Current reviews of allergy and clinical immunology - CU

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Journal of Allergy and Clinical Immunology

Volume 105 • Number 4 • April 2000

Copyright © 2000 Mosby, Inc.

Current reviews of allergy and clinical immunology

Chronic urticaria

Malcolm Greaves MD

Key words

Chronic urticaria

immunology

allergy

urticarial vasculitis

idiopathic urticaria

intravenous Ig

itching

cold urticaria

From St 's Institute of Dermatology, St 's Hospital, United Medical

and Dental School, London, United Kingdom.

Series editor: Harold S. , MD

Received for publication Dec 3, 1999.

Revised Jan 14, 2000.

Accepted for publication Jan 14, 2000.

Reprint requests: Malcolm Greaves, MD, St 's Institute of Dermatology,

St 's Hospital, United Medical and Dental School, Lambeth Palace Road,

London SE1 7EH, United Kingdom; fax 44 .

Copyright © 2000 by Mosby, Inc.

0091-6749/2000 $12.00 + 0 1/1/105706

London, United Kingdom

Chronic urticaria remains a major problem in terms of etiology,

investigation, and management. It is important to identify patients in whom

physical urticaria is the principal cause of disability. Once confirmed by

appropriate challenge testing, no further investigation is required.

Urticarial vasculitis (UV) is a major differential diagnosis of " idiopathic "

urticaria (CIU). I perform biopsy of most patients in this category because

UV cannot be considered confirmed in the absence of histologic evidence.

Patients with confirmed UV need to be thoroughly investigated for

paraproteins, lupus erythematosus hepatitis B and C, and inflammatory bowel

disease. Of patients with CIU, a few (<5%) prove to have food additive

reactivity confirmed by placebo-controlled challenge testing. There is no

convincing evidence of the involvement of Helicobacter pylori or parasite

infestation as a cause of chronic urticaria, although H pylori could have an

indirect role. Recently it has become clear that 27% to 50% of patients with

CIU have functional autoantibodies directed against the alpha-chain of the

high-affinity IgE receptor or less commonly against IgG. These antibodies,

whose involvement has now been independently confirmed in several centers,

are identified by autologous serum skin testing and confirmed by histamine

release studies or immunoblotting. Their removal (by intravenous Ig or

plasmapheresis) or treatment by cyclosporine has proved highly beneficial in

severely affected patients. However, the routine treatment of all CIU

patients, irrespective of etiology, remains the judicious use of H1

antihistamines. (J Allergy Clin Immunol 2000;105:664-72.)

Abbreviations used

CIU:

Chronic idiopathic urticaria

FcepsilonRI:

High-affinity receptor for IgE

UV:

Urticarial vasculitis

Recently, new light has been shed on the pathomechanisms of so-called

chronic " idiopathic " urticaria (CIU), and this has in turn led to new

approaches to diagnosis and, at least for some patients, treatments.

However, it has to be admitted that, in many patients with chronic

urticaria, the etiology still remains unclear despite our best efforts and

these patients have to be managed symptomatically.

CLINICAL FEATURES OF CHRONIC URTICARIA

The cardinal clinical features of urticaria that distinguish it from any

other type of inflammatory eruption are the repeated occurrence of

short-lived cutaneous wheals accompanied by redness and itching (Fig 1).

Fig. 1. Chronic idiopathic urticaria.

Wheals are lesions ranging from a few millimeters to several centimeters in

diameter, although if they run together and become confluent much larger

plaques may occur. Individual wheals normally, by definition, last less than

24 hours, although there are exceptions. Wheals of the physical

urticaria-delayed pressure urticaria may individually last for as long as 48

hours and the wheals of urticarial vasculitis (UV) by definition should last

in excess of 24 hours. Urticarial wheals are generally paler than the bright

red of the surrounding skin because of the compressing effect of dermal

edema on the normally blood-engorged postcapillary venules. The surrounding

skin may sometimes be conspicuously pale rather than red, giving the

impression of a white halo. This phenomenon, more common in acute physical

urticarias such as cholinergic urticaria and in acute allergic urticarias,

is the result of a " steal " effect, increased arteriolar blood flow

associated with the central wheal leading to deprivation of blood flow in

the perilesional skin. Wheals may be round or irregular with pseudopodia.

