Biomarkers of chronic urticaria: what are their role?

Full text

Biomarkers of chronic urticaria:
what are their role?
Biomarcadores na urticária crônica: qual o seu papel?
249
ABSTRACT RESUMO
A urticária é uma doença com comprometimento universal, e debi-
litante para a maioria dos pacientes. Caracteriza-se pela ocorrên-
cia de episódios de urticas, angioedema ou ambos, determinados
pela ativação de mastócitos e outras células inflamatórias com
a liberação de vários mediadores. Apresenta etiologia complexa
com fenótipos e terapias bem específicas. A urticária crônica
possui evolução recorrente e imprevisível, podendo estender-se
por anos. Caracteristicamente possui maior prevalência no sexo
feminino, com pico de ocorrência entre 20 e 40 anos. A doença
pode ser diferenciada pela gravidade, impacto na qualidade de
vida do paciente e resposta terapêutica. Biomarcador é uma
característica clínica ou laboratorial mensurável de algum estado
ou condição biológica, o qual pode influenciar ou prever a inci-
dência de desfecho ou doença. O objetivo deste artigo é realizar
uma revisão dos principais biomarcadores promissores e com
melhor evidência relacionados à duração, atividade da doença
e resposta terapêutica.
Descritores: Urticária crônica, angioedema, biomarcadores,
autoimunidade.
Urticaria is a disease of global importance that can be debilitating
for most patients. It is characterized by episodes of wheals,
angioedema, or both, determined by the activation of mast cells
and other inflammatory cells with the release of several mediators.
The etiology is complex, involving specific phenotypes and
therapies. Chronic urticaria has a recurrent and unpredictable
course that can last for years. The prevalence is typically higher in
females, with a peak incidence between 20 and 40 years of age.
The disease can be classified by severity, impact on quality of life,
and therapeutic response. A biomarker is a measurable clinical or
laboratory characteristic of a biological state or condition that can
influence or predict the incidence of outcome or disease. This study
provides a review of the main biomarkers considered promising
and with the best evidence related to duration, disease activity,
and therapeutic response.
Keywords: Chronic urticaria, angioedema, biomarkers,
autoimmunity.
Arq Asma Alerg Imunol. 2023;7(3):249-58.
Submitted June 09 2023, accepted Sep 16 2023.
Rossy Moreira Bastos-Junior1, Gabriela Andrade Dias2, Sérgio Duarte Dortas-Junior1,
Fabio Chigres Kuschnir2, Solange Oliveira Rodrigues Valle1
1. Hospital Universitário Clementino Fraga Filho - HUCFF-UFRJ, Immunology - Rio de Janeiro, RJ, Brazil.
2. Hospital Universitário Pedro Ernesto - HUPE-UERJ, Immunology - Rio de Janeiro, RJ, Brazil.
© 2023 ASBAI
Review Article
Introduction
Chronic urticaria (CU) is a common skin disease
with a negative impact on several aspects of patients’
lives. CU is characterized by the occurrence of wheals
and/or angioedema for a period of 6 weeks or longer.
It can be classified as chronic spontaneous urticaria
(CSU), when there is no specific trigger, or chronic
inducible urticaria (CIndU), in which symptoms are
induced by specific triggers.1,2
The lesions result from activation of mast cells
and other inflammatory cells, such as basophils and
eosinophils, and the subsequent release of their
mediators.3 CU has a recurrent and unpredictable
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250 Arq Asma Alerg Imunol – Vol. 7, N° 3, 2023
course that can last for years, with about 20% of
patients remaining symptomatic after 5 years. The
prevalence is typically higher in females, with a peak
incidence between 20 and 40 years of age. The
disease can be classified by severity, impact on quality
of life, and clinical outcome.1,3
Over the last decade, numerous studies have
been conducted in an attempt to elucidate the
mechanisms involved in the development of CU and
to identify potential biomarkers.4 A biomarker is a
measurable clinical or laboratory characteristic of a
biological state or condition that allows us to know,
for example, the state of a disease or the response
to a drug.5
The main difficulty in establishing biomarkers of
CU lies in the heterogeneity of the clinical presentation
and its complex pathogenesis. There are multiple
ways of mast cell activation, with the participation of
numerous cells and molecules, leading to different
endotypes and phenotypes. A better understanding
of these endotypes, through biomarkers, will help
better understand the course of CU and find targets
for new therapies.6
This study aimed to review the main biomarkers
considered promising and with the best evidence
related to disease activity, therapeutic response, and
natural course of CU.
