PATHOPHYSIOLOGY OF PRURITUS AND ITS MANANGEMENT

MODERATOR:DR. PUNEET BHARGAVA

INTRODUCTION

• Pruritus or itch refers to an uncomfortable sensation and emotional experience associated with an actual or perceived disturbance to the skin that provokes the desire to scratch

HISTAMINES

• prototypic pruritogen

PROTEASE PATHWAY

• binds to protease-activated receptors (PAR) to stimulate cutaneous mechanical-sensitive C-fibers

• The protease pathway plays an important role in itch transmission in AD and probably also in other chronic pruritic conditions

• the management of pruritus is to target the specific components in the protease pathway, which consists of PAR-2 and endogenous proteases.

• These endogenous proteases includes serine proteases, such as mast cell tryptase26,27 and kallikreins28, and cysteine proteases, such as Cathepsin S29

Opioid system

• that an excess of mu-opioid receptor activity in comparison to kappa-opioid receptor activity results in pruritus and stimulation of the kappa-opioid receptor was found to inhibit mu-receptor effects both centrally and peripherally

• cholestasis, uraemia and dermatologic diseases

Interleukin-31

• higher levels of IL-31 have been found in the lesions of patients with AD and prurigo nodularis.

• IL-31 may exert its pruritogenic effect by directly binding to its receptors on cutaneous nerve fibres

Vanilloids

• endogenous and exogenous agents that possess the ability to activate transient receptor potential vanilloid (TRPV) ion channels either directly or indirectly

• Activation of TRPV1 results in excitation and subsequent desensitisation of C-fibres through depletion of neuropeptides, a mechanism which has been utilised to alleviate pain and itch

• Mediate histamine-induced itch via activation of phospholipase A2 and 12-lipoxygenase

• A/w chronic pruritic diseases, particularly those of neuropathic origin

Neurotrophins• Neuropeptides that regulate the growth and function of nerve

cells• Neurotrophin is nerve growth factor (NGF), whose main

sources are keratinocytes and mast cells. • NGF has been shown to result in proliferation of nerve fibres

and upregulation of neuropeptides, such as substance P. In AD lesions, higher levels of NGF have been found in keratinocytes in the epidermal basal and spinous layers, and increased density of NGF receptors, known as tropomyosin-related kinase A (Trk A), have been noted in the epidermis and upper dermis.

• The level of NGF in the stratum corneum also correlated with the severity of itching and eruptions in AD.

• Increased NGF and TrkA immunoreactivities have been detected in prurigo nodularisand pruritic psoriatic lesions

Substance P-Neurokinin Receptor

• neuropeptide mediating itch and neurogenic inflammation.• It is a tachykinin that binds to neurokinin receptors (NKR) 1 to

3 but has the highest affinity for NKR-1.• NKR-1 is expressed in the central nervous system and the skin

and NKR-1-expressing neurons in the superficial dorsal horn of the spinal cord were found to be involved in itch transmission

• Sezary syndrome, erythrodermic cutaneous T-cell lymphoma, metastatic sarcoma and breast carcinoma, erlotinib-induced itch, and chronic refractory pruritus

OTHERS

• lysophosphatidic acid (LPA) functioned as a pruritogen in the sera of patients with cholestatic liver disease

• Mas-related G-protein-coupled receptors (Mrgprs), a family of G protein-coupled receptors expressed exclusively in peripheral sensory neurons,function as receptors in chloroquine-induced itch

• Acetylcholine is the main neurotransmitter in the autonomic nervous system, and may have a role in mediating pruritus. Elevated expression of acetylcholine has been found in the skin of AD patients

• Cannabinoids also have role in histamine-induced itch and vasodilatation in healthy volunteers

• functional Toll-like receptor 7 (TLR7) was found to be expressed in C-fibre sensory neurons and was important in mediating itch induced by nonhistaminergic pruritogens in mice

• Role in human isn’t well established

CLASSIFICATION OF PRURITUS• For differential diagnostic purposes, a classification

of 6 categories of pruritus is proposed• Category I: Dermatological diseases• Category II: Systemic diseases including diseases of

pregnancy and drug-induced pruritus• Category III: Neurological• Category IV: Psychiatric / psychosomatic diseases. • Category V: Mixed overlapping and coexistence of

several diseases• Category VI: Undetermined origins.

DERMATOLOGICAL DISEASES

• Pruritus is the most common accompanying symptom of many dermatological diseases

• Inflammatory diseases [e.g. atopic dermatitis (AD), psoriasis, urticaria]

• infectious diseases (mycotic, bacterial and viral infections, scabies, pediculosis, insect bites, folliculitis),

• autoimmune diseases (e.g. dermatitis herpetiformis, bullous dermatoses),

• neoplastic disorders (cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, and leukemic infiltrates),

• genodermatoses (e.g. ichthyosis vulgaris, Netherton syndrome)

MECHANISM OF PRURITUS

• Pruritus is generated in the epidermis and papillary dermis on nociceptors of unmyelinated C-fibers

T/T OF DERMATOLOGICAL PRURITUS

PRURITUS FROM SYSYTEMIC DISEASES

• Pruritus are renal insufficiency, cholestasis, lymphoma, polycythemia vera, solid tumors, and many others. Diseases of pregnancy and drug-induced pruritus are also divided into this group.

