Adalimumab in the management of psoriasis and psoriatic arthritis: Results from a Delphi investigation

Introduction

Immune-mediated inflammatory diseases (IMIDs) are chronic disorders sharing common epidemiological and genetic features, and underlying pathogenetic pathways.^[1,2] Indeed, evidence suggests that multiple IMIDs may coexist in the same patient.^[3] In the first year of disease, peripheral arthritis may occur in about 12% of patients with inflammatory bowel disease (IBD).^[4] These patients are also prone to develop psoriasis (PsO) or rheumatoid arthritis (RA).^[5] In women with PsO and psoriatic arthritis (PsA), the former is associated with a significantly increased risk of Crohn’s disease.^[6]

PsA occurs in 0.04%–1% of the general population and between 20%–40% of PsO patients.[7,8] Metabolic, cardiovascular,^[9] and psychological comorbidities overlap in PsO, with a significant impact on quality of life^[10] and increased mortality.^[11] The heterogeneous clinical presentation of PsA and PsO represents a clinical challenge when choosing a suitable therapy, in particular when treating concurrent comorbidities.^[12] Undertreatment is also significant,^[13,14] where up to 24% of patients with moderate-to-severe PsO are not treated, and 30% are only receiving topical therapy, which may not control the disease.^[13] Similarly, PsA is a heterogeneous and potentially severe disease, which may require a multidisciplinary approach to treatment.^[15]

In the last two decades, the number of disease-modifying antirheumatic drugs (DMARDs) has significantly increased.^[16] The introduction of biologic DMARDs, such as tumor necrosis factor (TNF) inhibitors has greatly improved patients’ quality of life,^[1] with anti-TNFs often prescribed as first-line treatment for PsO and/or PsA.^[15,17] Guidelines also recommend anti-TNFs when there is an insufficient response to nonsteroidal anti-inflammatory drugs (NSAIDs) or local glucocorticoid injections.^[1,15,18] In PsA, a biologic DMARD is recommended after an inadequate response to at least one conventional synthetic DMARD, while an interleukin (IL)-17 or IL-12/23 inhibitor may be preferred when there is significant skin involvement.^[15] However, IL-17 inhibitor treatment has been associated with exacerbations of and new onset IBD or colitis. Fortunately, the cessation of IL-17 inhibitors and initiation of an alternative treatment (e.g., corticosteroids and anti-TNF therapy) can generally lead to clinical remission.^[19,20]

The efficacy and tolerability of adalimumab have been demonstrated in PsA, plaque PsO, RA and IBD (including Crohn’s disease, ulcerative colitis, pediatric Crohn’s disease, and pediatric ulcerative colitis),^[21,22] Assessment of the clinical efficacy and cost-effectiveness of adalimumab has shown it to be a valid treatment choice in a large number of patients.^[1] Two Italian studies have demonstrated that, economically, adalimumab is below the threshold value for health care interventions for all its main indications, as it significantly reduces societal costs for RA, PsO and PsA, ankylosing spondylitis, and Crohn’s disease.^[23,24] The longterm safety profile of adalimumab has also been well established in multiple clinical trials,^[25] with infections being the most commonly reported serious adverse event, and in the real-world setting.^[26,27]

It is generally accepted that patients with IMIDs should receive effective treatment as early as possible to prevent and limit organ damage, comorbidities, and the natural progression of the disease.^[28] Recent patent expiration has introduced numerous anti-TNF biosimilars, which have markedly increased the overall uptake of biological therapies for patients with PsO.^[29] Anti-TNF biosimilars provide cost reduction and increased patients’ access to biological treatment, positively influencing the course of their disease.^[1]

The aim of the present work was to convene rheumatologists and dermatologists experienced in the use of anti-TNF agents, to achieve a consensus on the use of adalimumab in patients with PsO and/or PsA.

Materials and Methods

A total of eight Italian clinicians (four rheumatologists and four dermatologists, hereafter referred to as the Board), with longstanding expertise in the treatment of PsA and PsO, gathered to reach a consensus on the management of both diseases with anti-TNF agents, by adopting the Delphi methodology.^{[28, 29, 30, 31]} The Delphi method is a highly regarded approach which involves an iterative process, characterised by multiple rounds of voting, to ascertain consensus on clinical matters in healthcare where there is limited guidance and/or a scarcity of evidence.^[30]

In the present study, the methodology was stratified into four phases: [1] the Board identified 12 statements lacking clinical consensus and developed a Delphi questionnaire (Table 1), [2] the questionnaire was then submitted to a panel of 36 Italian clinical experts in the field of PsO and PsA through an online platform for a first Delphi round. The voting panel were chosen by the Board members, who nominated 4–5 collaborators or colleagues, each operating in distinct geographic regions (e.g., North-East, North-West). Geographical criteria were adhered to, ensuring homogeneous coverage of the Italian national territory. The panel were then asked to express their agreement or disagreement on each item using a Likert-type scale from 1 to 7 (1 = strongly disagree to 7 = strongly agree) for a maximum of three rounds. [3] Responses were collected and analysed. [4] Common and conflicting viewpoints were identified. At the end of Round 1, the median value, the 25th (Q1) and 75th (Q3) percentiles and the interquartile range (IQR) of each statement were calculated.

