itch without a rash compartmentalize - healthed · pregnancy, prurigo of pregnancy, pemphigoid...

02-Sep-16

1

Itch without a rash

Commercial in-confidence. Not for distribution.

Prof. Pete SmithAllergist, Clinical Medicine

Griffith UniversityDirector Allergy Medical Brisbane and Sydney

Objectives

• Why do we itch?

• How do we itch?

• Compartmentalize

• Acute and Chronic models

• What investigations should we do

• How should we manage it?

Disclosures

• Patent in molecular pain 2 commercial

products + 2 Pipeline

• GU have patent

pending related to TRPs

and ACh in hypersensitivity

conditions

• Recent Wool Industry Advisory Board NFP Aus

• I also have a

multimedia / graphic design / medical

illustration company

• I also have a cosmetic

company

• Director of Allergy Medical in Sydney and

Brisbane

Pruritis, Itch is largely an aberrant response to a threat

• We have not evolved to have allergies or itch, but we have preferential evolution because of our responses to threat.

• Scratch and itch.

Threat and evolution Scratch, itch and dermatitis

• Most morbidity is secondary to scratching

• Scratching is a reflex designed to:

• 1. make the individual aware of a threat to avoid the threat

• 2. make the individual aware of a threat to remove it

• Part of the the activation of innate threat receptors in

the skin with atopic dermatitis activate ancient threat responses (epidermal, leukocytic and neural)

02-Sep-16

2

Itch is a key component of the morbidity of eczema

Buddhist philosopher Nagarjuna (C100-200)

There is a pleasure when an itch is scratched. ………

But to be without an itch is more pleasurable still

Scratching

Infection

MediatorRelease

Strips the

stratum

corneum

Fluid Loss

Dry skin

DefectiveBarrier

Neuronal Detection of Threat

Neuronal Detection of threat

Ruffini's corpuscle (sustained pressure/

stretch) Meissner's corpuscle (changes in texture, slow

vibrations) Pacinian corpuscle (deep

pressure, fast vibrations) Merkel's disc (sustained touch and pressure)

Free nerve endings (pain)

Neuronal Detection of threat

Ruffini's corpuscle (sustained pressure/

stretch) Meissner's corpuscle (changes in texture, slow

vibrations) Pacinian corpuscle (deep

pressure, fast vibrations) Merkel's disc (sustained touch and pressure)

Free nerve endings (pain)

Sensory nerves are normally protected

Skin

Airways

GI Tract

Conjunctiva

tight junctions

mucin layerIntercellular lipids

Cornified envelope

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Antidromic Neuropeptide Release

Substance P

CGRP

NO, Bradykinin

VasoactiveIntestinal

Peptide

Edema

* PrimedMast Cell

Nicholas K. Mollanazar, Peter K. Smith & Gil Yosipovitch. Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out? Clinic Rev Allerg Immunol MAY 1 2015

Nicholas K. Mollanazar, Peter K. Smith & Gil Yosipovitch. Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out? Clinic Rev Allerg Immunol MAY 1 2015

Causes of Itch?

Etiologic classification of itch according to the

International Forum for the Study of Itch

Dermatological Systemic Neurogenic

PsychogenicMixedUnknown

Ständer S, Weisshaar E, Mettang T, et al. Clinical classification of itch: a position paper of the International Forum for the Study of Itch. Acta Derm Venereol 2007; 87: 291–4

Dermatologic: arising from skin; dry skin and any

specific skin disease

Inflammatory: contact dermatitis, atopic dermatitis, asteatotic eczema,

nummular eczema, stasis dermatitis, seborrheic dermatitis, urticaria, psoriasis,

lichen planus, drug reactions, polymorphous light eruption, mastocytosis,

pemphigoid, dermatitis herpetiformis, dermatomyositis

Infections: pediculosis, scabies, parasitic disease, tinea corporis, impetigo,

smallpox

Neoplastic: cutaneous T cell lymphomas

Dermatoses of pregnancy: pruritic urticarial papules and plaques of

pregnancy, prurigo of pregnancy, pemphigoid gestationis


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Systemic: arising from diseases of organs other than

the skin, metabolic or other multifactorial disturbances or from drugs

Endocrine and metabolic disorders: chronic renal failure (dialysis), liver

diseases

with or without cholestasis, thyroid diseases

Infections: HIV, parasites, hepatitis C virus

Hematologic diseases: polycythemia vera, lymphomas

Tumors: solid organ tumors, carcinoid

Drug induced pruritus (with or without cholestasis


Neurologic (neurogenic/neuropathic): arising from

disorders of the central or peripheral nervous system and possibly also from liver disease

Multiple sclerosis; spinal or cerebral neoplasms, abscesses, or infarcts;

phantom itch; postherpetic neuralgia; transverse myelitis; notalgia

paresthetica; brachioradial pruritus; meralgia paresthetica; other conditions

associated with nerve damage, compression or irritation, such as

entrapment neuropathy, radiculopathy, or polyneuropathy (including

diabetes mellitus, vitamin B12 deficiency, etc.)


