# Treatment of Early Oligoarticular Psoriatic Arthritis With Apremilast: Primary Outcomes at Week 16 From the FOREMOST Randomised Controlled Trial

Laure Gossec, Laura Coates, Dafna Gladman, Jacob Aelion, Jitendra Vasandani, Andreas Pinter, Joseph Merola, Arthur Kavanaugh, Jyotsna Reddy, Rebecca Wang, et al.

► To cite this version:

Laure Gossec, Laura Coates, Dafna Gladman, Jacob Aelion, Jitendra Vasandani, et al. Treatment of Early Oligoarticular Psoriatic Arthritis With Apremilast: Primary Outcomes at Week 16 From the FOREMOST Randomised Controlled Trial. Annals of the Rheumatic Diseases, 2024, 83 (11), pp.1480-1488. 10.1136/ard-2024-225833. hal-04969401

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# Treatment of Early Oligoarticular Psoriatic Arthritis With Apremilast: Primary Outcomes at Week 16 From the FOREMOST Randomised Controlled Trial

Laure Gossec,¹,² Laura C. Coates,³ Dafna D. Gladman,⁴ Jacob Aelion,⁵ Jitendra Vasandani,⁶ Andreas Pinter,⁷ Joseph F. Merola,⁸ Arthur Kavanaugh,⁹ Jyotsna Reddy,¹⁰ Rebecca Wang,¹⁰ Michele Brunori,¹⁰ Yuri Klyachkin,¹⁰ Cynthia Deignan,¹⁰ Philip Mease¹¹

¹Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris France;
²AP-HP, Pitié Salpêtrière Hospital, Rheumatology Department, Paris, France; ³Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK;
⁴Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada; ⁵West Tennessee Research Institute, Jackson, TN, USA; ⁶West Texas Clinical Research, Lubbock, TX, USA; ⁷University Hospital of the Goethe University, Frankfurt am Main, Germany; ⁸Department of Dermatology and Department of Medicine, Division of Rheumatology, UT Southwestern Medical Center, Dallas, TX, USA; ⁹School of Medicine, University of California San Diego, La Jolla, CA, USA; ¹⁰Amgen Inc., Thousand Oaks, CA, USA; ¹¹Swedish Medical Center/Providence St. Joseph Health and University of Washington School of Medicine, Seattle, WA, USA

**Running title:** Apremilast in early oligoarticular PsA

**Address for correspondence:**

Prof. Laure Gossec
Service de Rhumatologie, Hôpital Pitié Salpêtrière,
47-83 Bd de l'Hôpital, 75013 Paris France
ORCID: 0000-0002-4528-310X
Phone: +33 1 42 17 78 14
Fax: +33142177959
E-mail: laure.gossec@aphp.fr

## ABSTRACT

### Objectives

Oligoarticular psoriatic arthritis (PsA) is frequent but rarely studied. The objective was to assess the efficacy of apremilast in early oligoarticular PsA.

### Methods

FOREMOST (NCT03747939) was a Phase 4 multicentre, randomised, double-blind, placebo-controlled trial. Patients had early (symptom duration ≤5 years) oligoarticular PsA (>1 but ≤4 swollen and >1 but ≤4 tender joints; 2-8 total active joints). Patients were randomised 2:1 to apremilast 30 mg twice daily or placebo for 24 weeks, with an early escape at Week 16. The primary endpoint was the proportion of patients at Week 16 who achieved minimal disease activity (MDA)-Joints (modification of MDA mandating ≤1 swollen joint and ≤1 tender joint) based on sentinel joints (those affected at baseline) with a combination of non-responder imputation and multiple imputations. Exploratory analysis assessed all joints.

### Results

Of 308 patients randomised (apremilast: n=203; placebo: n=105), mean (standard deviation [SD]) PsA duration was 9.9 (10.2) months, mean (SD) age was 50.9 (12.5) years, and 39.9% of patients were using a csDMARD. MDA-Joints (sentinel joints [primary endpoint], all joints) was achieved by significantly more patients with apremilast (33.9% and 21.3%) vs placebo (16.0% and 7.9%) at Week 16 (P=0.0008
and nominal *P*=0.0028, respectively). Greater improvements in patient-reported outcomes, clinical disease activity, and skin involvement also were seen with apremilast vs placebo.

**Conclusions**

FOREMOST is the first randomised controlled trial designed for early oligoarticular PsA and showed apremilast improves clinical and patient-reported outcomes. This trial may inform optimal management of PsA in these patients.

ClinicalTrials.gov Registration: NCT03747939

**Keywords:** oligoarthritis, oligoarticular psoriatic arthritis, minimal disease activity, apremilast

**INTRODUCTION**

Psoriatic arthritis (PsA) is a heterogeneous inflammatory rheumatologic disorder characterised by inflammatory arthritis which, based on the number of actively inflamed joints, can be divided into oligoarticular PsA and polyarticular PsA [1]. The oligoarticular phenotype has been frequently observed in different real-world cohorts, occurring in up to 50% of PsA patients [2-5].

Despite fewer involved joints and generally lower rates of enthesitis and dactylitis [3], oligoarticular PsA can significantly impact quality of life [3, 4, 6]. Additionally, similar levels of pain and disease burden, including a high proportion of patients who found the state of their symptoms to be unacceptable, have been seen in oligoarticular PsA compared with polyarticular PsA [4, 7].

Both the European Alliance of Associations for Rheumatology (EULAR) recommendations and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations have put forward oligoarticular PsA as part of the research agenda, noting there are little data on the treatment of patients with oligoarthritis since published clinical trials have generally enrolled patients with at least 3 swollen joints and at least 3 tender joints, with the actual mean active joint counts being much higher [8-10]. Knowledge regarding the efficacy of drugs in oligoarticular forms would be of great value to clinicians.

Apremilast is an oral phosphodiesterase 4 inhibitor approved for the treatment of active PsA [11]. The efficacy and safety of apremilast were demonstrated in patients with long-standing PsA in the Phase 3 Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial programme [12-15]. In the PALACE studies, mean swollen joint count (SJC) was approximately 10 and mean tender joint count (TJC) was approximately 20. The efficacy of apremilast in early oligoarticular PsA has not yet been evaluated.

The objective of the FOREMOST randomised controlled trial was to assess the efficacy of apremilast vs placebo for treatment of early oligoarticular PsA. Here we report the primary results of this trial.

**METHODS**

**Study design**

FOREMOST (ClinicalTrials.gov identifier: NCT03747939) was a Phase 4 international, multicentre, randomised, double-blind, placebo-controlled, parallel-group study conducted from December 2018 to December 2022 in 80 sites in 10 countries. Patients were randomised 2:1 to receive either apremilast 30
mg twice daily (BID) or placebo. The study consisted of a 4-week screening period, followed by a 24-week double-blind, placebo-controlled phase (Figure 1). Starting at Week 16, patients who showed no improvement in SJC (assessed using sentinel joints) were eligible for early escape whereby patients initially randomised to placebo were switched to apremilast 30 mg BID and those initially randomised to apremilast continued to receive apremilast 30 mg BID. After Week 24, all patients had the option to enter an active treatment extension phase in which all patients received apremilast through Week 48.

The study was approved by an institutional review board/ethics committee at each site before commencement (Supplementary Table 1) and conducted in compliance with Good Clinical Practice, the International Council for Harmonisation Guideline E6, the Declaration of Helsinki, and applicable regulatory requirements. Patients provided written informed consent before study-related procedures.

## Patients

Patients had PsA according to the Classification Criteria for Psoriatic Arthritis (CASPAR). As we aimed to include oligoarticular PsA, joint involvement was limited to >1 but ≤4 swollen and >1 but ≤4 tender joints, of 66/68 SJC/TJC. Overall, patients could have 2-8 total active joints, considering there was no formal consensus on definition of oligoarticular disease when the study was designed. Disease duration was originally required to be ≤2 years but was revised to ≤5 years after symptom onset in a protocol amendment dated July 2021 to reach a sufficient sample size. Patients taking a csDMARD (either methotrexate or sulfasalazine) to treat PsA at baseline could continue treatment provided the treatment was taken at a stable dose for ≥3 months prior to baseline and patients remained at a stable dose (≤25 mg/week for methotrexate and ≤3 g/day for sulfasalazine) during the first 24 weeks of the study. Patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) at baseline were required to be on a stable dose for ≥2 weeks before baseline to be enrolled in the study and were required to remain on this dose through Week 24. Stable low doses of glucocorticoids (prednisone ≤10 mg/day or equivalent) were allowed. Patients were excluded if they had received prior treatment with >2 csDMARDs, a Janus kinase inhibitor, or a biologic DMARD.