Urticaria may occur anywhere on the skin, including the scalp, palms, and

soles. Unlike angioedema, urticaria of the mucous membranes is rare,

although the physical urticaria-cold urticaria may involve the tongue or

palate.

The itch of urticaria is almost invariable, although some patients may have

more intense pruritus than others. Qualitatively, the itching may be

pricking or burning in quality. It is usually worse in the evening or

nighttime[1] and is relieved by rubbing the skin rather than by scratching:

heavily excoriated skin is rarely if ever a consequence of urticaria.

At least 50% of patients with chronic urticaria also have angioedema. [2]

Angioedema can be defined as short-lived deep dermal and subcutaneous or

submucosal edema. Like the wheals of urticaria, the swellings of angioedema

normally last less than 24 hours, but large swellings tend to last longer.

Disfiguring when they occur in the skin, they can be extremely alarming and

occasionally life threatening when they occur in the oropharynx. The

swellings of angioedema are red or skin colored. Itching is less

consistently associated with angioedema than with urticaria. Indeed, these

swellings may not itch at all.

The classification of chronic urticaria, for the purposes of this

discussion, is given in Table I.

Table I. Classification of chronic urticaria

Physical urticaria

Symptomatic dermographism

Delayed pressure urticaria

Cold urticaria

Aquagenic urticaria

Solar urticaria

Cholinergic urticaria

Vibratory angioedema

CIU

Urticarial vasculitis*

* Mentioned for the sake of completeness, but not considered in detail in

this account.

PHYSICAL URTICARIAS

It is most important to distinguish the physical urticarias from CIU. This

is because, if it turns out that a physical urticaria is the main cause of

chronic urticaria in an individual, it almost invariably obviates the

necessity for investigation beyond any challenge testing necessary to

confirm the diagnosis. There are rare exceptions; for example, it is

desirable to exclude the (rare) presence of plasma cryoproteins in patients

with cold urticaria. However, it is my everyday experience that patients

with physical urticarias are burdened with a costly host of unnecessary

investigations and diet restrictions that shed no light whatever on the

cause and do not influence the treatment of the disease.

The physical urticarias are characterized by the development of whealing and

itching promptly after application of the appropriate physical stimulus. The

exception is delayed pressure urticaria. A period of 2 or more hours usually

elapses before whealing develops in response to applications of pressure to

the skin. It is common for more than one physical urticaria to afflict a

patient concurrently. For example, symptomatic dermographism and cholinergic

urticaria frequently occur simultaneously. Characteristically the wheals of

physical urticarias are transitory, lasting for only a few minutes or no

more than an hour or 2 after removal of the provoking stimulus. Again,

delayed pressure urticaria is an exception; wheals, often painful as well as

itchy, last for 24 hours or more.

After whealing has been evoked and has subsided, the affected skin is

frequently refractory to further provocation for a period ranging from a few

hours to a day or 2 and this fact has been made use of in the management of

some physical urticarias, including cold urticaria and solar urticaria.

We have published consensus guidelines for challenge testing in confirmation

of the diagnosis of physical urticarias.[3] This is important because

accurate characterization of a physical urticaria enables useful advice to

be given to the patient regarding avoidance of symptoms, as well as for

prognosis and treatment.

Only the more common physical urticarias will be detailed further here.

SYMPTOMATIC DERMOGRAPHISM (FACTITIOUS URTICARIA)

The diagnosis of symptomatic dermographism can be made by drawing the tip of

a blunt-pointed instrument firmly across the skin. This causes an immediate

linear red wheal that (in contrast to " ordinary " dermographism that can

occur in a healthy person) manifests itching.

