Australian consensus: Treatment goals for moderate to severe psoriasis in the era of targeted therapies – Adult patients

Over the last decade, the treatment landscape for moderate–severe psoriasis has rapidly evolved. The Australasian College of Dermatologists sought to review and update previously published treatment goals for moderate–severe psoriasis.


INTRODUCTION
Psoriasis is a common, chronic immune-regulated, inflammatory skin disorder. 1The prevalence of psoriasis in adults in Australia is amongst the highest globally, with an estimated physician-diagnosed lifetime prevalence of 2.38% (95% uncertainty interval 0.78% to 7.01%). 24][5][6] The impact of psoriasis is not limited to the skin; its association with psychological, metabolic, musculoskeletal, and cardiovascular comorbidities further add to an already high burden of disability, reduced quality of life and lowered life expectancy. 7This increasing evidence linking psoriasis with various comorbidities makes early diagnosis, appropriate referral and optimal treatment critical.
While topical therapies remain the cornerstone for managing mild psoriasis, the treatment armamentarium for moderate to severe disease has substantially advanced with the introduction of new targeted therapies. 1,8,9ncreased understanding of the pathogenesis of psoriasis suggests an initial inflammatory event followed by a maintenance phase in which keratinocyte activation is driven via a positive feedback loop involving activated immune cells, proinflammatory cytokines (e.g.tumour necrosis factor-α [TNF-α] and interleukins [IL] IL-17, IL-23, IL-1 α/β and IL-36), chemokines and antimicrobial

What This Research Adds
An updated framework for the assessment, classification, and management of adults with moderate-to severe psoriasis in Australian clinical practice, which aligns with current international recommendations, is presented to account for the changing treatment landscape and to improve appropriate treatment selection and patients' satisfaction with their care.peptides. 10,11As a consequence, the treatment landscape for moderate to severe psoriasis has rapidly evolved.New therapeutic agents target these molecular and cellular pathways, supporting high rates of response associated with the specificity of their action.][14] In response to this changing treatment landscape, the Australasian College of Dermatologists sought to review and update Baker et al's 2013 Australian treatment goals for moderate to severe psoriasis. 15

MATERIALS AND METHODS
The focus of this work was to establish consensus on treatment goals in adult patients with a confirmed diagnosis of moderate to severe psoriasis.The PICO model was used to guide a comprehensive literature search (Table S1), which was conducted with search terms constructed to provide relevant information to inform the following core considerations: (1) whether the definition and classifications in the prior Australian treatment goals 15 were still valid, (2)  what changes had occurred in the treatment landscape and how they impacted treatment goals and response criteria and (3) whether there was any impact of these changes on wider management issues.A core working group (PF, CB and AJ) reviewed the outputs from the search and considered them in context with published guidelines and consensus opinions, [16][17][18][19][20][21][22][23][24] and developed a framework of clinical statements of relevance to the Australian setting.
The findings were developed into a 43-question survey, which included 29 clinical statements and other questions to establish current clinical practices.This survey was provided online to a panel of 13 participants, comprising 10 dermatologists, a general practitioner (GP), a junior medical officer and a consumer representative from Psoriasis Australia.The panel reviewed and voted anonymously on the draft clinical statements using a modified Delphi process by assigning their level of agreement with the statements using a 9-point scale (1 strongly disagree; 9 strongly agree).The overall consensus was defined as achievement of ≥75% agreement in the range 7-9.After round 1 voting (April 2022), a medical writer generated an overall strength score (the median score) and a level of consensus (proportion of voters with a score of 7-9) for each statement.In accordance with this, the consensus results are presented as (X, Y%,) where X denotes the average score and Y% the proportion of voters with a score of 7-9.
In May 2022, a hybrid group meeting was held wherein each of the contributors had the opportunity to discuss the results of the voting, review the clinical statements and make suggestions and changes.During this meeting, two members of the original voting panel opted to transfer to a sister project dealing with paediatric psoriasis and the group concurred to expand the adult voting panel by including an additional dermatologist, a rheumatologist, and a dermatology nurse.The new voting members were allowed to remark on the existing clinical statements, after which the revised panel then voted on a 20-question survey comprising 10 modified and 10 new clinical statements.At the completion of both voting rounds, final strength scores and consensus scores were assigned to each clinical statement.

Voting analysis
During voting round 1, the majority (N = 12) of participants answered all 43 survey questions.One participant did not answer 3 questions on the grounds that they were outside of their area of expertise.Consensus (≥75%) was achieved on 26/29 clinical statements.During voting round 2, 14 participants answered the revised 20-question follow-up survey and consensus (≥75%) was achieved on all clinical statements.A detailed summary of the clinical statements and voting outcomes is provided in Table S2.