Methods
We conducted a search in Science Direct, PubMed,
and Latin American and Caribbean Health Sciences
Literature (LILACS) databases for original articles,
reviews, guidelines, and consensus statements
published in the past 20 years by using the following
search terms: chronic urticaria, biomarkers, duration,
prediction, prognosis, and treatment.
Biomarkers
In CU, biomarkers are useful in assessing disease
severity, duration, and response to treatment.
Disease severity and duration
Several biomarkers of disease severity have
been studied, including exacerbations with the use
of nonsteroidal anti-inflammatory drugs (NSAIDs),
increased basophil CD203c expression, basopenia,
eosinopenia, autologous serum skin test (ASST),
C-reactive protein (CRP), erythrocyte sedimentation
rate (ESR), D-dimer, mean platelet volume (MPV),
vitamin D, interleukin (IL)-6, IL-18 IL-17, IL-23, tumor
necrosis factor alpha (TNF-α), lipocalin (LCN2), and
prothrombin fragment 1 + 2 (F1+2). However, the
strongest association has been demonstrated with
D-dimer, CRP, F1+2, MPV, and IL-6 3,7 (Figure 1).
Factors such as disease severity, presence of
angioedema, age, NSAID-induced exacerbation,
association with CIndU, presence of thyroid
autoantibodies, increased IL-6 levels, basophil high-
affinity IgE receptor (FcεRI) expression, and positive
ASST have been evaluated as predictors of disease
duration, but with conflicting results. There is weak
evidence that the presence of thyroid autoantibodies
is related to longer disease duration.3-5
Some studies have demonstrated that the
coagulation cascade may be activated in patients
with CSU.8,9 Plasma markers of thrombin generation
and fibrinolysis, such as D-dimer and F1+2, are
elevated in patients with CSU, suggesting that, upon
activation of endothelial cells, tissue factors are
released with subsequent activation of the extrinsic
coagulation cascade and secondary fibrinolysis. The
resulting thrombin can increase vascular permeability
and induce mast cell degranulation. However, there
are no changes in hemostasis or a higher frequency
of thrombotic events in CSU.8,9
F1+2 and D-dimer levels correlate with disease
activity. Mean F1+2 levels were higher in patients
with CSU than in controls (2.54 [SD 2.57] nmol/L vs.
