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Accepted Manuscript

Autoimmune chronic spontaneous urticaria: what we know and what we don’t know

Pavel Kolkhir, MD, Martin K. Church, PhD, Dsc, Karsten Weller, MD, Martin Metz,MD, Oliver Schmetzer, MD, Marcus Maurer, MD

PII: S0091-6749(16)31212-X

DOI: 10.1016/j.jaci.2016.08.050

Reference: YMAI 12415

To appear in: Journal of Allergy and Clinical Immunology

Received Date: 22 June 2016

Revised Date: 2 August 2016

Accepted Date: 12 August 2016

Please cite this article as: Kolkhir P, Church MK, Weller K, Metz M, Schmetzer O, Maurer M,Autoimmune chronic spontaneous urticaria: what we know and what we don’t know, Journal of Allergyand Clinical Immunology (2016), doi: 10.1016/j.jaci.2016.08.050.

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http://dx.doi.org/10.1016/j.jaci.2016.08.050

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Autoimmune chronic spontaneous urticaria: what we k now and what we don’t know

Pavel Kolkhir, MD,1, 2 Martin K Church, PhD, Dsc,2 Karsten Weller, MD,2 Martin Metz, MD,2 Oliver Schmetzer, MD,2 and Marcus Maurer, MD2

1Dept. of Dermatology and Venereology, I.M. Sechenov First Moscow State

Medical University, Moscow, Russia

2Dept. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin,

Berlin, Germany

Disclosure of potential conflict of interest: none.

Sources of funding: none.

Corresponding author:

Marcus Maurer, MD

Dept. of Dermatology and Allergy

Charité – Universitätsmedizin Berlin

Charitéplatz 1

D-10117 Berlin, Germany

Phone: +49-30-450-518 043

Fax: +49-30-450-518 972

Email: [email protected]

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Abstract

Chronic spontaneous urticaria (CSU) is a mast-cell driven skin disease,

characterized by the recurrence of transient wheals, angioedema, or both for

more than 6 weeks. Autoimmunity is thought to be one of the most frequent

causes of CSU. Type I and type II autoimmunity, i.e. IgE to autoallergens

and IgG autoantibodies to IgE or its receptor, respectively, have been

implicated in the etiology and pathogenesis of CSU. We analyzed the

relevant literature and assessed the existing evidence in support of a role for

type I and II autoimmunity in CSU with the help of Hill’s criteria of causality.

For each of these criteria, i.e. strength of association, consistency,

specificity, temporality, biological gradient, plausibility, coherence,

experiment and analogy, we categorized the strength of evidence as

“insufficient”, “low”, “moderate” or “high” and then assigned levels of causality

for type I and II autoimmunity in CSU, from level 1 (causal relationship) to

level 5 (causality not likely). Based on the evidence in support of Hill’s

criteria, type I autoimmunity in CSU has level 3 causality (causal relationship

suggested) and type II autoimmunity has level 2 causality (causal

relationship likely). There are still many aspects of the pathologic

mechanisms of CSU that need to be resolved, but it is becoming clear that

there are at least two distinct pathways, type I and type II autoimmunity, that

contribute to the pathogenesis of this complex disease.

Keywords : chronic spontaneous urticaria; autoimmunity; IgE-anti-self; IgG-

anti-FcεRI/IgE; causality; Hill’s criteria of causality

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Abbreviations:

AAbs: autoantibodies

ASST: autologous serum skin test

BAT: basophil activation test

BP: bullous pemphigoid

CSU: chronic spontaneous urticaria

dsDNA: double stranded DNA

FcεR: receptor of IgE Fragment c

IgE: immunoglobulin E

IgG: immunoglobulin G

IgM: immunoglobulin M

SLE: systemic lupus erythematosus

TPO: thyroperoxidase

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Introduction

Chronic spontaneous urticaria (CSU) is a mast cell driven skin disease,

characterized by the recurrence of transient wheals (hives), angioedema, or

both for more than 6 weeks.1 Several mechanisms have been investigated

as possibly contributing to the pathogenesis of CSU including infections,

food intolerance, coagulation cascade, genetic factors and autoimmunity.1

Autoimmunity, i.e. autoimmune mechanisms of skin mast cell activation, is

held to be a frequent underlying cause of CSU. Two types of Gell and

Coombs hypersensitivity reactions 2 have been postulated to be relevant in

autoimmune CSU.

A Type I hypersensitivity to self, also called autoallergy, in which antigens

crosslink the IgE on mast cells and basophils to cause the release of

vasoactive mediators (Figure 1), was first suggested by Rorsman in 1962 to

explain urticaria-associated basopenia.3 A role of autoallergy in urticaria was

also postulated from the finding in 1999 of IgE-autoantibodies (AAbs)

against the thyroid microsomal antigen in the serum of a female CSU

patient.4 This work has been confirmed and extended to propose autoallergy

in the pathogenesis of both CSU and chronic inducible urticaria.5-10

A Type II hypersensitivity reaction in which antibodies, usually IgG or IgM,

bind to antigen on a target cell (Figure 1), was originally postulated following

the identification of IgG-AAbs against IgE in 3 of 6 CSU patients.11 The

presence of these AAbs was confirmed by Grattan and co-workers in 1991

in patients whose sera induced a wheal and flare response when injected

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intradermally, the autologous serum skin test (ASST).12 The presence of

