Does Antihistamine Up-dosing Solve Chronic Spontaneous Urticaria?

Abstract

Opinion Statement
Urticaria is primarily a disease driven by the actions of mast cell-derived histamine on the dermal vasculature and sensory nerves. Initial treatment with second generation minimally sedating H1-antihistamines is recommended. Start with the standard dose of one tablet daily. Because of the high local levels of histamine in the skin, standard doses of H1-antihistamines are often not able to control the symptoms. Thus, if symptoms persist after 2 weeks, then double the dosage of H1-antihistamines, usually giving one in the morning and one in the evening. If this is still not effective after 2 weeks, double the dose to fourfold of the original dose, two tablets given approximately 12 h apart. For patients still not responsive, then other medication, such as omalizumab or cyclosporine A should be introduced. Omalizumab treatment is highlighted in this review.

Full text

1 23
Current Treatment Options in Allergy
e-ISSN 2196-3053
Curr Treat Options Allergy
DOI 10.1007/s40521-016-0098-9
Does Antihistamine Up-dosing Solve
Chronic Spontaneous Urticaria?
Martin K.Church

1 23
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Curr Treat Options Allergy
DOI 10.1007/s40521-016-0098-9
Urticaria and Atopic Dermatitis (M Ferrer-Puga, Section Editor)
Does Antihistamine Up-dosing
Solve Chronic Spontaneous
Urticaria?
Martin K. Church, PhD, DSc
Address
Department of Dermatology and Allergy, Charité –Universitätsmedizin Berlin,
Charitéplatz 1, D-10117, Berlin, Germany
Email: mkc@soton.ac.uk
*Springer International Publishing AG 2016
This article is part of the Topical Collection on Urticaria and Atopic Dermatitis
Keywords H
1
-antihistamines IChronic urticaria IChronic spontaneous urticaria ICSU IOmalizumab IAnti-IgE
Abbreviations IgE Immunoglobulin E IIg Immunoglobulin G ICSU Chronic spontaneous urticaria ICindU Chronic
inducible urticaria IPET Positron emission tomography
Opinion Statement
Urticaria is primarily a disease driven by the actions of mast cell-derived histamine on the
dermal vasculature and sensory nerves. Initial treatment with second generation mini-
mally sedating H
1
-antihistamines is recommended. Start with the standard dose of one
tablet daily. Because of the high local levels of histamine in the skin, standard doses of H
1
-
antihistamines are often not able to control the symptoms. Thus, if symptoms persist after
2 weeks, then double the dosage of H
1
-antihistamines, usually giving one in the morning
and one in the evening. If this is still not effective after 2 weeks, double the dose to
fourfold of the original dose, two tablets given approximately 12 h apart. For patients still
not responsive, then other medication, such as omalizumab or cyclosporine A should be
introduced. Omalizumab treatment is highlighted in this review.
Introduction
The activation of dermal mast cells and the release of
their inflammatory mediators are regarded as the final
common pathway in all forms of urticaria. This is sup-
ported by the findings of increased concentrations of
histamine in the skin tissue fluid [1] and the clinical
responsiveness of urticaria to H
1
-antihistamines.
The main option for the management of chronic
urticaria of all types is pharmacological therapy aimed
at symptomatic relief. The EAACI/GA2LEN/EDF/WAO
urticaria guideline [2••] recommendations for drug
Author's personal copy

