investigation.

Anti-interleukin 5

IL-5 is involved in the eosinophil development, migration, and activation.[61] Eosinophils numbers are increased in urticarial lesions which cause activation of coagulation cascade and subsequently cause mast cell degranulation.[62] Mepolizumab and reslizumab are IL-5 inhibitors, and benralizumab inhibits IL-5 receptor (IL-5Ra) present on eosinophils. In a single-blinded, repeated-measures study, Bernstein et al. treated 12 resistant CSU with benralizumab, 5 patients had complete remission (UAS = 0).[6364] Mepolizumab and reslizumab also have been found to be effective in case reports.[6566]

TNF-α Inhibitors

TNF-a is one of the important preformed mediators of urticaria present in the mast cells. Interestingly TNF-a is upregulated in both lesional and nonlesional skin. Anti-TNF-a agents bind to soluble and transmembrane TNF-a and inhibit its activity. Sand et al.[67] reported that treatment with adalimumab (n = 14) and etanercept (n = 4) in 18 patients with CSU had led to complete remission in 12 and partial remission in 3 patients. Another case series by Bangsgaard et al.[68] of nine patients with CSU treatment with adalimumab had led to complete remission in three and partial remission in four. Currently, TNF-a can be considered in CSU resistant to anti-IgE therapy.[68]

Anti-CD20

Rituximab is a mAb against CD20 which depletes memory B cells by antibody-dependent and complement-dependent cellular cytotoxicity, apoptosis, and antibody-dependent phagocytosis, which subsequently cause a reduction in the autoantibodies. The dose of rituximab is 375 mg/m2 or 1 gm 2 weeks apart. Rituximab has been tried in five case reports in the literature, four patients had complete remission, and one patient did not respond.[69-73] Because of the risk of serious adverse effects, currently rituximab can be considered only in severe CSU resistant to other treatment options.

Anti-IL-1

IL-1 is implicated in the development of urticaria in Schnitzler syndrome, Muckle–Wells syndrome, and other autoinflammatory syndromes. Canakinumab is an IL-1b inhibitor, in an open-label study by Krause et al.[74] in 10 patients with urticarial vasculitis, 70% of the patients had >50% improvement. A double-blinded RCT by Maul et al.[75] in 20 patients showed no significant difference as compared to placebo. Anakinra is an IL-1 receptor antagonist and is effective in cold urticaria and refractory delayed pressure urticaria in individual patients.[7677] Rilonacept is a recombinant IL-1 antagonist which binds to IL-1b and blocks binding of IL-1 with its receptor. A phase-II placebo-controlled study is undergoing on cold contact urticaria (NCT02171416).

Bruton Tyrosine Kinase Inhibitors

Bruton tyrosine kinase (BTK) is an important protein of the downstream signaling pathway of FceRI and B-cell receptor. Fenebrutinib binds to BTK noncovalently and inhibits BTK leading to inhibition of the FceRI signaling pathway. In a phase-II RCT in 93 patients, fenebrutinib at a dose of 150 mg and 200 mg showed a significant reduction in UAS7 and no significant difference in adverse events as compared to placebo.[78] In contrast to fenebrutinib, remibrutinib binds to BTK covalently; hence, it has faster onset of action and long-lasting inhibition.[79] There is an ongoing phase-II trial on remibrutinib (NCT03926611, NCT04109313) in resistant CSU.

Dupilumab

CSU is a Th2 (T-helper 2 cells)-mediated disease with elevated IL-4 and IL-13. Dupilumab is a human mAb that binds to the alpha subunit of IL-4 receptor (IL-4Ra) and blocks IL-4 and IL-13 action. Dupilumab has shown significant improvement in six patients with omalizumab-resistant CSU.[80] There are ongoing phase-II and phase-III clinical trials (NCT03749148, NCT03749135) assessing the safety and efficacy of dupilumab in resistant CSU.

Anti-IL-17

There is a dense infiltration of IL-17 expressing CD4+ T cells and increased expression of IL-17A on mast cells in CSU patients. Secukinumab blocks IL-17 produced by mast cells. In a case series by Sabag et al.[81] on eight severe AHs and omalizumab-resistant CSU, secukinumab 150 mg q4w led to 55% and 82% reduction in UAS7 after 1 month and 3 months of therapy and significant improvement in angioedema in all patients.

