Omalizumab as a treatment option for antihistamine-refractory aquagenic urticaria

Abstract

A teenage girl presented with symptoms of itching and hives on contact with water for 3 years. On specific provocative testing and ruling out underlying systemic conditions, she was diagnosed with aquagenic urticaria. Following failed attempts to control her symptoms with second-generation antihistamines, she was started on monthly subcutaneous injections of the monoclonal antibody, omalizumab. The patient demonstrated significant improvement, with symptoms being well-controlled for 2 years now. She enjoys a good quality of life and can take a shower without developing itching or hives.

Background

Water, an indispensable part of our lives, can be a source of nuisance for individuals with aquagenic urticaria (AU). AU is a rare and extraordinary form of chronic urticaria (CU) elicited by exposure to water.¹ While the diagnosis is a combination of clinical history and provocation testing, the exact pathogenesis remains elusive. Since avoidance of the trigger, that is, water, is nearly impossible, symptomatic control is the basis of treatment. Treatment remains a challenge for patients whose symptoms are not controlled with the conventionally used second-generation H1 antihistamines for CU.^2–5 With the scarcity of literature on AU and alternative therapies yielding variable results,⁶ it becomes imperative to shed more light on this rare disease entity and its management. We have attempted to do the same through a patient of antihistamine-refractory AU whose symptoms were well controlled with monthly omalizumab therapy. There has been only one similar case reported in the literature so far.⁷

Case presentation

We present a case of a teenage girl with a 3-year history of pruritus and hives on contact with water. Severe itching and hives were described, with a perception of ants biting the skin, mainly on the legs. These symptoms occurred after showering, swimming, sweating or getting caught in the rain or humid weather, irrespective of the water temperature. The onset of symptoms coincided with menarche. The itching started at the end of the shower and increased over the next 10 min before spontaneously subsiding over 45 min. Trials of saltwater, distilled water or washing without soaps yielded similar results. The patient’s records showed 1–3 mm raised pink papules on the upper chest after getting out of the shower. Her family history was unrevealing of a similar disorder. There was no associated angioedema, hypotension or respiratory difficulty. However, the patient reported a significant reduction in her quality of life. A water-challenge test was performed, in which wet clothes washed at room temperature were applied to her chest and the left thigh for 30 min. This resulted in the neck itching 5–10 min later and formation of 2–4 mm pink and raised papules on the chest 30 min later. Additionally, a laboratory evaluation was done which was unrevealing, with a normal complete blood cell count with differential, comprehensive metabolic profile, thyroid profile, antithyroid peroxidase antibody, C reactive protein and tryptase. She was, therefore, diagnosed with AU.

Differential diagnosis

The main challenge in diagnosing AU lies in differentiating this condition from other types of physical urticaria, like cholinergic, heat, cold, pressure and exercise-induced urticarias by specific provocative testing.⁸ The lesions of cholinergic urticaria appear extremely similar to those of AU but arise only in response to cholinergic stimuli such as exercise, sweating, stressful emotions or eating spicy food. In our patient, the typical medical history clearly suggested an aquagenic disorder. Additionally, the appearance of wheals following a water challenge test ruled out the possibility of other forms of CU and that of aquagenic ‘pruritus,’ in which pruritus without skin lesions develops after water contact. Unlike AU, aquagenic pruritus is associated with polycythemia vera and is unresponsive to conventional AU therapies.⁹

Treatment

Previous treatment trials with moisturisers, 20 mg cetirizine per day, which is two times the recommended daily dose,¹⁰ and two tablets of 180 mg fexofenadine two times a day combined with cetirizine had been unsuccessful. Failure to respond to higher doses of second-generation antihistamines, thus, prompted the beginning of therapy with subcutaneous injections of omalizumab, 300 mg every 28 days.

Outcome and follow-up

After the first injection, a significant improvement in symptoms and quality of life (symptoms rated as 2/5 as compared with 5/5 before omalizumab) was reported. In addition, the patient was able to take a shower without having pruritus. Two years later, she is doing well without any adverse effects to omalizumab or recurrence of symptoms; however, she did report the medication-effect weaning off by day 25 of the monthly injection. Based on already published reports for CU, the dose was increased to 450 mg every 28 days to achieve a better response. Our approach will be to increase the dosing interval from every 4 weeks to every 6 weeks if the patient remains asymptomatic. Following that, the interval will be increased to every 8 and then 12 weeks as tolerated. If the patient remains asymptomatic, we will recommend discontinuation of therapy.

Discussion

AU, first described by Shelley and Rawnsley, has been classified as an inducible CU by the latest guidelines.^{1 6} Prevalence among women is higher, with onset occurring during puberty or later. Most cases are sporadic; some cases of familial disease and others associated with systemic conditions have also been reported.^11–13

Pathogenesis is poorly understood, with the first proposed hypothesis being the reaction of water with sebum or sebaceous glands, thus stimulating mast-cell degranulation.¹⁴ Sudden changes in osmotic pressure surrounding the hair-follicles have also been proposed.¹⁵ Another mechanism involves water-soluble antigens in the epidermis diffusing across the dermis, resulting in histamine release.¹⁶ A consensus on the pathogenesis, therefore, remains elusive.