Psychogenic/psychosomatic

Delusion of parasitosis, psychogenic excoriations, somatoform pruritus, associated with psychiatric disorders

Mixed

Coexistence of dermatologic and neurologic itch in HIV infected patients or in patients with atopic dermatitis, association of uremic itch with skin xerosis, association of Hodgkin disease with potentially misleading paraneoplastic

cutaneous manifestations, such as unexplained adult onset eczema

Idiopathic

Senile 'idiopathic' pruritus, aquagenic 'idiopathic' pruritus, pruritus in anorexianervosa


Etiologic classification of itch according to the

International Forum for the Study of Itch

Dermatological Systemic Neurogenic

PsychogenicMixedUnknown


How do we develop itch / dermatitis?

• IgE & Non IgE

• Inflammatory

• Infection

• Acids, Hormones

Allergy /

InflammationIrritant

Hormonal• Proteolysis

• Disruption of outer lamellar layer increased TEWL

• ALARMINS

• Keratinocyte injury alarmins, ACh, TSLP, IL-33, IL-25

EpithelialIntegrity/Damage

Neurogenic

• ACUTE

• Neural-receptor activation

• Neuro-mediator release

• CHRONIC

• Upregulation

Compartmental Amplification

Immunological

Lymphocyte

Eosinophil

Dendritic

CellMast Cell

IgE

AMPLIFICATION

NeurogenicEpithelial

Substance

P

CGR

P

NO, Bradykinin

Vasoactive

Intestinal

Peptide

Edema

* Primed

Mast Cell

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5

Histamine works via TRPV1

Histamine and Itch: sensory C fibres

TRPV1H1

Histamine

Phospholipase C

&

12 Lipoxygenase

Phosphorylation

ITCH

Inward fluxof Ca++

TRPV1antagonist

No inward flux of Ca++

No ITCH

capsazepine

Shim WS, et al. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 2007, 27:2331-2337.

TRPV1H1

Histamine

Phospholipase C

&

12 Lipoxygenase

Phosphorylation

Histamine and Itch: sensory C fibres

TRPV1H1

Histamine

Phospholipase C

&

12 Lipoxygenase

Phosphorylation

ITCH

Inward fluxof Ca++

No ITCH

No inward flux of Ca++

Shim WS, et al. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 2007, 27:2331-2337.

H1

Histamine

Phospholipase C

&

12 Lipoxygenase

Phosphorylation

TRPV1 KO

TRPV1 (capsaicin receptor)

• Preferential Calcium Channel

• (5-10x > Na+)

ION CHANNEL

• SP

• CGRP

• High Affinity NGF TrkA

• TNFa

• DRG

• Trigeminal Nerve

• Nerve Ganglia

• Epithelium

• Endothelium

• Glandular structures

TRIGEMINALASSOCIATE

DEXPRESSION

EXPRESSED

Caterina, MJ et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997 389, 816–824Seki N, et al. Expression and localization of TRPV1 in human nasal mucosa. Rhinology 2006 44: 128–134, 2006

• Polymodalsensory molecule

• Preferential calcium channel

• Hot, burning noxious stimuli

• Cumulative stimuli effect

TRPV1

Carlos Belmonte* and Félix Viana. Molecular and cellular limits to somatosensory specificity. Molecular Pain 2008, 4:14

Voltage (mV)50 100 150-50-100

5

10

control 25oC

heat 44oC

pH 6

capsaicin

Cu

rre

nt

(nA

)

HEK239 transfected with TRPV1:Whole cell ion channel – voltage relationship

Temperature / Acid / Capsaicin 100nM

PKA

CaM

CaM

Allicin

ATP

CaMKII

T370

Capsaicin

PKC

RTXK160, L 163

C157

K155T144

S116

R114

S502Y511 M547

E761

S512

E600

T550

S800

T704

E636

D645

E648

C66

C621

C634

N604

N

C

H+ Mg2+

TRPV1

Heat

>42.6oC

Pete Smith

AWI Adv isory Board

12 Dec 2015

02-Sep-16

6


Smith PK and Nilius B. Transient Receptor Potentials (TRPs) and Anaphylaxis. Curr Allergy Asthma Rep. 2013 Feb;13:93-100.


Smith PK and Nilius B. Transient Receptor Potentials (TRPs) and Anaphylaxis. Curr Allergy Asthma Rep. 2013 Feb;13:93-100.

