# Efficacy and safety of pharmacological treatment of psoriatic arthritis: a systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis

Andreas Kerschbaumer, Josef Smolen, Ricardo Ferreira, Heidi Bertheussen, Xenofon Baraliakos, Daniel Aletaha, Dennis Mcgonagle, Désirée van der Heijde, Iain Mcinnes, Bente Appel Esbensen, et al.

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## ► To cite this version:

Andreas Kerschbaumer, Josef Smolen, Ricardo Ferreira, Heidi Bertheussen, Xenofon Baraliakos, et al. Efficacy and safety of pharmacological treatment of psoriatic arthritis: a systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis. Annals of the Rheumatic Diseases, 2024, 83 (6), pp.760-774. 10.1136/ard-2024-225534. hal-04977903

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Efficacy and safety of pharmacological treatment of psoriatic arthritis: a systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis.

Andreas Kerschbaumer, Josef S Smolen, Ricardo J. O. Ferreira, Heidi Bertheussen, Xenofon Baraliakos, Daniel Aletaha, Dennis McGonagle, Désirée van der Heijde, Iain B. McInnes, Bente Appel Esbensen, Kevin L. Winthrop, Wolf-Henning Boehncke, Jan W. Schoones, Laure Gossec

<table><thead><tr><td>Name and degree</td><td>Email</td><td>Affiliation</td><td>ORCID</td></tr></thead><tbody><tr><td>Andreas Kerschbaumer, MD, PhD</td><td>andreas.kerschbaumer@meduniwien.ac.at</td><td>Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria</td><td>0000-0002-6685-8873</td></tr><tr><td>Josef S. Smolen, MD</td><td>josef.smolen@meduniwien.ac.at</td><td>Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Austria</td><td>0000-0002-4302-8877</td></tr><tr><td>Ricardo JO Ferreira, RN, PhD</td><td>ferreira.rjo@gmail.com</td><td>Nursing Research, Innovation and Development Centre of Lisbon (CIDNUR), Nursing School of Lisbon (ESEL), Lisbon, Portugal; Rheumatology department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal</td><td>0000-0002-2517-0247</td></tr><tr><td>Heidi Bertheussen, patient research partner</td><td>heidi.bertheussen@gmail.com</td><td>EULAR Patient Research Partner, Oslo, Norway</td><td>None</td></tr><tr><td>Xenofon Baraliakos, MD, PhD</td><td>xenofon.baraliakos@elisabethgruppe.de</td><td>Rheumazentrum Ruhrgebiet, Herne, Ruhr-Universität Bochum, Germany</td><td>0000-0002-9475-9362</td></tr><tr><td>Daniel Aletaha, MD, MSc</td><td>daniel.aletaha@meduniwien.ac.at</td><td>Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Austria</td><td>0000-0003-2108-0030</td></tr><tr><td>Dennis McGonagle, FRCPI, PhD</td><td>d.g.mcgonagle@leeds.ac.uk</td><td>NIHR Leeds Biomedical Research Centre; LTHT, Leeds, UK; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK</td><td>0000-0001-7715-8226</td></tr><tr><td>Désirée van der Heijde, MD, PhD</td><td>mail@dvanderheijde.nl</td><td>Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands</td><td>0000-0002-5781-158X</td></tr><tr><td>Iain B. McInnes, MD, PhD</td><td>iain.mcinnes@glasgow.ac.uk</td><td>College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK</td><td>0000-0002-6462-4280</td></tr><tr><td>Bente Appel Esbensen, CN</td><td>bente.appel.esbensen@regionh.dk</td><td><sup>1</sup> Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.<br/><sup>2</sup> Department of Clinical Medicine, University of</td><td>0000-0001-5331-8221</td></tr></tbody></table>
<table><tr><td></td><td></td><td>Copenhagen, Denmark</td><td></td></tr><tr><td>Kevin Winthrop, MD, MPH</td><td>winthrop@ohsu.edu</td><td>Divisions of Infectious Diseases, School of Medicine, School of Public Health, Oregon Health and Sciences University, Portland, OR USA</td><td>0000-0002-3892-6947</td></tr><tr><td>Wolf-Henning Boehncke, MD</td><td>Wolf-Henning.Boehncke@hcuge.ch</td><td>Division of Dermatology and Venereology, Geneva University Hospitals, Geneva, Switzerland</td><td>0000-0002-1225-7124</td></tr><tr><td>Jan W. Schoones, MA</td><td>J.W.Schoones@lumc.nl</td><td>Leiden University Medical Center, Leiden, the Netherlands.</td><td>0000-0003-1120-4781</td></tr><tr><td>Laure Gossec, MD, PhD</td><td>laure.gossec@aphp.fr</td><td>Sorbonne Université, Institut Pierre Louis d'Epidémiologie et de Santé Publique; AP-HP, Pitié Salpêtrière Hospital, Department of rheumatology, Paris, France</td><td>0000-0002-4528-310X</td></tr></table>

**Corresponding author:**

Andreas Kerschbaumer, MD, PhD

Medical University of Vienna

Department of Medicine III, Division of Rheumatology

Spitalgasse 23

1090 Vienna, Austria

E-Mail: andreas.kerschbaumer@meduniwien.ac.at

Tel.: +431 40400 43000

**Key words:** psoriatic arthritis, DMARDs (biological), DMARDs (synthetic), treatment algorithms, recommendations

**Word count:** 7591
**Abstract**

**Objectives:** To obtain an overview of recent evidence on efficacy and safety of pharmacological treatments in psoriatic arthritis (PsA).

