Updated consensus guidelines for management of moderate-to-severe atopic dermatitis in Singapore: Integrating biologics, Janus kinase inhibitors and conventional therapies

ABSTRACT

Introduction: Since 2016, several therapies have been approved for treating atopic dermatitis (AD) in Singapore, including biologics, oral Janus kinase (JAK) inhibitors and topical crisaborole. This study supplements the 2016 Singapore treatment guidelines for AD, focusing on newer therapies for moderate-to-severe disease, while revisiting older treatment regimens to accommodate changes in knowledge and practice.

Method: A modified Delphi panel was held, led by 2 co-chairs. The voting expert panel consisted of 12 dermatologists experienced in managing AD in Singapore. Delphi survey rounds were conducted between 24 July and 27 October 2023. Panellists indicated their agreement with drafted statements using a 5-point Likert scale. Consensus was defined as ≥80% agreement. An expert meeting was held to facilitate the consensus process between rounds 1 and 2 of voting.

Results: All expert panellists participated in both survey rounds, with a 100% response rate. Thirty-nine statements, classified into general principles, conventional treatments, biologics and JAK inhibitors, were proposed. Of these, 27 statements reached consensus at the end of round 1. After the expert meeting, 17 statements were included in round 2, of which 16 statements reached consensus. One statement did not reach consensus. Key updates are the inclusion of dupilumab and JAK inhibitors as potential first-line treatments for moderate-to-severe AD, in certain populations.

Conclusion: This modified Delphi study generated consensus among Singapore dermatology experts, to update treatment guidelines in moderate-to-severe atopic dermatitis. The consensus statements developed are intended to supplement the 2016 Singapore treatment guidelines for AD. Further revisions may be required when new evidence and/or treatments become available.

CLINICAL IMPACT

What is New

• This updated treatment guideline for moderate-to-severe atopic dermatitis (AD) is based on consensus statements generated via a modified Delphi panel of dermatologists in Singapore.
• The statements address newer approved treatments such as biologics and oral Janus kinase (JAK) inhibitors, while revisiting older therapies to accommodate changes in knowledge and practice.

Clinical Implications

• The consensus statements are intended to supplement the 2016 Singapore treatment guideline for AD.
• Dupilumab and JAK inhibitors have been included as potential first-line treatments for moderate-to-severe AD in certain populations.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterised by dry skin, localised red scaly patches, intense itching and skin pain.^1-4 Although its onset most commonly occurs before the age of 5, AD can develop during later childhood, adolescence or adulthood.^1-3 Recurrence can also follow extended periods of remission.^1-3 A 2018 community-based cross-sectional survey confirmed a high AD prevalence of 13.1% in Singapore (20.6% in children aged ≤18 years; 11.1% in adults).⁵ Heat, dust and physical exercise were the most common aggravating factors.⁵

In the 2021 Global Burden of Disease study, AD was ranked first among skin diseases in terms of burden measured by disability-adjusted life years.⁶ Among children and adults in Singapore, a significantly higher proportion of AD patients (89%) reported suboptimal quality of life (QoL), measured using the EQ-5D visual analogue scale, compared to those without AD (77.4%).⁵

Several treatment options can alleviate the symptoms of AD and improve QoL.⁷ In the 2016 guidelines developed by the Dermatological Society of Singapore (DSS), treatment strategies are tailored to the severity of AD.⁸ In general, patients are advised to moisturise their skin with emollients and are prescribed topical anti-inflammatory therapies such as corticosteroids or topical calcineurin inhibitors (TCIs).⁸ For severe disease, more potent topical corticosteroids, phototherapy and systemic therapy can be considered.⁸ Individualised therapy,⁴ in combination with patient education, is key to achieving good outcomes.⁸

Since 2016, several new therapies have been approved for the treatment of AD in Singapore, including biologics (e.g. dupilumab) in 2019,^9-11 as well as oral Janus kinase (JAK) inhibitors (e.g. abrocitinib,^12,13 baricitinib,^14,15 upadacitinib^16,17) and crisaborole ointment in 2022.^18,19