Other Newer Biologics

Anti-siglec-8 therapy

Siglec-8 is a cell surface receptor present on the eosinophils and mast cells which is involved in the apoptosis of eosinophils and inhibition of FceRI-mediated histamine release. Antolimab and lirentelimab are monoclonal anti-siglec-8 antibodies that deplete eosinophils and can be utilized as therapeutic options in CSU. In phase-IIa open-label study by Altrichter et al.,[82] lirentelimab has been found to be effective in both omalizumab naive and resistant spontaneous and inducible urticaria. The dose of lirentelimab was 0.3 mg/kg and gradually increased to 3 mg/kg every month if tolerated. The complete remission in omalizumab-naive, omalizumab-resistant, chronic inducible urticaria and symptomatic dermographism was 92%, 36%, 82%, and 40%, respectively. The common side effects included infusion reactions, nasopharyngitis, and headache. There is an ongoing phase-IIa clinical trial (NCT03436797) assessing the safety and efficacy of antolimab in resistant CSU.

Anti-IL-31

IL-31 is one of the mediators of Th2 response elevated in CSU. IL-31 is expressed on mast cells, eosinophils, macrophages, and basophils. It is one of the key mediators of itch in urticaria, atopic dermatitis, psoriasis, and prurigo nodularis. The levels of IL-31 are significantly elevated in CSU patients as compared to psoriasis and healthy individuals. Nemolizumab can be another treatment alternative for CSU.[83]

Anti-oncostatin M receptor

Oncostatin M receptor (OSMR) is upregulated in chronic autoimmune urticaria and inhibition of OSMR leads to a decrease in inflammatory factors (IgE, IL-1, IL-6, and IFN-g) and eosinophils. Vixarelimab is a mAb against oncostatin M receptor beta (OSMRb) which mediates the IL-31-signaling pathway and might be a treatment option in CSU.[84] Currently, there is an ongoing phase-II trial on vixarelimab (NCT03858634) in chronic urticaria including CSU.

Anti-C5a

Complement 5a (C5a) is a complement agonist that enhances IgG-mediated mast cell degranulation and basophil-mediated inflammation. Eculizumab is a mAb against C5a and has been used in the treatment of paroxysmal nocturnal hemoglobinuria and asthma. Avdoralimab is mAb against C5a receptor, currently under investigation in the treatment of bullous pemphigoid. Avacopan is a small-molecule against C5a used in antineutrophilic cytoplasmic antibody associated vasculitis. Anti-C5a therapy can be future treatment option in CSU.[85]

Anti-KIT antibodies

Mast cells are the key cells involved in the pathogenesis of urticaria. KIT is a cell surface receptor present on mast cells. Stem cell factor is a ligand for this receptor, a potent activator of mast cells. Treatment with anti-KIT antibody CDX-0159, a mast cell depletor leads to significant reduction in the mast cells and tryptase without any major side effects.[86] In an open-label study by Molawi et al.[87] in chronic inducible urticaria, single dose of intravenous CDX-0159 led to significant improvement in UAS and response was maintained at the end of 12 weeks.

Spleen tyrosine kinase inhibitors

Spleen tyrosine kinase (SYK) is a protein-tyrosine kinase involved in allergen-mediated mast cell degranulation through IgE-signaling pathway. In an phase-Ia/Ib randomized double-blind placebo-controlled study by Disckson et al.,[88] treatment with GSK2646264 (topical inhibitor of SYK) has led to significant reduction in critical temperature threshold of cold urticaria as compared to placebo. Due to the small number of patients with CSU, no conclusion was drawn on the same. There were no serious adverse effects or dose-limiting toxicity noted.

CRTh2 inhibitors

CRTh2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) is a surface receptor present on eosinophils and basophils and is involved in eosinophil chemotaxis and degranulation. AZD1981 is an oral reversible antagonist of CRTh2 which inhibits prostaglandin D2 (PGD2)-mediated eosinophil shape alteration, chemotaxis, and degranulation. In a randomized, placebo-controlled study by Oliver et al.[89] on 28 patients of AH-resistant CSU, treatment with AZD1981 led to significant reduction in UAS and itch score compared to placebo in resistant CSU. There was also increase in the circulating eosinophils due to altered recruitment of eosinophils into skin. AZD1981 was well tolerated without any major side effects. The improvement of urticaria with CRTh2 inhibitor, AZD1981, supports the role of PGD2/CRTh2 pathway in the pathogenesis of urticaria.

