Atopic dermatitis is a chronic inflammatory skin disease evolving

through a pattern of flares and remission, which affects 1–17% of adults

( Sacotte & Silverberg 2018). It is a chronic, relapsing inflammatory skin
condition that greatly affects patients’ quality of life, psychological
condition, and social relationships (Huang et al, 2021). The disease
typically manifests with eczematous lesions and itching and is
characterized by several pathogen tic features, such as dysfunction of the
epidermal barrier with skin impairment due to the mutation of skin
proteins and immune response misbalance (Nettis et al., 2020 & Morelli
et al., 2021).

Sometimes, it is difficult to determine how much disease severity affects

AD patients and their quality of life; there are many instruments for
assessing disease severity, but they are primarily used in clinical studies
and rarely used in clinical practice. Patients often struggle with various
mental disorders and illnesses, e.g., adult patients have a higher risk of
developing depression. Furthermore, with severe AD, there is an
increased incidence of depression, anxiety, behavioral disorders, and
autism; in adolescents with AD, the risk of developing attention deficit
hyperactivity disorder (ADHD) is 1.5 times higher on average (Dalgard et
al., 2015).

The aim of this study was to assess the association between level of
serum IL-33 in AD patients and healthy control subjects to determine the
association of high level of serum IL33 with AD. Also to determine
possible association between the serum level of IL-33 and severity of the
disease.
Most of our AD patients group (55%), had positive family history while
45% of them didn’t have with a significant difference p<0.05.

SCORing for Atopic Dermatitis (SCORAD) is a tool developed by the

European Task Force on Atopic Dermatitis (AD) which is used by
physicians to assess AD severity during consultations with their patients.
The SCORAD and its subcomponents (extent and intensity criteria for
lesions, and subjective symptoms composed of purities and sleep loss
scores) were calculated by the physician. The SCORAD score range is
between 0 and 103 points and defines three classes of AD severity (i.e.
mild if SCORAD <25, moderate if 25 ≤ SCORAD ≤ 50 and severe if
SCORAD > 50) (Faye et al., 2020).

In accordance to our results, where we found by comparison of serum

total non-specific IgE between healthy control subjects and AD patients
groups there was a significant statistical increase in patients group vs.
control where p-value was <0.001, Sanmeet Atwal & Peck, 2023
mentioned in their study that AD is associated with elevated serum total
IgE and specific IgE sensitizations. The reason for the elevation of IgE in
AD is not completely understood. We found also a positive correlation
between serum IL-33 & serum IgE in AD patients group, r=0.54 which is
statistically significant (p<0.05). This was agreed by Zhang et al., 2023
where they found the total IgE, eosinophil percentage, eosinophil and
serum IL-33 count were all significantly higher in children with allergic
asthma than those in healthy subjects.

Interleukin (IL)-33 is a member of the IL-1 cytokine family and a

promoter of T helper type 2 (Th2) inflammations. IL-33 may be involved
in the pathogenesis of AD, but its relationship with disease severity,
laboratory markers, and eruption types in patients with AD are unclear
( Tamagawa-Mineoka et al., 2014). Patients often single out itching as the
main symptom of the disease, but other symptoms are also common
(itching, 54.4%; excessive dryness and scaling, 19.6%; and inflamed skin,
7.2%) (Silverberg et al., 2018), which was similar with this study and
positive correlation between serum IL-33 & itching, was statistically
significant (p<0.001).

The pathogenic immunity of allergic diseases is characterized by

refractory inflammation and Th2-mediated immune responses. IL-33 has
been considered as an emerging key factor in the development of allergic
diseases. Increasing genomewide association studies have reported the
loci of IL-33 gene plays important roles in susceptibility of several
diseases such as asthma and allergic rhinitis. It can aggravate allergic
diseases by inducing pro-inflammatory cytokines production and Th2
type immune cell activation. The studies summarized current findings
regarding IL-33 and discussed its pathogenic role in allergic diseases
including atopic dermatitis, asthma, allergic rhinitis, chronic
rhinosinusitis, food allergy, allergic keratoconjunctivitis (Gupta et al.,
2017). Moreover, IL-33 down-regulates the β-defensin 2 expression in
human primary keratinocytes (Alase et al., 2012) and influences the
susceptibility to bacterial superinfection in acute allergic eczema of AD.

As mentioned by Metwalli et al., 2017, IL-33 is significantly high in atopic

and correlated with severity of the disease. This explains the role of IL-
33 in the pathogenesis of AD. IL-33 was statically higher in patents
(p=0.000) in patients than in healthy individuals. Our results showed
SCORAD score in all AD patients and was statistically significant and
positively correlated with serum IL-33 where p<0.001. But as regards
dividing the AD patients group according SCORAD score into severe and
mild & moderate groups, serum IL-33 was positively significant
correlated only with the severe group where p<0.001 while not
correlated with the mild & moderate group where p>0.05.

This study found also in the group of AD patients a highly significant

positive correlation between serum IL-33 pg/ml & itching, where
r=0.804; p<0.001. This was illustrated by Langanet al., 2020 that the
release of the alarmins TSLP, IL-33, and IL-25, together with
neuropeptides, not only trigger the induction and perception of itch; but
they also eventually stimulate the innate and adaptive immune systems.
This stimulation initiates and further propagates the predominant Th2
immune response in AD. Subsequently, several pro-inflammatory
mediators are released, either directly by type 2 innate lymphoid cells
(ILC2) or Th2 effectors lymphocytes or indirectly via the stimulation of
mast cells, basophils, or eosinophils. Many of these mediators can either
directly or indirectly stimulate purities in AD.

Also we found in this study that there was a statistically non-significant

correlation between serum IL-33 & duration, in month, of AD disease,
where r=-0.119; p>0.05. We suggested that it is the matter of AD disease
severity to make the elevation in serum IL-33 rather than the disease
duration.

The traditional treatment as corticosteroids are associated with systemic

adverse events and application site reactions, such as burning and
stinging (Eichenfield et al., 2014 & Åkerström et al., 2015). As such, new
treatments are needed for AD with robust efficacy and fewer adverse
reactions. Several therapeutic agents have been developed to inhibit the
IL-1 family members and their signalling pathways (Calabrese et al.,
2022). These have shown therapeutic efficacy in several chronic
inflammatory skin disorders. The aim of thier review was to thoroughly
describe the consequences of pathological dysregulation of the IL-1, IL-
33, IL-36 and IL-18 pathways in dermatological conditions and to
provide a forward-looking update on therapeutic strategies targeting
signalling by IL-1 family cytokines.

Conclusion & Recommendations:

- IL-33 may play a role in the inflammatory reaction in AD.

- There was elevation of IL-33 levels in sera of AD patients which
correlated with the disease severity and SCORAD score so it can be
considered as a severity marker in AD patients.

Recommendations for future studies:

- Large scales of patients in multicentre areas were needed to

confirm the findings of the study.
- The therapeutic potential of targeting IL-33 and ST2 is needed.
- The hope is that the elevated IL-33 levels will significantly reduce
after improvement of skin lesions by drug treatment.
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