## Assessments

The primary endpoint was the proportion of patients who achieved minimal disease activity (MDA)-Joints at Week 16, based on sentinel joints (those affected at baseline). This outcome is a modified MDA [16] that requires achievement of both SJC ≤1 and TJC ≤1 plus achieving ≥3 of the following remaining MDA criteria: psoriasis body surface area (BSA) ≤3%, patient pain visual analogue scale (VAS) ≤15 mm on a 100-mm scale, Patient Global Assessment of Disease Activity (PtGA) ≤20 mm on a 100-mm scale, physical function Health Assessment Questionnaire Disability Index (HAQ-DI) ≤0.5, and enthesitis count ≤1 based on the Leeds Enthesitis Index (LEI) [16]. This was selected as the primary endpoint to allow for capture of different dimensions of PsA with a particular focus on improvement in the number of active joints.

Secondary endpoints assessed at Week 16 included the proportion of patients achieving Clinical Disease Activity in Psoriatic Arthritis (cDAPSA) remission (≤4) or low disease activity (LDA, >4 to ≤13); SJC ≤1, TJC ≤1, or PtGA ≤20 (based on the MDA criteria); patient assessment of pain ≤15 (based on the MDA criteria); change from baseline in the Psoriatic Arthritis Impact of Disease (PsAID-12), a self-administered questionnaire that measures the impact of PsA from the perspective of the patient; and Psoriatic Arthritis Disease Activity Score (PASDAS) good or moderate response. For assessments involving joint counts, primary and secondary analyses were based on sentinel joints. Exploratory analyses were performed for all joints (including those that were unaffected at baseline) to fully assess the impact of apremilast on disease activity. Treatment-emergent adverse events (TEAEs) were assessed throughout the study. Exploratory endpoints assessed at Week 16 included PsAID-12 score ≤4 (considered a patient-
acceptable symptom state [17]), change from baseline in physician's assessment by VAS of nail psoriasis, and the proportion of patients with skin clearance defined by BSA of 0. SJC and TJC over time, the proportion of patients whose total joint involvement increased from ≤4 at baseline to >4 over time, the proportion of patients achieving MDA, and the proportion of patients achieving MDA-Joints among those with ≤4 active joints at baseline were assessed as post hoc analyses.

## Statistical analysis

It was estimated that 285 patients would be needed to provide 80% power to detect a 15% absolute difference in the proportion of patients who achieved MDA-Joints with apremilast vs placebo using a chi-square test with 2-sided significance level of 0.05.

Efficacy analyses used the full analysis set (FAS), which consisted of all randomised patients. The safety population consisted of all patients who received at least 1 dose of study medication. A sequential test procedure (in the order of the list of endpoints above) was applied to the primary and 7 secondary efficacy endpoints to preserve the family-wise type I error rate. The primary endpoint and binary secondary endpoints were assessed using a Cochran-Mantel-Haenszel test controlling for concomitant use of glucocorticoids at baseline (yes or no) and use of a csDMARD (csDMARD naive, csDMARD use before baseline, or csDMARD use before and concomitant at baseline). For binary response parameters, the missing data were imputed using non-responder imputation (NRI) for patients who discontinued the study prior to Week 16 due to adverse events or lack of efficacy, and multiple imputations (MI) for the remaining missing values at Week 16. The number of responders was rounded based on the value given by multiple imputations. For the continuous secondary endpoint, a mixed-effect model for repeated measures (MMRM) was used that included change from baseline as the dependent variable and treatment group, time, treatment-by-time interaction, use of glucocorticoids, and use of a csDMARD (as above) as factors, and baseline value as a covariate. Treatment differences in least squares (LS) mean, the associated standard errors (SEs), and 2-sided *P*-values were obtained from the MMRM model.

# RESULTS

## Baseline characteristics and patient disposition

Of 308 patients randomised (apremilast: n=203; placebo: n=105), mean PsA duration was 9.9 (SD: 10.2) months, mean age was 50.9 (SD: 12.5) years, and 39.9% (123/308) of patients were using a csDMARD, mostly methotrexate (107/123) (Table 1). Mean (SD) SJC was 2.6 (0.7), and TJC was 3.2 (0.8), and these were similar between treatment groups; however, a slight imbalance was observed in median (Q1, Q3) SJC (apremilast: 3.0 [2.0, 3.0]; placebo: 2.0 [2.0, 3.0]) due to a greater proportion of placebo patients with an SJC of 2 (apremilast: 45.8%; placebo: 54.3%). Small joints were most commonly affected. Close to 90% of study patients had ≤4 active joints at baseline (apremilast: n=176 [86.7%]; placebo: n=92 [87.6%]).

Twenty-one (10.3%) apremilast-treated patients and 24 (22.9%) placebo-treated patients underwent early escape (Figure 2). A total of 255 (82.8%) patients completed the 24-week placebo-controlled phase (apremilast: n=167 [82.3%]; placebo: n=88 [83.8%]) and 53 (17.2%) discontinued the study (apremilast: n=36 [17.7]; placebo: n=17 [16.2]) (Figure 2).

## Primary endpoint

The primary endpoint was met: MDA-Joints response based on sentinel joints was achieved by significantly more patients with apremilast (69/203, 33.9%) vs placebo (17/105, 16.0%) at Week 16 (treatment difference [95% confidence interval (CI)]: 18.5% [8.9, 28.1], *P*=0.0008) (Figure 3A).
## Secondary endpoints

At Week 16, a significantly greater proportion of patients treated with apremilast achieved cDAPSA remission or LDA vs placebo (70.2% vs 51.8%; P=0.0017) (Table 2). Proportions of patients achieving SJC ≤1 based on sentinel joints at Week 16 were higher with apremilast vs placebo, although not statistically significant (74.0% vs 69.0%; P=0.35). More patients treated with apremilast achieved TJC ≤1 at Week 16 than placebo (based on sentinel joints, 66.2% vs 44.4%; nominal P=0.0003) (Table 2).

Improvements in patient-reported outcomes were more frequent with apremilast; achievement of PtGA ≤20 was greater with apremilast vs placebo at Week 16 (30.4% vs 19.1%), as was achievement of low pain levels (29.4% vs 13.1%), and decreases in PsAID-12 (−1.5 vs −0.4) (Table 2). Greater proportions of patients achieved a good or moderate response in PASDAS score with apremilast vs placebo (59.9% vs 42.7%) at Week 16 (Table 2).

## All joints analysis

When outcomes were evaluated based on all joints, MDA-Joints response at Week 16 was seen in 21.3% vs 7.9% for apremilast vs placebo (treatment difference [95% CI]: 13.6% [5.9, 21.4]; nominal P=0.0028) (Figure 3B). More patients treated with apremilast achieved SJC ≤1 (57.9% vs 41.5%; nominal P=0.0068) or TJC ≤1 (38.0% vs 16.7%; nominal P=0.0002) at Week 16 than placebo (Table 2). At Week 16, a significantly greater proportion of patients treated with apremilast achieved cDAPSA remission or LDA vs placebo (60.3% vs 38.0%; nominal P=0.0004) (Table 2). However, 28.6% of placebo-treated patients and 22.2% of apremilast-treated patients had LDA at baseline. Among those not already in LDA or remission at baseline (apremilast: n=153; placebo: n=75), 54.4% of patients treated with apremilast achieved remission or LDA at Week 16 vs 30.1% of patients who received placebo (Supplementary Figure 1). PASDAS response rates at Week 16 were consistently higher with apremilast vs placebo when evaluated by all joints impacted (Table 2).

## Exploratory endpoints

At Week 16, there was a difference in the proportion of patients achieving response in nonmusculoskeletal manifestations. More patients achieved skin clearance at Week 16 with apremilast vs placebo (31.2% vs 16.9%; nominal P=0.0073) (Supplementary Figure 2A). Improvement from baseline in nail VAS was significantly greater with apremilast (LS mean change −13.9) than placebo (−6.8) at Week 16 (nominal P=0.0094) (Supplementary Figure 2B).

## Post hoc analysis

Among patients with baseline PsAID-12 >4, more patients achieved a PsAID-12 score ≤4 (considered a patient-acceptable symptom state) with apremilast (50.7%) vs placebo (23.1%; nominal P=0.0005) at Week 16 (Supplementary Figure 3). Decreases in the mean number of swollen and tender joints were seen over time with apremilast treatment, with noticeable differences observed with apremilast vs placebo when evaluated by all joints at Week 16 (Supplementary Figure 4).