AAbs to the high affinity receptor for IgE on mast cells and basophils (IgG-

anti-FcεRI) in a subset of CSU patients was reported by the same group 2

years later.13 In theory, IgG-anti-FcεRII/CD23 autoantibodies that were

identified in CSU sera may also elicit mast cell degranulation, via activation of

eosinophils with the consequent release of major basic protein and other mast

cell secretagogues (Figure 1).14

We assessed the evidence for the role of these two forms of autoimmunity in

CSU by the use of Hill’s nine criteria of causality, which were developed by

Sir Austin Bradford Hill, an English epidemiologist and statistician as a

research tool for the medical field (Table 1).15 These criteria should be viewed

as guidelines rather than a checklist of definite causes.15, 16 Furthermore, Hill

did not indicate how many of the nine criteria need to be fulfilled to define the

relationship as causal. When we reviewed the data on autoimmunity and CSU

we categorized the strength of evidence for each criterion as “insufficient”,

“low”, “moderate” or “high” (Tables 2, 3) as previously described.17, 18 Finally,

we assigned established levels of causality based on Hill’s criteria (Table 4,

see Systematic review methodology in the Online Repository).19

1: Strength of association and 2: Consistency

Type I autoimmunity

The strength of association between IgE-AAbs and CSU is currently unknown,

and the relative risks have not been assessed. Six independent studies from

different teams evaluated the link between CSU and IgE-AAbs such as IgE-

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anti-dsDNA 9 and IgE-anti-thyroperoxidase (TPO) 5, 6, 10, 20, 21 (Table 5). Three

of these studies show that serum levels of IgE-AAbs (anti-dsDNA or anti-TPO)

are significantly higher in CSU patients than in normal subjects.6, 9, 10

Three studies failed to reproduce an association between IgE-AAbs and

CSU.5, 9, 20 In the first of these studies, all of 23 CSU patients showed serum

IgG-anti-TPO, but no patient was positive for IgE-anti-TPO.20 In the second

study, only 2 of 20 CSU patients with IgG-anti-thyroid antibodies had

detectable IgE-anti-thyroid antibodies.5 Hatada and colleagues, in the third

study, failed to find differences in levels of IgE against thioredoxin,

peroxiredoxin, or thyroglobulin between patients with CSU and healthy

subjects.9 A radioimmunoassay or direct ELISA5, 9, 20 approach was used in all

of these 3 studies, where IgG-AAbs to the antigen can mask the presence of

IgE-AAbs due to competition.22 In contrast, Altrichter et al., who showed a

high prevalence of IgE-anti-TPO in CSU, used a site-directed human IgE

capture ELISA, in which IgE-anti-TPO does not compete with IgG-anti-TPO

antibodies.6

Strength of evidence: Low.

Type II autoimmunity

Although the presence of IgG-AAbs to IgE and FcεRI has been repeatedly

observed in CSU (Table 6), the strength of association and relative risks have

not been formally assessed. However, many independent studies have

reported higher rates of IgG-anti-IgE and/or IgG-anti-FcεRI in immunoassays

in CSU patients in comparison with healthy controls,23-26 atopic patients,27, 28

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patients with inducible urticaria24 and patients with psoriasis.28 However, this

was not the case in all studies.29-33

The rates of IgG-anti-FcεRI positivity in CSU were investigated by 16 studies,

and the prevalence of these autoantibodies ranged from 0 to 64%. In healthy

controls, the prevalence of IgG-anti-FcεRI ranged from 0 to 57% as reported

by 11 studies (Table 6). The rates of IgG-anti-IgE positivity in CSU ranged

from 0 to 69% (7 studies) as compared to 0 to 30% in healthy controls (6

studies, Table 6). In all studies, IgG-AAbs were detected by Western blot

and/or ELISA or immunoenzymetric assays.

Strength of evidence: Moderate.

3: Biological plausibility and 4: Coherence

Type I autoimmunity

Several independent findings support the plausibility and coherence of type I

autoimmunity as a relevant cause of CSU (Table 7). IgE-AAbs in the blood of

CSU patients, such as IgE-anti-TPO and IgE-anti-dsDNA, have been shown

to bind to basophils and to induce degranulation after interaction with their

specific antigen.9, 10

A second reason why it is plausible that IgE-anti-self can induce the signs and

symptoms of CSU is the analogy with acute urticaria due to IgE-mediated

immediate hypersensitivity. IgE against a wide range of environmental

allergens is known to cause acute urticaria.34 Also, IgE-AAbs in some CSU

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patients may contribute to higher levels of total IgE10, which was proposed to

be a potential marker for severe CSU.35 One study reported significantly

higher levels of total IgE in CSU patients with IgE-anti-TPO compared with

those without autoantibodies.10 Additional evidence-based arguments for the

coherence of type I autoimmunity as a cause of CSU are that other

autoimmune diseases are common comorbidities of CSU patients6, 36, and

that wheals in CSU patients show features of IgE/allergen-induced late-phase

cutaneous reactions including T cell infiltrates37-39 (Table 7).

Strength of evidence: Moderate for biological plausibility and high for

coherence.


Direct evidence that type II autoimmune CSU, according to the revisited

Witebsky’s postulates 40, is plausible comes from studies that show that IgG-

AAbs from the serum of CSU patients are able to release histamine from

healthy donor mast cells 41 and basophils.12 IgG-mediated basophil activation

in vitro has also been demonstrated repeatedly with the serum of CSU

patients.42 Moreover, these IgG-AAbs can activate complement and generate

C5a, a potent inducer of human skin mast cell degranulation.43, 44

Significant circumstantial evidence for the coherence of autoimmunity type II

as a cause of CSU includes the fact that IgG-AAbs-positive CSU patients

often have other autoimmune comorbidities such as autoimmune thyroiditis,

36, 45 can show T lymphocytic infiltration of wheals,37-39 exhibit decreased

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numbers of regulatory T cells46, appear to have a HLA-associated genetic

predisposition for autoimmune diseases (class I and II alleles)47, exhibit

cytokine profiles indicative of autoimmunity.48

Strength of evidence: High.

