Itch without a rash. Pruritis, Itch is largely an aberrant response to a threat. 02-Sep-16. Objectives. Disclosures. Scratch, itch and dermatitis

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1 Itch without a rash Objectives Why do we itch? How do we itch? Compartmentalize Acute and Chronic models Prof. Pete Smith Allergist, Clinical Medicine Griffith University Director Allergy Medical Brisbane and Sydney Commercial in-confidence. Not for distribution. 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 Threat and evolution Scratch, itch and dermatitis We have not evolved to have allergies or itch, but we have preferential evolution because of our responses to threat. Scratch and itch. 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) 1

2 Itch is a key component of the morbidity of eczema Scratching There is a pleasure when an itch is scratched. But to be without an itch is more pleasurable still Strips the stratum corneum Mediator Release Fluid Loss Defective Barrier Dry skin Infection Buddhist philosopher Nagarjuna (C ) 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 Sensory nerves are normally protected mucin layer Intercellular lipids 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) tight junctions Airways GI Tract Conjunctiva Cornified envelope Skin 2

3 Antidromic Neuropeptide Release * Primed Mast Cell CGRP Substance P Edema NO, Bradykinin Vasoactive Intestinal Peptide Nicholas K. Mollanazar, Peter K. Smith & Gil Yosipovitch. Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out? Clinic Rev Allerg Immunol MAY Causes of Itch? Nicholas K. Mollanazar, Peter K. Smith & Gil Yosipovitch. Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out? Clinic Rev Allerg Immunol MAY Etiologic classification of itch according to the International Forum for the Study of Itch Dermatological Systemic Unknown Mixed Psychogenic 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 Forum for the Study of Itch. ActaDermVenereol2007; 87: Forum for the Study of Itch. Acta DermVenereol2007; 87:

4 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 Forum for the Study of Itch. ActaDermVenereol2007; 87: 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.) Forum for the Study of Itch. Acta DermVenereol2007; 87: 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 anorexia nervosa Forum for the Study of Itch. ActaDermVenereol2007; 87: Etiologic classification of itch according to the International Forum for the Study of Itch Dermatological Systemic Unknown Mixed Psychogenic Forum for the Study of Itch. Acta DermVenereol2007; 87: How do we develop itch / dermatitis? Compartmental Amplification Allergy / Inflammation Irritant Hormonal IgE & Non IgE Inflammatory Infection Acids, Hormones Integrity/Damage Proteolysis Disruption of outer lamellar layer increased TEWL ALARMINS Keratinocyte injury alarmins, ACh, TSLP, IL-33, IL-25 ACUTE Neural-receptor activation Neuro-mediator release CHRONIC Upregulation IgE Eosinophil Dendritic Cell Mast Cell Lymphocyte Immunological AMPLIFICATION * Primed Mast Cell CGR P Substance P NO, Bradykinin Edema Vasoactive Intestinal Peptide 4

5 Current (na) Histamine and Itch: sensory C fibres ITCH No ITCH Histamine works via Histamine H1 Inward flux of Ca ++ Histamine H1 No inward flux of Ca ++ capsazepine antagonist Phospholipase C & 12 Lipoxygenase Phosphorylation Phospholipase C & 12 Lipoxygenase Phosphorylation Shim WS, et al. mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 2007, 27: Histamine Histamine and Itch: sensory C fibres H1 Phospholipase C & 12 Lipoxygenase ITCH Inward flux of Ca ++ Phosphorylation Histamine H1 Phospholipase C & 12 Lipoxygenase No ITCH No inward flux of Ca ++ Phosphorylation KO EXPRESSED (capsaicin receptor) DRG Trigeminal Nerve Nerve Ganglia Epithelium Endothelium Glandular structures TRIGEMINAL ASSOCI ATE D SP EXPRESSION CGRP High Affinity NGF TrkA TNFa ION CHANNEL Preferential Calcium Channel (5-10x > Na+) Shim WS, et al. mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 2007, 27: Caterina, MJ et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature , Seki N, et al. Expression and localization of in human nasal mucosa. Rhinology : , Voltage (mv) Carlos Belmonte* and Félix Viana. Molecular and cellular limits to somatosensory specificity. Molecular Pain 2008, 4: capsaicin ph 6 heat 44 o C control 25 o C HEK239 transfected with : Whole cell ion channel voltage relationship Temperature / Acid / Capsaicin 100nM Polymodal sensory molecule Preferential calcium channel Hot, burning noxious stimuli Cumulative stimuli effect CaM PKA N T370 K160, L 163 C157 K155 T144 S116 R114 S502 H+ Mg2+ N604 E648 C66 E600 D645 C621 E636 C634 S512 T550 Y511 M547 Capsaicin E761 ATP S800 CaMKII Allicin PKC C T704 RTX CaM Pete Smith AWI Advisory Board 12 Dec 2015 Heat >42.6 o C 5

