Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with a significant decline in function and quality of life1. Patients with PsA are at increased risk of obesity, insulin resistance, type 2 diabetes mellitus, hypertension, hyperlipidaemia, and cardiovascular disease2. Patterns of involvement in PsA have several features, including the presence of dactylitis and enthesitis1.

A diagnosis of PsA is an indication for treatment with systemic therapies3. Current therapeutic options for PsA and its complications include4,5 non-steroidal anti-inflammatory drugs, corticosteroids, conventional disease-modifying antirheumatic drugs (DMARDs) (cDMARDs), and biologic drugs6. New drugs with new, more specific mechanisms of action against PsA have been developed in recent years, including synthetic disease-modifying antirheumatic drugs with a specific target, such as apremilast7. Apremilast is an oral phosphodiesterase-4 inhibitor approved to treat PsA, alone or in combination with other DMARDs, in adult patients who have had an inadequate response or intolerance to previous treatment with a DMARD, and to treat moderate to severe chronic plaque psoriasis8. In contrast to non-specific immunosuppressive drugs, apremilast has an immunomodulatory action9, reducing the risk of severe opportunistic infections and reactivation of tuberculosis10.

Although the evidence from clinical studies is strong and consistent, there remain doubts about the positioning of apremilast within the therapeutic algorithm for PsA, as these studies are relatively recent and no direct comparative clinical trials are available4,11. Therefore, information from routine clinical practice is very important to draw strategic conclusions12,13. The aim of this project was to gather scientific evidence and the experience of a group of rheumatologists with expertise in the management of PsA on the use of apremilast in clinical practice in Spain using the Delphi methodology, generating a series of recommendations on the management of PsA with an eminently practical approach aimed at rheumatologists.

The study was conducted in 4 phases using the Delphi technique14 modified by Rand/UCLA recommendations15: 1) identification of clinical scenarios of interest by the Scientific Committee overseeing the management of the project; 2) development of the questionnaire by a panel of rheumatology experts; 3) e-mail survey in 2 rounds; and 4) collection and final analysis of the results.

• 1)

  The Scientific Committee comprised a national coordinator and 5 regional coordinators11,16–19. Each regional member proposed several clinical scenarios where, due to the lack of consensus, it would be interesting to make therapeutic recommendations on the use of apremilast in PsA. After analysing and discussing the proposals, the following scenarios were chosen: 1) efficacy in peripheral PsA; 2) efficacy in enthesitis and dactylitis; 3) efficacy in PsA with skin involvement; 4) management of comorbidities in patients with PsA; and 5) safety implications in the use of apremilast.

• 2)

  The expert panel for this study was made up of a total of 17 rheumatologists with expertise in the treatment of PsA from different regions of Spain, including the 5 regional coordinators (Appendix A). This panel of experts attended a round table where different cases of apremilast use in routine clinical practice in the 5 proposed scenarios were discussed. This discussion, together with the previous literature review, was the basis for the questionnaire that had 50 questions and a total of 156 items to be assessed. All questions, in the form of statements (affirmative or negative), were designed to be answered on a Likert scale, where 1 meant strongly disagree with the statement and 9 meant strongly agree with the statement (Fig. 1).

  
  

  Fig. 1.

  Summary outline of the conditions used to assess the Delphi questionnaire.

  (0.32MB).
• 3)

  This questionnaire was sent to the expert panel in electronic format and answered anonymously. After analysing the results of the first round of voting, the items that had not reached consensus in the first round were submitted again to the expert panel for voting. The questionnaire of the second round included the medians of the scores of the first round for each question.

• 4)

  Following the Rand/UCLA methodology15, each item’s level of appropriateness was ranked according to the median and the mean of the absolute deviation from the median. Also, following the definitions of the BIOMED Concerted Action on Appropriateness for different panel sizes, the level of agreement for each item was classified as “agree”, “neutral” or “disagree” (Fig. 1). Agreement on an item was determined when at least 77% of the panellists scored within the predefined 3-point interval (Likert score intervals: 1–3, 4–6, 7–9) in which the median score for that item fell. Disagreement on an item was determined when the scores of one third or more of the panellists were in the Likert interval 1–3, and of another third or more in the interval 7−9. Items where there was no agreement or disagreement were considered to have an “uncertain” level of consensus.

The study was conducted over 3 months, from 30 November 2017 to 14 February 2018.

The 17 experts on the panel reached consensus in the first round on 58 of the 156 items (37.2%) (46 appropriate and 12 inappropriate). Of the remaining 98 items, consensus was reached on 35 more (21 appropriate and 14 inappropriate) in the second round.