5: Temporality

Type I autoimmunity

The temporal relationship between IgE-AAbs and CSU development has not

yet been investigated. However, the efficacy of anti-IgE (omalizumab) and the

relapse of the disease after withdrawal of drug may be seen as indirect

evidence for temporality.7, 49

Strength of evidence: Insufficient.


Currently, there are no published data on the temporal relationship between

IgG-AAbs and CSU development. Positive ASSTs reportedly persist after

CSU remission in some studies50, 51, whereas in other studies the ASST

became negative after remission of CSU in most patients.52, 53 Grattan and

colleagues demonstrated that ASSTs are positive in CSU patients in

remission when done with stored sera, but not fresh sera.52 These findings

suggest that IgG-anti-FcεRI and IgG-anti-IgE antibodies may decrease during

remission in some patients.

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6: Dose–response relationship (biological gradient)

Type I autoimmunity

There have been no studies that assessed the link between the incidence or

severity of CSU and levels of IgE-AAbs.



The link between the risk to develop CSU and levels of IgG-AAbs against

FcεRI or IgE has not been studied. However, it has been shown that serum

levels of histamine-releasing IgG-anti-FcεRI-AAbs, but not of non histamine-

releasing IgG-anti-FcεRI-AAbs, correlate with disease severity,24, 54 and their

removal by plasmapheresis may lead to CSU remission.55 Histamine-

releasing activity followed IgG concentrations and clinical activity of CSU

before and after plasmapheresis.55

Additional indirect evidence appears to support this: Disease activity in CSU

is correlated with blood basopenia,56 which, in turn, is reportedly linked to

serum basophil histamine releasing activity57 and to high levels of IgG-anti-

FcεRI and IgG-anti-IgE.29

Strength of evidence: Low – Moderate.

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7: Experiment

Type I autoimmunity

Omalizumab, a humanized monoclonal anti-IgE antibody, has been shown in

a randomized placebo-controlled clinical trial to be effective in CSU patients

with high levels of IgE-anti-TPO.7 This suggests that omalizumab may protect

from urticarial symptoms by reducing IgE-AAbs such as IgE-anti-TPO (Figure

2).

Provocation testing is another way to assess the effects of altered

autoantibody/autoantigen levels. Successful passive transfer of serum from a

patient with symptomatic dermographism, a form of chronic inducible urticaria,

to monkey was shown.58 In 1942, Rajka described the successful passive

transfer of solar urticaria from a patient to a healthy subject after intradermal

injection of patient`s serum with subsequent light exposure of injected skin 59.

These data were later confirmed by Kojima and colleagues 60. These types of

passive transfer approaches are based on the Prausnitz-Küstner test, a test

for the presence of IgE-associated immediate hypersensitivity reactions.61

However, serum transfer studies do not necessarily confirm presence of IgE-

AAbs. In some cases, transfer of other histamine-releasing serum factors

such as IgG-AAbs or thrombin may also take place.



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Experimental evidence for a pathogenic role of IgG-AAbs come from the

demonstration that heterologous and autologous injections of IgG-anti-FcεRI-

positive serum can induce wheal and flare reactions. Grattan and Francis

reported the development of wheals in vivo after the intradermal injection of

plasma from a CSU patient into the skin of a healthy volunteer with previously

negative ASST.62 However, the attempts to perform a cross-species passive

transfer of sera from ASST-positive CSU patients to guinea pigs 63 or

macaque monkeys 64 did not bring any success.

The ASST is considered to be a screening test for autoimmune CSU due to

IgG-anti-IgE and/or anti-FcεRI AAbs.65 The rates of ASST positivity were

higher in CSU patients compared to healthy control subjects,26, 66-68 atopic

patients 66, 69 and patients with inducible urticaria 66 in some studies but not by

others.70, 71 A positive ASST is significantly associated with CSU and with

female gender 69. A negative ASST has a high predictive value for the

absence of circulating functional AAbs. Direct evidence of mast cell

degranulation in wheals of ASST-positive responses of CSU patient has

been provided by electron microscopy.38

Autoimmune CSU in ASST-positive patients requires in vitro demonstration of

IgG-AAbs against FcεRI or IgE by ELISA or Western Blot and testing of these

IgG-AAbs for functional activity, e.g. by use of a basophil activation test

(BAT).65 IgG autoreactivity measured by BAT was observed more frequently

in CSU patients than in healthy controls in many studies.13, 24, 26, 41, 57, 66

Approximately 25% of CSU patients have both, a positive ASST and BAT.65

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Furthermore, ASST and BAT positivity in CSU are associated with longer

duration of the disease in some studies 72, 73 but not in all 74, higher disease

severity 54, 69, 75 and a poor response to antihistamine treatment.73

The efficacy of omalizumab also supports a type II autoimmune

pathomechanism in CSU. 76 In CSU patients with IgG-AAbs against IgE or

FcεRI, the effect of omalizumab may be associated with the decrease of mast

cell–bound IgE with the subsequent downregulation of FcεRI on mast cells

and basophils (Figure 2).49, 76 Thus, CSU patients with type II autoimmunity

can be expected to show a slow response to omalizumab treatment, although

this has not yet been confirmed experimentally.