Designed ankyrin repeat protein

DARPins (designed ankyrin repeat protein) are antibodies that have high specific and high-affinity binding property. IgE-specific DARPins bind to IgE and cause unbinding of IgE from its receptor, which inhibits mast cell degranulation. DARPins can be potential therapeutic options in the management of FceRI-induced allergic reactions. The major limitations of DARPins are immunogenicity and increased risk of parasitic infections.[90]

Anti-IL-6

IL-6 is elevated in CSU making IL-6 receptor antagonist tocilizumab, a potential alternative for CSU. In a case report by Makol et al.[91] treatment with tocilizumab led to significant improvement in lupus-associated urticarial vasculitis which was resistant to methotrexate, anakinra, etanercept, and intravenous immunoglobulin therapy. Apart from urticarial vasculitis, there was significant improvement in arthritis, cutaneous lesions, and fever.

MRGPRX2 inhibitors

MRGPRX2 is a cell surface receptor present on mast cells, eosinophils, and basophils and activation of MRGPRX2 leads to mast cell degranulation independent of IgE. MRGPRX2 levels are significantly elevated in CSU. MRGPRX2 inhibitors directly inhibit the receptor and downstream signaling pathway and could be a future target in the treatment of urticaria.[92]

Neurokinin receptor antagonists, aprepitant, and tradipitant are under investigation for pruritus, which can be a potential alternative for CSU.[93] Thymic stromal lymphopoietin (TSLP) is a Th2 response promoter which is elevated in CSU; TSLP inhibitor tezepelumab could be future treatment option in CSU.[86] Natalizumab is a cell adhesion inhibitor that inhibits a4-integrin and endothelial activation and can be future therapeutic option. Vedolizumab is mAb against a4b7 integrin which inhibits release of proinflammatory meditators from blood monocytes and also inhibits endothelial activation.[94] Although most have been utilized in urticaria management, still larger studies are required to assess the efficacy and safety profile. The emerging biologicals for urticaria are summarized in Tables 3 and 4 and Figure 3.

T3
Table 3:
Summary of the biologicals for urticaria
T4
Table 4:
Future targets for chronic spontaneous urticaria
F3
Figure 3:
Biological targets in urticaria. BTK, Bruton tyrosine kinase; TNF-α, tumor necrosis factor-alpha; C5a, complement 5a; NK1R, neurokinin-1 receptor; SYK, spleen tyrosine kinase; EP, eosinophil peroxide; EBP, eosinophil binding protein; FcεRI: high-affinity IgE receptor; TSLP: thymic stromal lymphopoietin; IL-4R, IL-4 receptor; IL-5R, IL-5 receptor; MRGPCRX2, Mas-related G protein-coupled receptor X2