Any region of the body can be affected. The condition, which occurs at any

age, runs on average a course of 2 to 3 years before resolving

spontaneously. The wheals, which last for up to 30 minutes, fade, leaving no

mark. Unlike urticaria pigmentosa caused by cutaneous mastocytosis (which

also manifests dermographism--Darier's sign), there is no increase in skin

mast cell numbers. Rarely, symptomatic dermographism is a sequel of scabies,

lasting for several weeks after successful treatment of this infestation.

There is no association with systemic disease.

The cause is unknown, but passive transfer has successfully been carried out

with patient serum and nonhuman primate skin as a recipient.[4] Although

conceivably IgE, the identity of the transferable factor has yet to be

positively established.

With use of an in vivo dermal perfusion method we[5] established many years

ago that histamine released locally is a major mediator of symptomatic

dermographism. Because the condition responds well to combined H1 and H2

antihistamines,[6] it seems likely that dermal mast cell-derived histamine

is the main, if not the only, mediator of this physical urticaria. The

transitory time course of the wheals and itch would also support this

notion.

DELAYED PRESSURE URTICARIA

It is not generally appreciated how common delayed pressure urticaria is.

Our results show that at least 40% of all patients with CIU have concurrent

delayed pressure urticaria.[7] Indeed, it is doubtful if it ever occurs in

isolation. This explains the frequency of wheals at local pressure sites

(waistband, palms, soles, etc) in CIU. It also explains the poor response to

H1 antihistamines in some patients with CIU because delayed pressure

urticaria is generally poorly responsive to this treatment.

Characteristically the wheals of delayed pressure urticaria occur 2 to 6

hours after application of pressure to the skin and last for more than 24

hours. These wheals are itchy or quite often painful, especially on the

feet. They can be disabling, especially to a manual worker, and are often

associated with arthralgia. The diagnosis is made by applying a

dermographometer (a spring-loaded pen-like instrument calibrated to

administer a range of pressures within a continuously variable range)

perpendicularly to the skin, which is examined 4 hours later. By varying the

duration of application and pressure, a quantitative assessment of the

severity of delayed pressure urticaria can be made.[3]

The cause of delayed pressure urticaria is unknown. The prolonged time

course of the wheals distinguishes them from other categories of chronic

urticaria and there is no vasculitis histologically. Our studies revealed

elevated tissue levels of IL-6 but not arachidonate metabolites in lesional

skin[8] [9] and close similarities to late-phase reactions has been

noted.[7]

The practical importance of establishing the diagnosis is evident. Apart

from the predictably poor response to antihistamines and the poor prognosis

(delayed pressure urticaria pursues a very long-term course), there are

important management implications. If delayed pressure urticaria turns out

to be an important component of the symptoms of a patient with CIU, there is

little point in further autoimmune laboratory workup because delayed

pressure urticaria is independent of the patient's autoantibody status (see

below), and establishing an autoimmune basis for the patient's CIU is of no

assistance at all in the management of the delayed pressure urticaria. Large

doses of systemic steroids may be needed to control this physical urticaria

in severely afflicted patients.

COLD URTICARIA

There are a number of rare subtypes of cold urticaria, but for the purposes

of this account only 2 subtypes need to be considered: primary acquired cold

urticaria ( " essential " cold urticaria) and secondary acquired cold

urticaria. Compared with most other physical urticarias, these have been

intensively studied.

Primary acquired ( " essential " ) cold urticaria

Primary acquired cold urticaria is a physical urticaria of children and

young adults. Characteristically, local whealing and itching occur within a

few minutes of applying a solid or fluid cold stimulus to the skin. The

wheal persists for about a half hour or less before fading without a

residual trace. This physical urticaria may also occur in the oropharynx

(eg, after a cold drink), which may present as urticaria or angioedema.

Systemic symptoms, occasionally severe and anaphylactoid, may occur after

extensive exposure such as immersion in cold water.

