Pruritus in Atopic Dermatitis Martín Bozzola, MD Pediatric Allergy and Immunology Dept. of Pediatrics British Hospital – Buenos Aires

Disclosure No conflict of interest for this conference

Bieber, T. Atopic dermatitis. Global Atlas of Allergy. EAACI 2014 We have been listening about the immunological and pathophysiology mechanims in AD. I’d like to highlight a very important concept. Genetics is a neccesary condition, but it is not sufficient to cause any allergic disease. The environment trigger the genetical predisposition to provoke the atopic dermatitis or any allergic disease. In other words, genetics and environment interact between them to generate an allergic disease Bieber, T. Atopic dermatitis. Global Atlas of Allergy. EAACI 2014

AD – Diagnostic criteria Chronic relapsing inflammatory skin disease Xerosis – Epidermal barrier dysfunction IgE reactivity Increased prevalence 15%-20% in children 1-10% in adults The diagnostic criteria are known from many years ago. It is a chronic relapsing inflammatory skin disease, with xerosis, and a dysfunction of the epidermal barrier. It could be an IgE reactivitiy, and its prevalence have been increasing in the last 30 years. Nowadays, the prevalence rise 15-20% in children, and 1-10% in adults

Cardinal Symptom PRURITUS But the cardinal symtom in AD is pruritus

Pruritus - Definition Itch (or pruritus) has been defined as an unpleasant sensation that provokes the desire to scratch. And the definition of pruritus is: “pruritus (or itch) has been defined as an unpleasent sensation that provokes the desire to scratch. This is a simple definition that hides many aspects that we are going to talk in the next minutes

Modify of AAAAI Mechanical Trauma Nerve Elongation Factors Sweat Enviromental factors Irregular habits Mechanical Trauma Production of proinflammatory cytokines and chemoquines Leukocyte recruitment Leukocyte activation Atopic skin inflammation Pruritus IL-31 Histamine Proteases Neuropeptides Stress IL-31 IFN-g, IL-12, IgE, IL-4, IL-13, TSLP IL-1, IL-18, TNF-a, GM-CSF, TSLP, CCL17, CCL22, CCL27, CCL1, CCL18, CCL26, IL-16 TH-1 This is the cycle of AD. Many years ago it began with the production of proinflamatory mediators like cytokines and chemokines. The expression of these mediators induce the leukocyte recruitment to the site of inflammation. At this point the leukocytes became in an activated and express another profile of mediators that increase the recruitment of inflammatory cells. The TH2 cells induce a suppression of anti-microbial peptides that induce the bacterial colonization of the skin and the amplification of leukocyte recruitment. Il-31 appears close to another cytokynes that cause the atopic skin inflamation, and then the releasing of histamine, proteases, neuropeptides induce pruritus. But today the concept is different. The process of the cycle begin with pruritus. Itch is the key of the whole cycle. Nowadays, we should consider that AD is an inflammatory skin disease caused by pruritus. Itch is the first symptom in AD, and preceed the inflammation itself. Many environment factors trigger the pruritus in an hyperinnervated skin, causing the inflammation as a reflex TH-2 Allergens Bacterial products Suppression of anti-microbial peptides Bacterial colonization of the skin Modify of AAAAI

The nerve ending in skin has many receptors for the mediators of inflammation. The signal goes to the spinal cord and bring back a reflex that induced scratch, the mechanical trauma, and the inflammatory process in the skin.