treatment are as follows. Modern second-generation H
1
-
antihistamines are the first line of treatment. If symp-
toms persist after 2 weeks, then the second line is to
increase the dosage of second-generation H
1
-antihista-
mines up to fourfold. If symptoms persist after 1–4
further weeks, the third line treatment is to add
omalizumab, cyclosporine or montelukast on to second
line. Further, a short course (max 10 days) of corticoste-
roids may also be used at all times if exacerbations
demand this.
H
1
-antihistamines
H
1
-antihistamines were developed originally from anticholinergic drugs more
than 70 years ago. They act as inverse agonists rather than antagonists of
histamine H1-receptors [3], i.e. histamine binds to receptor and activates it,
while an H
1
-antihistamine binds to a different part of the receptor to stabilize it
in the inactive form and so prevent histamine activating it.
The older first-generation H
1
-antihistamines, including chlorphenir-
amine, diphenhydramine, hydroxyzine and ketotifen, penetrate readily into
the brain where they cause sedation, drowsiness, fatigue and impaired
concentration and memory causing detrimental effects on learning and
examination performance in children and on impairment of the ability of
adults to work and drive motor vehicles [4,5]. Also, the cumulative use of
first-generation antihistamines with anticholinergic activity in the elderly is
associated with an increased risk for dementia [6]. Consequently, the use of
first-generation H
1
-antihistamines should be discouraged. Furthermore,
physicians should advise their patients not to purchase these drugs from
the pharmacy for self-medication.
The newer second‑generation H
1
‑antihistamines are safer, cause less
sedation and are more efficacious. Of these, azelastine, olopatadine,
cetirizine and loratadine may cause drowsiness in some individuals [7],
but this is generally mild. Recent publications have suggested that, at
manufacturer’s recommended doses, levocetirizine is less sedating than
cetirizine and desloratadine causes negligible somnolence [4]. However, it
should be pointed out that ‘mean results’do not reveal everything as
patients are individuals and, as such, may show considerable somnolence
whereas others are unaffected.
While discussing somnolence, special mention should be made of
fexofenadine and bilastine. Positron emission tomography (PET) scanning
has shown that the occupancy of histamine H1-receptors in the brain of
these two drugs is negligible [7,8]andinpsychomotortests,theyarenot
significantly different from placebo [9,10]. This is because both drugs are
substrates for P-glycoprotein, a membrane pump that limits their passage
across the blood-brain barrier.
What patients require from an H
1
-antihistamine is a rapid onset of
action, good efficacy and a long duration of action. In general, all second-
generation H
1
-antihistamines have an onset of action of about 1 to 4 h.
Also, they are clinically effective for at least 24 h, making once daily dosing a
practicality. With regard to efficacy, very few back-to-back studies have been
performed with H
1
-antihistamines in CSU so comparisons are largely anec-
dotal. However, studies have compared levocetirizine and desloratadine
Urticaria and Atopic Dermatitis (M Ferrer-Puga, Section Editor)
Author's personal copy

and have shown levocetirizine to be the more effective in both mild and
moderate severe conic urticaria [11,12].
Histamine released from mast cells reaches high local concentrations in
the skin because of poor diffusion from the site of degranulation. This is
different from histamine release at mucosal sites, for example in the nose,
where the looser structure of the nasal lining facilitates histamine diffusion
and consequently histamine does not build up to similarly high levels.
Because of the high local levels of histamine in the skin, standard doses of
H
1
-antihistamines are often not able to control the symptoms. In this case,
the EAACI/GA2LEN/EDF/WAO urticaria guideline [2••] recommends if
symptoms persist after 2 weeks, then the second line is to increase the
dosage of second-generation H
1
-antihistamines up to fourfold. This is
usually done in two steps. First is to increase the dose to two tablets given
approximately 12 h apart and then, if the symptom control is still not
achieved, increase to four tablets, again given in two divided administra-
tions.AfurtherpointthatshouldbemadehereisthatH
1
-antihistamines act
in the same way with no other additional mechanisms of action demon-
strated clinically. Therefore, mixing different antihistamines will not have
additional benefits in terms of adding other potential actions. These results
have to be confirmed in controlled trials. Schulz and colleagues [13]report-
ed that the combination of H
1
-antihistamines was not more effective than
the high-dosage monotherapy probably due to unknown interactions and
addition of side-effects in combination therapies. Also, choosing a single
antihistamine, preferably the most potent one, which suits the patient [12]
for up-dosing will reduce patient confusion regarding the treatment admin-
istration and help patient compliance, and, consequently, increase effec-
tiveness [13]. In a recent study with bilastine in cold urticaria [14], increas-
ing the daily dose fourfold from the recommended level of 20 to 80 mg
decreased the critical temperature threshold to 4 °C or less in 75 % of
patients with no patient reporting somnolence. This indicates that bilastine
is indeed an effective drug for up-dosing. It is also important to advise your
patients to take their medicines regularly rather than just when their symp-
toms are getting worse (on demand) [15].
Many clinicians believe that to treat urticaria effectively, a non-sedating
H
1
-antihistamine should be given in the morning and a sedating drug, such
as hydroxyzine, should be given at night to aid sleep. However, a recent
study has compared treatment with levocetirizine alone with treatment
where the evening dose of levocetirizine was replaced with hydroxyzine
[16]. The results showed that the regimens were similarly effective in reduc-
ing symptoms night-time sleep disturbances. However, daytime somno-
lence was significantly higher in patients taking an evening dose of hydroxy-
zine. It is clear, therefore, that it is better to aim at the effective control of
urticaria symptoms with a non-sedating antihistamine than to offer a se-
dating antihistamine at night.
In conclusion, the current standard therapy with regularly dosed H
1
-
antihistamines leads to an absence of symptoms in G50 % of patients with
chronic spontaneous urticaria. Increasing the dose up to fourfold improves
Does Antihistamine Up-dosing Solve Chronic Spontaneous Urticaria? Church
Author's personal copy

