Use of Systemic Corticosteroids for Atopic Dermatitis

International Eczema Council Consensus Statement

A.M. Drucker; K. Eyerich; M.S. de Bruin-Weller; J.P. Thyssen; P.I. Spuls; A.D. Irvine; G. Girolomoni; S. Dhar; C. Flohr; D.F. Murrell; A.S. Paller; E. Guttman-Yassky

Disclosures

The British Journal of Dermatology. 2018;178(3):768-775.

Abstract and Introduction

Abstract

Background Guidelines discourage the use of systemic corticosteroids for atopic dermatitis (AD), but their use remains widespread.

Objectives To reach consensus among an international group of AD experts on the use of systemic corticosteroids for AD.

Methods A survey consisting of statements accompanied by visual analogue scales ranging from 'strongly disagree' to 'neutral' to 'strongly agree' was distributed to the International Eczema Council (IEC). Consensus was reached in agreement on a statement if < 30% of respondents marked to the left of 'neutral' towards 'strongly disagree'.

Results Sixty of 77 (78%) IEC members participated. Consensus was reached on 12 statements, including that systemic corticosteroids should generally be avoided but can be used rarely for severe AD under certain circumstances, including a lack of other treatment options, as a bridge to other systemic therapies or phototherapy, during acute flares in need of immediate relief, in anticipation of a major life event or in the most severe cases. If used, treatment should be limited to the short term. Most respondents agreed that systemic corticosteroids should never be used in children, but consensus was not reached on that statement. The conclusions of our expert group are limited by a dearth of high–quality published evidence. If more stringent consensus criteria were applied (e.g. requiring < 20% of respondents marking towards 'strongly disagree'), consensus would have been reached on fewer statements.

Conclusions Based on expert opinion from the IEC, routine use of systemic corticosteroids for AD is generally discouraged and should be reserved for special circumstances.

Introduction

In clinical practice guidelines and position statements concerning the management of atopic dermatitis (AD), the use of systemic corticosteroids (CS), including prednisone, hydrocortisone and celestone, is generally discouraged, with use limited to special circumstances (Table 1).^[1–8] While systemic CS can lead to rapid clearing of AD, their side–effect profile and the risk of severe rebound flares after discontinuation limit their use.^[9]

Evidence of the benefits and risks of systemic CS in AD is scarce.^[10] One randomized controlled trial (RCT) comparing ciclosporin with prednisolone ended early owing to rebound flares occurring in both groups, with 52% of subjects in the prednisolone arm experiencing such a flare.^[11] Systemic CS use in children with AD has been studied in two RCTs, but with very small sample sizes.^[12,13] Based on their use in other conditions, the long–term intermittent use of systemic CS is well known to cause a multitude of side–effects,^[14–16] and even use for 30 days or less has been associated with increased rates of sepsis, venous thromboembolism and fracture.^[17] A recent systematic review of studies in children taking systemic CS for > 2 weeks found significant increases in infections, growth delay and obesity.^[18]

Despite reasons for caution, systemic CS are still commonly used for patients with moderate–to–severe AD. In a recent clinical trial for adults with moderate–to–severe AD, which took place in North America and Europe, 36% of participants reported use of systemic CS in the year prior to the trial.^[19] Baseline data from a German registry of moderate–to–severe AD revealed that 13% of participants had been on systemic CS in the 3 months prior to enrollment,^[20] and in another German study, 10% of patients with AD had used systemic CS over 2 years.^[21] In a survey of 61 U.K. consultant dermatologists, 42% listed systemic CS as their first–line systemic agent for adult moderate–to–severe AD.^[22] In surveys of European and North American paediatric dermatologists, oral CS were the first–line systemic agents for severe paediatric AD for 31% and 5% of respondents, respectively.^[23,24]

To address the concern of inappropriate use and overuse of systemic CS for AD in clinical practice and to provide guidance for clinicians as to what circumstances may constitute appropriate use, a consensus process was initiated among the councillors and associates of the International Eczema Council (IEC).