Conclusion

Chronic urticaria is significantly associated with poor quality of life and forms a major cause of economic burden for those who suffer with it for a long time. With the development of biologicals, management of AHs refractory urticaria has been eased with a good success rate in up to 80–90% patients. Omalizumab is the most commonly used biologic which is safe and effective, but less effective in autoimmune urticaria. Ligelizumab is a newer anti-IgE biologic which is more effective and has rapid onset of action as compared to omalizumab. Even with good success rate in resistant CSU with biologicals, treatment of CSU is challenging, because of high rate of recurrence after stopping the therapy. Further studies are required to understand the key mediators involved in the pathogenesis of urticaria, to target these mediators to achieve higher success rate and reduce the recurrence rate. Robust RCTs are required to assess the efficacy of newer biologicals such as anti-IL-5, anti-TNF-a, and anti-IL-1 drugs in the management of urticaria.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1. Gaig P, Olona M, Muñoz D, Caballero MT, Domínguez FJ, Echechipia S, et al. Epidemiology of urticaria in Spain. J Investig Allergol Clin Immunol 2004: 14; 214–20.
2. Sachdeva S, Gupta V, Amin SS, Tahseen M Chronic urticaria. Indian J Dermatol 2011: 56; 622–8.
3. Balp MM, Halliday AC, Severin T, Leonard SA, Partha G, Kalra M, et al. Clinical remission of chronic spontaneous urticaria (CSU): A targeted literature review. Dermatol Ther 2021: 12; 1–13.
4. Nosbaum A, Augey F, Nicolas JF, Bérard F Pathophysiology of urticaria. Ann Dermatol Venereol 2014: 141; 559–64.
5. Kolkhir P, Church MK, Weller K, Metz M, Schmetzer O, Maurer M Autoimmune chronic spontaneous urticaria: What we know and what we do not know. J Allergy Clin Immunol 2017: 139; 1772–81.
6. Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, et al. Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: Evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol 1994: 10; 471–80.
7. Zuberbier T, Abdul Latiff AH, Abuzakouk M, Abuzakouk M, Aquilina S, Asero R, et al. The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy 2022: 77; 734–66.
8. Normansell R, Walker S, Milan SJ, Walters EH, Nair P Omalizumab for asthma in adults and children. Cochrane Database Syst Rev 2014: 1 CD003559. doi: 10.1002/14651858.CD003559.pub4.
9. Easthope S, Jarvis B Omalizumab. Drugs 2001: 61; 253–60.
10. Kaplan AP Therapy of chronic urticaria: A simple, modern approach. Ann Allergy Asthma Immunol 2014: 112; 419–25.
11. Niimi N, Francis DM, Kermani F, O'Donnell BF, Hide M, Kobza-Black A, et al. Dermal mast cell activation by autoantibodies against the high affinity IgE receptor in chronic urticaria. J Invest Dermatol 1996: 106; 1001–6.
12. Holgate ST, Djukanovic R, Casale T, Bousquet J Anti-immunoglobulin E treatment with omalizumab in allergic diseases: An update on anti- inflammatory activity and clinical efficacy. Clin Exp Allergy 2005: 35; 408–16.
13. Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 2015: 135; 337–42.
14. Rorsman H Basophilic leucopenia in different forms of urticaria. Acta Allergol 1962: 17; 168–84.
15. Grattan CE, Dawn G, Gibbs S, Francis DM Blood basophil numbers in chronic ordinary urticaria and healthy controls: Diurnal variation, influence of loratadine and prednisolone and relationship to disease activity. Clin Exp Allergy 2003: 33; 337–41.
16. Grattan CE, Walpole D, Francis DM, Niimi N, Dootson G, Edler S, et al. Flow cytometric analysis of basophil numbers in chronic urticaria: Basopenia is related to serum histamine releasing activity. Clin Exp Allergy 1997: 27; 1417–24.