**Methods:** This systematic literature research (SLR) investigated the efficacy and safety of conventional synthetic (cs), biological (b) and targeted synthetic (ts)DMARDs in patients with PsA. A systematic database search utilizing Medline, EMBASE, Cochrane CENTRAL was conducted to identify relevant articles published since the previous update in 2019 until December 28th, 2022. Efficacy was assessed in trials while for safety observational data was also considered. Adverse events of special interest were infections (including herpes zoster, influenza and tuberculosis), malignancies, major adverse cardiovascular events, venous thromboembolisms, liver disease, laboratory changes, and psychiatric adverse events. No meta-analyses were performed.

**Results:** For efficacy, of 3946 articles screened, 38 articles (30 trials) were analysed. The compounds investigated included csDMARDs (leflunomide, methotrexate), bDMARDs inhibiting IL17 (bimekizumab, brodalumab, ixekizumab, izokibep, secukinumab,), IL-23 (guselkumab, risankizumab, tildrakizumab), IL-12/23 (ustekinumab) as well as TNF (adalimumab, certolizumab-pegol, etanercept, infliximab, golimumab) and Janus Kinase inhibitors (brepocitinib, deucravacitinib, tofacitinib, upadacitinib). The compounds investigated were efficacious in improving signs and symptoms of PsA, improving physical functioning and quality of life. For safety, 2055 abstracts were screened, and 24 articles analysed: 15 observational studies and 9 long-term follow-ups of trials, assessing glucocorticoids, TNFi, IL-17i, JAKi, IL-12/23i and PDE4i (apremilast). Safety indicators were generally coherent with the previous SLR in 2019.

**Conclusion:** The results of this SLR informed the taskforce responsible for the 2023 update of the EULAR recommendations for pharmacologic management of PsA.
## Key messages

### What is already known about this subject?

Many drugs have become available over the last years in psoriatic arthritis (PsA); trials of new drugs have consistently been positive in terms of the primary outcomes, but it is difficult to obtain an overview of the efficacy and safety of systemic therapies for PsA, including conventional synthetic, biologic and targeted synthetic disease-modifying anti-rheumatic drugs.

### What does this study add?

This systematic literature research (SLR) provides an overview of the efficacy and safety results of

* Established disease-modifying anti-rheumatic drugs (DMARDs), trials investigating efficacy of DMARDs on specific domains of PsA (axial, dactylitis, synovitis)

* novel biological DMARDs, including inhibitors of IL23-p19 (risankizumab, guselkumab, tildrakizumab), IL17A (izokibep), IL17A/F (bimekizumab)

* novel Janus Kinase inhibitors, including brepocitinib (JAK1/TYK2), deucravacitinib (TYK2) and upadacitinib (JAK1/JAK2)

* Studies on treatment tapering and stopping

Safety analyses of observational data investigating established DMARDs on adverse events of special interest (infections, malignancies, cardiovascular and thrombotic events).

### How might this impact on clinical practice or future developments?

This SLR informed the 2023 EULAR PsA management recommendations task force with the available evidence published since the previous update published in 2019.
## Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory disease occurring in patients with psoriasis, leading to the typical clinical hallmarks of oligo- or polyarthritis, enthesitis and dactylitis; if left untreated, radiographic damage and, although rare, potentially mutilating joint destruction may occur.[1] Axial disease in PsA was recognized already by Moll and Wright as an important musculoskeletal manifestation, however many new insights were gained over the past decades,[1] differentiating axial PsA from the manifestations observed in radiographic and non-radiographic axial spondyloarthritis, including genetics, pathological findings, clinical symptoms, subsequent radiographic changes and also potential implications for treatment.[2]

In 2012, the first EULAR management recommendations on pharmacologic therapies for PsA were developed,[3] with subsequent updates in 2015[4] and 2019.[5] With an increasing depth of understanding immunological pathways of PsA, the body of evidence on the efficacy of new molecules targeting different modes of action (MOAs), such as inhibition of the p19 subunit of interleukin (IL)-23,[6–8] and IL-17,[9] but also Janus Kinase (JAK) including the Tyrosine Kinase 2 (TYK2) pathway, has significantly increased in recent years.[10–12]

Besides the mere development of new MOAs using established composite endpoints, recent studies also provided evidence on the efficacy of established disease-modifying anti-rheumatic drugs (DMARDs) on specific musculoskeletal manifestations, including synovitis,[13] axial disease,[14] and dactylitis.[15] Furthermore, head-to-head trials, comparing different MOAs,[16–18] as well as conventional synthetic (cs) DMARD regimens[19] and strategic trials, also on tapering strategies, were published.[20,21] Increasing emphasis on adverse events of DMARD therapies gained attention over the past years due to safety signals identified in patients with rheumatoid arthritis and cardiovascular risk factors receiving a JAKi, namely tofacitinib.[22] This may also be important in PsA, given the high prevalence of comorbidities and risk factors, such as obesity, dyslipidaemia, metabolic syndrome, cardiovascular disease and smoking in patients with PsA.[23]