There may be a recent history of an intercurrent virus infection (Mycoplasma

pneumoniae)[10] and passive transfer has been successfully demonstrated to

recipient human[11] and nonhuman primate[12] skin, indicating the role of a

serum factor, possibly IgM or IgE.[13] Heterozygous deficiency of the

protease inhibitor alpha1 -antichymotrypsin has been demonstrated and may be

etiologically important in some patients.[14]

The dermal mast cell population density is within normal limits and there is

normally no evidence of vasculitis.[15] However, repeated cold challenge at

the same site can evoke evidence of structural dermal postcapillary venular

damage, raising the possibility of involvement of circulating

immunoreactants.[16] We and others have studied the pharmacologic mediators

involved in cold urticaria by a variety of methods, including examination of

venous effluent recovered from the antecubital vein of the cold-challenged

forearm. Histamine has been consistently recovered, although it is probably

not by itself accountable for the whealing,[15] and other mediators are

implicated as well.[17] [19] Exactly how dermal mast cells are triggered to

release histamine and other mediators is unclear, although interesting

studies by Gruber et al[20] raise the possibility of an autoimmune (possibly

anti-IgE) mechanism. The prognosis is good, with spontaneous improvement

occurring in an average of 2 to 3 years. Diagnosis is usually made by

applying an ice cube for 5 to 15 minutes to skin and, after allowing an

interval for skin rewarming, observing development of whealing.

Secondary acquired cold urticaria

The diagnosis of secondary acquired cold urticaria depends on being able to

demonstrate a cryoglobulin, cold agglutinin, or possibly cryofibrinogens in

a patient with cold urticaria. This finding occurs in about 5% of patients

with cold urticaria. The prognosis is that of the underlying disorder.

Demonstration of a cryoglobulin should prompt a search for an underlying

cause, including chronic hepatitis B or C infection, lymphoreticular

malignancy, or glandular fever. These considerations have been reviewed by

Wanderer.[21]

The clinical picture differs from that of the " essential " type. Wheals are

more persistent, may manifest purpura, and demonstrate the histologic

features of vasculitis on skin biopsy specimens. The cryoglobulins may be

polyclonal (post infection) or monoclonal (IgG or IgM) and complement

activation may be involved.[22] A positive serologic test for syphilis has

been described in cold urticaria, associated with a circulating

hemolysin.[23]

CHOLINERGIC URTICARIA

In its milder presentations, cholinergic urticaria is probably the most

common of all the physical urticarias. Often referred to trivially as " heat

bumps, " it probably occurs at some time during the lives of at least 15% of

the population. It has been the subject of several useful reviews.[24] [25]

Cholinergic urticaria is a physical urticaria predominantly in teenagers and

younger adults and carries a good prognosis for eventual improvement,

although I have had patients in whom troublesome symptoms have persisted

into middle age. At least 50% of patients are also atopic.

Characteristically itchy, small, red macules or papules occur on the neck,

trunk, forearms, wrists, and thighs in response to heat (environmental or a

hot bath or shower), exercise, or emotional stress. All these stimuli cause

eccrine sweating, but the latter is not necessary as such because the rash

has been described in patients with anhidrosis.[26] However, it is likely

that activation of the cholinergic sympathetic innervation of sweat glands

is a key mechanism. The rash can be blocked by prior atropinization of the

skin. [27] The rash usually subsides within minutes if the patient " chills

off. " However, occasional patients in whom the rash is continuous and

persistent are well recognized and represent a diagnostic trap for the

unaware.[28] Severely affected patients may get associated angioedema of the

skin or mucous membranes. [29] Wheezing associated with attacks of

cholinergic urticaria are not uncommon even in milder cases; in more severe

attacks syncope has been known to occur.[29] Cholinergic urticaria can occur

without visible skin lesions (cholinergic pruritus).