treatment responses but still every third to fourth patient will remain
symptomatic [17]. In these patients, a trial of montelukast is a possible
option, especially in non-specialist settings. However, if no benefit is no-
ticed in 4–6 weeks, this treatment is unlikely to show further benefits. In
this situation or if patients experience severe symptoms despite stepping up
the H
1
-antihistamine dose, it is recommended to refer the patient to an
allergy specialist centre where one of the other third-line therapies can be
offered, i.e. omalizumab or cyclosporine. This review will consider only
omalizumab.
Omalizumab in Chronic Urticaria
Omalizumab is a humanized, monoclonal, anti-IgE antibody comprising a
human IgG framework onto which has been grafted the complementarity-
determining regions from a murine anti-IgE antibody [18••,19]. Omalizumab
binds to free IgE in the blood and interstitial space, forming biologically
inactive IgE complexes that are unable to bind to FcεRI on the surface of mast
cells and basophils [18••,20••]. Omalizumab, which was originally intro-
duced for treating IgE-mediated allergic diseases and approved for treating
patients with severe persistent allergic asthma in many countries, reduces the
amount of free IgE that may bind to mast cells and basophils and enable them
to be triggered for degranulation [20••].
Up to the present time, two phase II and four phase III multicentre, ran-
domized, placebo-controlled clinical trials [18••] have convincingly
established that omalizumab is efficacious and safe for treating CSU thatcannot
be adequately treated with H
1
-antihistamines.
To gain a deeper perspective of omalizumab in clinical usage, we recently
performed a retrospective clinical analysis of 51 antihistamine-resistant
patients in Germany in which we assessed responder rates, optimal dosage,
response to up-/down-dosing, time to relief of symptoms, rates of return
and time of relapse after omalizumab administration and safety [21]. Of the
51 chronic urticaria patients assessed,20hadCSUalone,21haddifferent
forms of chronic inducible urticaria (CindU) and 10 had both. The results
showed that omalizumab treatment led to total remission in 83 % of CSU
and 70 % of CindU patients. When starting with 150 mg omalizumab 4
weekly, only 2/15 CSU and 7/17 CindU patients required up-dosing to
achieve complete remission. In CSU, 57 % of complete responses occurred
within week one, all on the first day. Interestingly, efficacy was not corre-
lated to baseline IgE levels. No unwanted effects were noted. Consequently,
we concluded from our clinical experience from more than 1250 injections
in 51 patients over 4 years that omalizumab is a rapidly acting, highly
effective and safe drug in CSU and CindU patients. In a separate study of
18 patients [22], the duration of effectiveness following a single injection of
omalizumab peaked at 4–5 weeks. This indicates that omalizumab does not
‘cure’chronic urticaria but only suppresses the generation of symptoms
whilst present in the body at effective concentrations.
But how does anti-IgE suppress the symptoms of a condition of which an
allergic basis is somewhat speculative? Some 30 years ago, Grattan and
Urticaria and Atopic Dermatitis (M Ferrer-Puga, Section Editor)
Author's personal copy