Finally, the effectiveness of immunosuppressive treatments, e.g. with

cyclosporine A77, intravenous immunoglobulins78, rituximab79, methotrexate80,

mycophenolate mofetil, 81 and the removal of autoantibodies by

plasmapheresis55 provide experimental evidence for a role of IgG-AAbs in the

pathogenesis of CSU. Treatment with cyclosporine A reduces the level of

histamine-releasing IgG-AAbs, decreases ASST response rates 82 and leads

to the inhibition of dose-dependent histamine release from mast cells and

basophils.83, 84 BAT-positive CSU patients respond better to cyclosporine A

treatment than BAT-negative ones.82

Arguments that challenge the concept of type II autoimmunity include the

reported ASST positivity in some CSU patients during remission50, 51 and the

lack of a clear correlation between immunoassays and functional assays.65, 85

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Strength of evidence: High.

8: Specificity

Type I autoimmunity

It is still unknown whether or not IgE-AAbs, by themselves, can induce CSU.

CSU patients who express IgE against one autoantigen are likely to exhibit

IgE against other autoantigens.6, 9



It is still not known whether or not IgG-AAbs alone are able to induce CSU. It

is thought that an IgG-anti-FcεRI/IgE-mediated activation of mast cells and

basophils may be dependent on or augmented by other factors such as

complement C5a, which can activate skin mast cells via its CD88/C5aR

receptor (Figure 1).43, 44, 85 However, there is evidence that complement is not

necessary for CSU serum-induced basophil activation.12, 28 Functionality of

these IgG-AAbs also depends on IgG1,3 subclasses.86

IgG-AAbs against the low affinity IgE receptor (FcεRII) can activate

eosinophils, and their release of major basic protein and other mast cell

secretagogues may contribute to the induction of CSU signs and symptoms

(Figure 1).14

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9: Analogy

Type I autoimmunity

IgE against environmental allergens is responsible for the activation of mast

cells in allergic diseases including anaphylaxis.34 IgE-AAbs (directed to skin

antigens) and autoallergic mast cell activation have been observed and

described in other chronic inflammatory skin diseases such as bullous

pemphigoid (BP) 87, 88 and atopic dermatitis.89 IgE-anti-BP180 has been

described to occur in up to 90% of untreated BP patients, and mast cell

degranulation by BP180 has been suggested to be a key trigger for the

development of BP skin lesions, which often first manifest as wheals.88

Recently, elevated levels of IgE-AAbs against nuclear antigens, dsDNA or

TPO were described in other autoimmune diseases such as systemic lupus

erythematosus (SLE) 89, 90 and autoimmune thyroiditis.91 Levels of

autoreactive antinuclear IgE were found to be significantly higher in patients

with SLE and rheumatoid arthritis than in healthy controls 92.



The causal association between IgG autoantibodies and different autoimmune

diseases such as pemphigus vulgaris, dermatomyositis, SLE, and bullous

pemphigoid, is well established.93

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Strength of evidence: High

Overall evidence and conclusion

Taken together, the evidence in support of Hill’s criteria is suggestive of a

causal relationship (level 3 causality) for type I autoimmunity in CSU and a

likely cause of CSU (level 2 causality) for type II autoimmunity. In both cases,

activation of dermal mast cells to release histamine appears critical to the

development of symptoms. Type I and type II autoimmunity are likely to be

relevant in CSU subpopulations rather than the same patients (although some

patients may exhibit IgE-AAbs and IgG-anti-IgE/FcεRI). Arguments in support

of this theory include the identification of 2 distinct subgroups of CSU patients

– one IgE-anti-TPO-low and the other IgE-anti-TPO-high6, the absence of a

correlation between IgE-AAbs and ASST response6, 9, the correlation of IgG-

AAbs with disease activity/severity24, 54 and the absence of such correlation in

the case of IgE-AAbs6, 9, and different speeds of onset of action of

omalizumab.7, 49, 76, 94, 95 More than half of all omalizumab-treated CSU

patients become symptom free within one week of their first injection. This

would be consistent with type I autoimmunity in which omalizumab rapidly

binds free IgE-AAbs and omalizumab-IgE complexes bind autoallergens and

thus reduce mast cell activation (Figure 2).49 The remainder of patients

responds more slowly to omalizumab. This would be consistent with type II

autoimmunity in which the slow loss of membrane-bound IgE and

subsequently FcεRI from skin mast cells95 renders them less susceptible to

activation by IgG-anti-IgE and IgG-anti-FcεRI, respectively.

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On the one hand, the existence of natural anti-FcεRIα autoantibodies found in

healthy people as confirmed by ASST and BAT results might be explained by

the concept of “conditional autoimmunity”.65 It is suggested that these

autoantibodies can cause CSU only under certain conditions and they

become pathogenic over time, depending on the state of occupancy of the

FcεRI by its natural IgE ligand. On the other hand, autoantibodies do not lead

to clinical manifestations in many rheumatologic and allergic diseases, and

may be nonfunctional.93

Future studies should be aimed at closing the gaps of knowledge on the role

and relevance of type I and I autoimmunity in CSU (Tables 2 and 3). For type

I autoimmune CSU, standardized diagnostic tests need to be developed, the

associations of IgE-AAbs and the risk for CSU development and CSU severity

need to be characterized, the temporal relationship of IgE-AAbs and CSU

development needs to be determined and IgE-AAbs transfer and depletion

studies need to be performed. For type II autoimmune CSU, the use of tests

for functional IgG-anti-IgE and IgG-anti-FcεRI needs to be harmonized to

assess if these IgG-AAbs are risk factors for CSU, the link between these

AAbs and disease severity should be determined, and the temporal

relationship between IgG-anti-IgE/FcεRI expression and CSU development

and remission must be clarified. Finally, autoimmune type I and II CSU

patients should be compared for clinical differences and therapeutic

responses, to facilitate optimal treatment of both subpopulations of CSU

patients.

