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Introduction

 

Itching, or pruritus, is associated with a wide range of
disorders from skin disease to systemic and psychiatric dysfunction, and
represents the most common skin presentation. It presents a major burden to
sufferers and is associated with a significant reduction in quality of life. Dermatological
presentations involving itch include atopic dermatitis, psoriasis and
urticaria, whilst systemic causes range from diabetes, cholestasis, uraemia and
malignancy to Grave’s disease, iron deficiency anaemia and polycythaemia vera
rubra. Despite itch being the commonest presentation secondary to skin disease,
historically, the topic has lacked detail. However, in the last 15 years, the
study of itch has intensified and has brought forward important considerations
for the future. This essay aims to analyse the burden associated with itch, the
mechanisms that lie behind it, as well as current treatment options and future
prospects.

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The burden of itch

 

Pruritus is defined as the sensation (itch) that induces
scratching behaviour 1. Pruritus can either be acute or chronic, with chronic
pruritus defined as lasting more than 6 weeks. Pruritus has been reported to be
the most prevalent skin symptom, with prevalence reported in the range of 8.4%
23. Other studies have reported higher rates, for example a German study
looking at pruritus prevalence in the general population reported a lifetime
prevalence of 22.6% 4.

Itch comes with many conditions, as will be described in
more detail below and is associated with a significant reduction in quality of
life, with interference with sleep being a profound factor 1. Chronic
pruritus presents a particularly difficult clinical problem; it has been found
to be as debilitating as chronic pain, and, moreover, psychological
comorbidities such as mood disturbances and anxiety are common and can
sometimes exacerbate the problem 56.

Itch in dermatology

 

It has been reported that in general practice, 50% of
patients presenting with a dermatological issue report pruritus as their main
symptom 2. Several dermatological disorders are associated with pruritus;
these include but are not limited to atopic dermatitis, psoriasis,
infestations, advanced age pruritus and chronic urticaria 1. Atopic
dermatitis is one of the most pruritic skin diseases, with sufferers often
scratching until bleeding results 7. Atopic dermatitis is thought to arise
from skin barrier disruption, which increases the inflammatory component of the
disease, compromising the skin barrier even further. The pruritus also promotes
inflammation, as does the altered Microbiome of the patient 8. With regard to
therapy, there is a clear unmet need. Current research is investigating the
promise of biological agents in the future treatment of this disease 8.

Itch in systemic disease

 

Cholestatic itch, itch in Chronic Kidney Disease (CKD) and
haematological causes of pruritus are all examples of how a systemic
dysfunction can lead to itch 1. Systemic causes vary from metabolic disorders
to infections, haematological diseases, endocrine disorders and paraneoplastic
diseases 9. Uraemic patients represent one of the commonest patient groups to
experience pruritus with more than 40% of haemodialysis patients suffering from
it 1011.

 

Other causes of itch

 

Certain psychiatric and neurological disorders and certain
drugs can also cause itch 1. Drugs known to produce itch include opioids,
anti-malarials such as chloroquinine and hydroxyethyl starch (12). One example
of a neurological cause is Brachioradial pruritus, which is thought to occur
due to nerve compression and usually presents with itch in the C4-C7 dermatomes
1. Pruritus is a common problem among psychiatric patients and presents
specifically in somatic symptom disorder, dermatitis artefacta and
obsessive-compulsive disorders (13). The role of pruritus in psychiatry can be
thought of as both a causative or exacerbating agent and a consequence of
certain psychiatric issues (14).

 

Mechanisms of itch

Peripheral mechanisms

 

Itch is detected by pruriceptors in the epidermis and
transferred to the dorsal root and trigeminal ganglia in the spinal cord via
afferent nerve fibres and then to the brain, where the central processing and
motor output (scratch) of the itch stimulus takes place 1516. Both
exogenous and endogenous mediators interfere with sensory nerve fibres in the
skin to produce itch. The sensory itch-relaying fibres are either A-delta
fibres or C fibres, with the former being the myelinated, fast-transmission
type. C fibres are subdivided into CMH fibres, responsive to mechanical and
heat stimuli, and CMi, which are responsive to histamine 15. Both of these
fibre sub-types are implicated in itch, with the histamine-sensitive fibre
releasing substance P and calcitonin gene-related peptide, thus potentiating
mast cell activation. On the other hand, the CMH fibres have been shown to
respond to cowhage, which mimics the sensation of clinical itch, such as in
atopic dermatitis 15. The histaminergic and non-histaminergic pathways are
entirely separate starting from the periphery in the skin. Each path involves
unique sets of receptors and mediators and travel separately to the central
nervous system 17. On a similar note, it is known that itch and pain are similar
modalities, however, it has not been elucidated fully whether there exits
fibres specifically responsible for transferring itch as a separate modality to
pain 15. When it comes to chronic itch, both the peripheral and the central
nervous systems can become sensitised such that the itch persists despite lack
of the stimulus. It has been shown though histological observation that in
cases of chronic itch due to atopic dermatitis, the epidermis is
hyper-innervated, thus allowing for itch sensitisation 18.

Three main receptor sub-types are
activated by itch stimuli, such as proteases and contact allergens leading to
the release of itch mediators. These include certain G protein coupled
receptors (GPCRs), Toll-like receptors (TLRs), cytokine families (IL 2 & IL
31) and, finally, the Transient Receptor Protein (TRP) channel family has also
been implicated in itch 1519. 

Given that anti-histamines are
not effective in most cases of itch, the previous importance attributed to
histamine as an itch mediator has subsided and current focus is placed on
GPCRs. Although the H1 receptor is a known player in itch, and is used as a
pharmacological target (H1 receptor blockers), it is no longer considered to be
the most salient 1518. Histamine-dependent itch signalling works mainly
through the subsequent activation of TRPV1 channels, whilst non
histamine-dependent signalling involves GPCRs and TRPA1 channels 20. TRPA1 is
a universal chemo-irritant receptor implicated in nociceptive and inflammatory
pain, headaches and migraines, and, of course, itch. Both TRPA1 and TRPV1
integrate information from several different noxious stimuli 21. Many
endogenous compounds that have implications for itch act upon this receptor.
These include, endothelin and serotonin, which acts on this receptor indirectly
via the serotonin receptor HTR7 22. The majority of currently recognised
pruritogens activate GPCRs, of which Mas-related G-protein receptors are of
importance. They are activated by some proteases and other substances including
anti-microbial peptides. Furthermore, Substance P (implicated in atopic
dermatitis) is not only active at Mas-related G-protein receptors but also the
neurokinin 1 receptor, targets for which are currently being investigated
further in clinical trials. GPCRs, as well as being implicated in synthesis of
the itch signal are also known to potentiate the signal mainly in the spinal
cord through being activated by prostaglandins and leukotrienes. Similarly, the
role of TLRs has not yet been found to be anything more than potentiating itch
transmission, despite certain variants being present in the nerve fibres in the
skin 15. TLR7, expressed by C-fibres, seems to play an important part in
non-histaminergic signalling 19.

Another important indirect
mediator of itch is interleukin 31 (IL 31), which has been shown to have a role
in atopic dermatitis and, moreover, the receptor is expressed on sensory
neurones. However, the indirect role is apparent given the slow onset of itch
after activation of the receptor via injection 1523. However, antibodies
for this receptor are currently being developed for the treatment of pruritus
15. 

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