What's new in atopic dermatitis: JEADV updated guidelines

Atopic dermatitis (AD) is a chronic inflammatory multifactorial cutaneous disorder that can have a high impact on quality of life, especially due to itch and pain. Itch is responsible for two of the cardinal clinical signs of AD (excoriations and lichenification). Itch and pain are the aspects of AD which patients' assess to see whether a treatment is working or not.

Though there are multiple treatments approved for it, a proper guideline to treat it is the need of the hour. International Society of Atopic Dermatitis (ISAD)/Oriented Patient-Education Network in Dermatology (OPENED) task force have laid down an update about and recommendations on management of atopic dermatitis which was published recently in the Journal of European Academy of Dermatology and Venereology.

Updates in pathophysiology of pain and itch in AD

Pain and itch are generally regarded antagonistic. There is overlap in mediators and functions of primary afferents of itch and pain. So, the development of chronic itch and pain including spontaneous activity and sensitization of primary afferents as well as spinal cord sensitization may overlap to a great extent.

Itch is partially or totally related to non-histaminergic nerve fibres and histamine effects may be restricted to acute itch. New data suggest antagonism of H4 receptors on inflammatory cells and sensory nerves may be effective in AD.

IL-31, IL-33 and TSLP can activate sensory neurons to evoke itch. Cytokines such as IL-1β, IL-6, TNF-a and IL-17A have been associated with pain. Agonists of protein-activated receptor PAR-2 agonists provoke enhanced and prolonged itch.

Therapy for atopic dermatitis

Topical therapy

Emollients

Protective action of emollients in preventing formation of potentially painful lesions as more important than direct pain relief because of their application. Cochrane systematic review on emollients and moisturizers for eczema did not find reliable evidence to support a particular emollient's superiority. Emollients should not contain any common contact allergens or ingredients that are irritating or sensitizing to the patient. Emollients should be prescribed in adequateamounts, and these should be used liberally and frequently, in a minimum amount of 250 g/week for adults and up to 100 g/week in young children

Topical corticosteroids (TCS)

TCS are the pharmacologic agents of choice. TCS are recommended for moderate and severe AD and for patients who do not respond to emollients alone. They are often very effective in reducing itch. The effect of TCS on pain in AD is not clear. The frequency of application varies upon the TCS used, and it is applied once to twice daily and then tapered progressively with two applications a week on the frequent flared areas for maintenance.

Topical calcineurin inhibitors (TCIs)

TCIs induce TRPV1 phosphorylation on neurons leading to their action. TCIs are applied twice a day and the duration of the treatment is until resolution of the acute phase. Use of TCI (2–3 times per week) on areas that flare frequently prevents relapses. It can also be a good option to start with a TCS to reduce inflammation and then switch to a TCI.

Antimicrobials and antiseptics

These are used to treat localized/widespread infections to which AD patients are predisposed to due to defective skin barrier.

Newer topical therapies

Crisaborole- It is a topical phosphodiesterase 4 (PDE4) inhibitor that reduces inflammation and itching by decreasing the levels of IL-4 and IL-31. It can rapidly relieve atopic dermatitis-associated pruritus as shown by its statistically significant results in many studies.

Topical Janus kinase (JAK) inhibitors- They are effective in AD associated pruritus by acting directly on sensory nerve fibres by blocking the transphosphorylation of cytokine receptors and consequently their activity. Tofacitinib and delgocitinib have showed statistically significant decreases in pruritus scores in patient of AD. They can be promising treatments for future. Only drawback that has been noticed is that they might induce pain on application.

Tapinarof- It modulates the aryl hydrocarbon receptor and is effective in decreasing pruritus in AD.

Wet-wrap therapy and bandage-It increases penetration of topical agents, decreases water loss and protects against scratching thus reducing complications (prurigo, lichenification, infection). It is suggested as a second-line treatment for severe or refractory AD in patients older than 6 months of age.

UV therapy

It is recommended in patients ≥ 18 years of age, while it may be considered in adolescents > 12 years of age. UV treatment has been demonstrated to be effective in the acute stage (UV-A1) of AD as well as in cases with chronic itch but effect on pain is poorly known. Treatment with narrowband UV-B is more effective than UV-A and narrowband is preferred over broadband UV-B. UVA1 is more effective than topical steroids. The application of medium-dose UVA1 (i.e. max. dose of 65 J/cm2) and narrowband UV-B is equally recommended for AD. It can easily be combined with other treatments, except for topical calcineurin inhibitors and systemic immunosuppressants.

Systemic treatments for AD

These are indicated in moderate-to-severe AD and refractory forms of disease, in association with the topical treatments.