The objective of this study was to supplement the 2016 Singapore treatment guidelines for AD, focusing on the newer therapies for moderate-to-severe AD, while revisiting older treatment regimens to reflect any changes in current practice. A modified Delphi panel method—a technique widely used in health services research to generate consensus²⁰—was employed as it offers a systematic, robust and reproducible methodology for developing consensus statements via iterative rounds of anonymised voting.^21,22

METHOD

This guideline update was initiated by the DSS, led by 2 co-chairs (YWY and HYL), who provided subject matter expertise in developing consensus statements for voting by an expert panel. Costello Medical, a third-party healthcare consultancy, generated evidence to inform statements by completing a targeted literature review and coordinated anonymised voting on consensus statements by the expert panel, ensuring that all experts were blinded from each other’s inputs.

Recruited panellists were practising dermatologists in Singapore with expertise and interest in managing AD in adults and/or children, as demonstrated by authorship of AD publications (including the previous 2016 AD guidelines), participation in advisory boards or as invited speakers on relevant topics, experience as primary or site investigators for AD trials/research studies, and extensive senior consultant experience at specialist clinics, including eczema clinics at hospitals in Singapore. Additionally, recruitment aimed to ensure representation from both the public restructured healthcare institutions and the private sector. To avoid bias, the co-chairs did not participate in voting on consensus statements during the Delphi rounds. All participating experts are authors of this guideline.

Targeted literature review

Key recommendations from the 2016 Singapore AD treatment guidelines were summarised.⁸ The reference list for the Global Guidelines in Dermatology Mapping Project (GUIDEMAP) systematic literature review (SLR) publication was hand-searched to identify international AD guidelines published between 1 April 2016 and 1 April 2021.²³ Additional supplementary Google searches were performed to identify guidelines published after 1 April 2021 up to 10 April 2023. Google was used because some treatment guidelines published in grey literature (e.g. medical society websites) may not be indexed in medical literature databases like MEDLINE.

Identified guidelines were assessed for relevance based on the population of interest being patients with moderate-to-severe AD, discussion of new therapies such as JAK inhibitors, biologics and topical crisaborole, and inclusion of treatment recommendations outside of the 2016 Singapore guidelines. Consensus statements were drafted based on the outputs of the targeted literature review and finalised with feedback from the co-chairs.

Modified Delphi process

The Delphi technique refers to a structured method for consensus generation, characterised by its iterative process, allowing the incorporation of controlled feedback, with participant anonymity, to avoid social pressure to conform to a dominant view.^24,25

Delphi survey rounds were conducted between 24 July 2023 and 27 October 2023, using an online survey platform that maintained anonymity. During each survey round, panellists indicated their agreement with each statement on a 5-point Likert scale (strongly disagree; disagree; neutral; agree; strongly agree).²⁶ In addition, free text boxes allowed for qualitative feedback and comments, which were used to inform revisions or the formulation of additional statements. An a priori consensus threshold of ≥80% agreement (selection of “strongly agree”/“agree”) or disagreement (selection of “strongly disagree”/“disagree”) among the expert panel was defined.

An expert meeting was convened following the circulation of results from round 1. The meeting allowed for the exchange of clinical opinions, insights and knowledge to support the reformulation of statements that did not reach consensus. During the expert meeting, panellists were advised to prioritise the best available treatment approaches, without being influenced by cost considerations, given that subsidy status in Singapore may change over time.

Revisions of non-consensus statements and the formulation of additional statements were conducted under the guidance of the co-chairs, based on the discussions during the expert meeting. Panellists then voted on the updated statements in round 2 of the Delphi survey. All voting took place via online surveys under standard Delphi conditions of participant anonymity.²⁴ Statements that did not reach consensus in round 2 were excluded from the final guideline supplement.