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Table 1. Approach to systemic corticosteroid (CS) use in atopic dermatitis (AD) in various clinical practice guidelines and position papers
Group publishing manuscript	Selected statements on the use of CS for AD
ETFAD/EADV³	'[Systemic CS] should only be used for a few weeks for severe acute exacerbations due to the many long–term side–effects. A typical regimen for severe acute exacerbations would be methylprednisolone maximal 0·5 mg kg⁻¹ per day for 1–2 weeks and tapering over 1 month…In severe chronic cases, starting of another oral immunosuppressive therapy while tapering the [systemic CS] should be considered. [Systemic CS] must not be used for long periods of time due to significant risk of severe side–effects'.
EDF, EADV, ETFAD, EFA, ESPD and GA²LEN¹	'Systemic steroids have a largely unfavourable risk/benefit ratio for treatment of AE. Short–term (up to 1 week) treatment may be an option to treat an acute flare in exceptional cases of atopic eczema. Restrictive use, largely limited to adult patients with severe atopic eczema, is recommended. The recommended daily dose should be adjusted to body weight. Long term use in AE patients is not recommended. The indication for oral steroids in children should be handled even more cautiously than in adults'.
AAD²	'Although systemic steroids are used by some providers to treat AD because they rapidly improve clinical symptoms, caution is warranted to ensure their administration is time–limited and judicious…Thus, although temporarily effective, systemic steroids (oral or parenteral) should generally be avoided in adults and children with AD because the potential short– and long–term adverse effects…largely outweigh the benefits. Systemic steroids may be considered for short–term use in individual cases whereas other systemic or phototherapy regimens are being initiated and/or optimized'.
Japanese Dermatological Association⁴	'Although they are known to be effective, long–term oral corticosteroid therapy induces various serious systemic adverse reactions; therefore, long–term AD control with oral corticosteroids is not recommended. If necessary, administration should be completed in a short period'.
KADA⁵	'Although systemic corticosteroids dramatically improve the clinical symptoms of AD, their administration should generally be avoided because of adverse effects and the rebound phenomenon…Once clinical improvement has been achieved, it is very important to taper the dosage gradually over time to minimize the likelihood of a rebound effect…Continuous or chronic intermittent use of systemic corticosteroids in AD is discouraged. However, acute usage may be considered as a transitional therapy in severe, rapidly progressive, or debilitating cases during the initiation of treatment with nonsteroidal systemic immunomodulatory agents that have more favorable side–effect profiles, or phototherapy'.
Asia–Pacific Consensus Group for Atopic Dermatitis⁶	'There was a lack of consensus among the committee members regarding the use of oral corticosteroid therapy. However, some clinicians find it useful to administrate short–term steroid therapy, up to a maximum of 6 weeks, in combination with other standard modalities such as TCS or TCI (e.g. for acute flare). Long–term systemic steroids have little to no value and should be avoided in the management of AD due to adverse effects and rebound flare'.
Joint Task Force on Practice Parameters: AAAAI, ACAAI, the Joint Council of Allergy, Asthma and Immunology⁷	'The use of systemic corticosteroids, such as oral prednisone, might be required in the treatment of severe chronic AD, although there is a paucity of controlled studies, despite widespread use of this therapy…Nevertheless, the PRACTALL consensus report states that in cases of acute flare–up, while patients might benefit from a short course of systemic therapy with corticosteroids, long–term use and use in children should be avoided…If a short course of oral corticosteroid therapy is given for a patient with severe AD, it is important to taper the dosage as it is discontinued. Intensified skin care with topical anti–inflammatory therapy should also be instituted during the corticosteroid taper to suppress rebound flaring of AD'.
ISPD AD treatment Guidelines 2016³⁰	'Systemic corticosteroids are recommended only in adults and as short term bridging therapy while buying time for other immunosuppressants to act. We do not recommend use of [systemic CS] in children below 18 years for concern of high incidence of rebound flares on discontinuation, immediate and long–term adverse effects'.
Dutch Society of Dermatology and Venereology 2014⁸	Oral corticosteroids are not recommended as prolonged monotherapy in the maintenance treatment of serious atopic dermatitis. Oral corticosteroids can be given shortly as acute intervention therapy for the treatment of exacerbations or as temporary co–medication to start up another immunomodulatory agent, such as azathioprine, mycophenolate or methotrexate.^a