An analysis was conducted to assess achievement of each domain of MDA other than SJC and TJC in patients who did not meet response criteria for that domain at baseline (Supplementary Figure 5). Of patients with BSA >3% at baseline, more achieved BSA ≤3% with apremilast vs placebo at Week 16 (52.2% vs 25.1%; nominal P=0.0043). Of patients with a patient assessment of pain score >15 at baseline, patient assessment of pain ≤15 was reached by more patients with apremilast vs placebo at Week 16 (27.1% vs 9.9%; nominal P=0.0012). Of patients with PtGA >20 at baseline, more achieved PtGA ≤20 at Week 16 with apremilast vs placebo (28.5% vs 13.0%; nominal P=0.0044). Of patients with HAQ-DI >0.5 at baseline, more achieved HAQ-DI ≤0.5 at Week 16 with apremilast vs placebo (32.4% vs 19.0%; nominal P=0.0302). In the small number of patients with LEI >1 at baseline (placebo: n=27, apremilast:
n=41), numerically greater proportions achieved LEI ≤1 at Week 16 with apremilast vs placebo, although this was not significant (53.1% vs 41.0%; nominal *P*=0.3815).

The proportion of patients achieving MDA at Week 16 was consistent with rates of MDA-Joints. A higher proportion of patients receiving apremilast (30.7%) achieved MDA (all joints) than patients receiving placebo (15.1%; nominal *P*=0.0026) (Figure 4).

In light of the more stringent definition of oligoarthritis as ≤4 active joints [8], we assessed outcomes in a subgroup of the FOREMOST population that met this definition (n=268/308, 87.0%). Clinical characteristics were similar between patients with ≤4 active joints at baseline and patients with >4 active joints (**Supplementary Table 2**). MDA-Joints response rates (based on sentinel or all joints) were similar in this population compared with the overall study population (**Supplementary Figure 6**).

More patients in the placebo group progressed from a baseline total active joint count ≤4 to a total active joint count >4 at Week 16 than patients in the apremilast group, with separation between the 2 groups observed at the Week 12 study visit (data as observed; **Figure 5**).

## Safety

TEAEs were reported in 59.3% of patients taking apremilast and 47.1% of patients taking placebo (**Table 3**). The most frequently reported (≥5% of patients in either group) adverse events were diarrhoea (apremilast: 23.0%; placebo: 10.6%), nausea (apremilast: 10.8%; placebo: 3.8%), and headache (apremilast: 7.8%; placebo: 2.9%). Incidence of severe TEAEs was similar with apremilast (3.9% of patients) and placebo (3.8% of patients). Incidence of serious TEAEs was similar with apremilast (4.4% of patients) and placebo (5.8% of patients). The proportions of patients with TEAEs leading to drug interruption were 7.8% with apremilast and 2.9% with placebo. TEAEs leading to drug withdrawal occurred in 10.3% of apremilast patients and 6.7% of placebo patients. The most common TEAEs (occurring in >2 patients) leading to withdrawal were diarrhoea (apremilast: 2.5%; placebo: 1.0%), nausea (apremilast: 2.9%; placebo: 0.0%), and fatigue (apremilast: 1.5%; placebo: 0.0%). Two deaths were reported during the study in the apremilast group and none in the placebo group. One patient died of sudden cardiac death 2 months after initiation of apremilast. The other patient died of anoxic brain injury following a planned routine abdominal herniorrhaphy, 88 days after the last dose of apremilast. Both deaths were assessed by the study investigators as not related to the study drug. These 2 deaths were not adjudicated.

## DISCUSSION

Clinical trial data to support treatment guidelines for oligoarticular PsA are currently limited. FOREMOST is, to our knowledge, the first large, randomised, placebo-controlled trial only enrolling patients with oligoarticular PsA and provides valuable information on how patients with early disease and limited joint involvement respond to apremilast treatment.

The FOREMOST study enrolled patients with PsA with limited joint involvement and early disease, despite prior treatment with NSAIDs or ≤2 csDMARDs. At baseline, the vast majority of patients had ≤4 active joints and mean disease duration was 10 months. More patients achieved the primary endpoint (MDA-Joints) with apremilast vs placebo when evaluated by sentinel joints, with a treatment difference of 18.5%. When evaluated by all joints, the rate of MDA-Joints was 21.3% with apremilast, with a consistent treatment benefit vs placebo. Apremilast-treated patients showed a higher level of benefit in the different dimensions of the MDA score, overall higher level of disease activity control as measured by cDAPSA and PASDAS, and better patient-reported outcomes. TEAEs were consistent with the known apremilast safety profile and no new safety signals were observed [12-15]. Although there were 2
deaths in the apremilast group during this study, they were not suspected to be related to apremilast treatment. According to a pooled analysis of 15 randomised, placebo-controlled trials of apremilast including 4763 patients, 9 treatment-emergent deaths were reported during apremilast exposure. Only 1 was suspected by the investigator to be related to apremilast [18].

Separation between the placebo and apremilast groups was seen for both mean SJC and mean TJC over time. We also found that in the placebo arm, approximately 35% of patients with ≤4 active joints at baseline developed an active joint count >4 after 16 weeks. In contrast, 20% of patients with ≤4 active joints at baseline receiving apremilast developed a joint count >4 over 16 weeks. SJC ≤1 was achieved by 69.0% of placebo patients at Week 16 and was not significantly different from apremilast response rates (74.0%) when evaluated by sentinel joints. This may be due to the low median SJC at baseline (2.0 with placebo, 3.0 with apremilast). Due to limited knowledge on disease evolution in patients with early oligoarticular PsA, sentinel joints were considered in the study protocol when defining primary and other secondary endpoints. However, evaluation by all joints is clinically relevant as it considers development of arthritis in new joints. When evaluating all joints, overall response rates were lower than those observed with sentinel joints but still significantly greater with apremilast than placebo. These results may reflect a recently diagnosed population whose disease presentation is still evolving, as well as the waxing and waning course of the disease.

Oligoarticular PsA is highly prevalent in clinical practice, present in up to 50% of patients in certain cohorts [3, 4]. It is the most frequent clinical pattern reported in early disease, and it has been shown to be a less erosive form of PsA [20, 21]. EULAR recommendations emphasise the value of earlier, more aggressive treatment in patients with oligoarthritis [8]. The FOREMOST study illustrates the risk of undertreatment for progression from oligoarticular to polyarticular disease, arguing for earlier and more proactive intervention for oligoarthritis and the value of apremilast in this approach.

The need for treatment optimisation in patients with oligoarticular PsA is supported by our observations of early oligoarticular disease in FOREMOST compared with those of the Phase 3 PALACE trials, which required ≥3 swollen and ≥3 tender joints [12, 14, 15]. Mean TJC and SJC were much lower in FOREMOST (3.2 and 2.6, respectively) than in the PALACE trials (18.0-23.3 and 9.2-12.8, respectively). Despite this, baseline PtGA scores were similar between FOREMOST (51.3) and the PALACE trials (52.3-58.8) [12, 14, 15]. However, the Physician's Global Assessment (PhGA) was lower in the FOREMOST population (42.6) than in PALACE 1-4 (51.7-56.1). Baseline HAQ-DI was similar between patients in FOREMOST (1.0) and in PALACE 1-4 (1.0-1.2) [12-15]. These observations highlight the discordance between patient and physician assessments of disease, as well as how oligoarticular disease appears to have a similar impact on HAQ-DI as polyarticular PsA despite fewer joints involved. However, it should be considered that there may be an index event bias and patients with greater pain may be disproportionately driven to seek care, resulting in higher HAQ-DI scores. Thus, not all oligoarticular patients in clinical practice may have been captured in the FOREMOST study. A post hoc analysis evaluating secukinumab efficacy in patients with 1 to 4 swollen and 1 to 4 tender joints in a pooled analysis of 5 Phase 3 trials found similar levels of disease burden and demonstrated potential for oligoarticular patients to benefit from systemic treatment, in line with results from FOREMOST [19].