RESULTS 

Targeted literature review

A total of 54 AD guidelines were identified from the literature search. Prioritisation strategies were implemented to identify the most relevant guidelines for the Singapore context. Guidelines not in the English language (n=8) and with Appraisal of Guidelines for Research & Evaluation (AGREE) II average scores <5, as reported in the GUIDEMAP SLR, were deprioritised (n=21).²⁷ Additionally, only the most recent guideline from each country was included (n=4 excluded). For guidelines identified via supplementary Google searches, documents from lower-income countries (based on the World Bank categorisation of economies)²⁸ were deprioritised (n=3).

In total, 18 guidelines were included and reviewed (Supplementary Fig. S1). Data extraction focused on divergences from the 2016 Singapore guidelines, identifying 4 broad categories of treatment: new systemic, new topical, older systemic and older topical therapies. Where reported, the patient indication for each treatment, the recommendation (recommended, not recommended, unclear), and the level of evidence supporting the statements were extracted, in order to identify gaps that formed the basis for the development of consensus statements for voting in round 1 of the Delphi survey.

Delphi survey

The voting expert panel consisted of 12 experts, 58% (n=7) of whom practised primarily in public healthcare settings, with the remaining 42% (n=5) practising in private healthcare. The majority (58%, n=7) had an even mix of adult and paediatric patients, with 4 panellists who treated adults more often and 1 panellist who mostly treated children. The expert panel included members with subspecialty interests in paediatric dermatology (n=4), immunodermatology (n=4), inpatient dermatology (n=3) and photodermatology (n=1). All panellists participated in both survey rounds with no missing responses.

The virtual expert meeting was attended by 10 of 12 experts. While 2 individuals were unable to attend due to scheduling conflicts, all panellists were invited to comment over email and minutes were circulated post-meeting to collect any further feedback.

Fig. 1. Summary of results of the modified Delphi panel.

Fig. 1 summarises the results of the modified Delphi panel. There were 39 statements initially proposed, classified into general principles, conventional treatments, biologics and JAK inhibitors. Of these, 27 statements reached consensus at the end of round 1. After the expert meeting, 17 statements were included in the round 2 survey, of which 16 statements reached consensus. A full illustration of the evolution of the consensus statements in the Delphi rounds, alongside voting results, is available in Supplementary Table S1.

General principles     

Table 1 summarises the consensus statements under general principles for the management of AD.

Table 1. Consensus statements on general principles of moderate-to-severe atopic dermatitis treatment.

Disease assessment

It is recommended to assess disease severity based on objective clinical signs, symptom severity and QoL impact. Outcome measures, such as the SCORing Atopic Dermatitis (SCORAD) and Eczema Area and Severity Index (EASI),^29,30 may be useful for monitoring disease and guiding therapy.

Treatment goals

The establishment of disease control, minimisation of symptoms and reduction of QoL impact are key goals of AD treatment. Initial targets to measure treatment response are SCORAD-50, EASI-50, a ≥4-point reduction of Dermatology Life Quality Index (DLQI),³¹ a ≥3-point reduction of Itch Numeric Rating Scale (NRS) or a ≥4-point reduction of Patient Oriented Eczema Measure (POEM) within 3 months of treatment initiation.^32,33 While not part of the consensus statement, the Investigator’s Global Assessment (IGA) scale score is another possible tool to assess treatment success,³⁴ as noted by some panellists.

Treatment approach

A collaborative approach between patients, caregivers and healthcare providers is essential. Discussions should encompass treatment goals, expectations, options and plans, taking into account potential adverse effects and patient/caregiver preferences in decision-making. This may also include consideration of the patient’s medical comorbidities.

When indicated, systemic therapies should be initiated by dermatologists as specialty knowledge is required for assessment, to prevent misdiagnosis, as well as to monitor for adverse effects.

Conventional treatments

Table 2 summarises the consensus statements concerning conventional treatments in moderate-to-severe AD.