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Thus, there are still many aspects of the pathologic mechanisms of CSU that

need to be resolved, but it is becoming clear that there are at least two distinct

pathways, type I and type II autoimmunity, that contribute to the pathogenesis

of this complex disease.

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Figure legends

Figure 1. Mechanisms of mast cell activation in chronic spont aneous

autoimmune urticaria. Type I autoimmunity: Type I autoantigens

(“autoallergens”) can activate mast cells and basophils by crosslinking IgE-

AAbs. Type II autoimmunity: IgG-AAbs can do the same by binding to IgE or

to the high affinity receptor for IgE (FcεRI), which may involve complement

C5a and the CD88/C5aR receptor. IgG-AAbs against the low affinity IgE

receptor (FcεRII) may activate eosinophils and induce subsequent mast cell

degranulation. AAbs: autoantibodies; MBP: major basic protein; ECP:

eosinophil cationic protein; LTs: leukotrienes; PAF: platelet-activating factor;

SCF: stem cell factor; VEGF: vascular endothelial growth factor

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Figure 2. Possible actions of omalizumab in CSU patients wit h type I or II

autoimmunity. Type I autoimmunity (rapid response to treatment): In patients

with type I autoimmune (“autoallergic”) CSU, omalizumab neutralizes IgE

autoantibodies and forms omalizumab-IgE immune complexes that may bind

type I autoantigens (“autoallergens”). Type II autoimmunity (slower response

to treatment): The downregulation of free IgE results in a downregulation of

FcεRI expression on mast cells, which reduces their activation by IgG-anti-IgE

and IgG-anti-FcεRI.

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Table 1. Hill’s criteria of causality 15, 16

Criteria

Description

1 Strength of association

The strength of association between exposure and outcome is defined as the size of the risk and measured in odds ratios, risk ratios or rate ratios.

2 Consistency (Reproducibility)

Different persons in different places with different samples should find the same association. It is usually evaluated to rule out other explanations for an outcome. A lack of consistency does not exclude a causal association.

3 Biological plausibility

Biological mechanisms through which the exposure leads to the outcome. The evidence generally comes from basic laboratory research.

4 Coherence Cause-outcome association does not conflict with what is known about the natural history and the biology of the disease.

5 Temporality Criterion is thought to be essential and is fulfilled when exposure precedes the outcome.

6 Biological gradient

Greater exposure leads to an increased risk of the development or stronger expression of the outcome

7 Experiment Evidence from epidemiological, clinical and/or laboratory studies demonstrates that altering the cause alters the outcome. Randomized clinical trials are thought to be the most persuasive studies.

8 Specificity A single cause leads to a specific outcome. Some researchers feel that specificity is the weakest of all the criteria and the lack of specificity does not exclude a causal association.

9 Analogy Evidence for similar exposure-disease relationships. It is one of the weakest criteria because it is dependent upon the subjective opinion of the researcher

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Table 2. Evidence for a causal relationship between type I autoimmunity and CSU according to Hill’s cr iteria

Criterion Questions to the literature Answers Evidence Unmet needs

Strength of association

1. What are the risk ratios for the association of IgE-AAbs and CSU? 2. Are IgE-AAbs increased in CSU patients vs HCs?

1. Unknown 2. Yes, in some studies, but not in all

Low

� Evaluate if functional IgE-AAbs are risk factors for CSU development � Develop and standardize screening tests for type I autoimmunity

Consistency (reproducibility)

1. Have the risk ratios of IgE-AAbs been reproduced by others? 2. Are increased IgE-AAbs levels reproducibly detected in CSU?

1. No 2. Yes, in some studies, but not in all

Low

� Harmonize the global use of IgE-AAbs tests � Study the association between IgE-AAbs and a risk for CSU development and CSU severity in different centers worldwide

Biological plausibility

Are there mechanisms that connect IgE-AAbs with CSU?

Yes (See Table 7) Moderate � Characterize the role and relevance of IgE-AAbs in CSU pathogenesis � Test if some IgE-AAbs are more likely than others to cause CSU? Coherence

Is the link of IgE-AAbs and CSU coherent?

Yes High

Temporality Does the appearance of IgE-AAbs precede the development of CSU?

Unknown Insufficient

� Study temporal relationship between IgE-AAbs and CSU

Biological gradient

Do higher levels of IgE-AAbs increase the risk or severity of CSU?


� Assess the link between IgE-AAbs levels and CSU development and severity/activity

Experimental evidence

Are there epidemiological, clinical and/or laboratory data that show that changes in IgE-AAbs can alter CSU?

Indirect evidence only

Moderate

� Develop type I autoimmune CSU animal model � Test IgE-AAbs+ CSU patients for response to AAs provocation and IgE-AAbs depleting therapies

Specificity

1. Can IgE-AAbs induce CSU? 2. In patients who have them, are IgE-AAbs responsible for their CSU?

1. Unknown 2. Unknown

Insufficient

� Perform IgE-AAbs transfer studies � Test IgE-AAbs+ CSU patients for response to AAs provocation and IgE-AAbs depleting therapies

Analogy Is there evidence for pathogenic functions of IgE-AAbs?

Yes, in BP, RA, and SLE

Moderate � To better understand pathogenic relevance of IgE-AAbs in other diseases

Overall

Overall, how strong is the strength of evidence for a causal relationship between IgE-AAbs and CSU? Low

What is the level of causality for type I autoimmunity in CSU? Level 3 (of 5)

Abbreviations: IgE-AAbs = IgE-Autoantibodies; AAs = autoantigens; HCs = healthy controls; BP = bullous pemphigoid, RA = rheumathoid arthritis, SLE = systemic lupus erythematosus.