17. Salman A, Ergun T, Gimenez-Arnau AM Real-life data on the effectiveness and safety of omalizumab in monotherapy or com- bined for chronic spontaneous urticaria: A retrospective cohort study. J Dermatolog Treat 2020: 31; 204–9.
18. Kaplan A, Ledford D, Ashby M, Canvin J, Zazzali JL, Conner E, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol 2013: 132; 101–9.
19. Maurer M, Rosén K, Hsieh H-J, Saini S, Grattan C, Gimenéz-Arnau A, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013: 368; 924–35.
20. Kaplan A, Ferrer M, Bernstein JA, Antonova E, Trzaskoma B, Raimundo K, et al. Timing and duration of omalizumab response in patients with chronic idiopathic/spontaneous urticaria. J Allergy Clin Immunol 2016: 137; 474–81.
21. Viswanathan RK, Moss MH, Mathur SK Retrospective analysis of the efficacy of omalizumab in chronic refractory urticaria. Allergy Asthma Proc 2013: 34; 446–52.
22. Boyce JA Successful treatment of cold-induced urticaria/anaphylaxis with anti-IgE. J Allergy Clin Immunol 2006: 117; 1415–8.
23. Kaplan AP, Joseph K, Maykut RJ, Geba GP, Zeldin RK Treatment of chronic autoimmune urticaria with omalizumab. J Allergy Clin Immunol 2008: 122; 569–73.
24. Saavedra MC, Sur S Down regulation of the high-affinity IgE receptor associated with successful treatment of chronic idiopathic urticaria with omalizumab. Clin Mol Allergy 2011: 9; 2. doi: 10.1186/1476-7961-9-2.
25. Spector SL, Tan RA Effect of omalizumab on patients with chronic urticaria. Ann Allergy Asthma Immunol 2007: 99; 190–3.
26. Vestergaard C, Deleuran M Two cases of severe refractory chronic idiopathic urticaria treated with omalizumab. Acta Derm Venereol 2010: 90; 443–4.
27. Tharp MD, Bernstein JA, Kavati A, Ortiz B, MacDonald K, Denhaerynck K, et al. Benefits and harms of omalizumab treatment in adolescent and adult patients with chronic idiopathic (spontaneous) urticaria: A meta-analysis of “real-world” evidence. JAMA Dermatol 2019: 155; 29–38.
28. Turk M, Kocaturk E, Cure K, Yılmaz İ Two-week intervals during omalizumab treatment may provide better symptom control in selected patients with chronic urticaria. J Allergy Clin Immunol Pract 2018: 6; 1389–90.
29. Zhao ZT, Ji CM, Yu WJ, Meng L, Hawro T, Wei JF, et al. Omalizumab for the treatment of chronic spontaneous urticaria: A meta-analysis of randomized clinical trials. J Allergy Clin Immunol 2016: 137; 1742–50.
30. Saini SS, Bindslev-Jensen C, Maurer M, Grob JJ, Baskan EB, Bradley MS, et al. Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: A randomized, placebo-controlled study. J Invest Dermatol 2015: 135; 67–75.
31. Chen YD, Krause K, Tu P, Zhao ZT, Maurer M Response of omalizumab in normocomplementemic urticarial vasculitis. J Allergy Clin Immunol Pract 2020: 8; 2114–7.
32. Zazzali JL, Kaplan A, Maurer M, Raimundo K, Trzaskoma B, Solari PG, et al. Angioedema in the omalizumab chronic idiopathic/spontaneous urticaria pivotal studies. Ann Allergy Asthma Immunol 2016: 117; 370–7.
33. Liu T, Bai J, Ying S, Li S, Li S, Pan Y, Fang D, et al. Real-world experience on omalizumab treatment for patients with normocomplementemic urticarial vasculitis. J Asthma Allergy 2021: 14; 433–7.
34. Asero R Chronic spontaneous urticaria treated with omalizumab: What differentiates early from late responders?. Eur Ann Allergy Clin Immunol 2021: 53; 47–8.
35. Metz M, Ohanyan T, Church MK, Maurer M Omalizumab is an effective and rapidly acting therapy in difficult-to-treat chronic urticaria: A retrospective clinical analysis. J Dermatol Sci 2014: 73; 57–62.
36. Vadasz Z, Tal Y, Rotem M, Shichter-Confino V, Mahlab-Guri K, Graif Y, et al. Omalizumab for severe chronic spontaneous urticaria: Real-life experiences of 280 patients. J Allergy Clin Immunol Pract 2017: 5; 1743–5.
