Jeuk anno 2016 Hok Bing Thio Dermatologie, ErasmusMC, Rotterdam Utrecht, 16 april 2016 h.thio@erasmusmc.nl

Disclaimer & Disclosure

The views as expressed in these slides are those of

Bing Thio.

The information shown in this slide deck may be

outside the current indications of presented drugs.

Please refer to the complete SmPCs for valid

prescribing information.

Bing Thio has been a consultant and invited speaker

for Biogen/Idec, Janssen, AbbVie, Celgene, Pfizer,

MSD, Galderma, Leopharma, Lilly, UCB and

Novartis. He has received educational grants from

AbbVie, Celgene, Janssen and Biogen/Idec.

zoom.nl

http://www.dermaamin.com

http://hubenyvonne.punt.nl

https://www.youtube.com/watch?v=_VhcZTGv0CU

https://www.youtube.com/watch?v=_VhcZTGv0CU

Laurent Misery, et al. Nature Reviews Neurology 10, 408–416 (2014)

“..an unpleasant sensation leading to a desire to scratch”

“..a pleasant sensation leading to a desire to scratch””

thesun.com

Pruritus: jeuk met eventueel verse excoriaties

Prurigo: jeuk met huidafwijkingen t.g.v.

chronisch krabben.

TERMINOLOGIE

http://www.dermaamin.com

Prurigo Nodules on Lichenified Skin in a Patient with Chronic Pruritus.

Yosipovitch G, Bernhard JD. N Engl J Med 2013;368:1625-1634.

Jeuk

Gegeneraliseerd

Gelokaliseerd

Fysiologisch

Huidziekte

Interne aandoening/paraneoplastisch

Geneesmiddelen

Psychogeen/psychiatrisch

Niet nader omschreven

Dermatological Atopic dermatitis

Bullous pemphigoid

Psoriasis

Urticaria

Pruritus ani

Systemic Cholestasis

Uremia

Hodgkin’s lymphoma and other malignancy

Polycythemia vera rubra

Graves’ disease

Iron-deficiency anemia

Diabetes mellitus

Infectious Human immunodeficiency virus (HIV) infection

Parasitosis (including scabies, trichinosis, ascariasis, and hookworm)

Varicella

Tinea pedis

Medication-related Mu-receptor opioids

Chloroquine

Neuropathic See Table 2

Psychiatric Depression

Delusional parasitosis

Neurotic excoriations

Other Pregnancy

Itch in the elderly

Dhand A, Aminoff MJ. The neurology of itch. Brain. 2013 Jun 22. [Epub ahead of print]

The “International Forum for the Study of Itch (IFSI)” several years ago proposed a purely clinical classification that primarily depends on the skin status: Pruritus associated with inflammatory skin diseases Pruritus associated with unaltered, non-inflamed skin Pruritus with chronic signs of scratching.

Staubach P, Metz M. Magistral formulations and pruritus therapy - What is established, what is confirmed, what is new? J Dtsch Dermatol Ges. 2013 Nov;11(11):1049-55.

Based on possible origin of pruritus

• pruritoceptive: pruritus arising in the skin

• neuropathic: pruritus resulting from peripheral nerve damage

• neurogenic: mediators produce pruritus in the CNS without nerve damage

• psychogenic

Classification of chronic pruritus Neuroanatomical classification

Metz M, Ständer S. J Eur Acad Dermatol Venereol. 2010 Nov;24(11):1249-60.

Hoofdluis

dermatology-s10.cdlib.org; BP

DH dermatlas.med.jhmi.edu

http://www.drguide.mohp.gov.eg/NewSite/E-Learning/Cases/Case62.asp

Jeuk

Gegeneraliseerd

Gelokaliseerd

Fysiologisch

Huidziekte

Interne aandoening/paraneoplastisch

Geneesmiddelen

Psychogeen/psychiatrisch

Niet nader omschreven

Jeuk (Pruritus)HUIDPASTA

Oorzaken van jeuk zonder zichtbare huidafwijkingen! H Hodgkin en andere maligniteiten zoals leukemie U Uremie (nierziekten), ook tijdens behandeling met haemodialyse I Icterus (leverziekten) D Diabetes mellitus en andere stofwisselingsziekten bijv. hyperthyreoidie en jicht P Psychogeen A Anemie (ijzergebreks- en andere bloedziekten als polycythemie) S Senilitas T Toxicodermie (geneesmiddeleneruptie) A Ankylostomiasis en andere worminfecties