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Table 3. Evidence for a causal relationship between type II autoimmunity and CSU according to Hill’s c riteria

Criteria Questions to the literature Answers Evidence Unmet needs

Strength of association

1. What are the CSU risk ratios for IgG-anti-FcεRI/IgE? 2. Are IgG-anti-FcεRI/IgE increased in CSU patients vs HCs?

1. Unknown 2. Yes, in many studies, but not in all

Moderate

� Evaluate if functional IgG-anti-FcεRI/IgE are risks factors for CSU development � Standardize and harmonize the use of tests for IgG-anti-FcεRI/IgE

Consistency (reproducibility)

1. Have the risk ratios of IgG-anti-FcεRI/IgE been reproduced? 2. Are increased IgG-anti-FcεRI/IgE levels reproducibly detected in CSU?

1. No 2. Yes, in many studies, but not in all

Moderate

� Multi-center use of IgG-anti-FcεRI/IgE tests � Study the association IgG-anti-FcεRI/IgE and CSU risk and CSU severity in different centers worldwide

Biological plausibility

Are there mechanisms that connect IgG-anti-FcεRI/IgE with CSU?

Yes (see Table 7)

High

� Characterize the role and relevance of IgG-anti-FcεRI/IgE in CSU pathogenesis � Determine why IgG-anti-FcεRI/IgE in some but not all CSU patients activate mast cells Coherence

Is the link of IgG-anti-FcεRI/IgE and CSU coherent?

Yes

Temporality Does the appearance of IgG-anti-FcεRI/IgE precede CSU?


� Study temporal relationship between IgG-anti-FcεRI/IgE and CSU

Biological gradient

Do IgG-anti-FcεRI/IgE levels correlate with CSU risk/severity?

Indirect evidence only

Low - Moderate

� Assess the link between IgG-anti-FcεRI/IgE levels and CSU development and severity/activity

Experimental evidence

Are there epidemiological, clinical and/or laboratory data that show that changes in IgG-anti-FcεRI/IgE can alter CSU?

Yes High

� Study type II autoimmune CSU animal models � Test responses to provocation with or neutralization of IgG-anti-FcεRI/IgE

Specificity 1. Can IgG-anti-FcεRI/IgE induce CSU? 2. Is CSU due to IgG-anti-FcεRI/IgE in patients who have them?


� Perform IgG-anti-FcεRI/IgE transfer studies � Test IgG-anti-FcεRI/IgE+ CSU patients for response to depleting therapies

Analogy Is there evidence for pathogenic functions of IgG autoantibodies?

Yes, e.g. in PV, DM, SLE, BP

High � To better understand pathogenic relevance of IgG-anti-FcεRI/IgE in other diseases

Overall

Overall, how strong is the strength of evidence for a causal relationship between IgG-anti-Fc εRI/IgE and CSU? Moderate

What is the level of causality for type II autoimmunity in CSU?

Level 2 (of 5)

Abbreviations: HCs = healthy controls; PV = pemphigus vulgaris; DM = dermatomyositis; SLE = systemic lupus erythematosus; BP = bullous pemphigoid

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Table 4. Definitions of strength of evidence and Le vels of causality for Hill’s criteria 17-19

Strength of evidence

Description

High High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect

Moderate Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate

Low Low confidence that the evidence reflects the true effect. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate

Insufficient Evidence either is unavailable or does not permit a conclusion

Levels of causality

Description

Level 1 Causal relationship; well-conducted studies using realistic exposures have been replicated, and chance, bias, and confounding can be ruled out with reasonable confidence

Level 2 Causal relationship is likely, similar evidence to that for a causal relationship but important uncertainties remain

Level 3 Causal relationship is suggested by the evidence, but chance, bias, and confounding cannot be ruled out

Level 4 Causal relationship cannot be adequately inferred, the available studies lack the quantity, quality, consistency, or statistical power on which to base a decision

Level 5 Causal relationship is not likely, the evidence from several studies suggests that a causal relationship is unlikely

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Table 5. Serum IgE autoantibody reactivity in CSU p atients and controls (HCs) measured by immunoassays

Study IgE-AAbs Method CSU patients with high levels of IgE-AAbs, % (n/total)

HCs with high levels of IgE-AAbs, % (n/total)

IgE-AAbs is higher in CSU patients vs HCs

Shin et al.10 anti-TPO dELISA 8.3 (8/961) 0 (0/69) Yes

Hatada et al.9 anti-dsDNA, anti-Th, anti-Pe, anti-TG

dELISA –* (–*/85) –* (–*/67) Yes2

Altrichter et al.6 anti-TPO sELISA 54.2 (259/478) –* (–*/127) Yes Concha et al.5 anti-TPO, anti-TG dELISA 10 (23/20) 0 (0/12)5 –

Tedeschi et al.20 anti-TPO RIA 0 (0/38) 0 (0/114) No Gimenez-Arnau et al.21 anti-TPO ELISA 16.7 (2/12) – –

1Patients with aspirin intolerant chronic urticaria were included; it was not defined whether patients with inducible urticaria were excluded; 2the anti-dsDNA IgE levels were significantly higher in patients with CSU than in normal subjects, but no differences in the levels of thioredoxin-, peroxiredoxin- and thyroglobulin-reactive IgE were seen; 3one patient had anti-thyroid peroxidase IgE antibody and one patient had anti-thyroglobulin IgE; 4one of control subjects had autoimmune thyroiditis and two others had allergic rhinitis; 5patients with known Hashimoto’s thyroiditis but with no history of urticaria; *data were not shown in the paper; IgE-AAbs: IgE-autoantibodies; TPO: thyroid peroxidase; TG: thyroglobulin; dsDNA: double-stranded DNA; Th: thioredoxin; Pe: peroxiredoxin; BAT: basophil activation test; ELISA: enzyme-linked immunosorbent assay; HCs: healthy controls; RIA: radioimmunoassay; dELISA: direct ELISA; sELISA: site-directed human IgE capture ELISA; –: no data

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Table 6. Prevalence of IgG-anti-Fc εRI and IgG-anti-IgE in CSU patients and control sub jects

Study Method

CSU patients with high levels of IgG-

anti-Fc εRI/IgE, % (n/total)

Controls with high levels of IgG-anti-Fc εRI/IgE, % (n/total)

AAbs in CSU > controls?