Due to the limited studies in patients with early oligoarticular PsA, the design of this study posed some challenges. At the time of protocol development, and to an extent at the time of this publication, there was no formal consensus on the definition of oligoarticular PsA. As a result, the study's inclusion criteria allowed for patients with up to 8 inflamed joints (≤4 swollen and ≤4 tender). Nonetheless, almost 90% of the patients in FOREMOST fit a more stringent definition of ≤4 actively inflamed joints [8]. Assessment of sentinel joints was chosen to follow joints initially impacted at baseline and evaluate differences at 16
weeks, as little information was available on the course of disease in patients with early oligoarticular PsA. In addition, examination of all joints was performed to comprehensively assess disease status and identify any extension of arthritis involvement over the study period. Apremilast showed consistent benefit over placebo whether assessed by sentinel joints or all joints. FOREMOST enrolled patients with short disease duration and limited joint involvement. Certain dimensions of psoriatic disease might be underrepresented in the study population, and the full variety of disease severity in patients with oligoarticular PsA may not be captured in the study. Because this is the first global prospective study in oligoarticular PsA and the only to use MDA-Joints, comparisons to other studies are unavailable. Although the inclusion criterion was extended from 2 to 5 years' disease duration, mean disease duration was 10 months, median was 6 months, and the third quartile was around 12 months, showing that most patients in FOREMOST had PsA of <1 year's duration. This is clinically relevant, as patients likely had lower chances of changing from an initial polyarticular phenotype to an oligoarticular one. Although this provides valuable data on how early disease responds to apremilast treatment, the results may not be applicable to patients with longstanding oligoarticular PsA who may have cycled through multiple conventional and biologic DMARD therapies.

In conclusion, FOREMOST is unique as a global randomised controlled trial exclusively studying early oligoarticular PsA. We report the primary results of FOREMOST and show better disease control was achieved with apremilast, with greater MDA-Joints response compared with placebo at 16 weeks. These findings show apremilast treatment of early oligoarticular PsA improved clinical and patient-reported outcomes. This study may inform appropriate management of disease in these patients, but further studies are needed.
## ACKNOWLEDGEMENTS

We thank the patients and investigators who participated in the study as well as Hamid Amouzadeh of Amgen Inc. for his contributions to the manuscript. Writing support was sponsored by Amgen Inc. and provided by Rebecca Lane, PhD, of Peloton Advantage, LLC, an OPEN Health company, and Dawn Nicewarner, PhD, employee of and stockholder in Amgen Inc.

## FUNDING

Funded by Amgen Inc.

## CONFLICTS OF INTEREST

LG has received medical writing support and honoraria as part of advisory boards for this study. Outside this work: grants or contracts from AbbVie, Biogen, Lilly, Novartis, and UCB; consulting fees from AbbVie, BMS, Celltrion, Janssen, Novartis, Pfizer, and UCB; honoraria for lectures from AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, and UCB; support for attending meetings and/or travel from MSD, Novartis, and Pfizer; and medical writing support from AbbVie, Janssen, Galapagos, and UCB.

LCC: AbbVie, Amgen, Biogen, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Medac, MoonLake, Novartis, Pfizer, UCB –grant/research support, consulting fees, and/or speaker honoraria. LCC was supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the author and not necessarily those of the NHS, the NIHR, or the United Kingdom Department of Health.

DDG: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, UCB – grant/research support or consulting fees.

JA: AbbVie, Amgen – speakers bureau; AbbVie, Ardea Biosciences, AstraZeneca, Bristol Myers Squibb, Celgene, Centocor, Eli Lilly, Galapagos, Genentech, GlaxoSmithKline, Human Genome Sciences, Janssen, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, Takeda, UCB, Vertex – grant/research support.

JV: Nothing to disclose.

AP: AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Boehringer Ingelheim, Celgene, GSK, Eli Lilly, Galderma, Hexal, Janssen, LEO-Pharma, Medac, Merck Serono, Mitsubishi, MSD, Novartis, Pfizer, Tigercat Pharma, Regeneron, Roche, Sandoz Biopharmaceuticals, Schering-Plough, UCB Pharma – investigator/speaker/advisor.

JFM: AbbVie, Arena, Avotres, Biogen, Bristol Myers Squibb, Dermavant, Eli Lilly, EMD, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, Sanofi, Serono, Sun, UCB – consultant and/or investigator.

AK: Amgen, AbbVie, BMS, Janssen, Novartis, Pfizer, Eli Lilly – grant/research support and consultant.

JR, RW, MB, YK, and CD: Employment by and stock ownership in Amgen.
PM: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun, UCB
– grant/research support and consultant; Boehringer Ingelheim, GlaxoSmithKline – consultant; AbbVie,
Amgen, Eli Lilly, Janssen, Novartis, Pfizer, UCB – speakers bureau.

## PREVIOUS PUBLICATION

This work was presented in part in a poster at EULAR 2022, The European Congress of Rheumatology, 1-4 June 2022, in Copenhagen, Denmark; in a poster and oral presentation at ACR Convergence 2023, 10-15 November 2023, in San Diego, California, USA; in a poster at EADV 2023, 11-14 October 2023 in Berlin, Germany; in a poster at Maui Derm Hawaii 2024, 22-26 January 2024 in Maui, Hawaii, USA; and in a poster at WCH 2024, 12-17 January, 2024 in Honolulu, Hawaii, USA, available in *Skin*.

## DATA AVAILABILITY

Qualified researchers may request data from Amgen clinical studies.
Complete details are available at http://www.amgen.com/datasharing

## AUTHOR CONTRIBUTIONS

Study design: LG, DDG, LCC, PM, MB

Study investigator: LG, JA, PM

Enrolled patients: JA, LG

Data analysis: RW

Data interpretation: All authors

Manuscript preparation: All authors

Manuscript review and revisions: All authors

Final approval of manuscript: All authors
# KEY MESSAGES

## What is already known on this topic

* Psoriatic arthritis (PsA) is frequently oligoarticular. Even with limited joint involvement, PsA can be associated with considerable disease burden and marked impact on quality of life.

* There are limited data on drug effectiveness in oligoarticular PsA since most trials exclude patients with low counts of involved joints.

## What this study adds

* FOREMOST is the first trial targeting early oligoarticular PsA. This trial provides data on an under-represented group of patients. We found that even with limited joint involvement, the impact of PsA was high at baseline.

* In this randomised controlled trial comparing apremilast and placebo, the primary outcome was met. Patients with oligoarticular PsA treated with apremilast showed improvements in clinical outcomes and patient-reported outcomes at Week 16.

## How this study might affect research, practice, or policy

* The results of FOREMOST suggest apremilast is effective for patients with early PsA and limited joint involvement.
REFERENCES

1. Moll JM, Wright V. Psoriatic arthritis. *Semin Arthritis Rheum* 1973;3:55-78.

2. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. *Ann Rheum Dis* 2005;64:ii14-ii7.

3. Gladman DD, Ye JY, Chandran V, Lee KA, Cook RJ. Oligoarticular versus polyarticular psoriatic arthritis: a longitudinal study showing similar characteristics. *J Rheumatol* 2021;48:1824-9.

4. Kasiem FR, Luime JJ, Vis M, et al. Lessons learned from clinical phenotypes in early psoriatic arthritis: the real-world Dutch south west Early Psoriatic ARthritis study. *Scand J Rheumatol* 2021;50:124-31.

5. Kane D, Stafford L, Bresnihan B, FitzGerald O. A classification study of clinical subsets in an inception cohort of early psoriatic peripheral arthritis--'DIP or not DIP revisited'. *Rheumatology (Oxford)* 2003;42:1469-76.

6. Ogdie A, Liu M, Glynn M, et al. SAT0343. Burden of disease at treatment initiation among biologic-naive patients with oligoarticular versus polyarticular psoriatic arthritis in the corona psoriatic arthritis/spondyloarthritis registry [abstract]. *Ann Rheum Dis* 2019;78:1251.

7. Tillett W, Ogdie A, Richette P, et al. Large joint involvement and substantial disease burden in patients with oligoarticular and polyarticular psoriatic arthritis in the multinational UPLIFT survey [abstract POS1077]. *Ann Rheum Dis* 2022;81(suppl 1):863-4.

8. Gossec L, Baraliakos X, Kerschbaumer A, et al. EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update. *Ann Rheum Dis* 2020;79:700-12.

9. Gossec L, Smolen J, Kerschbaumer A, et al. EULAR recommendations for the management of psoriatic arthritis: 2023 update [oral presentation]. Annual Congress of the European Alliance of Associations for Rheumatology; May 31-June 3, 2023; Milan, Italy.

10. Coates LC, Soriano ER, Corp N, et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA): updated treatment recommendations for psoriatic arthritis 2021. *Nat Rev Rheumatol* 2022;18:465-79.

11. Otezla [package insert]. Thousand Oaks, CA: Amgen, Inc., 2023.

12. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomized, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. *Ann Rheum Dis* 2014;73:1020-6.

13. Cutolo M, Myerson GE, Fleischmann R, et al. A phase III, randomized, controlled trial of apremilast in patients with psoriatic arthritis: results of the PALACE 2 trial. *J Rheumatol* 2016;43:1724-34.

14. Edwards CJ, Blanco FJ, Crowley J, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). *Ann Rheum Dis* 2016;75:1065-73.