In Round 2, experts were asked to answer the same statements taking into account the IQR of each question, as an index of the responses of their colleagues. In case of a score outside the IQR, experts were required to provide a reason. The results of the first and second rounds and the reasons were discussed by the Board, focusing on the motivations/theses of those who responded outside the IQR. After discussing and commenting on the results of each of the 12 statements, the Board members re-formulated the statements.

In Round 3, the panel were invited to express their agreement/disagreement with the same statements considering the antitheses and the new IQRs. At this time, those who answered outside the IQR were asked to provide a new motivation. The statements were ranked based on the Q1 and the IQR (Figure 1). The “level of agreement or disagreement” achieved was measured according to the following criteria: a) agreement and consent (Q1 ⩾4, Q3 > 4 and IQRS2), b) agreement and low consent (Q1 ⩽4 and IQR⩽3), c) indecision (Q1= Q3= 4 or Q1= 3 and Q3= 5), d) disagree and consent (Q1 < 4 and IQR ⩽ 2 and Q1 ≠3 and Q1 #5) and e) disagree and low consent (Q1 < 4 and IQR⩾3).

Figure 1

Flow diagram of the statement classification in terms of level of agreement or disagreement. IQR, interquartile range; Q, quartile.

Results

All 36 participants responded to Round 1, and 33 responded to the remaining two rounds. All statements reached a positive consensus, with variations in 29% of responses between the first and the second round, and in 17% of responses between the second and the third round. For the 4 statements with values outside the IQR (S6, S7, S9, and S12), the Board was asked to reclarify their statement to avoid confusion in the observations provided by the expert panel (Table 2).

Discussion

The results of this Delphi exercise clearly show that an overall, multidisciplinary consensus may be reached for the use of adalimumab in the management of PsO and PsA. The Delphi method is typically used in healthcare research to determine consensus in response to defined clinical questions.^[31] In this study the Delphi questionnaire received controlled feedback from a panel of experts in the field of PsO and PsA management. Moreover, the importance of collaboration between rheumatologists and dermatologists is unanimously accepted in Statement S1. In all statements, the Delphi procedure identified a high degree of consensus. Moreover, the statements are also widely supported in the literature, which further corroborates a satisfactory level of expertise, as well as a good level of communication between the centers. From a general point of view, the statements submitted to the panel have been shaped according to the following principles. Firstly, that the paradigm for the use of biologics in case of failure, intolerance, or contraindications to conventional synthetic DMARDs is getting stronger. Furthermore, in parts of the European Union where the use of biosimilars is characterised by an affordably low cost, their use as first-line treatment is moving progressively forward in light of their good long-term safety profile.^[32] Secondly, the association of a significant reduction in quality of life and ability to work with moderate-to-severe PsO and PsA^[33] may profit from a reduction in disease burden and the indirect costs of PsO.^[15,34] Moreover, adherence and patient satisfaction are higher with biologic agents when compared to conventional agents.^[35,36]

In the present study, five statements in the Delphi questionnaire were based on the pathogenesis of IMIDs and the dys-regulation of inflammatory cytokines. The inhibition of TNF results in a down-regulation of the abnormal inflammatory pathways implicated in the pathogenesis and progression of IMIDs, and anti-TNF inhibitors including adalimumab may improve long-term patient outcomes by preventing the development of future damage and comorbidities.^[28]

Among Delphi expert panel responses, adalimumab emerged as a drug with long-term sustained effectiveness in PsA and PsO. Moreover, the cost-effectiveness of adalimumab is a significant factor when considering treatment options for PsO and PsA. Therefore, the cumulative results of this study suggest that adalimumab offers a suitable first-line treatment for patients with PsO/PsA, offering an effective therapeutic option with an established long-term, risk/benefit profile. The panel also strongly agreed that adalimumab may be first choice for specific PsO and PsA subpopulations such as those with comorbid uveitis, IBD or hidradenitis suppurativa. The use of adalimumab in PsA patients with predominant enthesitis, and/ or peripheral arthritis, and/or axial involvement achieved a high agreement among the Board and expert panel.

In conclusion, the results of this Delphi exercise indicate the need to bridge the gap between patients’ expectations and physicians’ objectives, with a focus on improving the quality of life and personalized treatment of patients with PsO and PsA. Given the cost-effectiveness of biosimilars in Italy, adalimumab may represent an effective and safe first-line treatment for patients with moderate-to-severe PsO or PsA, as well as patients suffering from non-musculoskeletal symptoms affecting the gut (IBD) or the eyes (uveitis).