Psoriatic arthritis (PsA) is an inflammatory disease that affects 11–42% of patients with cutaneous psoriasis. PsA is characterized by inflammatory arthritis, enthesitis, dactylitis and spondylitis, and is associated with substantial healthcare costs and impaired health-related quality of life (HRQoL) and work productivity.1–3 Despite the availability of efficacious PsA treatments, not all patients achieve satisfactory disease control and patients unresponsive to first-line methotrexate require treatment with biological agents or target-specific disease-modifying anti-rheumatic drugs (ts-DMARDs).4 Apremilast is a non-biologic oral systemic ts-DMARD approved for the treatment of moderate to severe plaque psoriasis, PsA and mouth ulcers associated with Behçet's disease (BE) that are candidates for systemic treatment.5

In 2016, both the European League Against Rheumatism (EULAR) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) published updated recommendations for PsA management.2,4 More recently, the Spanish Society of Rheumatology (SER) updated its recommendations. These updates included new therapeutic agents such as apremilast and clearly distinguished apremilast from biological therapies.6 However, they did not define the profile of PsA patients who may benefit from apremilast treatment. Randomized clinical trials (RCTs) showed apremilast is effective in PsA patients naïve to biological agents.7 These RCTs had strict selection criteria, and observed effects may not be representative of clinical practice effects. For example, the PALACE 1, PALACE 2, and PALACE 3 trials excluded patients who had not responded to more than three PsA therapies and patients with other inflammatory comorbidities.8–10 To date, few observational studies have assessed the profile of patients receiving apremilast treatment for PsA in clinical practice.

Although clinical practice guidelines provide some recommendations to assess PsA treatment efficacy, the assessment of treatment response in routine practice is heterogeneous. The number of swollen or tender joints, the presence of enthesitis/dactylitis, C-reactive protein (CRP), or patient-reported pain and disease activity are often used in patient follow-up. Most of these evaluations are included in the Disease Activity index for PsA (DAPSA), a validated tool that classifies disease activity as in remission, low, moderate or high.11,12 While a clinical version of the DAPSA index (cDAPSA) that includes all items except CRP has also been validated, the DAPSA and cDAPSA are not widely used in clinical practice.11

Despite the proven efficacy of apremilast and guideline recommendations, data regarding apremilast use and effectiveness in the real-world setting is limited and few studies have assessed apremilast effectiveness using DAPSA. Our study evaluated the effectiveness and persistence of apremilast treatment for PsA in Spanish clinical practice, and describes the profile of patients initiating treatment with apremilast in Spain.

We report real-world evidence (RWE) from Spain on the use of apremilast in patients with moderately active PsA who had not previously received biologics. Most patients included in our study had moderate disease activity, as measured by the DAPSA score, and a high comorbidity burden. In addition to high apremilast persistence, physicians and patients reported good response rates during 6–12 months of apremilast treatment. Specifically, the number of swollen joints, the incidence of dactylitis and enthesitis, and disease severity scores (DAPSA and PGA) all decreased, with the greatest reductions observed at month 12. Two disease-specific instruments (PsAID-9 and VITACORA-19) used to evaluate HRQoL in patients with PsA showed positive outcomes in more than half of the patients.

As expected, the profile of patient's receiving apremilast in Spanish clinical practice differed from that of the pivotal clinical trials and was similar to other RWE studies.18–23 Most patients had long-standing active oligoarticular PsA (defined as <5 involved joints) of moderate severity (mean [SD] baseline DAPSA score, 20.8 [10.5]; mean [SD] time from start of PsA symptoms to apremilast initiation, 6.1 [4.7] years). Moreover, our study population reflected the Spanish Society of Rheumatology recommendations which include apremilast as a treatment option for patients with active PsA whose systemic treatment choices may be limited by efficacy, frequent laboratory safety requirements, and tolerability.6

As in other RWE studies, apremilast was likely prescribed due to co-existing and comorbid diseases, mainly hypertension, dyslipidemia, malignancy and cardiopathy. For example, in patients with oligoarticular PsA and more than 2 comorbidities receiving long-term apremilast treatment. Balato A. et al.20 reported history of malignancy and previous biologic treatment negatively influenced PASI responses. Mazzilli et al.24 and Arias et al.25 reported apremilast to be effective in psoriatic patients affected by cardiometabolic comorbidities. Chan et al.19 reported improved clinical outcomes in an unselected PsA group of patients with multiple co-existing conditions defined as any distinct additional entity that has existed or may occur during the clinical course (malignancy, bronchiectasis, multiple sclerosis) treated with apremilast over one year.

Our study included patients that had received previous conventional systemic therapies but were naïve to biologic agents. Chan et al. reported better response rates in biologic-naïve patients versus subjects with prior bDMARD use with shorter duration of PsA.19 Similarly, the phase IIIB ACTIVE study confirmed long-term apremilast efficacy in biologic-naïve PsA patients with one prior csDMARD according to the American College of Rheumatology 20 criteria (ACR20).7 In an interim analysis of the German LAPIS-PsA study, biologic-naïve patients reported a Patient's Global Assessment of Disease Activity (PtGA) score of 0/1 earlier and more frequently than biologic-experienced patients.22

Several composite measures of disease activity that assess multiple clinical domains have been validated in PsA clinical trials. Our study used the DAPSA score to assess disease activity. Importantly, two of the five DAPSA domains (PtGA and pain) are subjective, patient-reported items and TJC is influenced by a central sensitization of pain.26 The use of composite disease activity measures and response criteria in clinical practice is highly dependent on their feasibility. In this regard, DAPSA defined thresholds can be calculated easily, even in clinical settings with limited time resources.27 In a previous RWE study of patients with oligoarticular PsA (defined as ≤4 swollen joints), those receiving apremilast monotherapy reported larger improvements in cDAPSA score at 6 months than patients receiving methotrexate or bDMARD.20 Notably, in our study, the percentage of patients in remission increased from 7% at apremilast initiation to 22% at 12 months, indicating an overall favourable disease evolution.