37. Salman A, Comert E The real-life effectiveness and safety of omalizumab updosing in patients with chronic spontaneous urticaria. J Cutan Med Surg 2019: 23; 496–500.
38. Kocatürk E, Deza G, Kızıltac K, Giménez-Arnau AM Omalizumab updosing for better disease control in chronic spontaneous urticaria patients. Int Arch Allergy Immunol 2018: 177; 360–4.
39. Curto-Barredo L, Spertino J, Figueras-Nart I, Expósito-Serrano V, Guilabert A, Melé-Ninot G, et al. Omalizumab updosing allows disease activity control in patients with refractory chronic spontaneous urticaria. Br J Dermatol 2018: 179; 210–2.
40. Alizadeh Aghdam M, van den Broek F, Rijken F, Knulst AC, Röckmann H High-dose omalizumab use in patients with chronic spontaneous urticaria. J Allergy Clin Immunol Pract 2020: 8; 1426–7.
41. Kolkhir P, Church MK, Altrichter S, Skov PS, Hawro T, Frischbutter S, et al. Eosinopenia, in chronic spontaneous urticaria, is associated with high disease activity, autoimmunity, and poor response to treatment. J Allergy Clin Immunol Pract 2020: 8; 318–25.
42. Straesser MD, Oliver E, Palacios T, Kyin T, Patrie J, Borish L, et al. Serum IgE as an immunological marker to predict response to omalizumab treatment in symptomatic chronic urticaria. J Allergy Clin Immunol Pract 2018: 6; 1386–8.
43. Gericke J, Metz M, Ohanyan T, Weller K, Altrichter S, Skov PS, et al. Serum autoreactivity predicts time to response to omalizumab therapy in chronic spontaneous urticaria. J Allergy Clin Immunol 2017: 139; 1059–61.
44. Schoepke N, Asero R, Ellrich A, Ferrer M, Gimenez-Arnau A, E H Grattan C, et al. Biomarkers and clinical characteristics of autoimmune chronic spontaneous urticaria: Results of the PUR- IST study. Allergy 2019: 74; 2427–36.
45. Deza G, Bertolín-Colilla M, Pujol RM, Curto-Barredo L, Soto D, García M, et al. Basophil Fc3 RI expression in chronic spontaneous urticaria: A potential immunological predictor of response to omalizumab therapy. Acta Derm Venereol 2017: 97; 698–704.
46. Nettis E, Cegolon L, Di Leo E, Lodi Rizzini F, Detoraki A, Canonica GW, et al. Omalizumab in chronic spontaneous urticaria: Efficacy, safety, predictors of treatment outcome, and time to response. Ann Allergy Asthma Immunol 2018: 121; 474–8.
47. Magen E, Chikovani T, Waitman DA, Kahan NR Factors related to omalizumab resistance in chronic spontaneous urticaria. Allergy Asthma Proc 2019: 40; 273–8.
48. Ertas R, Ozyurt K, Atasoy M, Hawro T, Maurer M The clinical response to omalizumab in chronic spontaneous urticaria patients is linked to and predicted by IgE levels and their change. Allergy 2018: 73; 705–12.
49. Bérard F, Ferrier Le Bouedec MC, Bouillet L, Reguiai Z, Barbaud A, Cambazard F, et al. Omalizumab in patients with chronic spontaneous urticaria nonresponsive to H1-antihistamine treatment: Results of the phase IV open-label SUNRISE study. Br J Dermatol 2019: 180; 56–66.
50. Türk M, Carneiro-Leão L, Kolkhir P, Bonnekoh H, Buttgereit T, Maurer M How to treat patients with chronic spontaneous urticaria with omalizumab: Questions and answers. J Allergy Clin Immunol Pract 2020: 8; 113–24.
51. Zhao Z, Cai T, Chen H, Chen L, Chen Y, Gao X, et al. Expert consensus on the use of omalizumab in chronic urticaria in China. World Allergy Organ J 2021: 14; 100610. doi: 10.1016/j.waojou.2021.100610.
52. Kahveci M, Soyer O, Buyuktiryaki B, Sekerel BE, Sahiner UM Omalizumab treatment in adolescents with chronic spontaneous urticaria: Efficacy and safety. Allergol Immunopathol (Madr) 2020: 48; 368–73.
53. Saito J, Yakuwa N, Sandaiji N, Uno C, Yagishita S, Suzuki T, et al. Omalizumab concentrations in pregnancy and lactation: A case study. J Allergy Clin Immunol Pract 2020: 8; 3603–4.
54. EMA. Xolair Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/xolair Last accessed on 2020 Mar 22.