Table 2. Consensus statements on conventional treatments for moderate-to-severe atopic dermatitis.

Treatment paradigm for moderate-to-severe AD

For moderate-to-severe AD, emollients remain the mainstay of general disease management. Additionally, topical corticosteroids (TCS) are first-line therapy for both acute exacerbations as well as maintenance of AD control for non-sensitive areas. For sensitive areas (e.g. eyelids, neck and genital areas), TCIs or topical phosphodiesterase-4 inhibitors (e.g. crisaborole) should be considered, as TCS use is likely to be associated with adverse events. Phototherapy could be considered as an alternative for the control of chronic moderate-to-severe AD, before using any systemic anti-inflammatory agents.

In cases of persistent moderate-to-severe AD, a holistic assessment is needed for the initiation of systemic therapy. The assessment should take into account the severity of disease, QoL, adherence, alternative diagnoses and response to previous treatments, such as intensive topicals and phototherapy.

Among conventional systemic anti-inflammatory agents, ciclosporin has the best evidence in the treatment of moderate-to-severe AD.³⁵ Systemic corticosteroids should be considered only as rescue therapy for acute flares, and not for long-term use in chronic AD. Similarly, long-term high-potency TCS use for moderate-to-severe AD is not recommended. Wet-wrap therapy should be used with caution in combination with high-potency TCS, to minimise potential adverse events.

Steroid tapering and phobia

TCS are an effective treatment for moderate-to-severe AD, but tapering should be initiated upon achieving adequate control. Tapering strategies may include using less potent TCS, reducing the application frequency of potent TCS or using TCS in combination with TCIs or phosphodiesterase-4 inhibitors.

There is a need to address steroid phobia in order to improve adherence to TCS in the management of AD. This should include screening for steroid phobia at treatment initiation and follow-ups, although not all panellists agreed on the Topical Corticosteroid Phobia (TOPICOP)³⁶ scale as the most appropriate instrument for assessment. If patients express concerns about steroid use, they should be provided with individualised education to address their concerns.

Biologics

Twelve statements on biologics reached consensus, as summarised in Table 3.

Table 3. Consensus statements on biologics.

Dupilumab is currently approved for use in Singapore for the treatment of adult and paediatric patients aged ≥6 months, with moderate-to-severe AD requiring chronic treatment, and whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.¹¹ Dermatologists in Singapore agreed that dupilumab could be considered for first-line systemic treatment in patients with moderate-to-severe AD.

Dupilumab is recommended as a first-line systemic treatment for patients with concomitant type 2 allergic disease (e.g. moderate-to-severe asthma, severe chronic rhinosinusitis with nasal polyps). Dupilumab may also be preferred in moderate-to-severe AD patients with severe comorbidities, such as end-stage organ disease/dysfunction, or cardiovascular and venous thromboembolism risk factors. Based on the available evidence, dupilumab is considered safe and effective in elderly patients (e.g. ≥65 years) compared with conventional systemic agents.^37,38 However, dupilumab should be used with caution in patients who are pregnant or lactating, due to the lack of safety and toxicity data in this subpopulation.

In terms of adverse events, dupilumab-induced conjunctivitis can occur during treatment in AD patients. However, topical treatment with anti-inflammatory eyedrops can be considered for the management of conjunctivitis in selected cases, without needing to discontinue dupilumab treatment. In severe or persistent cases of dupilumab-induced conjunctivitis, referral to an ophthalmologist is recommended. For AD patients with a history of recurrent or moderate-to-severe eye inflammation or ocular surface disorders, such as conjunctivitis or keratitis, clinicians should consider consulting an ophthalmologist before starting treatment with dupilumab.

There is no routine pre-treatment laboratory screening recommended prior to starting dupilumab, and no specific laboratory tests are required to monitor AD patients using dupilumab. However, as live attenuated vaccines should be avoided while on dupilumab treatment, screening for age-appropriate vaccinations should be conducted at least 4 weeks prior to starting biologic treatment.