15. Wells AF, Edwards CJ, Kivitz AJ, et al. Apremilast monotherapy in DMARD-naive psoriatic arthritis patients: results of the randomized, placebo-controlled PALACE 4 trial. *Rheumatology (Oxford)* 2018;57:1253-63.

16. Coates LC, Helliwell PS. Defining low disease activity states in psoriatic arthritis using novel composite disease instruments. *J Rheumatol* 2016;43:371-5.

17. Di Carlo M, Becciolini A, Lato V, Crotti C, Favalli EG, Salaffi F. The 12-item Psoriatic Arthritis Impact of Disease questionnaire: Construct validity, reliability, and interpretability in a clinical setting. *J Rheumatol* 2017;44:279-85.

18. Mease PJ, Hatemi G, Paris M, et al. Apremilast long-term safety up to 5 years from 15 pooled randomized, placebo-controlled studies of psoriasis, psoriatic arthritis, and Behçet's syndrome. *Am J Clin Dermatol* 2023;24:809-20.
19. Ogdie A, Gladman D, Coates L, et al. Secukinumab provides clinical improvements in patients with active oligoarticular psoriatic arthritis: results from a pooled analysis of 5 phase 3 studies [abstract 1825]. *Arthritis Rheumatol* 2021;73(suppl 9):1825.

20. De Marco G, Zabotti A, Baraliakos X, et al. Characterisation of prodromal and very early psoriatic arthritis: a systematic literature review informing a EULAR taskforce. *RMD Open* 2023;9.

21. Lindqvist UR, Alenius GM, Husmark T, Theander E, Holmstrom G, Larsson PT. The Swedish early psoriatic arthritis register--2-year followup: a comparison with early rheumatoid arthritis. *J Rheumatol* 2008;35:668-73.
<table><caption>Table 1. Baseline demographics and disease characteristics</caption><thead><tr><th></th><th>Placebo<br>(n=105)</th><th>Apremilast<br>(n=203)</th><th>Total<br>(N=308)</th></tr></thead><tbody><tr><td>Age, mean (SD), years</td><td>50.2 (13.0)</td><td>51.3 (12.3)</td><td>50.9 (12.5)</td></tr><tr><td>Women, n (%)</td><td>51 (48.6)</td><td>118 (58.1)</td><td>169 (54.9)</td></tr><tr><td>Race, White, n (%)</td><td>99 (94.3)</td><td>192 (94.6)</td><td>291 (94.5)</td></tr><tr><td>PsA duration, mean (SD), months</td><td>10.0 (10.6)</td><td>9.8 (10.0)</td><td>9.9 (10.2)</td></tr><tr><td>Median (Q1, Q3)</td><td>6.0 (3.6, 12.7)</td><td>6.1 (3.7, 11.2)</td><td>6.0 (3.7, 11.7)</td></tr><tr><td>SJC (0-66), mean (SD)</td><td>2.6 (0.7)</td><td>2.7 (0.7)</td><td>2.6 (0.7)</td></tr><tr><td>Median (Q1, Q3)</td><td>2.0 (2.0, 3.0)</td><td>3.0 (2.0, 3.0)</td><td>3.0 (2.0, 3.0)</td></tr><tr><td>SJC category, n (%)</td><td></td><td></td><td></td></tr><tr><td>2</td><td>57 (54.3)</td><td>93 (45.8)</td><td>150 (48.7)</td></tr><tr><td>3</td><td>38 (36.2)</td><td>79 (38.9)</td><td>117 (38.0)</td></tr><tr><td>4</td><td>10 (9.5)</td><td>31 (15.3)</td><td>41 (13.3)</td></tr><tr><td>TJC (0-68), mean (SD)</td><td>3.2 (0.8)</td><td>3.2 (0.8)</td><td>3.2 (0.8)</td></tr><tr><td>Median (Q1, Q3)</td><td>3.0 (3.0, 4.0)</td><td>3.0 (3.0, 4.0)</td><td>3.0 (3.0, 4.0)</td></tr><tr><td>TJC category, n (%)</td><td></td><td></td><td></td></tr><tr><td>2</td><td>23 (21.9)</td><td>41 (20.2)</td><td>64 (20.8)</td></tr><tr><td>3</td><td>38 (36.2)</td><td>77 (37.9)</td><td>115 (37.3)</td></tr><tr><td>4</td><td>44 (41.9)</td><td>85 (41.9)</td><td>129 (41.9)</td></tr><tr><td>Active joint involvement*, n (%)</td><td></td><td></td><td></td></tr><tr><td>Small only</td><td>51 (48.6)</td><td>104 (51.2)</td><td>155 (50.3)</td></tr><tr><td>Large only</td><td>7 (6.7)</td><td>19 (9.4)</td><td>26 (8.4)</td></tr><tr><td>Small and large</td><td>47 (44.8)</td><td>80 (39.4)</td><td>127 (41.2)</td></tr><tr><td>PhGA (0-100 mm VAS), mean (SD)</td><td>43.2 (19.2)</td><td>42.2 (18.6)</td><td>42.6 (18.8)</td></tr><tr><td>PtGA (0-100 mm VAS), mean (SD)</td><td>50.5 (20.7)</td><td>51.6 (22.0)</td><td>51.3 (21.5)</td></tr><tr><td>Patient's assessment of pain (0-100 mm VAS), mean (SD)</td><td>51.1 (22.7)</td><td>52.3 (22.0)</td><td>51.9 (22.2)</td></tr><tr><td>cDAPSA (0-154), mean (SD)</td><td>15.9 (4.5)</td><td>16.3 (4.3)</td><td>16.2 (4.4)</td></tr><tr><td>PASDAS (0-10), mean (SD)</td><td>4.9 (1.0)</td><td>4.9 (1.1)</td><td>4.9 (1.1)</td></tr><tr><td>BSA, mean (SD), %</td><td>6.3 (10.9)</td><td>6.9 (12.3)</td><td>6.7 (11.8)</td></tr><tr><td>BSA >3%, n (%)</td><td>42 (40.0)</td><td>78 (38.4)</td><td>120 (39.0)</td></tr><tr><td>HAQ-DI (0-3), mean (SD)</td><td>1.1 (0.6)</td><td>1.0 (0.6)</td><td>1.0 (0.6)</td></tr></tbody></table>
<table><tr><td>LEI (0-6), mean (SD)†</td><td>2.6 (1.6)</td><td>2.4 (1.5)</td><td>2.5 (1.5)</td></tr><tr><td>LEI >0, n (%)</td><td>38 (36.2)</td><td>70 (34.5)</td><td>108 (35.1)</td></tr><tr><td>SPARCC Index (0-16), mean (SD)†</td><td>4.3 (3.9)</td><td>3.9 (3.5)</td><td>4.0 (3.6)</td></tr><tr><td>Physician's assessment of nail psoriasis (0-100 mm VAS), mean (SD)‡</td><td>28.9 (26.3)</td><td>30.8 (25.9)</td><td>30.2 (26.0)</td></tr><tr><td>PsAID-12 (0-10), mean (SD)</td><td>4.8 (2.2)</td><td>4.7 (2.0)</td><td>4.7 (2.1)</td></tr><tr><td>Prior csDMARD, n (%)</td><td>69 (65.7)</td><td>135 (66.5)</td><td>204 (66.2)</td></tr><tr><td>Concomitant csDMARD, n (%)</td><td>41 (39.0)</td><td>82 (40.4)</td><td>123 (39.9)</td></tr><tr><td>Methotrexate</td><td>34 (32.4)</td><td>73 (36.0)</td><td>107 (34.7)</td></tr><tr><td>Sulfasalazine</td><td>7 (6.7)</td><td>9 (4.4)</td><td>16 (5.2)</td></tr></table>

*Active joints defined as swollen and/or tender joints. Large joints included shoulder, elbow, hip, knee, and ankle. The remaining joints were considered small.

†In patients with pre-existing enthesopathy.

‡In patients with baseline nail VAS >0.

FAS.