55. Jensen-Jarolim E, Bax HJ, Bianchini R, Capron M, Corrigan C, Castells M, et al. AllergoOncology-the impact of allergy in oncology: EAACI position paper. Allergy 2017: 72; 866–87.
56. Busse W, Buhl R, Fernandez Vidaurre C, Blogg M, Zhu J, Eisner MD, et al. Omalizumab and the risk of malignancy: Results from a pooled analysis. J Allergy Clin Immunol 2012: 129; 983–9.e6.
57. Martina E, Damiani G, Grieco T, Foti C, Pigatto PDM, Offidani A It is never too late to treat chronic spontaneous urticaria with omalizumab: Real-life data from a multicenter observational study focusing on elderly patients. Dermatol Ther 2021: 34; 14841.
58. Maurer M, Gimenez-Arnau AM, Sussman G, Metz M, Baker DR, Bauer A, et al. Ligelizumab for chronic spontaneous urticaria. N Engl J Med 2019: 381; 1321–32.
59. Muntyanu A, Ouchene L, Ben-Shoshan M, Netchiporouk E Ligelizumab is superior to omalizumab for chronic spontaneous urticaria. J Cutan Med Surg 2020: 24; 201–2.
60. Harris JM, Cabanski CR, Scheerens H, Samineni D, Bradley MS, Cochran C A randomized trial of quilizumab in adults with refractory chronic spontaneous urticaria. J Allergy Clin Immunol 2016: 138; 1730–2.
61. Akdis M, Aab A, Altunbulakli C, Azkur K, Costa RA, Crameri R, et al. Interleukins (from IL-1 to IL-38), interferons, transform- ing growth factor b, and TNF-a: Receptors, functions, and roles in diseases. J Allergy Clin Immunol 2016: 138; 984–1010.
62. Altrichter S, Frischbutter S, Fok JS, Kolkhir P, Jiao Q, Skov PS, et al. The role of eosinophils in chronic spontaneous urticaria. J Allergy Clin Immunol 2020: 145; 1510–6.
63. Bernstein JA, Singh U, Rao MB, Berendts K, Zhang X, Mutasim D Benralizumab for chronic spontaneous urticaria. N Engl J Med 2020: 383; 1389–91.
64. Kiwamoto T, Kawasaki N, Paulson JC, Bochner BS Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions. Pharmacol Ther 2012: 135; 327–36.
65. Maurer M, Altrichter S, Metz M, Zuberbier T, Church MK, Bergmann KC Benefit from reslizumab treatment in a patient with chronic spontaneous urticaria and cold urticaria. J Eur Acad Dermatol Venereol 2018: 32; 112–113.
66. Magerl M, Terhorst D, Metz M, Altrichter S, Zuberbier T, Maurer M, et al. Benefit of mepolizumab treatment in a patient with chronic spontaneous urticaria. J Dtsch Dermatol Ges 2018: 16; 477–8.
67. Sand FL, Thomsen SF TNF-alpha inhibitors for chronic urticaria: Experience in 20 patients. J Allergy 2013: 2013; 1–4.
68. Bangsgaard N, Skov L, Zachariae C Treatment of refractory chronic spontaneous urticaria with adalimumab. Acta Derm Venereol 2017: 97; 524–5 6.
69. Mallipeddi R, Grattan CEH Lack of response of severe steroid- dependent chronic urticaria to rituximab. Clin Exp Dermatol 2007: 32; 333–4.
70. Combalia A, Losno RA, Prieto-González S, Mascaró JM Rituxi- mab in refractory chronic spontaneous urticaria: An encouraging therapeutic approach. Skin Pharmacol Physiol 2018: 31; 184–7.
71. Arkwright PD Anti-CD20 or anti-IgE therapy for severe chronic autoimmune urticaria. J Allergy Clin Immunol 2009: 123; 510–1.
72. Chakravarty SD, Yee AF, Paget SA Rituximab successfully treats refractory chronic autoimmune urticaria caused by IgE receptor autoantibodies. J Allergy Clin Immunol 2011: 128; 1354–5.
73. Steinweg SA, Gaspari AA Rituximab for the treatment of recalcitrant chronic autoimmune urticaria. J Drugs Dermatol 2015: 14; 1387.
74. Krause K, Mahamed A, Weller K, Metz M, Zuberbier T, Maurer M Efficacy and safety of canakinumab in urticarial vasculitis: An open-label study. J Allergy Clin Immunol. 2013: 132; 751–4.
75. Maul JT, Distler M, Kolios A, Maul LV, Guillet C, Graf N, et al. Canakinumab lacks efficacy in treating adult patients with moderate to severe chronic spontaneous urticaria in a phase II randomized double-blind placebo-controlled single-center study. J Allergy Clin Immunol Pract 2021: 9; 463–8.