Orthodromic and Antidromicneural signaling

Orthodromic and Antidromic signals

Orthodromic

Antidromic

Antidromic Neuropeptide Release

Substance P

CGRP

NO, Bradykinin

VasoactiveIntestinal

Peptide

Edema

* PrimedMast Cell

Protease / Anti-Protease Balancein the epidermis

02-Sep-16

7

Proteases and Itch

Cork M. J of Investigative Dermatology (2009).doi:10.1038/jid.2009.133

• Environment meets genes

• Proteases (or lack or anti-proteases) increased TEWL

• pH of skin increases and increases proteolyticenzyme activity increases TEWL

Protease-Anti-protease balance

exogenousproteases

block

block

endogenous proteins

Smith PK, Harper J. Serpins: their inhibitors and Allergy. Allergy. 2006 Dec ;61 (12):1441-7.

infection allergens

imbalance

trans-epidermal water loss

Anti-proteases

What investigations should we do?


• IgE & Non IgE

• Inflammatory

• Infection

• Acids, Hormones

Allergy /


Hormonal• Proteolysis

• Disruption of outer lamellar layer increased TEWL

• ALARMINS

• Keratinocyte injury alarmins, ACh, TSLP, IL-33, IL-25


Neurogenic

• ACUTE

• Neural-receptor activation

• Neuro-mediator release

• CHRONIC

• Upregulation


• IgE, specific RASTs

• Patch testing

• Pregnancy, TSH, T4

• Renal and LFTs

• FBE, ESR, CRP

Allergy /


Hormonal


Neurogenic

Medications that can cause itch without a rash


Antihypertensives ACE2Ra (sartans), b-adrenoreceptor antagonists, Ca channel blockers, Methyldopa, Sidenafil,

Antiarrhythmic drugs Amiodarone

Anticoagulants Ticlopidine, Fractionated heparins

Anti-diabetic drugs Biguanides, Sulphonylurea derivates

Hypolipidemic drugs HMG-CoA reductase inhibitors (statins)

Antibiotics Penicillins, Cephalosporins, Macrolides, Cabapenems, Monobactams, Quinones, Tetracyclines, Metranidazole, Rifampicin, Trimethoprim/Sulphamethoxazole,

Antimalarials

Psychotropic drugs Tricyclic antidepressants, SSRA, Antipsychotics

Anticonvulsants Carbamazepine, Phenytoins, Toprimates

Cytostatics Tamoxifen, Chlorambucil, Paclitaxel,

02-Sep-16

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Medications that can cause itch without a rash


Growth Factors and Monoclonal Antibodies

GM-CSF, IL-2, Mauzumab, Lapatinib, Epidermal growth factor receptor

Plasma Expanders Hydroxyethyl starch

Others Antithyroid agents

NSAIDs

Corticosteroids

Sex Hormones

Opioids

Okay !!So how can we treat itch?

How do we treat itch / dermatitis?

Allergy /

Inflammation


Neurogenic

Reduce Allergen Exposure / Irritation / Damage / Nerve Stimulation + Barrier

Corticosteroids (immune suppressants), Phototherapy

Antihistamines

LRTAMonoclonal Abs

Vitamin D

Treat infections

Ion Channel

Peripheral NerveCentral Pain

Cyclosporin, Antidepressants, Oral Retinoids, Pimecrolimus, Thalidomide

normal eczema

Straum cornuem

Lamellar envelope

subdermis

Atopic Dermatitis– a disrupted barrier

The Golden Ratio

Cholesterol, ceramides and essential / nonessential free fatty

acids (FFAs) in an equimolar ratio allows normal barrier

recovery whereas any 3:1:1:1 ratio of these four ingredients

accelerates barrier recovery

Zetterstin EM, et al. J. Am AcadDermatol 1997 Sept 47 (3 part 1) 403-8

The Barrier Function

Barrier

Sun Chemicals Infective Agents

Water

(and proteins)

Pete Smith

AWI Adv isory Board

12 Dec 2015

02-Sep-16

9

Natural Moisturizing

Factor

In the upper epidermis, water is found predominantly in a bound

form

urea, lactic acid, pyrrolidine carboxylic acid etc.

Filaggrin, intermediate filament and keratin

Water Balance

Pete Smith

AWI Adv isory Board

12 Dec 2015

If not improving within 2 weeks of skin care and treatment -

consider biopsy

Objectives

• Why do we itch?

• How do we itch?

• Compartmentalize

• Acute and Chronic models

• What investigations should we do

• How should we manage it?

itch without a rash compartmentalize - healthed · pregnancy, prurigo of pregnancy, pemphigoid...

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