EFTAD, European Task Force on Atopic Dermatitis; EADV, European Academy of Dermatology and Venereology; EDF, European Dermatology Forum; EFA, European Federation of Allergy; EPSD, European Society of Pediatric Dermatology; GA²LEN, Global Allergy and Asthma European Network; AE, adverse event; AAD, American Academy of Dermatology; KADA, Korean Atopic Dermatitis Association; TCS, topical corticosteroid; TCI, topical calcineurin inhibitors; AAAAI, American Academy of Allergy, Asthma and Immunology; ACAAI, American College of Allergy, Asthma and Immunology; ISPD, Indian Society for Pediatric Dermatology. ^aTranslated from Dutch by Dr Phyllis Spuls.

Table 2. Results of the International Eczema Council consensus process
Statement	Proportion (%) of respondents who marked from neutral to strongly agree
Statements reaching consensus
For CHILDREN under the age of 12, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids should generally be avoided in the treatment of severe atopic dermatitis	51/59 (86)
For CHILDREN under the age of 12, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids may be used rarely for severe atopic dermatitis	41/58 (71)
For CHILDREN between 12 and 17 years of age, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids should generally be avoided in the treatment of severe atopic dermatitis	47/56 (84)
For CHILDREN between 12 and 17 years of age, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids may be used rarely for severe atopic dermatitis	40/56 (71)
For ADULTS 18 and over, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids should generally be avoided in the treatment of severe atopic dermatitis	43/55 (78)
For ADULTS 18 and over, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids may be used rarely for severe atopic dermatitis	44/55 (80)
Specific circumstances
Systemic corticosteroids may be used for severe atopic dermatitis when there are no other viable treatment options	44/54 (81)
Systemic corticosteroids may be used for severe atopic dermatitis as a bridge to other systemic agents or phototherapy	39/54 (72)
Systemic corticosteroids may be used for severe atopic dermatitis in an acute flare in need of immediate relief	42/54 (78)
Systemic corticosteroids may be used for severe atopic dermatitis in anticipation of an important life event (e.g. wedding)	40/53 (75)
Systemic corticosteroids may be used for severe atopic dermatitis in cases that are the most severe (e.g. erythrodermic)	38/53 (72)
Dose and timing considerations
If used, treatment with systemic corticosteroids for severe atopic dermatitis should be limited to short–term use	50/53 (94)
Statements not reaching consensus
For CHILDREN under the age of 12, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids should never be used in the treatment of severe atopic dermatitis	33/58 (57)
For CHILDREN under the age of 12, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids may be used regularly for severe atopic dermatitis	4/59 (7)
For CHILDREN between 12 and 17 years of age, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids should never be used in the treatment of severe atopic dermatitis	30/56 (54)
For CHILDREN between 12 and 17 years of age, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids may be used regularly for severe atopic dermatitis	4/56 (7)
For ADULTS 18 and over, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids should never be used in the treatment of severe atopic dermatitis	21/55 (38)
For ADULTS 18 and over, given concerns of side–effects and rebound flares on discontinuation, systemic corticosteroids may be used regularly for severe atopic dermatitis	2/55 (4)
Specific circumstances
Systemic corticosteroids may be used for severe atopic dermatitis not responding to topical therapy	19/54 (35)
Systemic corticosteroids may be used for severe atopic dermatitis not responding to other systemic medications or phototherapy	35/54 (65)
Systemic corticosteroids may be used for severe atopic dermatitis in pregnancy	30/53 (57)
Dose and timing considerations
If used, treatment with systemic corticosteroids for severe atopic dermatitis should be limited to no more than 2 weeks	36/52 (69)
If used, treatment with systemic corticosteroids for severe atopic dermatitis should be limited to no more than 4 weeks	29/53 (55)
If used, treatment with systemic corticosteroids for severe atopic dermatitis should be limited to no more than 6 weeks	25/53 (47)
If used, treatment with systemic corticosteroids for severe atopic dermatitis should be tapered slowly over weeks	32/53 (60)
If used, treatment with systemic corticosteroids for severe atopic dermatitis should be low dose	22/52 (42)

