Diane Peacock is a retired academic (art and design education).
‘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
Last year, the UK Medicines and Healthcare products Regulatory Agency (MHRA) published two documents relating to topical steroid withdrawal (TSW) reactions and actions recommended for clinicians. These were: ‘Drug Safety Update: latest advice for medicines users, Volume 15 Issue 2 September 2021′2 and ‘Topical steroid withdrawal reactions: a review of the evidence, MHRA Public Assessment Report September 2021′.3
Advice for healthcare professionals in the MHRA’s Public Assessment Report is to: report suspected adverse reactions to the Yellow Card Scheme, including after discontinuation of topical corticosteroids (TCS).4 Based on the Yellow Cards the MHRA had analysed, it was noted that patients had difficulty getting a diagnosis from a healthcare professional. This (the MHRA stated) could be due to a lack of awareness or a lack of recognition of the condition.2 The literature cited by the MHRA linked overuse to dependence (or addiction) and to TSW when ceasing treatment.5
‘… no drug company would invest in investigating complications of its products … ‘
TCS remain the mainstay treatment for atopic eczema in the UK. There is no doubt that TCS, when judiciously prescribed and regularly monitored, have had enormous benefits for patients for decades. It is also evident from literature searches, and from communicating with dermatologists, that patient or parental underuse, non-compliance, and steroid phobia have been major concerns for some time.6,7 This lay article, however, focuses on the impact of TCS overuse. No matter how rare or infrequent overuse and withdrawal reactions are considered to be, given that GPs treat the majority of patients with eczema, their role is pivotal in relation to condition oversight.
A multinational US-led online patient self-reporting survey8 of patients with eczema explores the cumulative impact of long-term TCS treatment and the debilitating symptoms of patients reporting TSW syndrome (TSWS). While the limitations with evidence based on self-reporting data by patients and caregivers are made clear, the analysis provides valuable insights into the real-life experiences of adults, with an average duration of prescription-only TCS usage of 15.3 years for adults and 3.6 years for children.
Gaps in what is, otherwise, a wealth of research
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 safety. Many studies are of weeks or months duration, with very few more than 2 years.
In July 2021 the British Medical Journal published ‘Safety of topical corticosteroids in atopic eczema: an umbrella review’.9 The review, while finding no evidence that TCS caused harm or skin thinning when used intermittently to treat eczema flares or as ‘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.’
Given the management of flares is fundamental to patient treatment, a 2022 systematic review by the Cochrane Skin research group found ‘no trials on the optimum duration of treatment of a flare’.10
Recently there has been tacit acknowledgement of TSWS and its potential relationship to overuse of TCS from parts of the UK dermatological community. This is evident in the conclusion of the 2022 British Journal of Dermatology Perspectives article ‘Topical steroid withdrawal syndrome: time to bridge the gap’:11
‘Looking forwards, dermatologists can advocate and develop research to better understand the nature of TSWS and what population it is prevalent in. Observational studies leading to consensus on a clearer disease definition can be followed by epidemiological studies and investigation of the underlying pathophysiology. We also need to review critically the long-term safety data on TCSs, clarify optimal usage in terms of potency, frequency, duration and area of TCS application, and communicate this information more clearly and consistently to patients and caregivers than is the case at present. Above all, we must be open minded and listen to patient voices, understand their concerns and learn from them.’
It is clear that large scale research funding has for decades mainly focused 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, such as topical tacrolimus and pimecrolimus, and biologics such as dupilumab.
One US-based researcher, when asked about the lack of longer-term TCS studies, agreed to be quoted anonymously, stating: ‘Bluntly, I fear that lack of funding for such work will be a major hurdle. 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’ (anonymous, personal communication, 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’ (anonymous, personal communication, 2022).
“UK bodies responsible for regulating online prescribing and dispensing are not required to collate and publish national data … “
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.12 The NIHR also provide funding for the James Lind Alliance (JLA),13 an alliance of patients, carers, and clinicians who collectively identify key research questions that address uncertainties about the effects of a treatment across clinical disciplines.
The 2020 Cochrane Skin outcomes report14 included one of the JLA’s top shared priority questions: What is the long-term safety of applying steroids to the skin for eczema? It appears 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’12 will reveal new evidence. It is hoped research pending from NIHR and Cochrane Skin may address these issues.
According to a 2021 UK population-based cohort study of eczema management in primary care,15 the prescribing of TCS decreased from 57.3% in 2009 to 52.0% in 2018. This was based on information held in the Oxford–Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network database. The RCGP RSC database includes pseudonymised records of all individuals registered in a large network of general practices in the UK. Only when prescriptions issued privately online were part of a patient’s medical record would they have been included.