Tominaga M. Biol. Pharm. Bull. 36(8) 1241–1247 (2013) These nerve endings penetrate the epidermal layer in the AD patients. There is an imbalance between the nerve elongation factors and nerve repulsion factors. As we can see in the upper picture, the nerves are in direct contact with the skin surface. This hyperinnervation could be the cause of the hypersensitivity in these patients Tominaga M. Biol. Pharm. Bull. 36(8) 1241–1247 (2013)

Itch increases at night From evening to night Itch increases at night Tº Sweat contains components that help on honeostasis skin. On the other hand we known that sweat is an aggraviating factor in AD. There are three mechanisms that could explain this. 1) the alterated components of sweat in allergic patients, 2) an abnormal perspiration and 3) leaving the excess of sweat without rising out could be a csuse of worsening of AD. The other point to stop is the increase of deep boby temperature. In patients with AD the temperature increase from evening to night and the icth follow this pattern. The strategies in treatment should be into account those characteristics in order to give the best comfort to patient. Leaving excess without rising out Alterated components Abnormal perspiration Modify from Allergology International 2017 66, 8-13DOI: (10.1016/j.alit.2016.10.005) Copyright © 2016 Japanese Society of Allergology

Measuring the itch Not easy Decrease the Quality of Life QoL questionnaires are not adecuated in every circumstance Scratch monitors in wirsts do not correlate the subjective complaints with the objective measures Decrease the Quality of Life Could I measure the itch? It is not easy, because que QoL questionnaires are not adecuated to measure a subjective symptom And the scratch monitors in wirsts do not correlate the complaints with de objective measures. But all we known that pruritus decrease the QoL Yarbrough, KB et al. Dermatol Ther 2013;26:110-119

Effective Treatment in AD Skin hydratation Identification and elimination of exacerbating factors Pharmacological therapy Ameliorate subjective symptoms Pruritus Insomnia An effective treatment of AD is based in four pillars Sher, LG et al. Acta Derm Venereol 2012;92:449-581 Yarbrough, KB et al. Dermatol Ther 2013;26:110-119

Pharmacological treatment - Meta analysis Group of drugs Effect 95% Ci P Pruritus decrease Calcineurin inhibitors (topical) 0.64 0.61-0.68 <0.001 36% Corticosteroids (topical) 0.66 0.58-0.75 34% Antihistamines (topical) 0.73 0.63-0.83 27% Immunosuppressants 0.88 0.78-.99 =0.037 12% Antihistamines (oral) 0.71 0.49-1.01 =0.058 NS Placebo 0.55 1.02-1.61 24% The pharmacological treatment has been study by many meta-analysis. At the top of the chart are the calcineurin inhibitors with a pruritus decrease of 36% Topical corticosteroids could decrease the itch by 34%, but not all the corticosteroids have the same effect over pruritus. The oral antihistamines are not useful in the treatment of pruritus in AD. So, we should to consider that is not a good option in the treatment of AD patients. Since 1964 we known that placebo could release the itch. The result of a recent meta-analysis indicate that the placebo can reduce pruritus in a 24% in all skin disease with itch Sher, LG et al. Acta Derm Venereol 2012;92:449-581 van Laarhoven, AIM et al. Journal of Investigative Dermatology 2015;135:1234–1243

Pharmacological Treatment Other immunosuppressors Cyclosporine Azathioprine Methotrexate Mycofenalate Systemic Corticosteroids Other drugs are demonstrated that could decrease the itch. Cicloporine can reduce the pruritus by 70%, but we should consider the adverse effects of this drugs. So, the indication is reserved to special situations. New drugs are actually in process of development. Anti IL-31, Anti-alfa IL-4 receptor, and phosphodiesterase-4 inhibitor. The last one has been approved recently, but it is not available in our country and we have not experience with it.

Key messages about Pruritus in AD Is the cardinal symptom in AD Is the first step in the inflammation cycle of AD Epidermal hyperinnervation could be responsible for itch sensitization Many inflammatory mediators worse pruritus (histaminergic and no- histaminergic) Avoid pruritus could be the first step in the treatment of AD Many pharmacological agents improve the pruritus, including placebo The key messages about pruritus could be summurize in this way, It is the cardinal symptom in AD Actually is consider as first step in the inflammation cycle of AD The epidermal hyperinnervation could be responsible for itch sensitization Many inflammatory mediators worse pruritus Avoid and prevent pruritus could be the first step in the treatment of AD 6) Many pharmacological agents improve the pruritus, including placebo