The cause is unknown. A recent suggestion that some form of sweat allergy is

involved[30] has not been confirmed. That a transferable serum factor may be

implicated has been supported by successful transfer using serum to nonhuman

primates in some cases.[31]

A small subset of patients with cholinergic urticaria will have the rash

only as a consequence of food ingestion followed by exercise.[32] Some of

these patients appear to have IgE-mediated allergy to certain specific food

items, whereas in others the triggering factor appears to be nonspecifically

related to food ingestion. The diagnosis is confirmed by exercise or hot

bath challenge testing. This subject has been reviewed.[24]

We have also demonstrated reduced plasma levels of certain protease

inhibitors in cholinergic urticaria.[33] That this finding is clinically

significant is suggested by a placebo-controlled double-blind study that has

demonstrated the ability of oral anabolic steroid treatment to both correct

these lowered protease inhibitor levels and, in parallel, cause amelioration

of the rash.[34] However, the routine treatment remains the use of a

low-sedation H1 antihistamine with or without an anxiolytic such as oral

propranolol. Severely affected unresponsive patients may be treated

cautiously with an anabolic steroid such as stanazolol. This unlicensed

treatment, which is less satisfactory in women owing to the possibility of

causing mild virilization, should be monitored by regular liver function

tests and liver scans.

CHRONIC IDIOPATHIC URTICARIA

Clinical features

Conventionally, CIU is defined as the daily, or almost daily, occurrence of

urticarial wheals for at least 6 weeks. Intermittent urticaria, although a

common entity, is less well recognized. It consists of bouts of urticaria

lasting days or weeks with intervals of days, weeks, or months in between.

It will be considered jointly with classic CIU for the purposes of this

discussion. Angioedema occurs concurrently with CIU in about 50% of cases[1]

and delayed pressure urticaria in about 40%.[7]

As already discussed, care must be taken to exclude physical urticaria as

the sole, or predominant, cause of the patient's disability, especially

because physical urticarias frequently occur concurrently with CIU. UV is

also a very important differential diagnosis (see below). CIU is common,

occurring in 0.1% of the population, and 20% still have the disease after 20

years has elapsed. There is no increased frequency of atopy in CIU and the

clinical features of the urticaria and angioedema are as described above (p

664). However, in comparison with physical urticarias, the individual

urticarial wheals last longer--at least 8 to 12 hours. Unlike UV wheals,

wheals of CIU do not cause residual pigmentation. Systemic symptoms are

minimal. Patients frequently feel fatigued, especially during relapses, but

respiratory, gastrointestinal, and arthralgic symptoms are rare. Angioedema

may affect the oropharynx but is not life threatening. Its etiology is

assumed to be the same as that for the urticaria. Gastrointestinal symptoms

may occasionally accompany severe attacks. Pruritus is nearly always severe

and especially troublesome in the evening and nighttime.[1]

CIU and angioedema are rare in childhood; the average duration of the

disease is about 3 to 5 years in adults.[2] It is a cause of serious

personal, social, economic, and occupational disability comparable with that

associated with severe coronary heart disease.[35] Its clinical, pathologic,

and etiologic features have recently been reviewed.[36]

ETIOLOGY

The target cell for CIU and angioedema is the dermal mast cell, and any

hypothetic etiological mechanism should explain how this cell becomes

repeatedly and extensively activated, leading to release of histamine and

other mediators. No doubt other cell types are also involved, including the

basophil.[37] Until recently there has been a paucity of convincing

evidence-based causes. Chronic infection has frequently been cited--most

recently Helicobacter pylori. However, recent reports have failed to confirm

this association.[38] [39] I have yet to see a patient in whom parasite

infestation proved causative, but in regions where infestation with high

loads of parasites occur, an association is possible and this needs further

study. Most patients have at some time believed that food " allergy " is

causative. Certainly IgE-mediated type I allergy (Gell and Coombs) caused by

foods is an important cause of acute urticaria but can rarely, if ever, be

substantiated as a cause of CIU. Idiosyncratic reactions to food additives

are alleged to be important causes by a number of authors. However, at least

in my own practice, food additives can be substantiated to be causative in

no more than 5%. The gold standard must be positive placebo-controlled

challenge testing.[40] [42] Exclusion diets, favored by some authors, are

extremely difficult to carry out satisfactorily owing to the prolonged

duration of this procedure, poor patient compliance, and, invariably,

ambiguous results. Aspirin does exacerbate chronic urticaria

nonspecifically, as do intercurrent virus infections. However, neither are

causative. Thus, until recently, the cause in the majority of patients with

CIU remained enigmatic.