This systematic literature research (SLR) was conducted to summarise and update the evidence on pharmacologic treatments in PsA since 2019,[24] to inform the EULAR taskforce developing the 2023 update of the PsA management recommendations.[Gossec et al. ARD 2024]

## Methods

This SLR was conducted according to the EULAR updated standard operating procedures and based on a protocol developed and approved by the task force.[25]

To update the evidence from the previous SLR with the data cut on December 21st 2018,[24] articles published in English language between January 1st, 2018 and December 28th, 2022 were searched by an experienced librarian (J.W.S.) utilising Medline (PubMed), Embase (OVID version), the Cochrane CENTRAL Register of Controlled Trials (Central) and the abstract archives of the EULAR & ACR annual meetings. To prevent missing important publications, we included the year 2018 in the literature search, as manuscripts which carry the date of a specific year might be published with some delay. Like in previous SLRs, conference abstracts from the last three years (from 2020 to 2022) were eligible for inclusion. In the case of articles being published after the data cut of the literature search but before the EULAR task force meeting (April 17th, 2023), fully published manuscripts were eligible to be included only if they had been covered as a conference abstract in the initial systematic search. The search strategies are provided in the supplementary appendix (Text S1.1-S1.6).

During the first steering committee meeting (November 21st, 2022) a research protocol was developed. In total, ten research questions were defined. These research questions covered the areas of the efficacy and safety of already approved DMARDs, safety of Janus kinase inhibitors (JAKi), the efficacy and safety of new molecules, drug-drug interactions, the efficacy of DMARDs on different disease manifestations of PsA, evidence on strategic trials as well as evidence on dose reduction and treatment discontinuation. Based on the research questions, detailed PICO definitions (population, intervention, control, outcome) were developed. Details on the research questions as well as the PICO definitions are shown in Table S1.10. For efficacy, only randomised controlled trials (RCTs) investigating NSAIDs, cs, biological (b) or targeted synthetic (ts) DMARDs in adult patients classified as having PsA were eligible for inclusion. Phase 2 studies were eligible for inclusion, if no phase 3 studies were available, as efficacy but also safety profiles of new molecules, targeting similar pathways
as currently licensed drugs, might be informative. For safety, data of identified RCTs as well as long-term extensions studies of RCTs with adequately defined comparator arms (placebo [PBO] or active therapy) were eligible. In addition to RCT safety data (including long-term extensions with adequate comparator arms) also observational studies (including registry analyses, claims data, cohort studies and case-control studies) with adequately defined controls were eligible for inclusion.

Patient populations of interest were defined as patients classified as having PsA; patients could be either DMARD-naïve, or with intolerance and/or insufficient response (IR) to csDMARDs, patients who were bDMARD-IR and/or tsDMARD-IR or mixed populations with previous insufficient response to cs- or/and bDMARDs; in some studies patients with IR to non-steroidal anti-inflammatory drugs (NSAIDs) were also eligible. All interventions of interest are listed in the supplement (Table S1.7). Efficacy outcomes included composite measures of state (such as DAPSA or MDA) and of improvement (such as ACR criteria), individual core-set measures of signs and symptoms, patient-reported outcomes (including fatigue, physical function). Safety outcomes included infections (serious infections, herpes zoster [HZ], opportunistic & fungal infections, tuberculosis [Tb]); malignancies; major adverse cardiovascular events [MACE]; venous thromboembolic events [VTE]; liver disease; gastrointestinal side effects; incidence of inflammatory bowel disease (IBD), uveitis; depression, suicidal ideation and behaviour (Supplemental Table S1.8 and List S1.9).

Ten percent of all titles and abstracts were screened by two researchers (A.K., R.O.F.) with an agreement of 94%. All other titles and abstracts were screened and assessed by one researcher (A.K.). In the case of any uncertainties, these were discussed with the methodologist (L.G.).

The selected articles were then assessed in full detail for eligibility and data of finally eligible articles were extracted using standardised spreadsheet forms by one researcher (AK) and verified in detail for correctness by the co-methodologist (RJOF). Risk of bias (RoB) assessment was done using the Cochrane Collaborations RoB tool for RCTs (version 2), while the Newcastle-Ottawa scale was utilised for assessing RoB in cohort and case-control studies.[26] Conference abstracts were not assessed for RoB.[27] Due to the high heterogeneity of the finally selected studies, and for the purposes of recommendations, detailed information of each study rather than summary statistics was selected; thus, no meta-analyses were performed and results, including effect sizes derived from safety analyses were taken from the original articles and reported descriptively. Specific adverse events of special interest occurring during the double-blind period are reported in detail, while summary estimates derived from long term extension studies are reported directly following the respective sections on the double-blind period.