If 70% of respondents marked from neutral to strongly agree, consensus was reached. The proportion of respondents who marked from neutral to strongly agree on the visual analogue scale for each statement is given.

Appendix

Conflicts of Interest

A.M.D. is an investigator and has received research funding from Sanofi and Regeneron, is a consultant for Sanofi and RTI Health Solutions, and has received honoraria from Astellas Canada, Prime Inc. and Spire Learning. K.E. has received honoraria (advisor/speaker) from AbbVie, Almirall, Berlin Chemie, Eli Lilly, Hexal, Janssen and Novartis. M.S.d.B.–W. is a principal investigator for Regeneron/Sanofi/Genzyme, AbbVie, Roche and Novartis, an advisory board member for Regeneron/Sanofi/Genzyme, AbbVie and Anacor, and a consultant for Regeneron/Sanofi/Genzyme. J.P.T. is supported by an unrestricted grant from the Lundbeck Foundation and has attended advisory boards for Roche and Sanofi Genzyme and received a speaker's honorarium from LEO Pharma. P.I.S. has been a consultant for LEO Pharma, Anacor, AbbVie and Novartis, has received research funding from Schering Plough and LEO Pharma, and has been an investigator for AbbVie, Astellas, Almirall, Amgen, Boehringer Ingelheim, Celgene, Centocor, Clinitude, Dermira, Janssen (Cilag), LEO Pharma, Lilly, Novartis, Pfizer, Regeneron and Roche. A.D.I. has been a consultant for Sanofi Regeneron, Genentech and Chugai. G.G. has been principal investigator in clinical trials sponsored by and/or and has received personal fees from AbbVie, Abiogen, Almirall, Amgen, Bayer, Biogen, Celgene, Eli–Lilly, Galderma, Hospira, Janssen, LEO Pharma, Merck, MSD, Mundipharma, Novartis, Pfizer, Pierre Fabre, Regeneron, Sandoz, Sanofi and Sun Pharma. S.D. has been an advisory board member and key opinion leader for and has received honoraria from Galderma, Sanofi and Novartis. D.F.M. is an investigator for Regeneron, Novartis and Anacor, and a consultant for Sanofi, Novartis and Anacor. A.S.P. is a consultant with honoraria for Eli Lilly, Galderma, GSK/Stiefel, Pfizer, Pierre Fabre, Puricore, Regeneron/Sanofi, Roivant and Valeant, and an investigator for LEO, Novartis, Pfizer and Roivant. E.G.–Y. has received research support, consulting or lecture fees on atopic dermatitis from Regeneron, Sanofi, Merck, Stiefel/GSK, Pfizer, Genentech, Bristol–Myers Squibb, Galderma, Celgene, LEO Pharma, Janssen, Medimmune, Dermira, Anacor, AnaptysBio, Glenmark, Novartis, AbbVie, Sun Pharma, Mitsubishi Tanabe, Vitae, Allergan, Almirall, Puricore, Asana Biosciences, Gilead, Concert, Immune, Kyowa Kirin, Ziarco and DS Biopharma. E.G.Y. has no patents, ownership or financial gain from any atopic dermatitis drug.