Systemic diseases and pruritus • Liver diseases Primary biliary cirrhosis Primary sclerosing cholangitis Extrahepatic cholestasis Hepatitis B and C

• Kidney diseases Chronic kidney insufficiency

• Hematologic diseases Polycythemia vera Hodgkin disease Non-Hodgkin lymphomas Leukemias Myeloma multiplex Iron deficiency Systemic mastocytosis Hypereosinophilic syndrome Myelodysplastic syndromes

• Infectious diseases HIV infection/AIDS Infestations

• Endocrine disorders Hyperthyroidism

Hypothyroidism

Hyperparathyroidism Diabetes

• Neurologic diseases(neuro-pathic pruritus)

• Brain injury/tumor(frequently unilateral pruritus)

• Multiple sclerosis

• Small fiber neuropathy

• Solid tumors (paraneoplastic pruritus)

• Carcinoid syndrome

Reich A, Ständer S, Szepietowski JC. Clin Dermatol. 2011 Jan-Feb;29(1):15-23.

Table 1: Systemic diseases that can induce pruritus (examples) Metabolic and endocrine diseases o Chronic renal insufficiency o Liver diseases with or without cholestasis o Hyperparathyroidism o Hyper- and hypothyroidism o Iron deficiency Infective diseases o HIV and AIDS o Parasitoses including Helminthosis Haematological disorders o Polycythemia vera, myelodysplastic syndrome o Lymphoma e.g. Hodgkin lymphoma Neurological diseases o Multiple sclerosis o Brain tumors o Notalgia paresthetica o Brachioradial pruritus o Postzosteric neuralgia Psychiatric or psychosomatic diseases o depression o affective disorders o hallucinosis o obsessive and compulsory disorders o schizophrenia o eating disorders

Update of the Guideline on Chronic Pruritus, Feb 2014 Developed by the Guideline Subcommittee “Chronic Pruritus” of the European Dermatology Forum

Typical skin changes observed in patients suffering from chronic kidney disease-associated pruritus (CKD-aP). (a) Scratch marks with excoriations at the lower leg. (b) Typical hyperkeratotic partly excoriated nodules (prurigo nodularis) located on the forearm. (c) Deep scars and prurigo nodules at the shoulders and back of a female patient.

Mettang T, Kremer AE. Uremic pruritus. Kidney Int. 2014 Jan 8. doi: 10.1038/ki.2013.454. [Epub ahead of print]

drenginsayin.blogspot.com

Patient with postherpetic itch but no pain after ophthalmic zoster, who painlessly scratched through her skull during the first year after her zoster. She was left with residual traumatic brain injury.

Anne Louise Oaklander, Neuropathic Pain Study Group, Departments of Anesthesiology, Neurology, Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Pain 2002 96, Issues 1–2,, Pages 9–12 The Journal of Pain Volume 9, Issue 1, Supplement 2008 10 - 18

Diagnostic Workup for Chronic Pruritus.

Yosipovitch G, Bernhard JD. N Engl J Med 2013;368:1625-1634.

Pathways of Itch from Skin

to Brain.

Yosipovitch G, Bernhard JD. N Engl J Med 2013;368:1625-1634.

Buddenkotte J, Steinhoff M. Allergy. 2010 Jul;65(7):805-21.

Transient receptor potential cation channel subfamily M member 8 (TRPM8) Transient receptor potential cation channel subfamily A member 1 protein (TRPA1)

Metz M, Grundmann S, Ständer S. Vet Dermatol. 2011 Apr;22(2):121-31.

TRPV (Transient Receptor Potential Vanilloid)

In the healthy brain impermeant negatively charged proteins inside the neuron cause small cations such as sodium and calcium to enter from the extracellular space, producing a small dendritic inward current (Iin, pink arrow). Compensation for this constant inward current by dendritic outward current (Iout, green arrow) of the sodium pump establishes the so-called double Gibbs-Donnan equilibrium of the physiological ion distribution, characterized by iso-osmolality across the membrane and steep physiological ion gradients.

Jens P Dreier. Nature Medicine 17, 439–447 (2011)

Buddenkotte J, Steinhoff M. Allergy. 2010 Jul;65(7):805-21.