BSA = body surface area; cDAPSA = Clinical Disease Activity Index for Psoriatic Arthritis; csDMARD = conventional synthetic disease-modifying antirheumatic drug; FAS = full analysis set; HAQ-DI = Health Assessment Questionnaire Disability Index; LEI = Leeds Enthesitis Index; PASDAS = Psoriatic Arthritis Disease Activity Score; PhGA = Physician's Global Assessment of disease activity; PsA = psoriatic arthritis; PsAID-12 = Psoriatic Arthritis Impact of Disease 12-item; PtGA = Patient Global Assessment of disease activity; Q = quartile; SD = standard deviation; SJC = swollen joint count; SPARCC = Spondyloarthritis Research Consortium of Canada; TJC = tender joint count; VAS = visual analogue scale.
<table><caption>Table 2. Outcomes at Week 16 comparing apremilast and placebo</caption><thead><tr><th rowspan="2"></th><th colspan="3">Sentinel* Joints</th><th colspan="3">All Joints</th></tr><tr><th>Placebo (n=105)</th><th>Apremilast (n=203)</th><th>Difference (95% CI)</th><th>Placebo (n=105)</th><th>Apremilast (n=203)</th><th>Difference (95% CI)</th></tr></thead><tbody><tr><td>cDAPSA REM/LDA, n (%)</td><td>54 (51.8)</td><td>143 (70.2)</td><td>18.6%<br>(7.0, 30.2)<br>P=0.0017</td><td>40 (38.0)</td><td>122 (60.3)</td><td>22.5%<br>(10.7, 34.3)<br>P=0.0004<sup>†</sup></td></tr><tr><td>SJC ≤1, n (%)</td><td>72 (69.0)</td><td>150 (74.0)</td><td>5.1<br>(-5.8, 16.0)<br>P=0.3539</td><td>43 (41.5)</td><td>117 (57.9)</td><td>16.4<br>(4.7, 28.0)<br>P=0.0068<sup>†</sup></td></tr><tr><td>TJC ≤1, n (%)</td><td>47 (44.4)</td><td>134 (66.2)</td><td>22.1<br>(10.4, 33.7)<br>P=0.0003<sup>†</sup></td><td>17 (16.7)</td><td>77 (38.0)</td><td>21.4<br>(11.6, 31.2)<br>P=0.0002<sup>†</sup></td></tr><tr><td>PtGA VAS ≤20, n (%)</td><td>-</td><td>-</td><td>-</td><td>20 (19.1)</td><td>62 (30.4)</td><td>11.8%<br>(1.7, 22.0)<br>P=0.0286<sup>†</sup></td></tr><tr><td>Patient pain VAS ≤15, n (%)</td><td>-</td><td>-</td><td>-</td><td>14 (13.1)</td><td>60 (29.4)</td><td>16.3%<br>(6.9, 25.8)<br>P=0.0022<sup>†</sup></td></tr><tr><td>PsAID-12, LS Mean (SE) Change from baseline</td><td>-</td><td>-</td><td>-</td><td>-0.4 (0.2)</td><td>-1.5 (0.2)</td><td>-1.0<br>(-1.5, -0.6)<br>P&lt;0.0001<sup>†</sup></td></tr><tr><td>PASDAS Good/ Moderate Response, n (%)</td><td>45 (42.7)</td><td>122 (59.9)</td><td>17.7%<br>(5.7, 29.7)<br>P=0.0043<sup>†</sup></td><td>42 (39.8)</td><td>120 (59.3)</td><td>20.0%<br>(8.1, 32.0)<br>P=0.0014<sup>†</sup></td></tr></tbody></table>

FAS. The number of responders was rounded based on the value given by multiple imputations.

<footnote>*Sentinel joints defined as joints affected at baseline.</footnote>

<footnote>†Nominal *P*-value.</footnote>
cDAPSA = Clinical Disease Activity in Psoriatic Arthritis; CI = confidence interval; csDMARD = conventional synthetic disease-modifying antirheumatic drug; FAS = full analysis set; LDA = low disease activity; LS = least squares; MDA = minimal disease activity; PASDAS = PsA Disease Activity Score; PsAID-12 = PsA Impact of Disease; PtGA = Patient Global Assessment of disease activity; REM = remission; SE = standard error; SJC = swollen joint count; TJC = tender joint count; VAS = visual analogue scale.
<table><caption>Table 3. Summary of safety through Week 24</caption><thead><tr><th></th><th>Placebo<br>(n=104*)</th><th>Apremilast<br>(n=204*)</th></tr></thead><tbody><tr><td>Any TEAE, n (%)</td><td>49 (47.1)</td><td>121 (59.3)</td></tr><tr><td>Any drug-related TEAE, n (%)</td><td>20 (19.2)</td><td>67 (32.8)</td></tr><tr><td>Any severe TEAE, n (%)</td><td>4 (3.8)</td><td>8 (3.9)</td></tr><tr><td>Any serious TEAE, n (%)</td><td>6 (5.8)</td><td>9 (4.4)</td></tr><tr><td>TEAEs leading to drug withdrawal, n (%)</td><td>7 (6.7)</td><td>21 (10.3)</td></tr><tr><td>Deaths, n (%)</td><td>0 (0.0)</td><td>2 (1.0)<sup>†</sup></td></tr><tr><td>TEAEs occurring in ≥5% of patients, n (%)</td><td></td><td></td></tr><tr><td>Diarrhoea</td><td>11 (10.6)</td><td>47 (23.0)</td></tr><tr><td>Nausea</td><td>4 (3.8)</td><td>22 (10.8)</td></tr><tr><td>Headache</td><td>3 (2.9)</td><td>16 (7.8)</td></tr></tbody></table>

*Patients were included in the treatment group for the treatment they actually received. One patient randomised to the placebo group received apremilast and was included in the placebo group for the FAS and the apremilast group for the safety analysis set.

†Two deaths reported (sudden cardiac death and anoxic brain injury following a planned routine abdominal herniorrhaphy) in the apremilast group were not related to study drug as assessed by the investigator. Safety analysis set. Includes data through Week 16/Visit 5 for placebo-treated patients who escaped early and data up to Week 24 for all other patients.

FAS = full analysis set; TEAE = treatment-emergent adverse event.
<figure><img src="image_2.png" /><figcaption>Figure 1. FOREMOST Study Design</figcaption></figure>

APR = apremilast; csDMARD = conventional synthetic disease-modifying antirheumatic drug; MDA = minimal disease activity; NSAID = nonsteroidal anti-inflammatory drug; PBO = placebo; PsA = psoriatic arthritis.
<figure><img src="image_3.png" /><figcaption>Figure 2. Patient Disposition Through Week 24 in the FOREMOST Trial</figcaption></figure>

FAS. All 45 patients who escaped early completed 24 weeks.

BID = twice daily; FAS = full analysis set.
<figure><img src="image_4.png" /><figcaption>Figure 3. MDA-Joints Response at Week 16
A.</figcaption></figure>

<figure><img src="image_5.png" /></figure>

(A) Based on sentinel joints. (B) Based on all joints. FAS. Error bars represent SE. The number of responders was rounded based on the value given by multiple imputations. MDA-Joints is a composite of TJC ≤1 and SJC ≤1 plus achievement of 3 of the following: BSA ≤3%, patient pain VAS ≤15, PtGA ≤20, HAQ-DI ≤0.5, and LEI ≤1.

BSA = body surface area; CI = confidence interval; csDMARD = conventional synthetic disease-modifying antirheumatic drug; FAS = full analysis set; HAQ-DI = Health Assessment Questionnaire Disability Index; LEI = Leeds Enthesitis Index; MDA = minimal disease activity; PtGA = Patient Global Assessment of disease activity; SE = standard error; SJC = swollen joint count; TJC = tender joint count; VAS = visual analogue scale.
<figure><img src="image_6.png" /><figcaption>Figure 4. Proportion of Patients Achieving MDA at Week 16</figcaption></figure>

FAS. Based on all joints. Error bars represent SE.

CI = confidence interval; FAS = full analysis set; MDA = minimal disease activity; SE = standard error.
<figure><img src="image_7.png" /><figcaption>Figure 5. Proportion of Patients Who Switched to Active Joint Count >4 Among Patients With ≤4 Active Joints at Baseline</figcaption></figure>

FAS with ≤4 active joints at baseline. Error bars represent SE. Based on all joints. Data as observed.
FAS = full analysis set.
Supplementary Tables and Figures