Consensus recommendations based on expert opinion and developed using validated and rigorous methodologies produce useful guidelines, providing experts with valuable specific information. In this study, the Delphi methodology14 was used to achieve consensus and generate recommendations for rheumatologists in the management of PsA. The expert participation was good, with a 100% response rate in the 2 rounds.

According to the experts, the appropriate patient for treatment with apremilast would have moderately active, mildly disabling PsA, including those with skin involvement in difficult sites and other comorbidities commonly associated with the disease, with an inadequate response or contraindication to cDMARDS and not yet candidates for biologic therapies.

The presence of enthesitis and dactylitis, as well as psoriasis in difficult sites, would be factors that would positively influence the use of apremilast before that of biologic therapies. In the PALACE 1–3 studies18,20,21, which assessed the safety and efficacy of apremilast in adult patients with active PsA despite prior treatment with cDMARDs or biologics, improvements in peripheral activity parameters characteristic of PsA were observed at weeks 16 and 24. Apremilast also demonstrated greater ACR20 responses in patients who had not previously been exposed to biologic therapy21.

Regarding the items relating to the use of apremilast versus cDMARDs, the consensus among experts is in line with the approved indication for the drug, which recommends the use of apremilast in patients who have had an inadequate response or in whom there are contraindications to the cDMARDs8. In the PALACE study, the responses observed in the group treated with apremilast were similar between the patients who were receiving and those not receiving concomitant cDMARDs, including methotrexate. In addition, a greater ACR20 response was observed at week 16 in patients previously treated with cDMARDs or biologics receiving apremilast compared to patients receiving placebo8.

Regarding the use of apremilast versus biologic therapies, there was consensus among experts that apremilast is an appropriate choice in patients naïve to biologic therapies. Biologic therapies have an activity ceiling of around 60%22–26, which means that up to 40% of patients with PsA, at best, do not respond to initial treatment. Furthermore, these drugs have immunosuppressive activity, which can generate problems of immunogenicity or toxicity, depending on the patient22–26. In this regard, and due to their immunomodulatory action, the risk of serious opportunistic infections and reactivation of tuberculosis in patients treated with apremilast is lower than with other immunosuppressive drugs10 and does not require screening for tuberculosis8. Another advantage of apremilast over biologic therapies is that it does not require extensive drug monitoring8, which is consistent with the results of previous studies that concluded that there is no need for prior laboratory analysis or continuous monitoring of laboratory parameters27.

Regarding the management of comorbidities, the experts considered that apremilast would be an appropriate therapeutic option in patients with PsA and other comorbidities commonly associated with the disease. Furthermore, no prior screening or follow-up for most of the comorbidities commonly associated with PsA would be required, which is an advantage over cDMARDs and biologics.

Regarding the items relating to the safety of apremilast, in general, the experts' responses are in line with the results obtained in previous studies18,20,21, which demonstrated the efficacy of apremilast in PsA, with a very favourable safety and tolerability profile, and a very convenient dosage and form of administration27,28. The experts agreed that one of the most relevant features of apremilast was its good safety profile and that it could be considered a safer therapeutic option than conventional systemic treatments. The experts also agreed on the management of gastrointestinal adverse effects and headaches, 2 of the most common treatment-related adverse effects8.

In conclusion, apremilast, due to its efficacy, safety, and tolerability profile, is a new therapeutic option for patients with psoriasis and PsA, especially patients with comorbidities, including infections and/or neoplasms, and covers some hitherto unmet needs10,29,30.

Celgene collaborated in organising working meetings and bibliographic support, elaboration and implementation of the Delphi method undertaken by the independent scientific consultancy.

Amgen funded this manuscript.

JCTA has participated in presentations, consultancies and educational programmes at Amgen, Lilly, Novartis, Janssen and Pfizer. RAG has participated in presentations, consultancies, attending conferences, courses and educational programmes at AbbVie, Amgen, Gebro, Janssen, Lilly, MSD, Novartis, Pfizer and UCB. CMM has participated in presentations, consultancies, attending conferences, courses, and educational programmes at Amgen, Janssen, Lilly, Pfizer and UCB. JSS has participated in presentations, consultancies, attending conferences, courses and conducting educational programmes at AbbVie, Janssen, Lilly, Pfizer, Novartis, Celgene, and MSD. EPA is an employee and shareholder of Amgen S.A. JG has received funding in relation to courses and/or conferences, has acted as a speaker and/or has been a consultant on occasion for MSD, Pfizer, AbbVie, Janssen, Cilag, Novartis, Celgene, and Lilly.