Rituximab, omalizumab and ustekinumab treatment are not recommended for use in AD patients, due to limited evidence for their efficacy.

JAK inhibitors

Consensus statements on JAK inhibitors are summarised in Table 4.

Table 4. Consensus statements on Janus kinase inhibitors.

Baricitinib, abrocitinib and upadacitinib can be considered for first-line systemic treatment in certain adults with moderate-to-severe AD. In particular, systemic JAK inhibitor treatments can be considered when fast-acting treatments are required. Treatment with a JAK inhibitor can also be an option in moderate-to-severe AD patients with a history of severe ocular surface disease (e.g. corneal and conjunctival diseases). Abrocitinib and upadacitinib may be considered for adolescents (12–18 years old) with moderate-to-severe AD.

In moderate-to-severe AD patients with latent tuberculosis, JAK inhibitors should only be used after the latent tuberculosis has been adequately treated, or in consultation with relevant tuberculosis specialists. The use of JAK inhibitors in combination with other potent immunosuppressants, such as ciclosporin, is not recommended as it might cause an overly suppressed immune system and increased risk of infection and malignancies, such as lymphoma. Additionally, JAK inhibitors should not be used during pregnancy, in patients planning for pregnancy or lactating patients.

In the following patient groups, JAK inhibitor treatment should be used with caution: patients aged ≥65 years; patients at increased risk of major cardiovascular problems (stroke or myocardial infarction); smokers or patients who have smoked for a long time in the past; patients at increased risk of cancer; and patients with risk factors for venous thromboembolism.³⁹

Laboratory screening

Prior to treatment initiation with JAK inhibitors, routine screening for hepatitis B, hepatitis C and tuberculosis should be conducted. HIV screening should also be conducted for at-risk individuals. Pre-treatment laboratory screening of baseline full blood count (including a differential white cell count), liver enzymes (especially transaminases), renal function and lipid levels, is also recommended. Live attenuated vaccines should be avoided while on JAK inhibitors, but inactivated herpes zoster vaccination could be considered for all patients in view of possible herpes zoster reactivation. After JAK inhibitor treatment initiation, regular laboratory screening should be carried out as part of routine patient management.

DISCUSSION

Consensus statements generally aligned with recommendations in other international AD consensus statements and guidelines, including those from Europe (EuroGuiDerm), Portugal, Japan and Saudi Arabia.^40-44 Fig. 2 illustrates a proposed treatment algorithm, developed based on the consensus statements generated. A key outcome of the consensus process was that, in the appropriate context, biologics and JAK inhibitors could be considered as first-line treatments for moderate-to-severe AD in Singapore, in addition to conventional treatments.

Fig. 2. Proposed treatment algorithm based on the consensus statements.

Nevertheless, efficacy, safety and cost should always be considered during the initiation of systemic treatments. At the time of this Delphi survey, many newer AD treatments were not eligible for subsidy in Singapore via the Medication Assistance Fund (MAF) or the Ministry of Health Standard Drug List. Hence, treatment with such agents may result in significant out-of-pocket costs. A common theme expressed in open-ended comments and during the expert meeting was the importance of considering the affordability of a treatment for a specific patient, when making treatment decisions in clinical practice.⁴⁵

However, as of 1 March 2024, after the conclusion of the Delphi voting, abrocitinib has since been listed for subsidy under the MAF for the treatment of moderate or severe atopic dermatitis (Physician Global Assessment score of 3 or 4 and EASI ≥16) in patients who have had an inadequate response, intolerance or contraindication to at least 1 systemic therapy such as ciclosporin, methotrexate, azathioprine and mycophenolate mofetil.⁴⁶ This decision was based on an assessment of patient population size and unmet need, clinical effectiveness, cost-effectiveness, incremental cost and budget impact.⁴⁶ Initiatives like the MAF are crucial for mitigating financial barriers to effective treatments and promoting societal health equity.