## Results

### *Search results*

The efficacy search resulted in 3,946 articles of which 212 references were selected to be assessed in the detailed article review, resulting in 38 articles describing 30 unique trials eligible for final inclusion in the SLR (Figure 1). A detailed list of studies assessing the efficacy of DMARDs is shown in the supplemental appendix (Table S2.1). Table 1 provides an overview of the drugs evaluated for efficacy and table 2 summarizes the main reported efficacy outcomes of the studies included.

A total of 19 of the 30 trials (63.3%) were rated as having a low RoB; 7 of 30 trials (23.3%) received a rating of a high RoB - all due to an open-label or single-blinded trial design. Two trials (2/30, 6.6%) had an unclear RoB, both due to insufficient reporting of randomization sequence generation and allocation concealment methods. One trial was published as a conference abstract only and was not assessed for RoB. All RoB assessments of efficacy studies are provided in supplementary Table S2.2, baseline characteristics are presented in Tables S2.3-S2.4, and detailed efficacy results are shown in Tables S2.5-S2.7.

For safety, beyond the adverse event profiles presented in the RCT publications already included in the efficacy search, further 2055 references were screened, and 87 articles assessed in detail with 24 studies finally included (Figure 1). These 24 studies included 9 safety analyses of RCT data (long-term extensions and integrated safety analyses of adverse events of special interest, AESI) as well as 15 observational studies: 8/24 (33.3%) with a low RoB, 1/24 (4.2%) with unclear and 10/24 (37.5%) with a high RoB (5 conference abstracts were not assessed for RoB). Investigations of AESI in RCTs were concerned with influenza, tuberculosis,
malignancies and thromboembolic events. Cohort studies investigated serious infections, tuberculosis, solid and hematologic malignancies, liver disease, MACEs as well as anxiety and depression. Table S3.1 in the supplementary appendix provides a detailed list of safety studies included. RoB assessments of safety studies are shown in supplementary Table S3.2 and S3.3, population characteristics are presented in Table S3.4, with the main safety results shown in Tables S3.5.

### Efficacy of csDMARDs

Only one RCT was available: the COMPLETE-PsA trial (low RoB). [19] Patients with a diagnosis of PsA and without concomitant DMARD therapy were randomised to methotrexate (MTX) + leflunomide (LEF) combination therapy (n=39) or MTX + PBO (PBO n=39). MTX+LEF combination therapy was superior to MTX+PBO in achieving the primary outcome (mean change in Psoriatic Arthritis Disease Activity Score; PASDAS) at week 16 (3.1±1.4 vs. 3.7±1.3, treatment difference: -0.6, 90% CI -1.0 to -0.1; p=0.025). Nausea and vomiting was more frequent in the MTX+LEF arm (44% vs. 28%), as was alanine aminotransferase (ALAT) elevation (31% vs. 18%) and altered bowel habits (26% vs. 8%). [19]

### Efficacy of established bDMARDs

In total six placebo-controlled trials investigating approved bDMARDs (1 golimumab [GOL], 4 secukinumab [SEC], 1 ustekinumab [UST]) with or without concomitant csDMARD) were included (4 with low, 2 with unclear RoB). [15][28][13][14][29][30]

In GO-DACT (low RoB), MTX monotherapy was compared to MTX + GOL (TNFi) combination therapy in patients naïve to MTX and bDMARD with active dactylitis. An interim analysis at 50% of the planned recruitment suggested favourable results, which led to stopping of patient recruitment. A significantly higher median reduction in the dactylitis severity score at week 24 (primary endpoint) was observed for the MTX + GOL arm (n=21) compared to the MTX + PBO (n=23) arm (-5 vs. -2, p=0.026). Assessment of dactylitis via Leeds Dactylitis Index (LDI) also showed significant differences between the arms (-69.4 vs. 31.1, p=0.042), while dactylitis remission at week 24 was achieved in 6/20 (30%) vs. 4/22 (18%, p=0.477) of patients receiving MTX + GOL vs. MTX + PBO, respectively. MRI assessment of dactylitis (secondary exploratory endpoint) showed a significant difference in favour of the MTX+GOL arm (p=0.017). Outcomes assessing other domains beside dactylitis (enthesitis, tender joints, swollen joints, skin, physical function) showed a trend towards better efficacy for the combination therapy arm, without significant differences between the arms. [15]