HCs Other HCs Other

IgG-anti-Fc εRI

Sun et al.26 ELISA –* (–*/100) –* (–*/100) – Yes – Lee et al.96 ELISA 47 (19/40) 10 (2/20) – – –

Mozena et al.97 ELISA 60 (12/20) – – – – Eckman et al.29 IEMA 59 (43/73) 57 (13/231) – No – Vonakis et al.98 WB 21 (3/14) 0 (0/7) 25 (3/126) – – Vasagar et al.31 WB 22 (2/9) 43 (3/7) 25 (2/87) No No Staubach et al.73 ELISA, WB 18 (10/55) – – – –

Pachlopnik et al.32 ELISA 02 (0/19) 02 (0/3) – No – Hidvegi et al.25 WB 34 (17/50) 0 (0/9) – Yes – Sabroe et al.24 WB 41 (323/78) 0 (0/39) 0 (0/258) Yes Yes

Kikuchi and Kaplan85 WB 47 (122/260) – – – – Zuberbier et al.99 ELISA 35 (17/48) 0 (0/5) – Yes –

Ferrer et al.100 WB 64 (34/53) –* (–4,*/24) – Yes4 – Fiebiger et al.28 ELISA, WB 38 (106/281) 0 (0/41) 19 (339/17210) Yes Yes/No14

Tong et al.23 WB 4 (2/50) 0 (0/20) – Yes – Fiebiger et al.27 WB 37 (12/32) 0 (0/15) 0 (0/1511) Yes Yes

IgG-anti-IgE

Sun et al.26 ELISA –* (–*/100) –* (–*/100) – Yes – Cho et al.30 ELISA 0 (0/27) 0 (0/20) 0 (0/535) No No

Eckman et al.29 IEMA 47 (34/73) 30 (7/231) – No – Staubach et al.73 ELISA, WB 4 (2/55) – – – –

Atta et al.33 ELISA –* (–*/46) –* (–*/10) – No – Sabroe et al.24 WB 9 (7/78) 0 (0/39) 0 (0/258) Yes Yes Tong et al.23 WB 12 (6/50) 5 (1/20) – Yes –

Fiebiger et al.27 WB 69 (22/32) 26 (4/15) 73 (11/1511) No No Gruber et al.11 ELISA 50 (3/6) 0 (0/32) 52.9 (912/1713) Yes No

AAbs: autoantibodies; WB: Western blot; ELISA: enzyme-linked immunosorbent assay; IEMA: immunoenzymetric assays; HCs: healthy controls; AD: atopic dermatitis; SLE: systemic lupus erythematosus; BP: bullous pemphigoid;

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DM: dermatomyositis; RA: rheumatoid arthritis; PV: pemphigus vulgaris; AC: atopic control; CoU: cold urticaria; DU: dermographic urticaria; ChU: cholinergic urticaria; Ps: psoriasis; UV: urticarial vasculitis; 110 atopic and 13 non-atopic controls; 2low levels of anti-FcεRI autoantibodies in all tested blood samples; 3patients with immunoreactive histamine-releasing anti-FcεRI autoantibodies (n=20, 26%) and immunoreactive anti-FcεRI autoantibodies without histamine-releasing activity (n=12, 15%); 4some normal sera were positive and were considered to have insignificant titers; 5RA (27), SLE (26); 6AC (8), CoU (4); 7AC; 8DU (15), ChU (10); 9AD (0), Ps (0), SLE (3), BP (3), DM (16), PV (11); 10AD (32), Ps (30), SLE (15), BP (22), DM (45), PV (28); 11AD; 12CoU (5), UV (4); 13CoU (9), UV (8);14AD, Ps/other; *data were not shown in the paper; –: no data

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Table 7. Arguments that type I and II autoimmunity are underlying causes of CSU

Argument Type I

(IgE-AAbs) Type II

(IgG-AAbs)

Relevant? Evidence Ref Relevant? Evidence Ref Biological Plausibility

AAbs can activate mast cells / basophils � + 9, 10 � + 12, 41, 42 AAbs can activate mast cells via complement activation Ø N/A N/A � + 43, 44 Acute urticaria can be IgE/allergen-mediated � + 34 Ø N/A N/A Coherence

AAbs+ CSU patients have elevated total IgE levels � +/-5 6, 9, 10 Ø N/A N/A Other autoimmune diseases are common comorbidities � +1 6, 36 � + 36, 45 CSU wheals can show T cell infiltration � +2,4 37-39 � +2,4 37-39 Anti-autoimmune regulatory T cells are decreased in CSU � NPR NPR � + 46 Strong association with HLA alleles � NPR NPR � + 47 Cytokine profiles typical for autoimmunity � NPR NPR � +3 48 Biological Gradient

Presence of AAbs correlates with disease activity/severity � – 6, 10 � + 24, 54 Experiment