0.87 [SD 0.26] nmol/L; p < 0.001), with moderate or
severe disease activity in 9 of 11 (82%) and 9 of 26
(35%) patients with elevated or normal F1+2 levels,
respectively (p < 0.025). Mean plasma D-dimer levels
were higher in patients than in controls (329 [SD
188] ng/mL vs. 236 [SD 81] ng/mL; p < 0.01), with
moderate or severe disease activity in 6 of 8 (75%)
and 11 of 29 (38%) patients with elevated or normal
plasma D-dimer levels, respectively (p < 0.00).10
In a retrospective study evaluating the relationship
between D-dimer, CRP, and fibrin degradation
products in 82 patients with CSU, high levels of these
markers were associated with greater disease activity
and, conversely, a decrease in these markers was
observed in controls.11 In a study of 141 patients with
CSU, disease activity was associated with D-dimer
but not with CRP, fibrinogen, MPV, or number of
platelets.12
A retrospective Korean study evaluated whether
D-dimer, CRP, and total IgE would be associated with
disease activity in adult patients with CSU (n = 48) or
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Arq Asma Alerg Imunol – Vol. 7, N° 3, 2023 251
acute urticaria (n = 46). D-dimer levels were higher in
patients with acute urticaria (1.3 g/L) than in patients
with CSU (0.7 g/L) and significantly correlated with the
Urticaria Activity Score (UAS) (acute urticaria r = 0.30;
p < 0.001; CU r = 0.37; p < 0.05). However, there was
no significant correlation between disease activity and
CRP or total IgE.13
In an Egyptian study, plasma D-dimer and
activated factor VII (FVIIa) levels were significantly
higher in patients with active CSU (n = 30) than in
controls (n = 30). D-dimer levels were lower in patients
with grade 1 severity and higher in those with grade
4 severity. Factor VIIa levels did not differ significantly
according to disease severity grades. After complete
disease remission, there was a significant drop in
patients’ D-dimer and FVIIa levels.14
In Brazil, D-dimer and CRP levels and the ASST
and UAS were evaluated in 55 patients with CSU. Mean
D-dimer levels were 0.85 (SD 0.324) mg/L. Statistical
analysis showed a strong and positive relationship
between UAS and D-dimer, where serum D-dimer
levels were elevated (> 0.5 mg/mL) in 22 patients; 18
of them (81.81%) were classified as having CSU with
an elevated activity score. It was observed that 32.7%
of patients required 3 or more medications to achieve
CSU remission during follow-up.15
CRP is produced by the liver and is a sensitive
serum marker of inflammation. It is elevated in
several diseases, including infections, neoplasms,
autoimmune diseases, cardiovascular diseases, and
gastrointestinal diseases. Compared with ESR, CRP
is a better marker of inflammation as it is less affected
by other factors such as size, shape, and number
of red blood cells, female sex, and pregnancy. CRP
has proven useful in determining disease activity,
prognosis, and treatment efficacy.7,16
The role of inflammation has been demonstrated
in studies of patients with CU. Several inflammatory
biomarkers have shown an important role in disease
activity and response to CSU treatment, especially
CRP. Increased CRP levels were found in patients with
CU and associated with other inflammatory markers
Figure 1
Biomarkers of chronic urticaria severity
CRP = C-reactive protein, MPV = mean platelet volume, IL-6 = interleukin 6,
F1+2 = prothrombin fragment 1 + 2.
MPV CRP
F1+2 IL-6
D-dimer
Disease
severity
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252 Arq Asma Alerg Imunol – Vol. 7, N° 3, 2023
(leukocytosis, neutrophilia, and elevated levels of IL-6,
C3 and C4), greater disease severity, impaired quality
of life, and positive ASST.7,17,18
A retrospective study was conducted in 2 centers,
involving 1253 patients with CSU, with the purpose of
evaluating the prevalence and relevance of elevated
CRP levels. One third of the patients (n = 418) had
high CRP levels, which were associated with positive
ASST (p = 0.009) and hypertension (p = 0.005) but
not with other possible causes or comorbidities of
CSU. CRP correlated with disease activity (p < 0.001),
impaired quality of life (p = 0.026), and inflammatory
and coagulation markers (p < 0.001).7
Grzanka et al. demonstrated that IL-17 and
CRP levels were significantly higher in patients
with CSU than in healthy individuals. Also, there
was a significant difference in IL-17 and CRP levels
between patients with CSU with mild, moderate-
severe symptoms and healthy individuals, with the
following CRP levels, respectively (expressed as
median [IQR/min-max]): 1.4 (20.92-23.55/19.28-
48.60) vs. 9.8 (20.92-24.08/18.85-62.73) vs. 0.4
(0.20-0.40/0.10-0.60) mg/L (p < 0.001). CRP did not
correlate significantly with IL-17.19
Two other studies found higher CRP levels in
patients with positive ASST (5.81 [SD 4.70] and 5.31
[SD 2.74]) than in those with negative ASST (2.89
[SD 4.85] and 2.53 [SD 1.27]) and controls (2.76 [SD
4.52] and 2.34 [SD 1.38]), as well as a correlation
between disease activity and CRP levels.20,21 Magen
et al. also evaluated MPV, as some studies have
indicated that MPV correlates with platelet function.