PsA treatment aims to achieve the lowest possible level of disease activity and, if possible, remission, minimize joint damage, and gain acceptable physical function and QoL. In our study, patients reported improvements in their QoL 6 and 12 months after apremilast initiation. Moreover, these improvements were observed for both of the questionnaires used (PSAID-9 and VITACORA-19), reflecting a clinically meaningful improvement in QoL. In this regard, several recent studies have shown a good correlation between PSAID and disease activity, and PSAID has been identified as the main factor associated with treatment persistence.28

The 12-month apremilast discontinuation rate of 33.8% observed in our study is consistent with that reported by Balato A. et al. over 52 weeks.21 Among patients discontinuing apremilast, 20.3% stopped due to lack of efficacy, which is in line with the 14–37.5% reported in other RWE studies.21,29 The safety profile of apremilast was aligned with the apremilast SmPC and other RCTs and RWE studies.5,8–10,16,21–24,29–31 AEs were mostly mild (gastrointestinal) and in most cases did not require treatment discontinuations.

Our study has several strengths. The inclusion criteria were broad and we included adult patients with PsA who had initiated apremilast for the first time in the previous 6 months and were biologic-naïve. No other demographic and clinical criteria were considered and we captured the effectiveness of apremilast in real-world populations, supporting the generalizability of the results.

The main limitation of our study is the small sample size, which is, in part, due to the COVID pandemic. During the pandemic, prioritization of COVID-19 research, redeployment of research staff, and the need for social distancing has negatively impacted recruitment to non-COVD related studies. For example, Mirza et al. reported that patients were less willing to participate in observational and interventional rheumatology research studies whilst COVID-19 was present in the community.32 Also, our single-arm study was not designed to make comparisons or test hypothesis, and pain was not systematically assessed at apremilast initiation. While this limits our ability to assess whether symptoms improved over time, PGA values were available and indicated disease severity decreased during apremilast treatment. Despite these limitations, our study captures real-world data of apremilast use, effectiveness, and tolerability.

Our study shows that patients naïve to biologics initiating apremilast for the treatment of PsA in Spanish clinical practice have moderate, non-erosive PsA, and have a high comorbidity burden. Moreover, our data show the clinical benefits of apremilast in these patients, including a reduction in the number of swollen and tender joints, fewer dactylitis and enthesitis, and improved patient quality of life (QoL). Approximately two-thirds of the patients continued on apremilast at 12 months, with no new safety signals.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Jordi Gratacos-Masmitja, J.C. Torre Alonso and Eva Pascual contributed to the study conception and design. Material preparation, data collection and analysis were performed by all participant authors. The first draft of the manuscript was written by all participant authors and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Qualified researchers may request data from Amgen clinical studies. Complete details are available at the following: https://wwwext.amgen.com/science/clinical-trials/clinicaldata-transparencypractices/clinical-trial-data-sharing-request.

This study was funded by Celgene. Amgen acquired the worldwide rights to Otezla® (apremilast) on November 21, 2019.

Jordi Gratacos-Masmitja Speakers bureau: MSD, Pfizer, AbbVie, Janssen-Cilag, Novartis, Celgene y Lilly. Consultant of: MSD, Pfizer, AbbVie, Janssen-Cilag, Novartis, Celgene y Lilly. José Luis Álvarez Vega Speakers bureau: Abbvie, Amgen, MSD, Lilly, Roche, Esteve, UCB, Menarini, Pfizer, GSK, BMS, Janssen, Novartis, Gebro. Consultant of: Abbvie, Amgen, MSD, Lilly, Roche, Esteve, UCB, Menarini, Pfizer, GSK, BMS, Janssen, Novartis, Gebro. Grant/research support from: Abbvie, Amgen, MSD, Lilly, Roche, Esteve, UCB, Menarini, Pfizer, GSK, BMS, Janssen, Novartis, Gebro. Emma Beltrán Speakers bureau: Abbvie, Bristol, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB. Consultant of: Abbvie, Bristol, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB, Ana Urruticoechea-Arana: None declared. C. Fito-Manteca: None declared. Francisco Maceiras: None declared. Joaquin Maria Belzunegui Otano Speakers bureau: Lilly, Amgen, Novartis, Abbvie, Janssen. J. Fernández Melón Speakers bureau: Amgen SL, Eugenio Chamizo Carmona: None declared. Abad Hernández Speakers bureau: MSD, Abbvie, Pfizer, Kern, Novartis, Biogen, Sandoz, Amgen, Sanofi, Lilly, Roche and Janssen-Cilag. Consultant of: MSD, Abbvie, Pfizer, Kern, Novartis, Biogen, Sandoz, Amgen, Sanofi, Lilly, Roche and Janssen-Cilag. Grant/research support from: MSD, Abbvie, Pfizer, Kern, Novartis, Biogen, Sandoz, Amgen, Sanofi, Lilly, Roche and Janssen-Cilag, Inmaculada Ros. Consultant of: Amgen. Grant/research support from: MSD, Roche, Novartis, Lilly, Pfizer, Amgen, Eva Pascual. Shareholder of: Amgen. Employee of: Amgen, Juan Carlos Torre Speakers bureau: Amgen, Lilly, Novartis, Janssen, Pfizer. Consultant of: Amgen, Lilly, Novartis, Janssen, Pfizer. Grant/research support from: Amgen, Lilly, Novartis, Janssen, Pfizer.