Definition and classification
There was consensus to retain the categorisation of psoriasis into mild versus moderate-severe. 15This was further expanded in alignment with the International Psoriasis Council, 16 with unanimous consensus on the classification of patients based on whether they are candidates for topical or systemic therapies (strength: 8.5, consensus: 100%), and a high level of consensus (7.6, 85%) that quantitative metrics can further support this by indicating disease severity (Table 1).When asked to specify the assessment tools they currently use, the group members most frequently cited absolute psoriasis area and severity index (PASI), followed by the percentage change in PASI (ΔPASI), physician's global assessment (PGA), and body surface area (BSA), concurring that one or more validated metrics could be used to grade psoriasis signs (Table 1).The group unanimously agreed (8.1, 100%) that PGA was a validated objective score that could be used as an alternative to PASI for assessing psoriasis severity.The dermatology life quality index (DLQI) was identified as the most frequently used scale for measuring impact on healthrelated quality of life (HR-QOL) and there was unanimous consensus (8.0, 100%) that it should continue to be used to measure HR-QOL in clinical practice. 15here was unanimous consensus (8.9, 100%) that high-impact psoriasis sites comprise the scalp, face, nails, genitalia, palmoplantar (hands/feet) and intertriginous skin. 34While high-impact sites, by definition, classify patients as candidates for systemic therapy, the group felt that more emphasis was needed to highlight the use of validated tools specifically designed to assess disease severity at these sites.There was a very strong consensus (8.1, 93%) that the PASI was applicable only to generalised disease and was not a reliable measure of disease severity at high-impact sites.Where available, validated site-specific (modified) PASI should be used to assess the severity of high-impact sites (very strong consensus: 8.1, 93%).The group agreed that in the absence of validated site-specific PASI instruments, validated site-specific PGA scores could be used to assess psoriasis severity (high consensus: 7.8, 86%) and for monitoring treatment response (very strong consensus: 7.9, 93%) in patients with psoriasis affecting high impact sites (examples provided in Table 1).There was consensus agreement that HR-QOL was an important component in the assessment of disease severity (unanimous consensus: 8.9, 100%) and response to therapy (very strong consensus: 8.4, 93%) in patients with disease at high-impact sites.

Treatment goals and therapeutic strategies
There was unanimous agreement with the EuroGuiDerm Guideline 20 that the availability of new targeted therapies supports the possibility of attaining better treatment outcomes, and that the definitions of treatment success as set out in the 2013 Australian treatment goals consensus 15 should be reconsidered.There was a high level of consensus (7.5, 85%) with the concept of adopting a treatto-target approach, 17,35 with the need for flexibility within the definitions to accommodate (1) the physician's choice of assessment metric used (7.8, 92%) 21 and (2) differences in therapy-specific time to onset of action (7.9, 100%). 13,20here was unanimous consensus that in principle treatment should be continued in patients who achieve an adequate response (8.6, 100%) and modified in those with an inadequate response (8.3, 100%). 21Alongside this was the recommendation that clinical factors, such as drug dose and side effect profiles, and patient preferences also be considered when making treatment decisions.As with severity grading, there was a unanimous consensus (8.6, T A B L E 1 Classification and definitions.

Classification
Mild/mild-moderate psoriasis: disease which can be adequately controlled with topical therapy alone Moderate-severe/severe: disease which requires phototherapy or systemic therapy including targeted therapies (biological agents, targeted synthetic agents)