Large platelets are more reactive, and the presence
of large platelets in the blood is an in vivo indicator
of platelet activity. A significant positive correlation
was found between CU severity score and MPV in
patients with a positive ASST (r = 0.44; p = 0.001)
but not in patients with a negative ASST.21
Among pro-inflammatory mediators, IL-6 is
a promising biomarker in CSU due to its role in
promoting the inflammatory response. Elevated
IL-6 levels were detected in CSU, with a positive
correlation with CRP levels, and also in patients
with CSU in the active stage and with moderate to
severe disease.18,22,23 However, in a study evaluating
IL-18 and IL-6 levels in patients with CSU and
healthy controls, there was no statistically significant
difference between the groups, unlike other studies
that showed a correlation between higher levels of
these cytokines and disease activity.24
ASST is a non-specific test that assesses the
existence of autoreactivity, that is, the presence of
endogenous pro-inflammatory or wheal-inducing
factors, including autoantibodies, which are triggers
for mast cell and basophil degranulation. Positive
ASST is correlated with the presence of IgG anti-
FcεRI and IgG anti-IgE antibodies, responsible for
type IIb autoimmune CSU (aiCSU), whose diagnostic
criteria are as follows: (a) a positive in vitro bioassay
demonstrating autoantibody functionality (basophil
histamine release assay [BHRA] or basophil activation
marker expression, such as CD63 or CD203c by
flow cytometry); (b) positive autoreactivity (a positive
ASST) demonstrating the in vivo relevance of mast cell
degranulation and increased capillary permeability;
and (c) a positive immunoassay for autoantibodies
against FcεRIα (Western blot or ELISA) demonstrating
autoantibody specificity.25
Positive ASST has been associated with greater
disease activity, longer duration, and basopenia,15,26,27
but further studies are needed. A systematic review
of parameters associated with CSU duration and
severity found 8 studies demonstrating an association
between positive ASST and CSU severity, and 8
studies reporting no association.28
Increased FcεR1α expression with upregulated
CD203c expression on peripheral basophils is
observed in patients with CU. Aiming to investigate
whether increased basophil activation would be
associated with disease activity, basophil CD203c
expression was evaluated in 82 patients with CU and
21 healthy controls. Mean CD203c expression was
significantly higher in patients with CU than in controls
(57.5% vs. 11.6%, p < 0.001). Basophil CD203c
expression was significantly higher in patients with
severe CU than in those with non-severe CU (66.5%
[SD 23.3%] vs. 54.0% [SD 23.3%], p = 0.033).29
Autoimmune thyroid disease is frequently observed
in patients with CSU, as is the presence of
antithyroid antibodies. Anti-TPO IgG measurements
are recommended in international urticaria guidelines
to assess type IIb autoimmunity.1 The presence of anti-
TPO IgG has not been related to urticaria severity, but
some studies have associated it with disease duration.
A retrospective study found that 12% of patients with
CSU had anti-TPO IgG, and these patients had longer
disease duration than those without anti-TPO IgG.
However, there was no difference in disease severity.
The same study also reported that 70% of patients
had positive ASST and autologous plasma skin test
(APST), and both tests were associated with disease
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Arq Asma Alerg Imunol – Vol. 7, N° 3, 2023 253
severity.30 In 2004, Toubi et al. identified that ASST and
antithyroid antibodies were positive in 28% and 12%
of patients with CSU, with the disease lasting longer
in these patients than in those with negative ASST
and anti-TPO IgG. However, there was no association
with disease severity.31
Response to treatment
Non-sedating antihistamines at standard or high
doses are recommended as first- and second-line
treatment for CSU. However, up to 50% of patients
are refractory to high doses of antihistamines and
require other medications, such as omalizumab and
cyclosporine, to achieve complete symptom control.1
Predicting treatment efficacy before prescribing it is
essential to achieve remission, or if not possible, to
improve disease control, avoiding wasting time with an
ineffective therapeutic regimen. However, the validation
of biomarkers for this purpose remains poorly defined.