As early as 1962 it was reported that the absolute blood basophil count in

unselected patients with CIU was significantly lower than in otherwise

comparable nonurticarial controls.[43] Subsequently in 1974 I reported[44]

that the basophils of unselected CIU patients released less histamine when

challenged in vitro by a range of concentrations of anti-IgE than did

basophils of matched nonurticarial controls. However, release evoked by

nonimmunologic stimuli, which did not depend on IgE or the high-affinity IgE

receptor (FcepsilonRI), including compound 48/80, did not differ

significantly between the 2 groups. These findings suggested the presence of

a circulating factor causing desensitization via IgE.

In 1986 Grattan et al[45] reported the presence of a serum factor that

caused whealing on autologous intradermal injection in some but not all

patients with CIU. However, it was not until 1993[46] that my laboratory

confirmed the identity of this factor as an IgG with specificity for the

alpha-chain of the high-affinity IgE receptor (FcepsilonRIalpha). Subsequent

studies[47] demonstrated this autoantibody as a causative factor in about

25% of patients with CIU. A further 5% of patients proved to have functional

anti-IgE autoantibodies[47] (Fig 2).

Fig. 2. Functional autoantibodies of CIU. IgG-anti-IgE antibodies combine

with and cross-link adjacent receptor-bound IgE. IgG-anti-FcepsilonRI

antibodies combine with and crosslink adjacent alpha-chains of FcepsilonRI.

Black notched membrane structures represent alpha-chain of FcepsilonRI

expressed on the surface of a dermal mast cell.

That a subset of patients with CIU had an autoimmune basis as a result of

anti-FcepsilonRIalpha autoantibodies was subsequently confirmed by several

authors,[48] [50] the frequency ranging from 25% to 45% of the total

patients with CIU. The IgG subtypes proved to be predominantly IgG1 and

IgG3.[51]

That CIU is, at least in some patients, autoimmune is not too surprising. An

increased frequency of thyroid autoimmune disease in CIU has previously been

reported by ourselves [52] and others.[53] In accordance with the proposed

autoimmune basis of this subset of patients with chronic urticaria, we have

also demonstrated its positive association with certain HLA-DR and -DQ

alleles that are characteristically known to show increased frequency in

autoimmune diseases.[54] Our own data suggest that normally IgG

anti-FcepsilonRIalpha autoantibodies cause direct cross-linking of adjacent

receptors, thus triggering mast cell or basophil activation. However, recent

work[55] raises the possibility that monovalent combination may take place,

involving complement activation. This probably only occurs in instances

where there is a low population density of FcepsilonRI on the basophil or

dermal mast cell membrane. The reason why little or no activation of mast

cells occurs at other organ and tissue sites occurs is not clear. In vitro,

lung and other noncutaneous mast cells release histamine in response to

anti-FcepsilonRIalpha autoantibodies.[47] However, lung mast cells are

unresponsive to activated complement. Possibly, differences in interstitial

fluid levels of IgG between skin and lung may also play a part.

Immunoreactive non-histamine-releasing anti-FcepsilonRI autoantibodies have

been detected in other nonurticarial autoimmune diseases, including

dermatomyositis, pemphigus, and pemphigoid.[51] However, up to the present

only chronic urticaria patients have been shown to manifest functional

histamine-releasing anti-FcepsilonRI autoantibodies. They do not occur in

physical urticarias, atopic eczema, or other diseases in which activated

mast cells have been implicated.