Severity
Candidates for systemic therapy are patients who meet at least one of the following criteria: 100%) that HR-QOL should be included in disease management targets. 20,21here was high consensus (7.8, 85%) that with the availability of new treatments for moderate-severe psoriasis, a 90% reduction in PASI (ΔPASI90) better reflected a "clear"/"almost clear" status than did ΔPASI75.The group also agreed that PGA was a validated objective score which is useful for measuring response to treatment (very strong consensus: 8.2, 93%), that PGA clear/almost clear is an appropriate alternative absolute treatment end point (very strong consensus: 7.9, 92%) and that complete skin clearance (PGA = 0) is an important goal from the patient's perspective (very strong consensus: 8.0, 92%). 36On this basis, there was unanimous consensus with adopting PGA 0/1 (8.6, 100%) or ΔPASI90 (8.4,100%) as treatment targets, as has been proposed by others. 17,20,21,35From a practical perspective, there was a high-level consensus (7.5, 85%) that absolute PASI was easier to calculate than ΔPASI because it is independent of variations in baseline severity.Accounting for clinical preferences in the use of different assessment scales, consensus was reached on the criteria for adequate and inadequate treatment responses (Table 2).
The group agreed that, where available, validated site-specific assessment scales should be used to monitor treatment response in patients whose psoriasis affected high-impact sites (very strong consensus: 8.6, 93%), with unanimous consensus (8.5, 100%) that the criteria for adequate response should be either site-specific PGA = 0/1 or site-specific PGA = 2 with DLQI < 5.
There was unanimous consensus (8.5, 100%) that time to onset of targeted therapies is therapy dependent and therefore the assessment interval should ideally take this into account. 20In practical terms, there was agreement that assessment of initial response should occur at up to 16-24 weeks after therapy initiation based on the onset of action and that routine assessment be conducted at least every 6 months thereafter or as directed on the prescribing information of the therapy.
When asked to rank the importance of different factors that prescribers consider, efficacy, safety and individual patient needs were highlighted as the top three determinants relied on when individualising management plans for patients (Figure 1).There was a very strong consensus (8.1, 92%) that adopting patient-reported outcome measures could provide additional, relevant information to facilitate individualised treatment plans. 37here was unanimous consensus (8.4,100%) that targeted therapies should be initiated if the response to established systemic agents is inadequate or they are not tolerated. 20,21There was discordance (5.4,54% consensus) with the requirement to undertake a trial with established systemic agents before accessing targeted therapy, with unanimous consensus (8.6, 100%) that in cases of severe, active disease the initiation of targeted therapy was the preferred first-line choice and that combination treatment may be of benefit in some patients (8.7, 100%).
There was a high level of consensus (7.5, 85%) to adapt the previous treatment goals algorithm to align with that in the French guidelines, 21 and a revised algorithm (Figure 2) was developed to reflect the agreed upon treatment response criteria (as noted in Table 2).

DISCUSSION
Prior Australian guidance, published a decade ago, identified requirements for assessments and established

Adequate response Inadequate response
Treatment should be continued a in patients who achieve an adequate response Treatment should be modified a in patients with an inadequate response An adequate response to treatment is defined as either: An inadequate response to treatment is defined as either: If neither of these criteria are met DLQI should also be considered:

F I G U R E 1
Factors considered when personalising the choice of treatment in patients with moderate or moderate/severe psoriasis, ranked in order of importance to the prescriber.

F I G U R E 2 Treatment goals algorithm for adult patients with psoriasis in Australia.
(1) To be eligible for access to biological or targeted therapies, the Australian reimbursement body, the Pharmaceutical Benefits Scheme, requires that a patient has failed to achieve an adequate response following a minimum of 6 weeks of treatment to at least two of the following five treatments: phototherapy, methotrexate, cyclosporin, acitretin, apremilast.The Australian consensus group failed to reach a consensus with the requirement to use established systemic agents before moving on to targeted therapy and propose that in cases of severe, active disease the initiation of targeted therapy was reasonable and best practice.( 2) Targeted therapies available via the Australian reimbursement body, the Pharmaceutical Benefits Scheme, are adalimumab, apremilast, etanercept, guselkumab, infliximab, ixekizumab, risankizumab, secukinumab, tildrakizumab, ustekinumab.
(3) Appropriate time for review varies with each treatment and the range is 16-24 weeks.(4) For high-impact sites use validated, site-specific assessment tools where available.( 5) Continuation/discontinuation is modulated by: toxicity, contraindications, and patient preferences and may also include adding topical therapies, adding other systemic treatments, increasing the dose and/or frequency of treatment, or admission to the hospital.
treatment goals to facilitate decision-making, enhance the appropriate use of available medications, and increase patient satisfaction with care. 15The therapeutic landscape has since changed, warranting the need for updated guidance and practical advice on the management of adults with moderate to severe psoriasis.This guidance has focused on two key areas: (1) widening the scope of the classification and definition of psoriasis to include the use of a wider range of metrics and encourage consideration of how best to evaluate disease at high-impact sites, and (2) revising overall treatment goals, now that more efficacious products are available, and considering to strategies to help reduce treatment delays.