Four trials (two with low RoB, two with unclear RoB) investigated SEC (anti-IL-17A) treatment. CHOICE (unclear RoB) demonstrated superior efficacy of SEC 300mg (but not SEC 150mg) every 4 weeks versus PBO [ACR20 at week 16: 51.5% vs. 36.9% vs. 23.1% for SEC 300mg (p<0.001), SEC 150mg (p=0.10) and PBO respectively] in a biologic naïve PsA population. [28] The ULTIMATE trial investigated the change of ultrasound synovitis in biologic naïve patients treated with SEC 300mg Q4W, 150mg Q4W or PBO. The primary endpoint [the ultrasound Global EULAR and OMERACT Synovitis Score (GLOESS) change from baseline to week 12] was met with higher response rates in SEC (150mg/300mg combined group) treated patients vs. PBO [-9 (0.9) vs -6 (0.9), difference (95% CI): -3 (-6, -1); one-sided P=0.004]. [13] Baraliakos et al. conducted the first RCT investigating DMARD therapy in an axial PsA population. MAXIMISE (low RoB) demonstrated superior efficacy of SEC 300mg or 150 mg Q4W when compared to PBO, meeting the study's primary endpoint, ASAS20 response at week 12 (63% vs. 66% vs. 31%, respectively, p<0.001), as well as demonstrating improvement in MRI imaging (least square mean difference vs. PBO in total Berlin MRI score at week 12 for the entire spine: SEC 300mg: -0.4±0.1; p<0.01, SEC 150mg: -0.4±0.1; p<0.05; for the sacroiliac joints: SEC300mg -0.5±0.2; p<0.01; SEC150mg -0.5±0.2; p<0.01). [14] FUTURE-4 compared SEC 150mg Q4W with and without loading (i.e. SEC 150mg at week 0, 1, 2, and 3) to PBO. Both regimens showed superior efficacy compared to PBO and no meaningful differences between the active treatment arms. [29]

The MUST trial (low RoB) was an investigator initiated, non-inferiority trial, comparing UST (IL-12/23i) + MTX combination therapy (n=88) to UST + PBO (n=85) in PsA patients naïve to UST. While patients received open-label UST treatment, concomitant therapy with either MTX or PBO was masked. At week 24 non-inferiority was observed for the primary outcome (mean DAS28-ESR), further no meaningful differences in secondary outcomes were observed between the groups. [30]
## Efficacy of targeted synthetic DMARDs

Three trials investigating the efficacy of tsDMARDs were included (all low RoB).[12][11][10]

Inhibition of JAK 1 and 2 via upadacitinib (UPA; 15mg or 30mg once daily) was compared to PBO treatment in patients with prior IR to biological DMARDs in SELECT PsA 2 (low RoB). The trial met the primary endpoint, ACR20 at week 12, with significantly higher response rates in UPA treated patients [UPA 15mg OD: 120/211 (56.9%; p<0.001); UPA 30mg OD: 139/218 (63.8%); PBO: 51/212 (24.1%, p<0.001)]. Further, all secondary endpoints were met.[12]

Deucravacitinib (DEUC), a selective, oral TYK2 inhibitor, was investigated in a phase 2 double-blind RCT (low RoB) in patients with IR to ≥1 previous NSAID or DMARD therapy. The ACR 20 response at week 16 (primary endpoint) was demonstrated to be significantly higher in DEUC 6mg OD (37/70, 52.9%, p=0.013) and DEUC 12mg OD (42/67, 62.7%, p<0.001) treated patients compared to PBO (21/66, 31.8%). Higher response rates in improvement of physical function, skin disease as well as enthesitis and dactylitis resolution were observed.[11]

Another phase 2 RCT (low RoB) investigated brepocitinib (BREP), an inhibitor of TYK2 and JAK1 with active disease despite previous NSAID or DMARD treatment. BREP 30mg OD as well as 60mg OD (but not BREP 10mg OD) met the primary endpoint (ACR20 at week 16) when compared to PBO treatment PBO: 29/67 (43.3%) [BREP 10mg: 20/31 (43.4%; not significant); BREP 30mg OD: 40/60 (66.7%; p=0.0197); BREP 60mg OD: 44/59 (74.6%; p=0.0006)];. Significant differences compared to placebo were also observed in PASI 75/90% responses for BREP 30mg and 60mg OD. Exploratory analyses also showed benefit for BREP treated patients in achieving minimal disease activity (MDA) and improvement of enthesitis (only for BREP 60mg OD) and dactylitis outcomes (only for BREP 10mg and 60mg OD), as well as physical function and fatigue.[10]

## Head-to-head studies

Three head-to-head trials were included (RoB; Table 3).[31][16,32][18,33]

SPIRIT H2H (high RoB), an assessor-blinded, head-to-head trial compared open-label ixekizumab (IXE, IL17Ai) to adalimumab (ADA, TNFi) in bDMARD naïve patients with IR to csDMARDs. The primary endpoint was defined as simultaneous achievement of ACR50 and PASI100 response – assessed for superiority of IXE vs. ADA at week 24. Significantly more patients achieved the primary outcome in the IXE group [102/283 (36%; p=0.036)] vs. ADA [79/283 (27.9%)]. No significant difference was found between the arms when comparing ACR (20/50/70) response rates, HAQ-DI or dactylitis remission (LDI=0). However, comparing PASI75/90/100 results, these showed significantly higher response rates in IXE-treated patients compared to ADA. Other secondary endpoints like DAPSA remission, MDA, VLDA were also in favour of IXE treatment.[17] The results were maintained until week 54, with a significantly higher proportion of patients achieving a simultaneous ACR50 + PASI 100 response (39% vs 26%, p<0.001).[31]