Of course, other circulatory factors may well also be involved, including

the IgE-dependent histamine-releasing cytokine and other histamine-releasing

cytokines reported by different North American groups.[56] [57]

Diagnosis

Patients with autoimmune (anti-FcepsilonRIalpha or anti-IgE) autoantibodies

have no distinctive diagnostic clinical features. They do tend to have more

severe urticaria[1] and histologic examination shows pronounced eosinophil

degranulation in older lesions compared with nonautoimmune cases, but these

differences are not sufficiently distinctive to use diagnostically. [58]

There is no vasculitis, and direct immunofluorescence yields no specific

findings. However, re-examination of the blood basophil count has revealed

an extreme paucity of these cells in the peripheral blood of autoimmune

compared with nonautoimmune cases, which could form the basis of a screening

test.[37] Serum IgE levels are not significantly different from those of

nonautoimmune patients.[1] Currently the clinical diagnosis depends on

autologous serum skin testing. Maximum specificity and sensitivity is

obtained if serum or plasma, obtained by venisection during a phase of

disease activity, is injected, in a volume of 0.05 mL intradermally, into

clinically uninvolved skin. The reaction at the injected site is examined 30

minutes later. A wheal with a diameter at least 1.5 mm greater than a

control saline solution wheal is deemed positive[59] (Fig 3).

Fig. 3. Autologous serum-plasma skin test. PBS, Saline solution negative

control; serum and plasma are injected in a volume of 0.05 mL and the

reaction read at 30 minutes. Both serum and plasma have given positive

responses.

A positive test is suggestive but not diagnostic of an autoimmune basis for

the patient's chronic urticaria. Confirmation is needed by in vitro testing

of the patient's serum for anti-FcepsilonRIalpha or anti-IgE autoantibodies.

Regrettably, despite attempts by our own and other laboratories, no

satisfactory ELISA has been developed. We rely on demonstration of histamine

release from basophils of healthy low- and high-IgE donors,[47] and this

remains the gold standard. However, it is time consuming and inconvenient.

Western blotting is also widely used and we have shown a good concordance

between results with Western blotting and with basophil histamine release

using the same sera (Maurer et al, unpublished data). However, as previously

indicated, false-positive results may occur in sera of patients with

nonurticarial autoimmune disease because of the presence of

non-histamine-releasing anti-FcepsilonRIalpha immunoreactivity.

In summary, identification of disease-specific anti-FcepsilonRIalpha

histamine-releasing autoantibodies in 25% to 45% of CIU is clearly a useful

step forward, but what about the other 50%? A few of these (no more than 5%)

may have demonstrable food additive reactivity as confirmed by challenge

testing (see above). Indirect evidence suggests that many of the remainder

may also be autoimmune. Autoimmune and nonautoimmune cases are

indistinguishable clinically and histologically. The peripheral blood

basophil numbers, although almost unmeasurable in autoimmune cases, are also

lower than values in healthy controls in nonautoimmune patients. Finally,

the autologous serum skin test is frequently positive although in vitro

testing for histamine release from low- and high-IgE basophils turns out to

be negative. Regrettably, sensitivity has had to be sacrificed in the

interests of high specificity in the in vitro test.

Treatment of CIU

The routine management of autoimmune and nonautoimmune chronic urticaria is

the same. General measures including avoidance of alcohol overuse,

overtiredness, and overheated surroundings are important. It is also

important to reassure anxious patients that the eruption is not a hallmark

of cancer, HIV infection, or other underlying disease. On the other hand,

elaborate and unnecessary dietary restrictions should be discouraged.

Frequent tepid showers and " as-required " application of 1% menthol in

aqueous cream are useful measures during relapses and well appreciated by

patients.

All patients with frequent outbreaks of wheals and itching should be offered

H1 antihistamine treatment. It is important to impress on patients that

regular daily dosage is essential if maximum benefit is to be achieved.

Results after as-required dosage are almost always inferior and often

account for alleged treatment failures. It is my practice to offer an

average adult a single morning dose of a low-sedation H1 antihistamine such

as loratidine 10 mg, cetirizine 10 mg, or fexofenadine 180 mg. Cetirizine is

mildly sedative. Sedation occurs with doses of loratidine above 10 mg, but I

prescribe 360 mg of fexofenadine (this is twice the licensed dose) to more

severely pruritic patients without risk of sedation because this

antihistamine is lipophobic and does not penetrate the blood-brain barrier.