The major brain areas associated with the pleasurability of active scratching as revealed by GLM regression analysis. Regions which were activated (red) or deactivated (blue) by scratching are depicted. __(solid line) = positive correlation; ---- (dashed line) = inverse correlation with pleasurability ratings. Box size for each area is proportional to the magnitude of Z scores obtained in the regression analysis.

Papoiu AD, Nattkemper LA, Sanders KM, Kraft RA, Chan YH, Coghill RC, Yosipovitch G. Brain's Reward Circuits Mediate Itch Relief. A Functional MRI Study of Active Scratching. PLoS One. 2013 Dec 6;8(12):e82389.

Schematic synopsis of potential pathogenic factors in chronic kidney disease-associated pruritus (CKD-aP). CNS, central nervous system.

Figure 2. Overview of the itch-scratch cycle.

Papoiu ADP, Nattkemper LA, Sanders KM, Kraft RA, et al. (2013) Brain’s Reward Circuits Mediate Itch Relief. A Functional MRI Study of Active Scratching. PLoS ONE 8(12): e82389. doi:10.1371/journal.pone.0082389 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082389

Actief krabben

Passief krabben

Papoiu AD, Nattkemper LA, Sanders KM, Kraft RA, Chan YH, Coghill RC, Yosipovitch G. Brain's Reward Circuits Mediate Itch Relief. A Functional MRI Study of Active Scratching. PLoS One. 2013 Dec 6;8(12):e82389.

The dynamic effect of active or passive scratching an itch were analyzed in direct contrast to the itch condition. Actively scratching an itch (blue) deactivated the ACC, the ventromedial prefrontal Cortex, midbrain (VTA), while the effect of passive scratching was found only in the ACC (green). Standard Talairach space coordinates (x, y, z). The color tones displayed correspond to Z score values as depicted in the color bars (at the same scale). R = Right; L = Left.

Alfred J. Robison & Eric J. Nestler

Nature Reviews Neuroscience 12, 623-637 (November 2011)

http://www.brain.riken.jp/

Jeuk

Bing Thio H, Ronner E, Van Os-Medendorp A, Van der Snoek E (redactie). Jeuk. Diagnostiek en behandeling. Maarssen: Elsevier Gezondheidszorg, 2008. 142 pagina’s, prijs € 30,-. ISBN 978-90-2992-1.

Huisarts en Wetenschap, jaargang 2009, nummer 5:261-261

“……De kwaliteit van de verschillende hoofdstukken is zeer wisselend. Wat ik zelf het meest miste in het boekje is een goed hoofdstuk over de anamnese. Dit is nu beperkt tot een tabel met een aantal vragen. Wat de betekenis van een vraag is voor de diagnose wordt niet duidelijk. “

Francien Pingen

Anamnese bij jeuk

• Hoelang jeuk? Acuut, chronisch? Nocturnaal?

• Zichtbare huidafwijkingen? Constant aanwezig of aanvalsgewijs?

• Andere mensen in de omgeving ook jeuk?

• Kwaliteit en kwantiteit jeuk: VAS score, oppervlakkig, diep?

• Leeftijd: atopisch, paraneoplastisch, lever en nierfunctie, zwanger, postmenopausaal etc.

• Verergerende factoren: zweet, warmte, voeding, vakantie tropen, drugs etc.

• Andere ziektes inclusief psychiatrische

• Huidige medicatie

• Beroep

• Allergie/ Atopie

• Familie anamnese

Lichamelijk onderzoek bij jeuk • Algehele conditie: kenmerken van interne aandoening

• Huid: indien afwijkingen, primair of secundair tgv krabben? infectieus ?

• Dermografie

Dermatoses (in order of decreasing frequency)

Systemic diseases Neurogenic and psychogenic diseases (rare in children)

Infectious diseases by bacteria, viruses or fungi Urticaria Atopic dermatitis Psoriasis vulgaris Epizoonoses, for example, scabies, insect bites, pediculosis Mastocytosis Autoimmune disease (e.g., collagenoses, dermatitis herpetiformis, IgA linear dermatitis) Genodermatoses (e.g., neurofibromatosis)

Renal disease Hepatic disease Hematologic disease Drug-induced exanthemas/pruritus Neoplastic disease Endocrine disease Histiocytoses HIV/AIDS GvHD

Skin-picking syndrome (e.g., prurigo nodularis) Depression Obsessive–compulsive disorders Schizophrenia and other psychoses (e.g., delusional parasitosis) Tumors or abscesses of the CNS

Metz M, Wahn U, Gieler U, Stock P, Schmitt J, Blume-Peytavi U. Pediatr Allergy Immunol. 2013 Sep;24(6):527-39.