Studies have been developed using CRP, D-dimer,
total IgE, basophil CD203c and FcεRI expression,
IL-31, ASST, and BHRA, among others.3
High disease activity and high levels of weekly
UAS (UAS7), CRP, and D-dimer appear to be good
predictors of refractoriness to H1-antihistamines
(Figure 2). Low total IgE levels are strongly related
to poor or no response to omalizumab, and good
response to cyclosporine is predicted by the BHRA,
as demonstrated in a systematic review.32
Refractoriness to antihistamines
Some clinical biomarkers have been related to
refractoriness to anti-H1, including the presence
of comorbidities such as atopic asthma, rhinitis,
rhinosinusitis, thyroid diseases, and hypertension.
However, the evidence for this correlation remains
weak.33,34
In a retrospective study of 549 patients with CU,
more than 75% of patients were refractory to anti-H1,
and baseline UAS7 was the only parameter able to
predict refractoriness; approximately 90% of patients
with UAS7 > 16 required treatment with omalizumab
or cyclosporine.35 Another retrospective study of 385
Figure 2
Biomarkers of refractoriness to antihistamines
ASST = autologous serum skin test, CRP = C-reactive protein,
UAS7 = urticaria activity score 7.
ASST CRP
UAS7
D-dimer
Refractoriness
to
anti-H1
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254 Arq Asma Alerg Imunol – Vol. 7, N° 3, 2023
patients with CSU reported that patients refractory
to anti-H1 were characterized by a higher incidence
of angioedema, concomitant CIndU, positive ASST,
and higher baseline UAS (5.28 in the refractory group
and 3.32 in anti-H1 responders). Higher CRP levels
were also observed.36 The finding was confirmed in
a sample of 1253 patients with CSU, in which high
CRP levels were also correlated with refractoriness
to anti-H1.
When evaluating biomarkers of response to
levocetirizine in 84 patients with CU, 7.1%, 9.5%,
12%, 31%, and 47.6% of responders had elevated
levels of D-dimer, fibrinogen, ESR, CRP, and total IgE,
respectively, as well as 54.8%, 26.2%, 35.7%, 54.8%,
and 23.8% of non-responders, respectively.37
Montjoye et al., in a prospective study of 95
patients with CSU, found elevated CRP levels in anti-
H1 non-responders (p < 0.0001) and in more severe
diseases (p = 0.033). Plasma D-dimer levels were also
higher in non-responders (p = 0.008) and in patients
with concomitant autoimmune disease and/or with
autoantibodies (p = 0.016). Blood basophil counts
were lower in anti-H1 non-responders (p = 0.023)
and in patients with more severe disease (p = 0.023),
positive ASST (p = 0.001), and autoimmune disease
(p = 0.057).38
Coagulation activation has been studied in the
pathophysiology of CU. Tissue factor is expressed in
the eosinophils present in the inflammatory infiltrate
in urticaria, and thrombin is able to degranulate mast
cells. Therefore, an increase in plasma levels of
D-dimer, a marker of fibrinolysis, may be a potential
biomarker of refractoriness to anti-H1.37-39 Asero
reported that D-dimer levels were elevated in 0 of
41 patients (0%) with an “excellent” response to
cetirizine, 3 of 14 (21%) with a “good” response,
3 of 5 (60%) with a “partial” response, 18 of 23
(78%) with a “poor” response, and 7 of 8 (88%) non-
responders.39
The role of ASST as a biomarker of anti-H1
refractoriness is still controversial. Although some
studies have demonstrated this correlation,36,40 others
have not.41 Ye et al. found that ASST can be a good
marker of good response to treatment.27 Chanprapaph
et al. observed a correlation with the APST, but not
with the ASST30 (Figure 2).