6 Histamine works via Histamine works via Smith PK and Nilius B. Transient Receptor Potentials (TRPs) and Anaphylaxis. Curr Allergy Asthma Rep Feb;13: Smith PK and Nilius B. Transient Receptor Potentials (TRPs) and Anaphylaxis. Curr Allergy Asthma Rep Feb;13: Orthodromic and Antidromic neural signaling Orthodromic and Antidromic signals Orthodromic Antidromic * Primed Mast Cell Antidromic Neuropeptide Release Substance P CGRP Protease / Anti-Protease Balance in the epidermis Edema NO, Bradykinin Vasoactive Intestinal Peptide 6

7 Protease-Anti-protease balance Proteases and Itch Environment meets genes Proteases (or lack or anti-proteases) increased TEWL block exogenous proteases infection allergens ph of skin increases and increases proteolytic enzyme activity increases TEWL block Anti-proteases imbalance trans-epidermal water loss endogenous proteins Cork M. J of Investigative Dermatology (2009). doi: /jid Smith PK, Harper J. Serpins: their inhibitors and Allergy. Allergy Dec ;61 (12): How do we develop itch / dermatitis? What investigations should we do? Allergy / Inflammation Irritant Hormonal IgE & Non IgE Inflammatory Infection Acids, Hormones Integrity/Damage Proteolysis Disruption of outer lamellar layer increased TEWL ALARMINS Keratinocyte injury alarmins, ACh, TSLP, IL-33, IL-25 ACUTE Neural-receptor activation Neuro-mediator release CHRONIC Upregulation How do we develop itch / dermatitis? Medications that can cause itch without a rash Allergy / Inflammation Irritant Hormonal IgE, specific RASTs Patch testing Pregnancy, TSH, T4 Renal and LFTs Integrity/Damage Antihypertensives Antiarrhythmic drugs Anticoagulants Anti-diabetic drugs Hypolipidemic drugs Antibiotics Psychotropic drugs Anticonvulsants Cytostatics ACE2Ra (sartans), b-adrenoreceptor antagonists, Ca channel blockers, Methyldopa, Sidenafil, Amiodarone Ticlopidine, Fractionated heparins Biguanides, Sulphonylurea derivates HMG-CoA reductase inhibitors (statins) Penicillins, Cephalosporins, Macrolides, Cabapenems, Monobactams, Quinones, Tetracyclines, Metranidazole, Rifampicin, Trimethoprim/Sulphamethoxazole, Antimalarials Tricyclic antidepressants, SSRA, Antipsychotics Carbamazepine, Phenytoins, Toprimates Tamoxifen, Chlorambucil, Paclitaxel, FBE, ESR, CRP Forum for the Study of Itch. Acta DermVenereol2007; 87:

8 Medications that can cause itch without a rash Growth Factors and GM-CSF, IL-2, Mauzumab, Lapatinib, Epidermal growth factor receptor Monoclonal Antibodies Plasma Expanders Others Hydroxyethyl starch Antithyroid agents NSAIDs Corticosteroids Sex Hormones Opioids Okay!! So how can we treat itch? Forum for the Study of Itch. ActaDermVenereol2007; 87: How do we treat itch / dermatitis? Allergy / Inflammation Integrity/Damage Reduce Allergen Exposure / Irritation / Damage / Nerve Stimulation + Barrier Corticosteroids (immune suppressants), Phototherapy Atopic Dermatitis a disrupted barrier Lamellar envelope Straum cornuem subdermis Cyclosporin, Antidepressants, Oral Retinoids, Pimecrolimus, Thalidomide Antihistamines LRTA Monoclonal Abs Vitamin D Treat infections Ion Channel Peripheral Nerve Central Pain normal eczema Pete Smith AWI Advisory Board 12 Dec 2015 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 The Barrier Function Sun Chemicals Infective Agents Barrier Water (and proteins) Zetterstin EM, et al. J. Am AcadDermatol 1997 Sept 47 (3 part 1)

9 Water Balance Pete Smith AWI Advisory Board 12 Dec 2015 In the upper epidermis, water is found predominantly in a bound form Natural Moisturizing Factor urea, lactic acid, pyrrolidine carboxylic acid etc. If not improving within 2 weeks of skin care and treatment - consider biopsy Filaggrin, intermediate filament and keratin Objectives Why do we itch? How do we itch? Compartmentalize Acute and Chronic models What investigations should we do How should we manage it? 9