In the EXCEED trial (low RoB) bDMARD naïve patients were randomised to SEC 300mg Q4W or ADA 40mg Q2W monotherapy in a double-blind manner. The study was powered to show superiority of SEC over ADA in achieving an ACR20% response at week 52. The primary endpoint was not met, with an ACR20 response of 67% vs. 62% (p=0.072) for SEC and ADA, respectively. Similar responses were observed between both treatment arms, with the exception of skin outcomes (PASI 75/100) showing higher responses in the SEC arm.[16,32]

Another double-blind head-to-head trial (SELECT-PsA 1, low RoB) compared UPA 15mg OD and 30mg OD to ADA 40mg Q2W and PBO treatment in patients with IR to csDMARDs. With ACR 20 response rates at week 12 of 303/429 (70.6%), 332/423 (78.5%), 279/429 (65.0%) and 153/423 (36.2%) for UPA 15mg OD, UPA 30mg OD, ADA 40mg Q2W and PBO, all active treatment arms showed superiority compared to placebo (p<0.001). Further, non-inferiority (margin 15%) of both UPA dosages was demonstrated when compared to ADA, while testing for superiority (versus ADA) was only shown for UPA 30mg OD (p<0.001) and not for UPA 15mg OD (hierarchical testing failed, no p-value reported). Radiographic progression at week 24 was low in all active treatment arms.[18,33]

A summary of the trial results is shown in Table 3.

## Efficacy of novel biologic DMARDs targeting the p19 subunit of IL23
In total six trials (five with low RoB, one with unclear RoB) were included.[34][7][35][36][8][37][38,39][6]

Three trials investigated guselkumab (GUS) an IL23-p19 inhibitor. DISCOVER-1 (low RoB) was a phase 3, double-blind RCT investigating patients with and without prior TNFi exposure. The ACR 20% response at week 24 (primary endpoint) was significantly higher in GUS treated patients compared to placebo [GUS100mg Q4W: 76/128 (59%; p<0.001); GUS 100mg Q8W: 66/127 (52%; p<0.001); PBO: 28/126 (22%). Results in favour of GUS vs. PBO, with a trend towards better efficacy in the Q4W arm, were observed also for more stringent outcomes (ACR70 response for GUS100mg Q4W: 26/128 [20%]; GUS100mg Q8W: 15/127 [12%]; PBO 7/126 [6%]), physical function, extra articular manifestations like dactylitis, enthesitis and skin disease. Consistent results (not multiplicity corrected) were also shown for patients with or without previous TNFi therapy.[34] In DISCOVER-2 (low RoB) only patients who were naïve to bDMARDs were included. GUS treatment was superior to PBO for ACR20 [GUS 100mg Q4W: 156/245 (64%; p<0.001); GUS 100mg Q8W: 159/248 (64%; p<0.001); PBO 81/246 (33%)], however, no clear difference in other outcomes between the two GUS regimens was observed in this study except for radiographic damage progression, with only GUS100mg Q4W but not GUS100mg Q8W being significantly different vs. PBO (ΔmTSS: PBO: 0.95; 95% CI: 0.61 to 1.29; GUS100mg Q4W: 0.29; 95% CI: -0.05 to 0.63 [p=0.011]; GUS100mg Q8W: 0.52 95% CI: 0.18 to 0.86 [p=0.072].[7] Assessing patients with axial involvement (as defined by the investigator) and evidence of sacroiliitis (MRI or pelvic radiograph as reviewed locally by the respective investigator) showed improvement in GUS treated patients compared to PBO when assessing axial involvement with the Bath Ankylosing Spondylitis Disease Activity Index [BASDAI; GUS 100mg Q4W (n=95): -2.7 (95% confidence interval -3.2 to -2.2); GUS 100mg Q8W (n=83): -2.7 (-3.2 to -2.2); PBO: -1.3 (-1.8 to -0.9) and the Ankylosing Spondylitis Disease Activity Score (ASDAS; GUS 100mg Q4W: -1.4 (95% CI -1.7 to -1.2; GUS 100mg Q8W: -1.4 (-1.7 to -1.2); PBO: -0.7 (-0.9 to -0.5)] in a pooled post-hoc analysis.[35] COSMOS (unclear RoB) investigated GUS 100mg Q8W compared to placebo in patients who were TNFi-IR, demonstrating superior efficacy of GUS over PBO in achieving the primary endpoint [ACR 20 at week 24: GUS 100mg Q8W: 84/189 (44.4%; p<0.001) vs. PBO: 19/96 (19.8%)] as well as all other secondary endpoints (MDA, DAPSA, physical function, skin disease, enthesitis, dactylitis and fatigue).[36]