It is possible that totals for UK overuse prevalence is mired by a lack of public access to information in a number of areas. UK bodies responsible for regulating online prescribing and dispensing are not required to collate and publish national data emanating from the growing UK-regulated private online provider market.*
“… unregulated overseas online providers operating in the UK are completely unquantifiable.”
Patient consent is required for private providers selling TCS online to notify a GP. It would take Freedom of Information (FoI) applications to each regulated online provider to establish what percentage of patients buying mid-high potency TCS agree to their GP being notified.
There is no requirement for private (online or place-based prescribing and dispensing) data to be sent to the National Health Service Business Services Authority (NHSBSA), unless it relates to a schedule 2 or 3 controlled drug (NHSBSA, personal communication, 2022).
Longitudinal annual national totals for the level of repeat prescribing and dispensing of the most common mid-high potency TCS British National Formulary items is not publicly available without an FoI application.** As well, unregulated overseas online providers operating in the UK are completely unquantifiable. Hospital TCS prescribing and dispensing data are not included in NHSBSA data unless the prescription is dispensed in the community. Totals for hospital-only prescribing and dispensing data are held at integrated care system level, although it is probable that these form part of the RCGP RSC database.
The monitoring of patients with chronic eczema in primary care
Funding for pre-determined chronic or acute conditions overseen primarily in primary care is available through Quality and Outcomes Framework (QOF) funding 2022–2023,16 a voluntary annual reward and incentive programme currently involving 98% of GP practices in England.17
The QOF outlines priority areas for improvement, using micro-incentives primarily to improve the care of patients falling within specific clinical, public health, and quality improvement domains.16 The outline includes annual asthma reviews,18 but there is no requirement for annual eczema reviews nor any mention of chronic eczema.
“… GPs … need urgent advice on how to help … patients experiencing severe … withdrawal rebound reactions after ceasing to use potent topical corticosteroids.”
A newly structured medication review (SMR) was introduced in England in 2020 with the formation of primary care networks emanating from the NHS Long Term Plan published in January 2019. In November 2021, in response to a written question in the House of Lords following the MHRA September 2021 publication,*** the Department of Health and Social Care clearly identified SMRs as the monitoring space for patients on long-term medication, yet there appears to be no evidence to suggest that this is the case for patients with chronic eczema.****
Currently, the dominant message from UK dermatologists, as embodied in the literature, is to emphasise adherence19,20 to the recommended TCS treatment (fingertip unit/duration/dose);21 warning that underuse risks treatment failure and worsening eczema.22 GPs also need guidance from dermatologists on how to treat those patients using mid-high potency TCS who experience increasingly frequent, debilitating flares. And, however rare such cases prove to be, GPs also need urgent advice on how to help those patients experiencing severe, often lengthy, withdrawal rebound reactions after ceasing to use potent TCS. Without specific guidance on the safety parameters of TCS treatment for unremitting flares, GPs will struggle to fully support these patients.
As a consequence of the above, and in the context of the immense physical, mental, and economic impact of chronic eczema flares on lives,23 this article is suggesting there may be more patients at risk of TCS overuse than the MHRA and the clinical community are aware.
A substantive research evidence-base***** will not be forthcoming, unless the case for longer-term TCS observational studies is strong enough in the dermatological community to attract governmental or other independent forms of funding. The outcomes of any prospective observational studies will be key to understanding the causes of TCS-treated unremitting flares, and to determining whether TSW syndrome is a resurgence of the condition for which TCS were primarily prescribed (atopic eczema) or a distinct clinical entity.
“Despite the personal efforts of primary care clinicians … regular monitoring of patients with chronic eczema [may have been compromised].”
The confluence of absent prescribing and dispensing data, NHS efficiencies (TCS are by far the cheapest option), commercial interests, and patient consent all make it impossible to accurately estimate overuse.
Whether TCS overuse and withdrawal reactions are due to what is often referred to as patient misuse,****** overprescribing, lack of funding or capacity in primary care to adequately monitor eczema patients, online access to purchase supplementary TCS, or as yet unidentified causes, it is vital that patients are listened to and supported.
Despite the personal efforts of primary care clinicians, it is probable that the widely acknowledged systemic pressures on UK primary care,24,25 the lack of targeted funding for annual eczema reviews, 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 in the UK 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 Scheme26 when adverse reactions from TCS overuse or TSWS are suspected.
*The NHSBSA confirmed in an email to the author on 26 July 2022: ‘there is no requirements [sic] for private prescription dispensing data to be sent to the NHSBSA for the products listed in your request as those products in British National Formulary 1304 topical corticosteroids are not a schedule 2 or 3 Controlled Drug’.
