‘Corticosteroids suppress the inflammatory reaction during use; they are not curative and on discontinuation a withdrawal reaction (rebound or flare) may occur. Withdrawal reactions are thought to occur after long-term continuous or inappropriate use of topical corticosteroids (particularly those of moderate to high potency).’ 1
Topical corticosteroids (TCS) remain the mainstay treatment for atopic eczema in the UK. When judiciously prescribed and regularly monitored, TCS have had enormous benefits for patients. It is also evident from literature searches and communicating with dermatologists that patient or parental underuse, non-compliance, and steroid phobia have been major concerns for some time.2
This lay article, however, focuses on the risks associated with overuse of mid-high potency of TCS, and the extreme and debilitating rebound reactions experienced by some adults and children when ceasing to apply TCS after long-term use, referred to as topical steroid withdrawal (TSW).
In mid-September 2021, the UK Medicines and Healthcare products Regulatory Agency (MHRA) published two significant documents relating to TSW.3,4 Advice for healthcare professionals in the MHRA documents is to: report suspected adverse reactions to the Yellow Card Scheme (a system for recording adverse incidents with medicines and medical devices in the UK), including after discontinuation of TCS. When considering Yellow Card data alongside the number of patients who use TCS, the MHRA were unable to estimate the frequency of TSW reactions. ‘However, given the number of patients who use topical corticosteroids, [they understood] reports of severe withdrawal reactions to be very infrequent’.4 The MHRA noted that patients had difficulty getting a diagnosis from a healthcare professional and considered that this could be due to a lack of awareness or a lack of recognition of the condition.
Literature searches reveal that after over 40 years of intensive prescribing in the UK there have been very few post-licensing, longer-term observational studies focusing on TCS safety. Many studies are of weeks or months duration, with very few more than 2 years. It is clear that large-scale research funding has for decades focused mainly on product development and shorter-term comparator trials largely funded by pharmaceutical companies; for example, new treatments and TCS comparator/concomitant studies on the efficacy of new generation topical calcineurin inhibitors (TCIs), such as topical tacrolimus and pimecrolimus (second-line agents for atopic dermatitis) and biologics such as dupilumab (also known as Dupixent®).
OBSTACLES, DETERRENTS, AND POSSIBILITIES
One US-based researcher, when asked about the lack of longer-term TCS studies, agreed to be quoted anonymously, stating: ‘Obviously, no drug company would invest in investigating complications of its products, and so it will require a government or NGO [non-government organisation] to be excited enough to launch something substantive’. (personal communication, anonymous, 2022). A US-based paediatric dermatologist in correspondence with the author wrote: ‘Lack of industry funding and long-term availability of TCS are major reasons why long-term safety data is lacking’. (personal communication, anonymous, 2022).
In July 2021, the BMJ published ‘Safety of topical corticosteroids in atopic eczema: an umbrella review’.5 The review, while finding no evidence that TCS caused harm or skin thinning when used intermittently to treat eczema flares or as a ‘weekend therapy’ to prevent flares, stated:
‘Rather than follow-up of perhaps just a few weeks, future RCTs [randomised controlled trials] […] should include lengthier follow-up to enable better safety assessment. However, it should be noted that longer-term prospect observational studies are better placed to explore longer-term safety of TCS and should be designed with years rather than months of follow-up to add useful information to the field. Perhaps equally as important as duration of follow-up in trials is resolution of adverse events which is often not reported.’
Recently, there has been tacit acknowledgement of TSW syndrome (TSWS) and its potential relationship to overuse of TCS, from parts of the UK dermatological community. This is evident in the content of two British Journal of Dermatology (BJD) Perspectives articles; the first (2022), ‘Topical steroid withdrawal syndrome: time to bridge the gap’6 and the second (2023), with contributors from UK patient advocacy group Scratch That, ‘Topical corticosteroid withdrawal syndrome: the patient community call for high-quality research, clear definitions and diagnostic criteria’.7
The National Institute of Health and Care Research (NIHR) established in 2006 is the single largest funder of the internationally renowned Cochrane Skin research group.8 The NIHR also provides funding for the James Lind Alliance (JLA),9 an alliance of patients, carers, and clinicians who collectively identify key research questions. The 2020 Cochrane Skin outcomes report10 included one of the JLA’s top shared priority questions: ‘What is the long-term safety of applying steroids to the skin for eczema?’ This research question has not as yet been fully prioritised.
While much can be learned from systematic reviews of earlier studies, when primary source trials and observational studies are lacking it appears doubtful that ‘review[ing] critically the long-term safety data on TCSs’6 will reveal new evidence. A substantive research evidence base will not be realised, unless the dermatological community’s case for long-term observational studies is strong enough to attract governmental or other sources of independent funding.
The outcomes of any prospective observational studies will be key to understanding the causes of TCS-treated unremitting flares and to determining whether TSWS is a resurgence of atopic eczema or a distinct clinical entity. It is hoped research pending from NIHR Dermatology and Cochrane Skin will address these issues.
Currently, the dominant message from UK dermatologists to primary care, as embodied in the literature, emphasises adherence to the recommended TCS treatment; warning that underuse risks worsening eczema.
GPs also need guidance from dermatologists on safety parameters when treating patients using mid-high potency TCS who experience unremitting flares, and urgent advice on how to help patients presenting with severe, often lengthy withdrawal rebound reactions after cessation of mid-high potency TCS.
Without research and accurate intelligence on TCS and/or TCIs overuse11 and TSW population prevalence,7 clinicians will be unable to confirm that TSW reactions ‘ are very infrequent’.4
The growing presence of individual user-generated TSW content and patient advocacy sites online is a concern for some clinicians. A recent review12 of TSW-related media, internet, and social media sites identified misinformation promulgated by patients and carers with ‘ vague negative feelings and/or erroneous beliefs’ about TCS as a driver of corticophobia and urged dermatologists to ‘be active in attempts to counteract [this] with evidence-based advice’. While some site content may be of serious clinical concern, polarisation reduces cooperation and may hinder positive developments highlighted in the two recent BJD Perspectives articles.
Despite the personal efforts of primary care clinicians, it is probable that the widely-acknowledged systemic pressures on UK primary care,13 the lack of targeted funding for eczema reviews,11 and the impact of COVID-19 have compromised regular monitoring of patients with chronic eczema.
In the absence of longer-term observational studies, this article is urging GPs and practice nurses to use practice-based prescribing data to identify and monitor patients who may be at risk of overuse and to notify the MHRA Yellow Card Scheme when adverse reactions from TCS overuse or TSWS are suspected.
Whether TCS overuse and TSW reactions are due to so-called patient ‘misuse’, overprescribing, lack of capacity and funding in primary care to adequately monitor patients, the private online purchase of supplementary TCS, or other as yet unidentified causes, the GP’s role is pivotal. Patients at risk of overuse must be identified, counselled, and, where possible, TCS potency reduced, and those presenting with TSW symptoms listened to, supported, and monitored until further guidance and research is forthcoming.
- © British Journal of General Practice 2023
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Cochrane skin. Funding and support.
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