However, it is important to take into account the diurnal periodicity of

symptoms in each patient. There is no point in prescribing a morning dosage

of an antihistamine if symptoms are restricted to evening and nighttime, as

is frequently the case.[1]

In the event that pruritus at night is troublesome, I add a sedative

antihistamine such as hydroxyzine 25 to 50 mg. In more severely afflicted

patients the tricyclic antihistamine doxepin 25 to 50 mg is useful as a

single nocturnal dose. Because anxiety and depression are a feature of

patients with severe chronic urticaria and angioedema, this drug, which is

also an H2 antihistamine, a powerful sedative, an anxiolytic, and an

antidepressant, is appropriate. However, doxepin is metabolized by the

cytochrome P450 enzyme system and care should be taken to avoid concurrent

administration of other drugs (eg, macrolide antibiotics) similarly

metabolized. It is also important to warn patients who may require, for

example, motor car driving skills in the morning that their cognitive

function and reflex activity may be impaired for up to 24 hours after a

nocturnal dose of hydroxyzine, doxepin, or similar sedative H1

antihistamine. The role of H2 antihistamines is controversial. We have shown

in several controlled studies[6] [60] [61] that there is a statistically

significant benefit from combination treatment with H1 and H2

antihistamines, but it is unclear whether this represents a significant

clinical benefit. I tend to give patients the benefit of the doubt on this

issue, especially if the patient happens to be troubled by gastric

hyperacidity, heartburn, or dyspepsia.

The role of systemic corticosteroids is limited. I occasionally prescribe

short tapering courses (eg, 30 mg of prednisolone daily reducing to zero

over 10 days) in special circumstances where, for example, rapid control is

needed to cover an important social or occupational event such as a wedding

ceremony or an important examination. However, prolonged daily treatment

nearly always leads to severe systemic toxicity accompanied by poor control

of urticaria and severe rebound on attempts to withdraw.

Leukotriene antagonists have received some attention as potential nonsteroid

therapies for chronic urticaria, but their role, if any, remains to be

established.

What can be done for the severely affected patient recalcitrant to the above

measures? If the patient turns out to be autoantibody positive, there are a

number of options (see below). Autoantibody-negative patients can be

considered for cyclosporine treatment. Cyclosporine is of proved value in

autoantibody-positive chronic urticaria[62] but is also effective in most

cases of severe autoantibody-negative disease. I use doses of 3 to 4.5 mg/kg

for up to 3 months at a time. Most (>75%) show an excellent response. Of

these, one third remain in remission after withdrawal, one third relapse but

only mildly, and one third relapse to the extent that they were affected

before cyclosporine treatment. I have only once seen what appeared to be a

" rebound " relapse on withdrawal. Obviously blood pressure and renal function

need to be monitored and the treatment is unsuitable for patients with risk

factors related to malignant disease such as a strong family or personal

history of cancer, positive cervical smear, etc.

Management of autoimmune urticaria

As previously indicated, the initial treatment is the same regardless of

whether the patient has an autoimmune etiology for the disease. However,

patients with autoimmune chronic urticaria tend to be more severely

affected[35] and on the whole less responsive to H1 antihistamine treatment.

In these circumstances, and where the disease is clearly causing severe

impairment of the patient's social, occupational, and domestic life, a

number of options can be considered. Cyclosporine has already been

mentioned. We have recently completed a placebo-controlled trial of oral

cyclosporine in autoantibody-positive patients with chronic urticaria,[62]

with impressive results. The details of the regimen for cyclosporine

treatment are as for nonautoimmune patients (see above). Other options

include intravenous Ig infusions [63] and plasmapheresis.[64] The reader is

referred to the appropriate references for further details. However, it

should be emphasized that none of these measures are curative and that they

are most appropriately carried out in a specialized center.

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