Additionally, it was highlighted that the decision to initiate systemic treatments should be made by dermatologists. Specialist knowledge is necessary to appreciate the differential diagnoses (such as mycosis fungoides, psoriasis, tinea),⁴⁷ reduce misdiagnosis as well as monitor adverse events. A skin biopsy may be considered prior to therapy initiation in cases where the AD diagnosis is unclear, especially for elderly patients.^48-50

As outlined in Supplementary Fig. S1, a number of statements did not reach consensus in round 1. After discussion and modification, almost all statements were able to reach consensus in round 2, except for 1 statement regarding the discontinuation of phototherapy. Panellists did not agree on the acceptability of co-administration of phototherapy with systemic anti-inflammatory agents. In the comments, it was highlighted that the contraindication may be true of some agents, such as ciclosporin and/or azathioprine, but that phototherapy may be used together with methotrexate and dupilumab. Experts also noted evidence that the risk of photocarcinogenesis may be lower in the Asian population,⁵¹ and highlighted that temporary overlaps between treatments may occur in clinical practice while bridging treatments.

The consensus statements reflect the current treatment availability in Singapore at the time of the study. Other treatment options, such as topical JAK inhibitors (delgocitinib ointment and ruxolitinib cream) and other biologics (tralokinumab, lebrikizumab and nemolizumab), may become available in the future and could play a role in AD management.^52,53 In clinical practice, some treatments may also be used off-label, such as mycophenolate mofetil, an oral systemic immunosuppressant that is considered by some clinicians in Singapore as third- or fourth-line treatment, when licensed options are exhausted.

The strengths of this supplementary guideline update include the use of Delphi methodology, which is a structured and robust technique for collecting opinions from experts and generating group consensus.²⁴ The process allows for controlled feedback between rounds, such that panellists are informed of the current status of collective opinion and may be reminded of considerations that they may have previously missed.²⁴ The Delphi process was modified in this study to include an expert meeting to support statement reformulation following round 1 voting. While this meant that members of the expert panel were aware of each other while exchanging clinical opinion, voting records were kept confidential and no voting took place during this meeting. This ensured that dominant perspectives did not shape the consensus generation.

Limitations

While a full systematic review to assess the level of evidence supporting each statement was not conducted, many existing guidelines are already available globally for AD. Thus, the statements were developed based on a review of relevant international treatment guidelines, with expert input from the co-chairs.

The sample size for the Delphi panel was limited to 12 participants; however, recruitment aimed to identify key opinion leaders in the field of dermatology in Singapore, who would have the expertise and experience to advise on best practice,⁵⁴ while ensuring representation across public and private practice. Future updates (supplementary or full) to the 2016 guidelines should consider including patients and policymakers, to gather input on the feasibility of implementing recommendations in clinical practice.

Lastly, although the current consensus discussed the risks associated with the use of biologics and JAK inhibitors, including the importance of pre-treatment screening and ongoing monitoring, it did not provide detailed guidance on specific monitoring timelines or adverse event management. This omission stems from the restricted scope of a 2-round Delphi panel and the intention to remain non-prescriptive, allowing flexibility for clinicians to tailor approaches based on local circumstances. While relevant screening and monitoring guidance has already been published, for example by Samuel et al. (2023),⁵⁵ these considerations should be included in future updates to the 2016 guidelines.

CONCLUSION

This modified Delphi study was undertaken to develop updated guidance, based on consensus among dermatologists in Singapore, regarding newer treatments in moderate-to-severe AD. The consensus statements developed are intended to supplement the original guidelines,⁸ particularly in treatment approaches for moderate-to-severe AD, and to ensure that the guidelines account for changing treatment paradigms. Further revisions to this guideline may be required when new evidence and/or new treatments in AD become available.

Supplementary materials

Acknowledgements

The authors acknowledge Yan Ran Wee, MSc, from Costello Medical, Singapore, for medical writing and editorial assistance based on the authors’ input and direction.

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