The efficacy and safety of risankizumab (RIS), another inhibitor of the IL23-p19 subunit, was investigated in two RCTs (both low RoB).[37][38,39] In patients with IR to csDMARDs (KEEPsAKE 1), patients were randomised to RIS 150mg (s.c. at week 0, 4 and 16). At week 24 the primary (ACR 20: RIS 150mg: 277/482 (57.3%; p<0.001); PBO: 161/481 (33.5%) and most secondary endpoints (including MDA, PASI90, enthesitis, dactylitis, fatigue, and physical function) except the secondary endpoint of radiographic damage progression (ΔmTSS at week 24 RIS 150mg: 0.23; 95% CI: 0.02 to 0.44) vs. PBO: 0.32 95% CI: 0.11 to 0.53; p=0.50) were met.[8] Half of the patients included in KEEPsAKE 2 (low RoB) had received bDMARD therapy before the study. Also, this study met its primary (ACR 20 at week 24: RZB 150mg: 115/224 (51.3%; p<0.001); PBO 58/219 (26.5%) and all secondary endpoints.[37] Further, improvements in patient-reported outcomes, work productivity and health-related quality of life could be observed in patients treated with RIS.[38,39] A phase 2b study (low RoB) investigated tildrakizumab (TIL; IL23-p19i) 200mg Q4W or Q12W, 100mg Q12W and 20mg Q12W in patients with previous iR to NSAIDs or DMARDs. The primary endpoint (ACR 20 at week 24) was met by all TIL arms compared to PBO (TIL response rates ranging from 71%-80% compared to 51%), with no clear dose-response.[6]

## Efficacy of novel bDMARDs targeting IL-17

Five trials on novel molecules targeting IL-17 were included (4 with low RoB, 1 conference abstract). [9][40][41][42,43]

Bimekizumab (BKZ), a selective inhibitor of IL17-A and IL17-F was investigated in two placebo-controlled RCTs. BE OPTIMAL (low RoB) investigated patients naïve to bDMARDs against PBO and active control and showed superior efficacy of BKZ 160mg Q4W over PBO in achieving the primary endpoint [ACR50% response at week 16: BKZ 189/431 (44%, p<0.001); PBO 28/281 (10%; Reference); ADA 64/140 (46%; no formal comparison)] as well as in reduction of signs and symptoms of other manifestations like skin disease, enthesitis, dactylitis and radiographic damage progression.[9] Similarly, BE COMPLETE showed superior efficacy of BKZ versus PBO in patients with IR to TNFi.[40]

Brodalumab (BRO; IL-17-A receptor) was investigated in csDMARD IR patients in AMVISION 1 & 2. After randomisation of 962 patients, both trials were terminated early due to the sponsors' decision based on observed events of suicidal ideation and behaviour. The primary endpoint (ACR 20 at week 16) was met in both
studies, with significantly higher response rates in achieving ACR50/70, PASI responses and resolution of dactylitis/enthesitis.[41]

Izokibep (IZO) is an antibody mimetic, a protein with a small molecular size that can inhibit IL17A and is thus a biological DMARD, but not an antibody. It is administered every other week. A 16-week phase 2 study (conference abstract, RoB not assessed) comparing IZO 40mg Q2W, 80mg Q2W and PBO showed significant results compared to placebo and a slight dose-response relationship [ACR50 at week 16: 20/42 (48%; p<0.001) vs. 24/46 (52%; p<0.001) vs. 6/43 (13%)).[42,43] Clinically relevant treatment benefits were also observed in enthesitis, dactylitis and nail disease.[44]

Figure 2 summarizes and updates the evidence on established and new therapies based on the data presented and previous SLRs.[24,45,46]

## Strategic trials

Three strategic trials were included in this SLR (all with high RoB due to their open-label design).[20,47,48]

The NOR-DRUM trial investigated therapeutic infliximab dosed based on therapeutic drug monitoring (TDM) versus infliximab therapy without TDM. In total 411 patients with inflammatory immune-mediated diseases were included in the induction part of the trial, with 42 patients diagnosed with PsA. The primary outcome was the achievement of remission (defined as DAS28-ESR<2.6 for PsA) at week 30, with no difference comparing TDM to standard dosing in the overall analysis, and looking at the PsA subgroup, numerically but not statistically better results for the standard dosing arm (DAS-28-ESR<2.6 at week 30: TDM: 5/20 (25%) vs. standard INF dosing: 12/22 (54.5%); adjusted difference 29.4% [95% CI: -0.2% to 59.0%]).[48] The second part of this trial investigated the sustainment of response in patients who achieved DAS28<2.6 receiving infliximab therapy, again comparing TDM to standard dosing. The PsA subgroup showed no clinically meaningful difference in the number of patients with sustained DAS28-ESR<2.6 from week 30-52 (TDM: 19/28 (67.9%) vs. standard INF dosing: 16/25 (64.0%); adjusted difference 6.2% [95% CI: -19.5% to 31.9%]).[47]