Consideration of other assessment metrics
The current Pharmaceutical Benefits Scheme (PBS) access criteria adopt an assessment of disease severity based only on PASI.Patient-reported outcomes that provide a measure of HR-QOL are not integrated into the reimbursement criteria.The residual minimal disease can still substantially impact HR-QOL. 38The extent of this psychological distress is often under-recognised 39 and far-reaching. 40elying only on PASI could therefore result in misalignment between physician-reported and patient-reported severity.Australian data highlights the importance of addressing the spectrum of physical and psychological manifestations associated with psoriasis. 6Adopting patient-reported outcome measures could provide additional, relevant information to facilitate individualised treatment plans. 37The prior Australian consensus recommended measurement of both severity (PASI) and impact on quality of life (DLQI). 15During this consensus process, the authorship group reported routine use of DLQI alongside PASI, PGA and BSA.Our current guidance, therefore, provides a choice of metrics, used at the discretion of the treating physician, which better aligns the Australian consensus with the metrics and cut-off points proposed by the International Psoriasis Council. 16

Widening the definition of high-impact sites
The current PBS criteria account only for face and palmoplantar psoriasis.However, high-impact sites are not restricted to these three areas.A key aspect of this consensus has therefore been to broaden the entry criteria to other high-impact sites by better defining where they are and providing guidance on their assessment.Consensus was reached that high-impact psoriasis sites should encompass disease affecting the scalp, face, nails, genitalia, palmoplantar and intertriginous skin.Diagnosis of disease in these sites may be impacted by patients' reluctance to disclose it, and confounded by other factors, such as concomitant fungal nail infection.Despite affecting a small surface area, visible lesions in these sites have a disproportionate impact on HR-QOL and are associated with reduced functional, social and occupational well-being. 34,41n appreciation of the extent of this impact may be hampered by the limited application of traditional assessment scales that focus on the total body area affected and that do not take dysfunctional limitations into account (e.g.pain, difficulty walking, manual dexterity, sexual health and interpersonal relationships).Optimal management of psoriasis at high-impact sites is further confounded by the limitations of available therapies.For example, application difficulties and cosmetic tolerability may limit the use of topical therapies and toxicity may become a problem when established systemic agents are concentrated to treat small surface areas. 34The use of scoring systems that consider site-specific disease and HR-QOL impact could better guide assessment and management.However, such tools should also be validated to be of clinical value.

PASI 90 as a realistic treatment goal
The new biological and targeted therapies have improved treatment outcomes to the extent that, in the clinical trial setting, the traditional gold standard of PASI 75 has been replaced by more rigorous outcome measures (PASI 90, PASI 100 and clear/almost clear skin).From the patient's perspective, complete clearance of psoriasis lesions represents a meaningful end goal of treatment and is associated with improvements in HR-QOL 36,38,42 and treatment satisfaction. 38However, in the context of setting treatment targets, these should be patient-centred by taking into account patient-expressed wishes and carefully balanced to ensure that the target is not beyond the reach of the majority of patients. 24,43Analysis of clinical trial data shows that not all patients achieve PASI 100 (response rates at 1 year: TNF inhibitors, 21.8-34.8%;IL-17 inhibitors, 41.4-67.5%;IL-12/23 inhibitors, 41.8-56.3%),suggesting that its utility be restricted to the research setting. 44By contrast, PASI 90 is achievable in a larger proportion of patients, 45 and is deemed to be a more realistic goal in the clinical setting. 46