Cyclosporine- It reduces the transcription of several itch mediators, such as interleukin (IL)-2 and IL-4. It can be used from the age of 2 years. It is generally recommended at an initial dose of 2.5-5 mg/kg/day for the first 2 weeks of treatment, with a gradual dosage reduction to 1.5–3 mg/kg/day, for a total treatment period of 6–12 months. Long-term cyclosporine therapy is not recommended for the risk of kidney toxicity.

Dupilumab- It is a monoclonal antibody (mAb) α-subunit of the IL-4 and IL-13 receptor complex. It has shown significant improvement in Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA) and SCORing Atopic Dermatitis (SCORAD) in studies. It rapidly reduces pruritus. It is well tolerated but non-infectious conjunctivitis is frequent.

Systemic corticosteroids- These should not be used in children and, in adults, should be reserved in cases of severe AD when other treatments are contraindicated or as a short-term therapy (up to 1 week) or for immediate relief before the beginning of other systemic therapies or phototherapy.

Other immunosuppressants- Methotrexate, azathioprine and mycophenolate mofetil are second-line treatment options of moderate-to-severe AD. Few studies have addressed the beneficial impact of methotrexate and mycophenolate mofetil on itch in AD but there is no study with azathioprine.

Antihistamines- They are frequently used but are not very effective compared to placebo. Hydroxyzine represents a common sedating H1-antihistamine choice. Long-term use of sedating antihistamines that is not recommended in children.

Newer therapies

Nemolizumab- It is a humanized anti-IL-31 receptor A mAb for treatment of AD-related pruritus. A single nemolizumab subcutaneous injection can reduce the pruritus score to approximately 50% by week 4.

Anti-IL13 mAbs- Tralokinumab or lebrikizumab are the drugs of this group. The dose of tralokinumab is 300 mg subcutaneously every 4 weeks which has demonstrated significant improvements in SCORAD, Dermatology Life Quality Index and pruritus numeric rating scale in AD patients at 12 weeks of treatment. The dose of lebrikizumab is 125 mg given every 4 weeks.

An orally administered histamine 4-receptor antagonist has shown good improvement in skin inflammation and itch in adults with moderate to severe AD at week 8 of treatment in a randomized controlled phase IIa study.

Systemic JAK/STAT inhibitors like baricitinib, tofacitinib and upadacitinib have been found effective for decreasing pruritus in AD.

Tezepelumab- It is a mAb targeting circulating thymic stromal lymphopoietin (TSLP) gave disappointing results in a phase 2a study on pruritis reduction in AD.

The European Guideline on Chronic Pruritus recently recommended glucocorticosteroids (topical and oral), cyclosporin A, mycophenolate mofetil, dupilumab, tacrolimus ointment, pimecrolimus cream and naltrexone for treatment of chronic pruritus. It described equivocal results with antihistamines (topical and systemic), azathioprine, methotrexate, apremilast and interferon γ. The antipruritic effects were only shown in case reports for intravenous immunoglobulins, UV-A1–/UV-B 311 nm/PUVA therapy, leucotriene antagonists, capsaicin, infliximab and omalizumab.

Gabapentinoids and antidepressants should be also used for treatment of AD associated pruritus and pain. When using analgesics (including gabapentinoids), the treatment of pain must be adapted to the intensity of pain as well as to the patient age and history.

Psychological approaches

Stress is also known to increase AD severity and itch. Therefore, treating the psychological aspects of itch is an important part of the management of chronic itch. Behaviour modifications should also be part of the programme in the intent to break the itch–scratch cycle. Studies have demonstrated the positive effect of psychological approaches on itch and scratching in AD. Relaxation techniques can also be very useful

A structured patient education on itch and pain in AD can lead to significant improvement of both the disease severity and coping behaviour in patients. Many treatments just have a placebo effect in AD so this placebo effect can also be an opportunity for healthcare professionals to verbal edify a treatment to bring out better results in AD patients.

In conclusion these guidelines highlight the importance of itch and pain management in atopic dermatitis, give a brief updated data on therapies to treat AD and show a path for better management of AD in todays' world.

Source-

Misery L, Belloni Fortina A, El Hachem M, Chernyshov P, von Kobyletzki L, Heratizadeh A, Marcoux D, Aoki V, Zaniboni MC, Stalder JF, Eichenfield LF. A position paper on the management of itch and pain in atopic dermatitis from the International Society of Atopic Dermatitis (ISAD)/Oriented Patient-Education Network in Dermatology (OPENED) task force. J Eur Acad Dermatol Venereol. 2021 Apr;35(4):787-796. doi: 10.1111/jdv.16916. Epub 2020 Oct 8. PMID: 33090558.