Response to omalizumab
Omalizumab is a humanized anti-IgE monoclonal
antibody indicated for the treatment of anti-H1-
resistant CSU that has demonstrated good efficacy
and safety in clinical trials and real-life studies.1
Response to omalizumab can be classified by the
time of occurrence as fast, slow, or absent after
6 months of treatment or by type as complete
(UAS7: 0), good (UAS7: 1-6), partial (UAS7: 7-15), or
absent (UAS7 > 16), as proposed by Arnau et al.42
Furthermore, after discontinuing treatment, some
patients experience relapse, which in the OPTIMA trial
occurred in 50% of patients.43 Determining biomarkers
of initial response and relapse profiles is necessary in
the discussion with patients about treatment indication
and their expectations44 (Figure 3).
Low serum total IgE levels have been associated
with poorer response to omalizumab treatment.
Straesser et al. evaluated serum IgE levels in patients
with CSU divided into 4 quartiles. The odds ratio for
response to omalizumab was 13.8 for patients with
serum IgE levels at the 75th percentile (> 168.0 IU/
mL) than for those at the 25th percentile (< 15.2 IU/mL)
(p < 0.001).45 Marzano et al. reported similar data in
a study of 470 patients in which responders had mean
total IgE levels of 131.6 kUA/L and non-responders of
42.1 kUA/L (p < 0.0001).46
Baseline total IgE levels above 43.0 IU/mL that
increased by 2-fold or more at week 4 of omalizumab
treatment were correlated with improvement in CSU
at week 12 of treatment.47 Furthermore, baseline
total IgE levels appear to correlate with time to CSU
relapse after discontinuation of omalizumab treatment.
Higher IgE levels were associated with shorter time
to relapse of CSU symptoms after discontinuation of
omalizumab.48 Cugno et al. demonstrated that not
only IgE but also baseline D-dimer levels were higher
in responders than in non-responders to omalizumab
in CSU.49 Regarding D-dimer, this finding was not
reported by Marzano et al.46 Asero et al. evaluated
D-dimer levels before and 3 weeks after omalizumab
administration and found no difference between
responders and non-responders in baseline D-dimer
levels. However, responders showed a significant
drop after the second dose, indicating that D-dimer
may be a good marker of efficacy.50 Other markers,
such as a decrease in IL-31 and CRP levels and an
increase in basophil levels, were also identified as
markers of efficacy.38,51 IL-31 is produced primarily
by activated Th2 lymphocytes and skin mast cells
and plays an important role in the induction of chronic
skin inflammation, especially pruritus. Elevated
levels were found in patients with CSU, but with no
relationship to severity.51
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Arq Asma Alerg Imunol – Vol. 7, N° 3, 2023 255
Markers of type IIb autoimmunity, such as positive
ASST, BHRA, and basophil activation test (BAT) and
basopenia, have been associated with delayed or no
response to omalizumab.52
ASST and BHRA are used in the diagnosis
of autoimmune CU by assessing the presence of
serum autoreactivity and autoantibody functionality,
respectively. Positive ASST and BHRA have been
associated with a slow response to omalizumab, but
the evidence remains inconsistent. In the study by
Gericke et al., an analysis of the profile of omalizumab
responders showed that most BHRA-positive patients
responded only after the second injection, with a
median time to response of 29 days, whereas BHRA-
negative patients had a median time to response of 2
days. Only 1 of 39 fast responders was BHRA-positive,
whereas 8 of 17 slow responders were BHRA-positive
(p < 0.0001). Regarding the ASST, 12 of 33 fast
responders and 10 of 13 slow responders showed a
positive ASST (p < 0.012).53
Another marker that has been the target of
several studies is basophil FcεRI expression. Deza
et al. described that basophil FcεRI expression levels
before omalizumab treatment were significantly higher
in responders than in non-responders. Also, after
initiating omalizumab, there was a significant reduction
of almost 90% in basophil FcεRI expression about
1 month after the first dose, with a lower reduction
in non-responders than in responders, as well as
speed response, which showed the same response
profile.54,55
The expression of some receptors on the surface
of basophils has been related to disease severity.