Toward reducing treatment delays
Consensus was not reached on the requirement for a treatment trial with established systemic agents, as specified in the PBS criteria, before commencing biologics/targeted therapy.Patient-focused management of chronic, moderate-severe psoriasis should ideally be designed to achieve targeted outcomes as optimally as possible.Within this framework, established systematic therapies may be of value in some patients, particularly where other issues are apparent (e.g., needle phobia).However, based on evidence of effectiveness and efficaciousness, there is no clinical reason to reserve targeted therapies for second-line systemic use and in cases of severe, active disease the initiation of targeted therapy is deemed reasonable and best practice.Requiring a trial of established systemic agents could delay access to targeted therapy for which patients already meet disease severity criteria and could put the patient at unnecessary risk of iatrogenic complications. 47To this point, treatment delay has been demonstrated in a recent interrogation of the Australasian Psoriasis Registry.Between 2008 and 2018 there was a statistically significant delay in the time from disease onset to commencing biologic therapies compared to phototherapy and established systemic treatments (overall the mean time from diagnosis to targeted therapy was 8.9 ± 12.3 years). 48rom the practitioner's perspective, efficacy and safety remain the primary drivers of treatment choice. 49Others have highlighted the importance of also considering patients' perceptions of disease severity and satisfaction as drivers of treatment choices. 50Nevertheless, a substantial proportion of patients with psoriasis report being uninvolved in treatment goal setting and dissatisfaction with their treatment remains high. 51Patients may not understand the nature of their disease, may harbour misconceptions about available treatments, or feel that their psoriasis is less worthy of treatment than other conditions.These longstanding beliefs may mean that patients are reluctant to present to primary care or lack the agency required to make informed treatment decisions. 52As with other chronic diseases, adequacy of health literacy has emerged as a determinant of self-management, 53,54 and a barrier to optimal interactions with health professionals. 43atients' participation in shared decision-making might be improved through better communication with their healthcare professional, 51 but this needs first to be underpinned by efforts directed toward patient education and disease knowledge. 55his consensus project is strengthened by the inclusion of specialists from various disciplines.However, consumer representation was restricted to one member of the voting panel, widening this may have afforded more insights into the current barriers and challenges faced by patients when navigating Australia's healthcare system.A companion consensus focused specifically on paediatric patients has been undertaken utilising the same methodology.The main limitation of this work was that it did not also encompass the assessment and management of comorbidities (psoriatic arthritis and obesity) or other specific circumstances (pregnancy, vaccination and elective surgery).Identification and management of the various co-morbidities associated with psoriasis is an important aspect of the overall patient-focused treatment plan.For example, in the case of psoriatic arthritis, risk factors such as a history of nail involvement should be borne in mind and where applicable screening tools (e.g.Psoriasis Epidemiology Screening Tool and Early Arthritis for Psoriatic Patients) incorporated into patient care to promote early detection. 56The importance of this aspect of patient care was acknowledged, including the involvement of primary healthcare providers and relevant specialities where indicated.However, an in-depth review of specific clinical scenarios was beyond the remit of the current consensus.The presence of specific comorbidities is also of relevance in treatment selection.For example, commencing a treatment with skin and joint efficiency if psoriatic arthritis is present or the use of weight-based dosing in the setting of high BMI.There was unanimous agreement that combination therapy may be of benefit to some patients.Holistic patient-centric management should ideally commence with the GP, who is well-placed to screen, diagnose and manage common comorbidities. 57,58Where appropriate, a multidisciplinary team approach, should be undertaken.Until such time that Australian guidance is available, clinicians are referred to recent guidelines and consensus reviews on the management of specific clinical and comorbid conditions in patients with psoriasis including psoriatic arthritis, [59][60][61] assessing and improving psychological well-being, 39,62 and women of childbearing age. 63,64he treatment landscape for moderate to severe psoriasis is rapidly changing.The availability of new targeted treatment options has the potential to reduce the burden of disease in these patients.However, that can only be properly realised if challenges to timely and equitable access are addressed.The proposed framework for assessment, classification and management of moderate to severe psoriasis aligns with current recommendations in Europe and internationally, [16][17][18][19][20][21][22][23][24] and it is hoped that its adoption into clinical practice in Australia will bring us one step closer to achieving complete or near complete lesion control and an associated improvement in HR-QoL.

AUTHOR CONTRIBUTIONS
Conceived the concept of this work and designed the study: Peter Foley, Christopher Baker.Involved in the conduct of the study and contributed to data collection: Peter Foley, Christopher Baker, Amelia James, Erin McMeniman, Morton Rawlin, Stephen Shumack, Shireen Sidhu, Murray Turner, Kurt Gebauer, Barbara Radulski, Jonathan Ng, John Sullivan, Dev Tilakaratne, Peter Nash.Contributed to data analysis and/or interpretation of the • Absolute PASI 3-6 with DLQI < 5 • PGA = 2 with DLQI < 5 If either of the above criteria are met, DLQI should be considered and an inadequate response to treatment defined as either: • Absolute PASI 3-6 with DLQI ≥ 5 • PGA = 2 with DLQI ≥ 5 If ΔPASI is being used as the metric, the corresponding criteria are: • ΔPASI ≥ 90 • ΔPASI ≥ 75 < 90 AND absolute PASI ≤ 3 • ΔPASI ≥ 75 < 90 AND absolute PASI > 3 with DLQI < 5If ΔPASI is being used as the metric, the corresponding criteria are: • ΔPASI ≥ 75 < 90 AND absolute PASI > 3 with DLQI ≥ 5 a Continuation/discontinuation is modulated by toxicity, contraindications, and patient preferences and may also include adding topical therapies, adding other systemic treatments, increasing the dose and/or frequency of a treatment, or admission to the hospital.