<table><caption>**Supplementary Table 1. Institutional Review Boards and Independent Ethics Committees That Approved the Study**</caption><thead><tr><td>Site Name</td><td>IRB/IEC Name</td></tr></thead><tbody><tr><td>West Tennessee Research Institute, llc</td><td>Advarra IRB</td></tr><tr><td>Health Research of Oklahoma</td><td>Advarra IRB</td></tr><tr><td>Arthritis and Osteoporosis Center of Southwest Ohio</td><td>Advarra IRB</td></tr><tr><td>Covina Arthritis Clinic</td><td>Advarra IRB</td></tr><tr><td>Advanced Rheumatology PC</td><td>Advarra IRB</td></tr><tr><td>Inland Rheumatology Clinical Trials Inc</td><td>Advarra IRB</td></tr><tr><td>University of Rochester</td><td>Advarra IRB</td></tr><tr><td>University of Florida College of Medicine</td><td>University of Florida Review Board</td></tr><tr><td>Arizona Arthritis and Rheumatology Research, PLLC</td><td>Advarra IRB</td></tr><tr><td>Klein and Associates MD, PA - Cumberland</td><td>Advarra IRB</td></tr><tr><td>North Georgia Rheumatology Group PC</td><td>Advarra IRB</td></tr><tr><td>Saint Paul Rheumatology PA</td><td>Advarra IRB</td></tr><tr><td>Center for Rheumatology, Immunology, and Arthritis</td><td>Advarra IRB</td></tr><tr><td>East Bay Rheumatology Medical</td><td>Advarra IRB</td></tr><tr><td>Arthritis, Rheumatic, and Back Disease Associates</td><td>Advarra IRB</td></tr><tr><td>Integral Rheumatology and Immunology Specialists</td><td>Advarra IRB</td></tr><tr><td>West Texas Clinical Research</td><td>Advarra IRB</td></tr><tr><td>Joint and Muscle Research Institute</td><td>Advarra IRB</td></tr><tr><td>Rhode Island Hospital</td><td>Lifespan Research Protection Office</td></tr><tr><td>Clinical Research Institute of Michigan</td><td>Advarra IRB</td></tr><tr><td>Arthritis Group</td><td>Advarra IRB</td></tr><tr><td>Altoona Center for Clinical Research</td><td>Advarra IRB</td></tr><tr><td>Klein and Associates MD PA</td><td>Advarra IRB</td></tr><tr><td>Precision Comprehensive Clinical Research Solutions</td><td>Advarra IRB</td></tr><tr><td>Carol and Frank Morsani Center for Advanced Health Care</td><td>Advarra IRB</td></tr><tr><td>Clinical Research of West Florida, Inc</td><td>Advarra IRB</td></tr><tr><td>Providence Medical Foundation</td><td>Advarra IRB</td></tr><tr><td>Arthritis and Rheumatic Disease Specialties</td><td>Advarra IRB</td></tr><tr><td>Paramount Medical Research and Consulting LLC</td><td>Advarra IRB</td></tr><tr><td>Accurate Clinical Research Incorporated Baytown</td><td>Advarra IRB</td></tr><tr><td>Denver Arthritis Clinic PC</td><td>Advarra IRB</td></tr><tr><td>Rheumatology Center of San Diego PC</td><td>Advarra IRB</td></tr><tr><td>Arthritis and Rheumatology Center of</td><td>Advarra IRB</td></tr></tbody></table>
<table>
  <tr>
    <td>Michigan</td>
    <td></td>
  </tr>
  <tr>
    <td>Advanced Rheumatology of Houston</td>
    <td>Advarra IRB</td>
  </tr>
  <tr>
    <td>Encino Research Center</td>
    <td>Advarra IRB</td>
  </tr>
  <tr>
    <td>Florida Center For Dermatology</td>
    <td>Advarra IRB</td>
  </tr>
  <tr>
    <td>Rheumatology and Pulmonary Clinic</td>
    <td>Advarra IRB</td>
  </tr>
  <tr>
    <td>University Hospitals Cleveland Medical Center</td>
    <td>Advarra IRB</td>
  </tr>
  <tr>
    <td>RC Research Inc</td>
    <td>Advarra IRB</td>
  </tr>
  <tr>
    <td>OrthoIllinois</td>
    <td>Advarra IRB</td>
  </tr>
  <tr>
    <td>Millennium Clinical Trials</td>
    <td>Advarra IRB</td>
  </tr>
  <tr>
    <td>Dr. Sabeen Anwar Medicine Professional Corporation</td>
    <td>Advarra Canada</td>
  </tr>
  <tr>
    <td>Institut de Rhumatologie de Montreal</td>
    <td>Advarra Canada</td>
  </tr>
  <tr>
    <td>Manitoba Clinic</td>
    <td>Advarra Canada</td>
  </tr>
  <tr>
    <td>Universitaetsklinikum Allgemeines Krankenhaus Wien Universitaetsklinik fur Innere Medizin I</td>
    <td>Ethikkommission der Medizinischen Universität und des AKH Wien</td>
  </tr>
  <tr>
    <td>Universitair Ziekenhuis Leuven</td>
    <td>ethische commissie onderzoek UZ / KU Leuven</td>
  </tr>
  <tr>
    <td>Ziekenhuis Netwerk Antwerpen Jan Palfijn</td>
    <td>ethische commissie onderzoek UZ / KU Leuven</td>
  </tr>
  <tr>
    <td>Hopital Erasme</td>
    <td>ethische commissie onderzoek UZ / KU Leuven</td>
  </tr>
  <tr>
    <td>Assistance Publique- Hopitaux de Paris AP-HP</td>
    <td>Comité de Protection des Personnes Ouest II</td>
  </tr>
  <tr>
    <td>CH Toulouse Hopital Pierre- Paul Riquet</td>
    <td>Comité de Protection des Personnes Ouest II</td>
  </tr>
  <tr>
    <td>Universitatsklinikum Freiburg</td>
    <td>Ethikkommission des Fachbereichs Medizin der Johann Wolfgang GoetheUniversität Frankfurt am Main</td>
  </tr>
  <tr>
    <td>Rheumazentrum Ruhrgebiet</td>
    <td>Ethikkommission des Fachbereichs Medizin der Johann Wolfgang GoetheUniversität Frankfurt am Main</td>
  </tr>
  <tr>
    <td>Klinikum der Johann Wolfgang Goethe-Universitaet Frankfurt/Main</td>
    <td>Ethikkommission des Fachbereichs Medizin der Johann Wolfgang GoetheUniversität Frankfurt am Main</td>
  </tr>
  <tr>
    <td>Kerckhoff-Klinik gGmbH</td>
    <td>Ethikkommission des Fachbereichs Medizin der Johann Wolfgang GoetheUniversität Frankfurt am Main</td>
  </tr>
  <tr>
    <td>Universitaetsklinikum Tuebingen</td>
    <td>Ethikkommission des Fachbereichs Medizin der Johann Wolfgang GoetheUniversität Frankfurt am Main</td>
  </tr>
  <tr>
    <td>Charité Campus Mitte</td>
    <td>Ethikkommission des Fachbereichs Medizin der Johann Wolfgang GoetheUniversität Frankfurt am Main</td>
  </tr>
  <tr>
    <td>Universita degli studi Messina</td>
    <td>Comitato Etico Territoriale Lombardia 5</td>
  </tr>
  <tr>
    <td>Fondazione Policlinico Tor Vergata</td>
    <td>Comitato Etico Territoriale Lombardia 5</td>
  </tr>
</table>
<table>
   <tr>
    <td>Azienda Ospedaliera Universitaria Integrata di Verona Ospedale G B Rossi Borgo Roma</td>
    <td>Comitato Etico Territoriale Lombardia 5</td>
   </tr>
   <tr>
    <td>Humanitas Research Hospital Humanitas Mirasole</td>
    <td>Comitato Etico Territoriale Lombardia 5</td>
   </tr>
   <tr>
    <td>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</td>
    <td>Comitato Etico Territoriale Lombardia 5</td>
   </tr>
   <tr>
    <td>Policlinico San Matteo Universita Di Pavia</td>
    <td>Comitato Etico Territoriale Lombardia 5</td>
   </tr>
   <tr>
    <td>Hospital Universitario de Cruces</td>
    <td>CEIm Hospital Universitario La Paz</td>
   </tr>
   <tr>
    <td>Hospital Galdakao-Usansolo</td>
    <td>CEIm Hospital Universitario La Paz</td>
   </tr>
   <tr>
    <td>Hospital de Merida</td>
    <td>CEIm Hospital Universitario La Paz</td>
   </tr>
   <tr>
    <td>Hospital Universitario Ramon y Cajal</td>
    <td>CEIm Hospital Universitario La Paz</td>
   </tr>
   <tr>
    <td>Wolverhampton Road</td>
    <td>London – Chelsea Research Ethics Committee</td>
   </tr>
   <tr>
    <td>Royal Berkshire Hospital</td>
    <td>London – Chelsea Research Ethics Committee</td>
   </tr>
   <tr>
    <td>Torbay Hospital</td>
    <td>London – Chelsea Research Ethics Committee</td>
   </tr>
   <tr>
    <td>Western General Hospital</td>
    <td>London – Chelsea Research Ethics Committee</td>
   </tr>
   <tr>
    <td>Luton and Dunstable University Hosptial</td>
    <td>London – Chelsea Research Ethics Committee</td>
   </tr>
   <tr>
    <td>Tomsk Regional Clinical Hospital</td>
    <td>Department for Regulation of Circulation of Medicines and Medicinal Products of Circulation of Medicinal Products</td>
   </tr>
   <tr>
    <td>Municipal Budgetary Healthcare Institution City Emergency Hospital</td>
    <td>Department for Regulation of Circulation of Medicines and Medicinal Products of Circulation of Medicinal Products</td>
   </tr>
   <tr>
    <td>Moscow Regional Research Institute n.a. Vladimirsky</td>
    <td>Department for Regulation of Circulation of Medicines and Medicinal Products of Circulation of Medicinal Products</td>
   </tr>
   <tr>
    <td>Medical Center Sanavita</td>
    <td>Department for Regulation of Circulation of Medicines and Medicinal Products of Circulation of Medicinal Products</td>
   </tr>
   <tr>
    <td>Mechnikov North-Western State Medical University</td>
    <td>Department for Regulation of Circulation of Medicines and Medicinal Products of Circulation of Medicinal Products</td>
   </tr>
   <tr>
    <td>Research Institute of Clinical and Experimental Lymphology</td>
    <td>Department for Regulation of Circulation of Medicines and Medicinal Products of Circulation of Medicinal Products</td>
   </tr>
   <tr>
    <td>Research Institute of Rheumatology named after V.A.Nasonova</td>
    <td>Department for Regulation of Circulation of Medicines and Medicinal Products of Circulation of Medicinal Products</td>
   </tr>
   <tr>
    <td>Republican Hospital na VA Baranov</td>
    <td>Department for Regulation of Circulation of Medicines and Medicinal Products of Circulation of Medicinal Products</td>
   </tr>
   <tr>
    <td>Kazan State Medical University</td>
    <td>Department for Regulation of Circulation of Medicines and Medicinal Products of Circulation of Medicinal Products</td>
   </tr>
  </table>
Medicines and Medicinal Products of
Circulation of Medicinal Products
<table><caption>Supplementary Table 2. Baseline demographics and clinical characteristics in patients with ≤4 active joints and >4 active joints</caption><thead><tr><th rowspan="2"></th><th colspan="2">≤4 Active Joints</th><th colspan="2">>4 Active Joints</th></tr><tr><th>Placebo (n=92)</th><th>Apremilast (n=176)</th><th>Placebo (n=13)</th><th>Apremilast (n=27)</th></tr></thead><tbody><tr><td>Age, mean (SD), years</td><td>49.4 (12.6)</td><td>50.9 (12.2)</td><td>56.2 (14.9)</td><td>53.9 (12.7)</td></tr><tr><td>Male, n (%)</td><td>47 (51.1)</td><td>73 (41.5)</td><td>7 (53.8)</td><td>12 (44.4)</td></tr><tr><td>Race, white, n (%)</td><td>86 (93.5)</td><td>167 (94.9)</td><td>13 (100.0)</td><td>25 (92.6)</td></tr><tr><td>Duration of PsA, mean (SD), months</td><td>10.3 (11.2)</td><td>10.0 (10.3)</td><td>7.3 (4.9)</td><td>8.2 (7.9)</td></tr><tr><td>Prior use of csDMARDs, n (%)</td><td>62 (67.4)</td><td>120 (68.2)</td><td>7 (53.8)</td><td>15 (55.6)</td></tr><tr><td>SJC (0–66), mean (SD)</td><td>2.5 (0.6)</td><td>2.6 (0.7)</td><td>3.2 (0.8)</td><td>3.1 (0.8)</td></tr><tr><td>TJC (0–68), mean (SD)</td><td>3.1 (0.8)</td><td>3.2 (0.8)</td><td>3.8 (0.4)</td><td>3.6 (0.7)</td></tr><tr><td>cDAPSA, mean (SD)</td><td>15.5 (4.5)</td><td>16.2 (4.3)</td><td>19.0 (2.9)</td><td>17.2 (4.2)</td></tr><tr><td>PASDAS, mean (SD)</td><td>4.8 (1.1)</td><td>4.9 (1.1)</td><td>5.3 (0.7)</td><td>5.2 (1.2)</td></tr></tbody></table>