Examples of differential diagnoses of pruritus in children

Wang H, Papoiu AD, Coghill RC, Patel T, Wang N, Yosipovitch G. Br J Dermatol. 2010 May;162(5):1023-9.

Real-time computerized visual analogue scale (VAS) recording of burning and/or pain intensity rating in four ethnic groups in response to capsaicin application

Jeuk onderdrukt pijn en vice versa

Davidson S, Giesler GJ. Trends Neurosci. 2010 December; 33(12): 550–558.

The synaptic wiring in the spinal dorsal horn is largely hypothetical. Wiring like that in the example postulated here would afford spatial contrast enhancement of itch and suppression of itch by pain. The immunocytochemical markers (acronyms) are not necessarily coexpressed in one and the same neuron. (Slashes separate three different Mrgpr receptors, for brevity.)

Barbara Namer & Peter Reeh. Scratching an itch. Nature Neuroscience 16,117–118(2013)

Therapie jeuk

Jeukbehandeling

Ilkka T Harvima, Gunnar Nilsson Expert Rev Clin Immunol. 2012;8(3):235-241.

Stress and skin mast cell activation. A hypothetical

model is shown for the activation of the central and

local hypothalamic–pituitary–adrenal (CRH, ACTH,

α-melanocyte-stimulating hormone and cortisol)

system as well as sensory nerves and mast cells in

the psoriatic lesion during physical or psychological

stress. As a result of stress, neuropeptides SP and

VIP are released from C-fibers, and CRH is

produced locally or enters the tissue from blood

vessels. These factors activate mast cells to release

mediators, such as Try and Hist, that can activate

the corresponding receptors PAR-2 and H1.

Concurrently, PAR-2 and H1 activation on C-fibers

leads to axon reflex and spread of the signal. In

addition, cytokines, chemokines and VEGF are

produced by mast cells. Hence, a feedforward loop

is developed and inflammation potentiated. ACTH:

Adrenocorticotropic hormone; CRH: Corticotropin-

releasing hormone; CRH-R: Corticotropin-releasing

hormone receptor; H1: Histamine receptor; Hist:

Histamine; PAR: Proteinase-activated receptor; SP:

Substance P; Try: Tryptase; VIP: Vasoactive

intestinal peptide

Thurmond RL et al. Nature Reviews Drug Discovery 7, 41-53 (January 2008)

Histamine receptors: expression and function

Histamine receptor (discovered)

Expression site in the skin

Function in the skin Use of antagonists in

1 (1937) Sensory nerves, endothelia

Pruritus, neurogenic inflammation (erythema, vasodilation, edema)

Allergies, urticaria, atopic dermatitis pruritus

2 (1966) Endothelia Vasodilation (less than H1) Allergy, antacid, gastrointestinal diseases

3 (1983) Sensory nerves (mouse)

Pruritus (mouse) Dementia, psychoses, sleeping disturbances

4 (2000)

Mast cells, fibroblasts, hematopoietic cells

Pruritus, chemotaxis, mediator release

Not yet on the market

Ständer S, Raap U, Weisshaar E, Schmelz M, Mettang T, Handwerker H, Luger TA. Journal der Deutschen Dermatologischen Gesellschaft Volume 9, Issue 6, pages 456-463, 5 JAN 2011

Thurmond RL et al. Nature Reviews Drug Discovery 7, 41-53 (January 2008)

Commonly Used Topical and Systemic Medications for

Chronic Pruritus.

Yosipovitch G, Bernhard JD. N Engl J Med 2013;368:1625-1634.

http://www.likecroatia.com/news-tips/how-to-get-dirty-in-croatia/

Indifferente therapie naar droogte huid

• NORMAAL:

Creme Cetomacrogolcrème, lanettecrème

• DROOG:

Vette crème Vaselinecmgcrème,vaselinelanettecrème

Zalf koelzalf

• ZEER DROOG:

Vette zalf Cetomacrogolzalf, lanettezalf

Commonly Used Topical and Systemic Medications for

Chronic Pruritus.

Yosipovitch G, Bernhard JD. N Engl J Med 2013;368:1625-1634.

Zhang H, et al. 2012, 78: 532-44.