The Care Quality Commission (CQC) was asked to confirm whether or not they ‘routinely’ collected and collated data on all medicines prescribed by regulated private online prescribing services, they confirmed in an email dated 20 September 2022 that they: ‘do not have regular data collections of all medication prescribed under our Regulation 17: Good Governance. As the regulator we expect the service registered with us to maintain their records and may ask the providers to produce them on demand during inspections of their services’.
When asked to confirm whether or not regulated private online prescribers are required to send details on what has been prescribed to a patient’s GP, CQC responded: ‘We expect that providers prompt patients on registration to provide informed consent to share information with their registered GP. Where a patient does not have a GP or declines consent to contact their GP, this should be explored with the patient. Where the clinician does not have consent to contact the registered GP or there is no registered GP, they have explored this with the patient, and lack sufficient and reliable enough information to provide a safe prescription, they should decline to prescribe and signpost the patient to suitable alternative services […] When the decision is made that it is safe to prescribe without informing the registered GP following the episode of care, or for patients without a registered GP, this should be clearly documented in the patient’s notes, together with any advice, monitoring arrangements or follow-up required […] essentially if a decision is made not to inform the patients GP about what they have been prescribed from a private provider then there should be clear explanation in the records why this is so. The decision not to inform the GP should have been risk assessed to ensure the patients safety is maintained and any risks mitigated. When a provider is inspected the notes will be reviewed to ensure this information is clear and demonstrates safe, quality, care’.
The General Pharmaceutical Council (GPhC) was asked on 7 September 2022 whether or not the GPhC collects and collates data on the numbers of particular medications dispensed by GPhC regulated private online pharmacies in the UK. On 9 September 2022 a GPhC representative responded by email: ‘I can confirm that we don’t collect and collate data on the numbers of medications dispensed by private online pharmacies. That information would be held locally by the pharmacy. Private prescriptions for schedule 2 and 3 controlled drugs (such as morphine etc.) have to be recorded on specific forms which are submitted to the NHS at the end of each month […] The NHS Business Service Authority (NHS BSA in England) may potentially hold this limited information, although we can’t advise whether they could separate out those dispensed by online pharmacies with non-online pharmacies’.
**NHSBSA data on the numbers of patients in England with repeat prescription flags for mid-high potency TCS are not publicly available without a FoI, which is ongoing.
***On 2 November 2021, following the publication of the September 2021 MHRA Public Assessment Report,3 a written question was submitted by Lord Hunt of Kings Heath in the House of Lords. The question concerned the support available nationally for patients experiencing topical steroid withdrawal symptoms identified in the MHRA report. On 16 November 2021 Lord Kamall, on behalf of the Department of Health and Social Care, replied: ‘No additional steps are being taken to identify patients at risk of overuse of, or experiencing withdrawal symptoms from, using topical steroids. Patients on long term medication are offered regular Structured Medication Reviews (SMRs) through their GP practice. SMRs are an evidence-based and comprehensive review of a patient’s medication, taking into consideration all aspects of their health. Patients should consult their doctor or a pharmacist if they have any concerns or experience any side effects or withdrawal symptoms’.27
****According to the NHS website the groups who would benefit from an SMR are: residents in care homes; patients prescribed ≥10 medications (polypharmacy); patients on medications associated with medication errors; patients with severe frailty leading to hospital admissions and or falls; and patients prescribed potentially addictive pain management medication.28
*****Evidence, for example, on the long-term physiological, cutaneous cellular, cumulative immune-suppressive impact on those patients with chronic, recurrent eczema prescribed potent TCS either as a monotherapy or combined with new generation medications and/or antimicrobials to control frequent flares.
******In the Global North the motivation for patients to overuse TCS has been far less researched than underuse. Alongside this, there is an acknowledged lack of longer-term TCS safety studies. There also appears to be no definitive figure for the numbers of patients in England living with chronic, unremitting flares when treated with TCS or experiencing devastating and protracted rebound TSW symptoms after ceasing treatment. Terms such as ‘addiction’ to and ‘withdrawal’ from TCS, used for a decade by TSW patient support groups and in small pockets of the literature, have until recently been dismissed by many in the clinical and research communities as inflammatory, scaremongering, and sometimes linked to fostering underuse and steroid phobia. In contrast, the literature, in the main, has adopted terms such as ‘misuse’ and ‘abuse’ to describe overuse, inherently implying flaws in patient behaviour.
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2. Medicines and Healthcare products Regulatory Agency. Drug Safety Update: latest advice for medicines users. Volume 15 Issue 2 September 2021. 2021. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1017844/Sept-2021-DSU-PDF.pdf (accessed 16 Dec 2022).
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