Patients present with characteristic 1–3 mm folliculocentric pruritic wheals and surrounding 1–3 cm erythematous flares within 20–30 min following skin contact with water.² These lesions, appearing on the trunk and upper arms and sparing the palms and soles, typically resolve within 30–60 min of cessation of water contact. Associated pruritus, burning and uncomfortable pricking are common.¹ Systemic symptoms like wheezing, shortness of breath, headache, lightheadedness, respiratory distress and palpitations are rare.^{17 18}

Diagnosis is based largely on clinical history combined with a ‘water challenge test,’ the standard method for which is to apply a cloth dampened with water at room temperature to the skin for 20 min, with an urticarial reaction indicating a positive test.⁸ The water temperature is important because significant heat or cold exposure can potentially induce other physical urticarias, giving a false-positive result.¹⁷

Management aims to achieve symptom mitigation. Approved doses of second-generation H1-antihistamines, like cetirizine, are the universally recommended first-line therapy for CU.¹⁹ A combination of H1 and H2 antihistamines has shown some effect at further reducing the wheal response in dermatographism, although without any added symptomatic relief.²⁰ Anecdotal reports indicate that many patients with AU fail to achieve symptomatic control with oral antihistamines alone.²¹ Adjunctively, topical barrier moisturisers like ceramide-containing creams, or ultraviolet therapy, have been used either alone or in combination with antihistamines, with some efficacy.^{22 23} There is evidence regarding some efficacy with acetylcholine antagonists, stanozolol, selective serotonin reuptake inhibitors, leukotriene-modifying agents (montelukast and zafirlukast) and agents with H1-antagonist and/or H2-antagonist activity such as hydroxyzine, cyproheptadine or doxepin, in AU or CU.8 18 24 25

Of the available agents recommended for patients with refractory CU, omalizumab, a humanised IgG monoclonal antibody, has the most robust data supporting its use.²⁶ The first reported case of its use was in a patient with chronic inducible urticaria by Boyce.²⁷ Administered as subcutaneous injections every 4 weeks at 150 mg or 300 mg doses, omalizumab has a favourable risk/benefit ratio and was well tolerated in clinical studies.^{28 29} Efficacy has been reported with omalizumab alone or as an add-on therapy to antihistamines or leukotriene-modifying agents.³⁰ Adverse events, although low in incidence, like anaphylaxis, gastrointestinal symptoms, injection-site reactions, worsening urticaria, headache, dizziness, arthritis and fatigue, have been reported but were generally well tolerated, not leading to discontinuation of treatment in the majority of patients.

While some studies have shown no apparent difference between doses of omalizumab, others have shown 150 mg to elicit a good response, with yet others supporting a higher efficacy with up-dosing.³¹ While dosing at 300 mg every 4 weeks for at least 3 months is most practised, up dosing to 450 mg has also demonstrated efficacy and safety.³² An early response to the first or second omalizumab injection has been associated with a higher chance of successfully extending the treatment interval.³³ Omalizumab has an increased safety and efficacy if used for more than a year.³⁴ This was also seen with our patient, who has remained symptom-free for 2 years on monthly omalizumab injections. However, a significant limiting factor in omalizumab therapy is the cumulative cost of treatment for this chronic form of urticaria. According to the National Library of Medicine, the annual cost for omalizumab for the treatment of CU is 15 912.00 U.S.D.

Patient’s perspective.

Before starting Xolair injections every 28 days, I had previously struggled with basic life maintenance like showers and getting dressed. When changing clothes, the humidity of the air and the sweat on my legs would cause my lower limbs to become extremely itchy. It was difficult preparing for showers because I knew I was going to have hives and be extremely itchy for the next hour after being exposed to the water. I would maintain hygiene through using wet wipes and limiting any shower time to 5 min at most. Sometimes, the impending pain of showering would cause me panic attacks, and to this day, even with the treatment, I have major bursts of anxiety around showering. The itching that came afterwards felt like fire ants crawling under my skin, and it persisted for a minimum of 40 min and up to an hour. I had issues with accidentally abrading my skin barrier and have permanent scratch scars on my legs and upper chest. After the first month of receiving Xolair injections, there was a noticeable change in the length of time I was itchy after my showers. It decreased by almost half the time. This subsequently gave me more energy in my day and made it easier to convince myself to stay hygienic. Since being on Xolair, I have had to increase my dosage because I did start to have relapses in my allergy symptoms, but with this increase, I was able to maintain a sense of normalcy in any water-related activities such as washing dishes, washing my face and surprisingly going swimming for the first time in 7 years since my aquagenic urticaria onset. I believe one of the worst parts of this condition is the stigma associated with talking to people about my symptoms and activities I am unable to do. I have experienced multiple dermatologists saying that I only have dry skin, and the treatment for that condition is to moisturise and use balms to lock in moisture. This was a painful experience for me but a necessary step in ruling out dry skin in the eyes of my doctors. Additionally, friends, family and even strangers have told me the classic phrase, ‘Your body is made of mostly water; you can't be allergic to yourself. How do you drink water if you're allergic to it?’ And to their credit, this is what being taught to them their whole life, so they are right to question the inner workings of my condition, but when I explained the role of mast cells in the outer skin barrier being different from the specialised cells inside the body, their eyes glaze over, and the science does not matter if they do not understand it by laymen’s terms. I have experienced this sort of interaction well over 20 times and have become a bit disheartened by the lack of understanding for the condition. I hope that this article helps bring a greater understanding for those like me with aquagenic urticaria and widens the knowledge of how to effectively minimise symptoms, so that we may live fulfilling lives.

Learning points.

• Aquagenic urticaria is a rare form of chronic urticaria of unknown aetiology that significantly affects the quality of life, affecting activities of daily living like showering.

• A combination of clinical history and specific provocative testing is required for the definitive diagnosis.

• Omalizumab is a well-tolerated treatment option for those cases of aquagenic urticaria that are refractory to antihistamines.

• Omalizumab therapy is limited by the cost of injections and the requirement of being administered in the physician’s office. Therefore, further studies, analysing the correct method of phasing off treatment, and balancing the cost of therapy with the psychological and economic burden of working days lost due to the disease, are mandated.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s)