FAS. Active joints were defined as swollen and/or tender joints.

FAS = full analysis set.
<figure><img src="image_8.png" /><figcaption>Supplementary Figure 1. Rate of cDAPSA Remission or LDA at Week 16 Among Patients With Baseline cDAPSA >13</figcaption></figure>

FAS with baseline cDAPSA >13. Error bars represent SE. Based on all joints. cDAPSA remission is defined as a score ≤4 and LDA is defined as a score >4 and ≤13.

cDAPSA = Clinical Disease Activity in Psoriatic Arthritis; CI = confidence interval; FAS = full analysis set; LDA = low disease activity; SE = standard error.
<caption>Supplementary Figure 2. Exploratory Endpoints at Week 16</caption>

A.

<figure><img src="image_9.png" /></figure>
B.

<figure><img src="image_10.png" /></figure>

(A) FAS (B) FAS with baseline nail VAS>0. Error bars represent SE.

BSA = body surface area; CI = confidence interval; FAS = full analysis set; LS = least squares; SE = standard error; VAS = visual analogue scale.
<figure><img src="image_11.png" /><figcaption>Supplementary Figure 3. Achievement of a Patient-Acceptable Symptom State in Patients With Baseline PsAID-12 >4</figcaption></figure>

FAS with baseline PsAID-12 >4. Error bars represent SE.

CI = confidence interval; FAS = full analysis set; PsAID = Psoriatic Arthritis Impact of Disease; SE = standard error.
<figure><img src="image_12.png" /><figcaption>Supplementary Figure 4. Swollen and Tender Joints Over Time</figcaption></figure>

FAS. Based on all joints. Error bars represent SE. Data as observed.

FAS = full analysis set; SE = standard error; SJC = swollen joint count; TJC = tender joint count.
<figure><img src="image_13.png" /><figcaption>Supplementary Figure 5. Achievement of MDA Domains Other than SJC and TJC in Patients With Baseline Disease Activity</figcaption></figure>

<table><thead><tr><th></th><th>Placebo, n</th><th>Apremilast, n</th><th>Adjusted<br>difference<br>(95% CI)</th><th>Nominal<br>P-value</th></tr></thead><tbody><tr><td>BSA ≤3%*</td><td>42</td><td>78</td><td>28.0<br>(10.2, 45.7)</td><td>0.0043</td></tr><tr><td>Patient's<br>Assessment of<br>Pain ≤15†</td><td>97</td><td>184</td><td>17.3<br>(8.1, 26.6)</td><td>0.0012</td></tr><tr><td>PtGA ≤20‡</td><td>93</td><td>179</td><td>15.9<br>(5.9, 25.8)</td><td>0.0044</td></tr><tr><td>HAQ-DI ≤0.5§</td><td>77</td><td>145</td><td>14.0<br>(1.9, 26.0)</td><td>0.0302</td></tr><tr><td>LEI ≤1||</td><td>27</td><td>41</td><td>11.3<br>(-13.4, 36.1)</td><td>0.3815</td></tr></tbody></table>

FAS. Patients who discontinued the study before the given week due to an adverse event or lack of efficacy were imputed as nonresponders. The remaining missing values at the given week were imputed by multiple imputation. P-value is based on the Cochran-Mantel-Haenszel test, adjusting for prior/concomitant use of csDMARD and baseline glucocorticoid use, that was normalised via the Wilson-Hilferty transformation.

<footnote>*In patients with baseline BSA >3%.</footnote>

<footnote>†In patients with baseline Patient's Assessment of Pain >15.</footnote>

<footnote>‡In patients with baseline PtGA >20.</footnote>

<footnote>§In patients with baseline HAQ-DI >0.5.</footnote>

<footnote>In patients with baseline LEI >1.</footnote>
BSA = body surface area; CI = confidence interval; csDMARD = conventional synthetic disease-modifying antirheumatic drug; FAS = full analysis set; HAQ-DI = Health Assessment Questionnaire Disability Index; LEI = Leeds Enthesitis Index; MDA = minimal disease activity; PtGA = Patient Global Assessment of Disease Activity; SJC = swollen joint count; TJC = tender joint count.
<figure><img src="image_14.png" /></figure>
<caption>Supplementary Figure 6. MDA-Joints Response Rates at Week 16 in Patients With ≤4 Active Joints at Baseline</caption>

A.

<figure><img src="image_15.png" /></figure>

B.

<figure><img src="image_16.png" /></figure>

(A) Based on sentinel joints. (B) Based on all joints. FAS with a baseline joint count ≤4. Error bars represent SE.

CI = confidence interval; FAS = full analysis set; MDA = minimal disease activity; SE = standard error.