Although chronic urticaria is not considered an allergic disease, IgE antibodies play an important role. Anti-IgE therapy with omalizumab is repositioned in the updated international guideline. Also, why not all patients respond equally quickly to omalizumab.
Chronic urticaria is a mast cell-mediated inflammatory disease with recurrent occurrence of transient itchy wheals or angioedema, or both, for longer than six weeks. Children can also develop chronic urticaria and suffer from it for several years, reported Prof. Dr. Frank Siebenhaar, Allergy Center, Charité – Universitätsmedizin, Berlin. Two-thirds of patients with chronic urticaria have chronic spontaneous urticaria (CSU) in which no specific trigger can be identified, whereas one-third have chronic inducible urticaria (CIndU) induced by specific triggers such as light, pressure, skin rubbing, cold, or heat.
What has been changed in the new guideline?
Recently, the international urticaria guideline was revised and updated [1]. The new four-step treatment recommendations for chronic urticaria begin on the first step, as before, with a second-generation nonsedating H1 antihistamine (nsAH) at approved standard doses (continuous daily dosing). If this does not achieve sufficient disease control after two to four weeks, the dose of nsAH should be increased up to fourfold at the second stage (off-label). If even this does not provide sufficient control, the current guideline recommends therapy with the recombinant anti-IgE antibody omalizumab, which has been shown to be very effective in studies in CSU, after two to four weeks on the third stage in addition to nsAH. Only at the fourth stage is ciclosporin recommended in addition to nsAH if control is not adequate after six months. No controlled studies are available on the efficacy of ciclosporin in chronic urticaria, but much experience is available, the speaker said.
Why is anti-IgE therapy useful in CSU?
Initially, urticaria experts were surprised that omalizumab worked very well as an anti-IgE therapy in CSU. Last year, a new disease concept was published that contains two solutions to the puzzle and may explain why not all patients respond equally rapidly to omalizumab [2]. Although CSU is not actually considered an allergic disease, IgE antibodies are pathophysiologically involved. Most often, CSU is due to an autoimmune event with activation of skin mast cells. This may be an autoallergy because some patients with CSU have formed IgE antibodies directed against an endogenous rather than an exogenous allergen. These patients are allergic to themselves (IgE-mediated type I autoimmunity). IgE antibodies directed against an autoantigen, located at the high-affinity IgE receptors of mast cells, can be cross-linked by the autoallergen, resulting in activation and degranulation of mast cells. IgE autoantibodies of CSU patients bind to more than 200 autoallergens (frequently e.g. interleukin-24 or thyroperoxidase). Most patients with CSU respond very rapidly to omalizumab. More than half become symptom-free within one week of the first injection [2]. Very rapid and good response matches type I autoimmunity (autoallergy) because omalizumab rapidly neutralizes free IgE antibodies and omalizumab-IgE immune complexes bind autoallergens, rapidly reducing mast cell activation [2].
Who has a delayed response to omalizumab?
That a proportion of CSU patients respond more slowly to omalizumab, sometimes after months, is consistent with another form of autoimmunity called type IIb autoimmunity [1]. In this process, IgG autoantibodies directed against the high-affinity IgE receptor or IgE bound to it cause mast cell degranulation [2]. Neutralization of free IgE by omalizumab causes downregulation of IgE receptor expression on mast cells. The number of IgE receptors and IgE antibodies bound to them slowly decreases and the activation of mast cells by IgG autoantibodies is gradually reduced [2]. If the basophil activation test is positive in patients with CSU, type IIb autoimmunity with a later response to omalizumab is likely present. If test result is negative, it is probably type I autoimmunity with rapid response to omalizumab.
Are cold and light urticaria autoallergies?
Autoimmune mechanisms are probably also responsible for skin mast cell degranulation in CIndU. However, in cold urticaria, for example, the question arises as to what acts as an autoallergen, since certainly no IgE antibodies are formed against cold. Physical stimuli (e.g., cold, friction, sunlight, pressure) acting on and altering proteins could give rise to autoallergens against which IgE autoantibodies are produced. If the autoallergen then cross-links IgE autoantibodies on mast cells, degranulation and release of histamine and proinflammatory mediators could occur.
Anti-IgE therapy useful in chronic inducible urticaria?
Omalizumab is also effective in patients with CIndU who often do not respond to antihistamines. The best evidence supports the benefit of omalizumab in symptomatic dermographism, cold and light urticaria [3]. Symptomatic dermographism (itchy wheals caused by rubbing) is the most common form of physical CIndU, usually lasts for years, and can significantly affect quality of life. In a ten-week, randomized, placebo-controlled trial, omalizumab (150 or 300 mg subcutaneously every four weeks) proved to be an effective therapy [4]. The threshold for triggering dermographism determined with the FricTest improved rapidly with omalizumab. 53% of patients had a complete response to omalizumab 300 mg within ten weeks (44% to omalizumab 150 mg, 11% to placebo). At both doses, omalizumab therapy improved quality of life [4]. Patients with cold urticaria, the most dangerous form of CIndU, also respond rapidly to anti-IgE therapy. In a 10-week, randomized, placebo-controlled trial, treatment with omalizumab 300 mg achieved symptom relief in 44% of patients who had not responded to antihistamines (with omalizumab 150 mg in 40%, with placebo in 0%) [5].
Source: Presentation by Frank Siebenhaar “Mast-cell-driven diseases” at the YIR 1 event “Year in Review: Dermatology”. EAACI Congress 2018, Munich, May 27, 2018.
Literature:
- Maurer M et al: Chronic urticaria – What does the new guideline bring? J Dtsch Dermatol Ges 2018 (Epub ahead of print).
- Kolkhir P et al: Autoimmune chronic spontaneous urticaria: What we know and what we do not know. J Allergy Clin Immunol 2017; 139: 1772-1781.
- Maurer M et al: Omalizumab treatment in patients with chronic inducible urticaria: A systematic review of published evidence. J Allergy Clin Immunol 2018; 141: 638-649.
- Maurer M et al: Omalizumab is effective in symptomatic dermographism – results of a randomized placebo-controlled trial. J Allergy Clin Immunol 2017; 140: 870-873.
- Metz M et al: Omalizumab is effective in cold urticaria – results of a randomized placebo-controlled trial. J Allergy Clin Immunol 2017; 140: 864-867.
DERMATOLOGIE PRAXIS 2018; 28(4): 31-32
