Autoimmune chronic spontaneous urticaria: What we know and...
Transcript of Autoimmune chronic spontaneous urticaria: What we know and...
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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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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.
Type II autoimmunity
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.
Type II autoimmunity
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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Strength of evidence: Insufficient.
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.
Strength of evidence: Insufficient.
Type II autoimmunity
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.
Strength of evidence: Moderate.
Type II autoimmunity
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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
Strength of evidence: Insufficient.
Type II autoimmunity
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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Strength of evidence: Insufficient.
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.
Strength of evidence: Moderate.
Type II autoimmunity
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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22
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?
Unknown Insufficient
� 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?
Unknown Insufficient
� 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?
Unknown Insufficient
� 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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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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