Dermatological Atopic dermatitis Psoriasis Chronic idiopathic urticaria Infestations (scabies, bed bugs, pediculosis, pinworms) Lichen planus Lichen simplex chronicus Prurigo nodularis

Non-Dermatological Liver disease Chronic kidney disease Hematopoietic disorders Neurological (e.g., brachioradial pruritus) Psychological (delusional ideations, depression, schizophrenia, stress) Substance abuse Advanced age (senile) pruritus Restless legs syndrome

Lavery MJ, et al. Int. J. Mol. Sci. 2016, 17(3), 425; doi:10.3390/ijms17030425

Nocturnal Pruritus: The Battle for a Peaceful Night’s Sleep

Lavery MJ, et al. Int. J. Mol. Sci. 2016, 17(3), 425; doi:10.3390/ijms17030425

Emerging pruritogens and potential new targeted therapies of some dermatological pruritic diseases

Zhang H, et al. 2012, 78: 532-44.

Pathogenesis of pruritus

Ständer S, Raap U, Weisshaar E, Schmelz M, Mettang T, Handwerker H, Luger TA. JDDG: Journal der Deutschen Dermatologischen Gesellschaft Volume 9, Issue 6, pages 456-463, 5 JAN 2011 DOI: 10.1111/j.1610-0387.2011.07585.x http://onlinelibrary.wiley.com/doi/10.1111/j.1610-0387.2011.07585.x/full#f1

Th2 cel dominantie en jeuk

Itchy mice: continu jeukende

muizen t.g.v. de afwezigheid

van de eiwit Itch, een E3

ubiquitine ligase.

De afwezigheid van Itch leidt

tot een Th2 cel dominant

immuunsysteem.

Deyu Fang et al. Dysregulation of T lymphocyte function in itchy mice: a role

for Itch in Th2 differentiation. Nature Immunology, March 2002.

Manolis Pasparakis, Ingo Haase & Frank O. Nestle. Nature Reviews Immunology 14, 289–301 (2014)

WanJun Chen. J Clin Invest. 2013;123(11):4576-4578.

Figure 1 TSLP bridging itch/scratch and AD progression. (A) Patients with AD scratch their pruritic skin promoting lesion formation and persistence. This patient had extensive chronic lichenified AD of his left arm but relative sparing of the right arm. ...

A new itch to scratch for TSLP

Matthew J. Turner , Baohua Zhou. Trends in Immunology null 2014 null

Schäkel K, Döbel T, Bosselmann I. Future treatment options for atopic dermatitis - Small molecules and beyond. J Dermatol Sci. 2014 Feb;73(2):91-100. doi: 10.1016/j.jdermsci.2013.11.009. Epub 2013 Dec 1.

acneeinstein.com

Gaffal E, Cron M, Glodde N, Tüting T. Allergy. 2013 Aug;68(8):994-1000. doi: 10.1111/all.12183. Epub 2013 Jul 29.

Anti-inflammatory activity of topical THC (∆9-tetrahydrocannabinol) in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors.

Transl Gastrointest Cnacer. Vol 1, No 2 (July 2012) / Hodges K et al.

Skin paraneoplastic syndromes that itch

Paraneoplastic syndrome Erythroderma Lesser Trelat Generalized granuloma annulare Grover's disease Dermatomyositis Bazex syndrome Malignant acanthosis nigricans

Associated malignancies Lymphoma, leukemia

Adenocarcinoma of gut, hematologic malignancies

Lymphoma, leukemia,

Hematological malignancies

Carcinoma of colon in men breast ovaries cancer in women

Nasopharangyeal carcinoma in Asians

Head and neck upper airway digestive tract carcinoma (pharynx, larynx, esophagous)

Adenocarcinoma of gut

Yosipovitch G. Dermatol Ther. 2010 Nov;23(6):590-6.

behavioralimmunology.com

Tomotaka Mabuchi et al. Journal of Dermatological Science. Volume 65, Issue 1, January 2012, Pages 4–11

http://medicalxpress.com/

Science News Magazine issue: Vol. 188, No. 11, November 28, 2015, p. 12

UP TO SCRATCH A group of nerve cells in the spinal cord of a mouse (red) curb mechanical itch, a new study suggests.

“Scratching is one of the sweetest gratifications of nature, and as ready at hand as any,”

16th-century French philosopher Michel de Montaigne.

Dank! h.thio@erasmusmc.nl