colleagues [23] reported that when autologous serum was injected into the
skin it produced a wheal and flare response. This is the so-called autologous
serum skin test (ASST) [24]. In adults, the prevalence of positive ASST
reactivity in patients with CSU is approximately 45 % [24]. Analysis of the
serum indicated that the ASST was due to the presence of IgG autoanti-
bodies against FcεRI, IgE or both, which can cross-link IgE-occupied or
unoccupied FcεRI to activate mast cells and basophils [25]. Interestingly,
the IgG subclasses that appear to be pathogenic are IgG1 and IgG3 [26,27],
both of which are capable of activating complement C5a, a known stimu-
latorofskinmastcells,butnotothermastcells,inhumansubjects[28]. In
the presence of omalizumab, there is a slow loss of mast cell-bound IgE
followed by a slower loss of FcεRI on the surface of mast cells and basophils
[29]. Consequently, these cells will no longer be able to be activated by IgG
autoantibodies and urticarial symptoms will no longer be seen. This may be
an explanation for the slower response (days to weeks), as is seen in many
cases of omalizumab treatment [18•• ].
The mechanism of the faster response to omalizumab is, as yet, still
unclear. However, two possibilities have been mooted. The first is that
urticaria is caused by local autoallergensintheskin.Itisknownthatmany
urticaria patients have high IgE levels to autoantigens, such as
thyroperoxidase and double-stranded DNA [20••,30]. By forming inactive
hexa-complexes with IgE, omalizumab can sequester free autoallergens and,
if they are involved in causing urticaria, cause a rapid reduction of symp-
toms [18••].
Other studies have extended into humans the suggestion that mouse
monoclonal IgE molecules are heterogeneous with respect to their ability to
induce survival and activation events in mast cells [31]. At one end of the
spectrum, highly cytokinergic (HC) IgEs induce enhanced survival, degran-
ulation, adhesion, migration and expression of cytokines, such as IL-6 and
TNF-a. At the other end of the spectrum, poorly cytokinergic IgEs mediate
these effector functions inefficiently [32]. Interestingly, most murine mono-
clonal HC IgEs exhibit reactivity to autoantigens, such as double-stranded
DNA (dsDNA), single-stranded DNA (ssDNA), β-galactosidase, thyroglob-
ulin and histamine-releasing factor. Autoantibodies to such autoantigens
are often also found in patients with autoimmune diseases. By contrast,
poorly cytokinergic IgEs do not react with these antigens. This IgE hetero-
geneity is not restricted to murine antibodies: Kashiwakura and colleagues
[33] recently reported that a human monoclonal HC IgE also shows
polyreactivity to dsDNA, ssDNA and histamine-releasing factor. It is tempt-
ing to speculate that a reduction of high cytokinergic IgE by omalizumab
may also induce rapid relief from urticaria.
Conclusion
In conclusion, it is clear that although many CSU patients are helped greatly by
H
1
-antihistamines, particularly at higher doses, not all are responsive. The
reason for this is not yet clear. However, the introduction of omalizumab into
the clinicians’armoury means that they may help the majority of H
1
-antihista-
mine non-responsive patients.
Does Antihistamine Up-dosing Solve Chronic Spontaneous Urticaria? Church
Author's personal copy

Compliance with Ethics Guidelines
Conflict of Interest
Martin Church has been a speaker or consultant for Almirall, FAES Pharma, Menarini, Moxie, MSD, Novartis, UCB
Pharma, Sanofi-Aventis and Uriach.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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Does Antihistamine Up-dosing Solve Chronic Spontaneous Urticaria? Church
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