Injection of heterologous AAbs induces wheal Ø N/A N/A � + 62 Injection of autologous AAbs+ serum induces wheal Ø N/A N/A � + 24 Positive Prausnitz-Küstner test with AAbs or AAbs+ serum � NPR NPR Ø N/A N/A Omalizumab is an effective treatment � +*,** 7 � +*,*** 76 Cyclosporine A is an effective treatment � NPR* NPR � +*,**** 82, 83 Corticosteroids can be effective � NPR* NPR � NPR* NPR Plasmapheresis can be effective � NPR* NPR � +*,*** 55 Anti-CD20 (rituximab) treatment can be effective � NPR* NPR � +*,*** 79 IVIG treatment can be effective � NPR* NPR � +*,*** 78 Methotrexate treatment can be effective � NPR* NPR � +*,*** 80 Mycophenolate mofetil treatment can be effective � NPR* NPR � +*,*** 81 AAbs = autoantibodies; ASST = autologous serum skin test; HLA = human leucocyte antigens; IVIG = intravenous immunoglobulin; � = argument is relevant; Ø = argument is not relevant; + = there is evidence for argument; – = there is evidence against argument; NPR = no published results; N/A = data not analyzed; 1Altrichter et

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al. found significantly higher levels of IgG-anti-TPO levels in IgE-anti-TPO+ CSU patients as compared to IgE-anti-TPO- CSU patients; 2T lymphocytes were found in the upper and mid-dermis with a perivascular distribution in CSU wheals and the ASST response; 3Serum concentration of IL-17, IL-23 and TNF-α was significantly higher in CSU patients and ASST positive patients as compared to healthy control subjects and ASST negative patients, respectively; 4The presence of functional IgE/IgG-AAbs was not assessed; 5IgE-AAbs+ CSU patients had elevated total IgE levels in one study (Shin et al., 2015) but not in other (Altrichter et al., 2011, Hatada et al., 2013); * As of yet, no studies that compare the efficacy of treatment in AAbs-positive and AAbs-negative CSU patients have been published; **Omalizumab has been shown to be an effective treatment option for CSU patients with IgE-anti-TPO who are refractory to conventional treatment; ***Only few case reports or case series on the efficacy of treatment in CSU patients with functional IgG-AAbs have been published; ****Cyclosporine A has been shown to be an effective treatment option in CSU patients with functional IgG-AAbs who are refractory to conventional treatment.

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different subtypes of urticaria. Allergy 2000; 55:951-4.

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Fc(epsilon)RIalpha (alpha-subunit) in chronic urticaria. J Allergy Clin Immunol 1998; 101:672-6.

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IgG-anti-FcεεεεRI

IgG-anti-IgE

Autoantigen

Mast

cell

DEGRANULATION

Type I autoimmunity Type II autoimmunity

IgE-anti-self

C5a

Release of MBP, ECP, LTs, PAF, SCF, VEGF

Eosinophil

IgG-anti-FcεεεεRII

Wheals Itch Angioedema Flare

Release of mediators, e.g. histamine

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Downregulation of FcεRI expression

Mast

cell

IgG-anti-FcεεεεRI/IgE

Anti-dsDNA

Omalizumab/IgE-AAbs complexes

URTICARIA

Type I autoimmunity Type II autoimmunity

Skin

BloodAutoantigens

IgE-AAbs Omalizumab

IgE/IgG-anti-IgE complexes

Omalizumab/IgE complexes

IgG-anti-FcεεεεRI

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Systematic review methodology

To find relevant trials, we performed a Medline and Google Scholar search of the

literature published before March 2016 with the keywords “chronic urticaria” or

“idiopathic urticaria” or “autoimmune urticaria” or “chronic spontaneous urticaria” or

“autoreactive urticaria”. 3902 publications were found for “chronic urticaria”, 1145 for

“idiopathic urticaria”, 770 for “autoimmune urticaria”, 401 for “chronic spontaneous

urticaria” and 30 for “autoreactive urticaria”. After checking for doubles, titles and/or

abstracts of 3950 reports were screened, and the remaining relevant 92 publications

were included in the review. Full texts were obtained if available.

The identified literature was primarily evaluated by the first author and the last author.

To be included in the review, studies had to meet the following inclusion criteria: 1)

direct relevance to the specific issue (studies on IgE and/or IgG autoantibodies, studies

that included comparison groups, studies that describe mechanisms of skin mast cells

and/or basophils activation due to autoantibodies, etc); 2) no serious methodological

limitations in the study with respect to the quality of the information for the selected

outcome as determined by the assessors.

The Grading of Recommendations Assessment, Development and Evaluation (GRADE)

approach was chosen for the evaluation of the quality of evidence for Hill's criteria.1 The

overall strength/quality of evidence for each criterion was categorized as “insufficient”

(very low), “low”, “moderate” or “high”.2 Finally, we assigned established levels of

causality based on Hill's criteria (Table 4).3

The quality and strength of evidence were assessed independently by all authors for

each criterion and then discussed in detail between the assessors, taking into

consideration bias and limitations of studies. A consensus regarding the strength of

evidence and levels of causality was finally achieved during discussion.

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1. Schunemann H, Hill S, Guyatt G, Akl EA, Ahmed F. The GRADE approach and

Bradford Hill's criteria for causation. J Epidemiol Community Health 2011; 65:392-5.

2. Owens DK, Lohr KN, Atkins D, Treadwell JR, Reston JT, Bass EB, et al. Grading the

Strength of a Body of Evidence When Comparing Medical Interventions. In: Methods

Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville (MD); 2008.

3. Phalen RF, Phalen RN. Introduction to air pollution science: a public health

perspective. Burlington, Mass.: Jones & Bartlett Learning; 2013.

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