– Primary biliary cirrhosis – 80%– CRF --15-49%– Dialysis --90%– Hodgkin’s disease -- 30%– Non Hodgkin’s disease -- 15%– Polycyathemia Vera --30-50%

• The mechanism underlying systemic pruritus is multifactorial• Pathogenesis of uremic pruritus

– an immune-system derangement that results in a proinflammatory state

– an imbalance of the endogenous opioidergic system– a neuropathic mechanism– interleukin-2 serum levels were elevated in patients with uremic

pruritus.

• Lysophosphatidic acid (LPA) and autotoxin (an enzyme that produces LPA) were identified as a potent pruritogen in pruritus of cholestasis

• Cytokines (such as interleukin-6 and interleukin-8) are found to be closely related to pathophysiology of pruritus of lymphoma.

Neurological Pruritus Neurological or neuropathic pruritus terms as pruritus arising from diseases

or disorders of the central or peripheral nervous system by nerve damage, nerve compression, and nerve irritation. Common peripheral neuropathic pruritic diseases are postherpetic neuralgia (PHN), brachioradial pruritus (BP), Notalgia paraesthetica, keloid, and burn scars. Central neuropathic pruritic diseases include spinal tumors, Creutzfeldt-Jakob disease and multiple sclerosis. The itch sensation in most cases is chronic, persistent, and always accompanied with painful qualities (burning, stinging, biting, piercing, or tingling) and sensory damage (experienced as parasthesia, hyperesthesia, or hypothesia) in the affected areas.

Mechanisms are incompletely understood. Some of the proposed mechanisms include itch associated with local nerve damage; central neuronal deprivation of afferent input, and central hypersensitivity of nerve fibers.

• Therapeutic options for neuropathic itch are sparse. • Neuroleptic drugs were proven to be effective in neuropathic

pain, such as gabapentin and pregabalin

Botulinium toxin A injection has been reported to be successful for notalgia paresthetica and PHN neuropathic pain. Clinical efficacy and side effects need to be assessed in further studies.

Novel drugs (Anti-NGF antibodies, TrkA inhibitors) targeting neurotrophin-induced pruritus pathway may be useful in neurological pruritus therapy.

Pruritus with Psychiatric / Psychosomatic Diseases

•

In some circumstances, chronic pruritus is indeed unrelated to skin diseases, and the skin lesions are simply secondary to scratching behavior and are highly associated with mental state.

Psychiatric pruritus is considered psychiatric in origin, which is characterized as an excessive impulse to scratch, gouge, or pick at normal skin.

•Clinically, it has long been recognized that both acute stress (stressful life events) and chronic psychoemotional stress can precipitate or exacerbate pruritus and the scratching response.

• Gupta et al, found a direct correlation between depression and pruritus severity in patients with AD, psoriasis, and chronic idiopathic urticaria (CIU). And, a close association between pruritus severity and anger in CIU was also showed.

• Stress activates the nervous system in a number of ways. • SP-NKR1 pathway has been shown to be activated in response to stressful

stimuli, both in the central and peripheral nervous system.• SP is an important pruritogen in the induction and maintenance of

pruritus by binding to NKR1. And, a correlation between pruritus intensity and number of SP-positive nerves in lesional skin of psoriasis patients was observed.

• Interestingly, the Beck's Depression Inventory (BDI) score of the patients positively correlated with the number of SP and NKR1-positive cells in lesional skin.

• These indicate that stress and depression may influence pruritus via substance P and NKR1.

• The noradrenergic system, which is highly relevant to emotional reaction, was found to play a role in itch transmission. Descending noradrenergic system exerts a tonic inhibition of itch transmission in the spinal cord mediated by α-adrenoceptors.

• Pharmacological treatment

Tricyclic anti-depressant (TCA), such as doxepin, amitriptyline, and trimipramine, has additional anti-histaminic effects and is of benefit in dermatological conditions such as urticaria and pruritus.

• Neuroleptic medications are useful for the treatment of delusions of parasitosis, and the current drug of choice is pimizode.

• New anti-psychotics (e.g. risperidone) are effective for psychotic syndrome and have a much safer adverse effect profile.

• Non-Pharmacological treatment

• Cognitive therapy• Behavior therapy• Combined therapy

Pruritus from Mixed Overlapping and Coexistence of Several Diseases

• Patients, especially elderly patients with chronic pruritus, always have multifactorial origins, among which, metabolic, endocrine, or hematological disturbances are most common

• Dry skin, reduced sweating, decreased production of sebum, thicker stratum corneum, impaired skin barrier also contributes to itching.

Pruritus of Undetermined Origin• Chronic pruritus with no detection of the underlying origin after

completion of diagnostic tests is called PUO, which accounts for up to 45% of all cases.

• Subclinical or subsided diseases are common reasons for PUO, and an association of as-yet unrelated diseases with pruritic conditions should be considered

• General principles should be followed before non-specific topical or oral anti-pruritus therapy (anti-histamine, corticosteroids). Opioid antagonists (naltrexone hydrochloride), and SSRIs were found to be effective treatment of severe PUO and gabapentin is recommended for treatment of PUO unresponsive to the usual treatment modalities

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