Ye et al. showed that basophil CD203c expression
was higher in patients with severe CSU, suggesting
that the quantification of basophil activation and
CD203c expression measured by flow cytometry
may be used as a potential predictor of CSU
severity.29 Also investigated as a marker of response
to omalizumab and disease activity, upregulation of
CD203c was present in 18/41 individuals (43.9%), and
omalizumab was effective in 29/41 patients with CU
(71%). Of the 18 individuals demonstrating CD203c-
upregulating activity, only 9 (50%) experienced clinical
improvement with omalizumab. However, of the 23
without CD203c-upregulating activity, 20 (87%) had
a satisfactory clinical response (p = 0.02). Therefore,
having a negative result in the expression of these
markers predicts a greater likelihood of responding
to omalizumab.56
UAS7, a tool that assesses disease activity over
7 days, is used to assess disease severity in daily
practice and in clinical studies, and also to assess
response to treatment. A study evaluating UAS7
as a predictor of relapse after discontinuation of
omalizumab demonstrated that patients with high
baseline UAS7 and late response experienced rapid
relapse57 (Figure 3).
Response to cyclosporine
For non-responders to omalizumab, the
recommended treatment is cyclosporine, an
immunosuppressant that has a moderate effect on
the inhibition of mediator release from mast cells. In
contrast to other immunosuppressants with cytotoxic
action, cyclosporine does not suppress the bone
marrow and has no known risk of teratogenicity in
humans. Its efficacy in combination with second-
generation H1-antihistamines has been demonstrated
in clinical trials, but it is used as third-line therapy
due to a higher incidence of adverse effects, which,
however, is lower than that with long-term use of
corticosteroids.10
A systematic review showed strong evidence that
positive BHRA and the presence of low total IgE levels
are predictors of a good response to cyclosporine.32
Grattan et al. conducted a randomized clinical trial
that demonstrated a positive baseline BHRA in
72% of cyclosporine responders (vs. 11% of non-
responders).58 Two other studies showed that positive
BHRA is a predictor of remission with cyclosporine
treatment,59,60 but ASST does not appear to be a
good biomarker.58
Serum IgE levels were significantly lower in
cyclosporine responders (43.0 IU/mL) than in non-
responders (148.5 IU/mL) (p < 0.001), being negatively
correlated with the decrease in UAS7 at 3 months of
treatment.61 Endo et al. showed that low baseline
total IgE levels were associated with low UAS7 after
cyclosporine treatment.62
Asero reported that D-dimer levels showed a
highly significant negative correlation with response to
cyclosporine (p < 0.017); with 10 of 11 (91%) patients
with normal plasma D-dimer levels vs . 7 of 18 (39%)
patients with elevated plasma D-dimer levels showing
a completely successful response to treatment.63
It is clear that CU is a heterogeneous disease with
different phenotypes, possible clinical characteristics,
associated factors, and different clinical course,
as well as different degrees of response to the
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256 Arq Asma Alerg Imunol – Vol. 7, N° 3, 2023
treatments administered. It is particularly relevant to
identify biomarkers able to classify patients according
to their phenotype, possibly identifying underlying
immunological mechanisms in order to stratify patients
according to disease severity and prognosis and to
identify the best responders to any therapy, especially
to biological products. We highlight the importance of
using accessible biomarkers in clinical practice, such
as CRP, D-dimer, anti-TPO, total IgE, and UAS7.
However, further prospective studies are needed to
confirm these predictors and identify others.
Figure 3
Biomarkers of response to omalizumab
ASST = autologous serum skin test, BHRA = basophil histamine release assay, FcεRI = high-affinity IgE receptor,
CRP = C-reactive protein, IL-31 = interleukin 31, UAS7 = urticaria activity score 7.
Response Efficacy Relapse
Total IgE
ASST
BHRA
Fc RI expressionε
CD203c
D-dimer
CRP
IL-31
Basophils
UAS7
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Corresponding author:
Rossy Moreira Bastos-Junior
E-mail: dr.rossymbastos@uol.com.br
No conflicts of interest declared concerning the publication of this
article.
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