76. Lenormand C, Lipsker D Efficiency of interleukin-1 blockade in refractory delayed-pressure urticaria. Ann Intern Med 2012: 157; 599–600.
77. Bodar EJ, Simon A, de Visser M, van der Meer JW Complete remission of severe idiopathic cold urticaria on interleukin-1 receptor antagonist (anakinra). Neth J Med 2009: 67; 302–5.
78. Metz M, Sussman G, Gagnon R, Staubach P, Tanus T, Yang WH, et al. Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: A randomized phase 2 trial. Nat Med 2021: 27; 1961–9.
79. Gabizon R, London N A fast and clean BTK inhibitor. J Med Chem 2020: 63; 5100–1.
80. Lee JK, Simpson RS Dupilumab as a novel therapy for difficult to treat chronic spontaneous urticaria. J Allergy Clin Immunol Pract 2019: 7; 1659–61.
81. Sabag DA, Matanes L, Bejar J, Sheffer H, Barzilai A, Church MK, et al. Interleukin-17 is a potential player and treatment target in severe chronic spontaneous urticaria. Clin Exp Allergy 2020: 50; 799–804.
82. Altrichter S, Staubach P, Pasha M, Singh B, Chang AT, Bernstein JA, et al. An open-label, proof-of-concept study of lirentelimab for antihistamine-resistant chronic spontaneous and inducible urticaria. J Allergy Clin Immunol 2022: 149; 1683–90.
83. Gangemi S, Quartuccio S, Casciaro M, Trapani G, Minciullo PL, Imbalzano E Interleukin 31 and skin diseases: A systematic review. Allergy Asthma Proc 2017: 38; 401–8.
84. Reszke R, Krajewski P, Szepietowski JC Emerging therapeutic options for chronic pruritus. Am J Clin Dermatol 2020: 21; 601–18.
85. Giang J, Seelen MAJ, van Doorn M, Rissmann R, Prens EP, Damman J Complement activation in inflammatory skin diseases. Front Immunol 2018: 9; 1–17. doi: 10.3389/fimmu.2018.00639.
86. Takai T TSLP expression: Cellular sources, triggers, and regulatory mechanisms. Allergol Int 2012: 61; 3–17.
87. Molawi DT, Hawro T, Grekowitz E, Kiefer L The Anti-KIT antibody, CDX-0159, reduces mast cell numbers and circulating tryptase and improves disease control in patients with chronic inducible urticaria (Cindu). J Allergy Clin Immunol 2022: 149 AB178.
88. Dickson MC, Walker A, Grattan C, Perry H, Williams N, Ratia N, et al. Effects of a topical treatment with SYK inhibitor in healthy subjects and patients with cold urticaria or chronic spontaneous urticaria: Results of a phase 1a/b randomised double-blind placebo-controlled study. Br J Clin Pharmacol 2021: 87; 4797–808.
89. Oliver ET, Chichester K, Devine K, Sterba PM, Wegner C, Vonakis BM, et al. Effects of an oral CRTh2 antagonist (AZD1981) on eosinophil activity and symptoms in chronic spontaneous urticaria. Int Arch Allergy Immunol 2019: 179; 21–30.
90. Kim B, Eggel A, Tarchevskaya SS, Vogel M, Prinz H, Jardetzky TS Accelerated disassembly of IgE receptor complexes by a disruptive macromolecular inhibitor. Nature 2012: 491; 613–7.
91. Makol A, Gibson LE, Michet CJ Successful use of interleukin 6 antagonist tocilizumab in a patient with refractory cutaneous lupus and urticarial vasculitis. J Clin Rheumatol 2012: 18; 92–5.
92. Subramanian H, Gupta K, Ali H Roles of mas-related g protein-coupled receptor X2 on mast cell-mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases. J Allergy Clin Immunol 2016: 138; 700–10.
93. Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA Targeting the neurokinin receptor 1 with aprepitant: A novel anti-pruritic strategy. PLoS One 2010: 5; 10968.
94. Kocatürk E, Maurer M, Metz M, Grattan C Looking forward to new targeted treatments for chronic spontaneous urticaria. Clin Transl Allergy 2017: 7; 1. doi: 10.1186/s13601-016-0139-2.
Keywords:

Biologicals; chronic urticarial; novel biologics; omalizumab; resistant urticaria

Copyright: © 2022 Indian Dermatology Online Journal