CONTROL was a strategic open-label study consisting of two parts: in part 1 patients with insufficient response to MTX 15mg/week were either randomised to dose escalation of MTX (20-25mg / week) or additional treatment with adalimumab 40mg Q2W in combination with MTX 15mg/week. The primary endpoint (minimal disease activity [MDA] at week 16) was met, with significantly more patients in the ADA+MTX 15mg/week arm (51/123 (41%)) vs. the MTX 20-25mg/week dose escalation arm [16/122 (13%; p<0.001) achieving MDA. In part 2 patients who achieved MDA at week 16 received therapy modification (ADA 40mg Q2W + MTX 15mg/week: ADA 40mg Q2W monotherapy) or continuation (MTX 20-25mg/weekly) with most patients maintaining MDA at week 32 (41/51 [80%] for ADA 40mg Q2W monotherapy vs. 10/15 [67%] for patients continuing MTX 20-25 mg/week monotherapy. Patients with insufficient response were re-randomised at week 16 to treatment intensification: Non-responders to ADA 40mg Q2W + MTX 15mg/week were escalated to ADA 40mg weekly + MTX 15mg/week while those receiving MTX 20-25mg/week received additional treatment with ADA 40mg Q2W. 17/57 (30%) of patients escalated from ADA 40mg Q2W (+MTX) to ADA 40mg weekly + MTX 15mg/week achieved MDA after 32 weeks, while 50/91 (55%) of patients with initial MTX non-response who received add-on ADA 40mg Q2W achieved MDA.[20]

## Tapering and withdrawal

Four trials investigated treatment tapering and/or stopping (2 with high, 2 with low RoB). [21][49–51]

Michielsens et al. conducted an open-label non-inferiority TNFi withdrawal trial (high RoB), using a treat-to-target (using PASDAS ≤3.2 as target) dose-reduction and withdrawal strategy (n=42) compared to T2T treatment continuation without tapering (n=22) in patients with sustained PASDAS ≤3.2. After 12 months, T2T tapering was shown to be non-inferior to a T2T strategy without tapering. Rates of patients in PASDAS LDA were comparable (71% vs. 73%) with 24% (T2T with tapering) vs. 77% (T2T without tapering) of patients receiving 100% of their daily defined dose and 36% (T2T tapering) vs. 0% (no tapering) had stopped any DMARD use.[21]

Another open-label study (high RoB) investigated interval prolongation (i.e. doubling the dosing interval) and subsequent stopping (after 6 months) of etanercept treatment versus etanercept continuation. After 6 months
57% (vs. 70%) of PsA patients could double their etanercept interval while still remaining in MDA after 6 months.[49]

SPIRIT P3 was a double-blind RCT, in which patients achieving MDA after receiving (open-label) ixekizumab for 36 weeks (158/394, 40%) were randomised to either undergo blinded withdrawal (receiving placebo) or continuation of ixekizumab treatment. The primary endpoint of time to relapse (i.e. loss of MDA) until week 64 occurred more rapidly in patients who withdrew ixekizumab (median 22.3 weeks; 95% CI: 16.1–28.3, p<0.001). From week 24 to week 104, 67/79 patients (85%) experienced a relapse in the withdrawal group, compared to 30/79 (38%; p<0.001) In the continuation group. After re-treatment, almost all patients re-achieved MDA (64/67, [95.5%]; median time to re-achievement of MDA 4.1 weeks [95% CI: 4.1-4.3]) in the ixekizumab withdrawal group.[50]

A withdrawal substudy (low RoB) of the long-term extension study of tofacitinib (OPAL Balance) investigated methotrexate withdrawal in patients receiving tofacitinib 5mg BID for at least 24 months as well as MTX (7.5-20mg/week) for at least 4 weeks. All patients received open-label tofacitinib and were randomised to either placebo (i.e. MTX withdrawal; n=90) or continued MTX background therapy (n=89). After 6 months, no difference was observed in the co-primary endpoints PASDAS (difference 0.09, 95% CI -0.13 to 0.31) and HAQ-DI (difference 0.03, 95% CI -0.05 to 0.10).[51]

Table 4 summarises the main results of studies investigating dose reduction and withdrawal.

## Safety

Of the 24 additional reports included in the safety analysis (RoB: 8 low, 1 unclear, 10 high, 5 conference abstracts [not assessed]), 9 were derived from long-term extension studies of RCTs, 12 were cohort studies including registry and claims analyses, two case-control studies and one prospective phase 4 observational study. Moreover, all trials included in the efficacy analysis were also assessed for safety. Detailed event rates of adverse events of interest are shown in supplementary Tables S3.4.1-S3.4.6. A summary of adverse events of special interest of trials investigating tsDMARDs is shown in Table 5.

## Infections and infestations

### Randomized controlled trials and long-term extension studies

In EXCEED comparison of SEC with ADA showed similar rates of serious infections (SEC: 7/426 [1,6%] vs. ADA: 6/427 [1.4%]), however candida infections occurred numerically more frequently in SEC treated patients (SEC 16/426 [4%] vs. ADA 7/427 [2%]).[16] Two cases of candida skin infection were observed in TIL treated patients (compared to none in the PBO arm).[6] Candida and other fungal infections were also more frequent in BKZ treated patients compared to PBO (BE COMPLETE: BKZ: 7/267 [3%] vs. PBO: 0; BE OPTIMAL: BKZ 20/431 [5%] vs. PBO: 4/281 [1%] vs. ADA: 1/140 [<1%]) with no systemic fungal infections observed.[9,40] No serious infection, HZ or opportunistic infection was observed in the DEUC phase 2 trial until week 16.[11] Also, in the GUS trials no signal for increased rates of serious infections was observed.[7,34,36]

Rates of candida and fungal infections were very low in studies investigating IL23-p19 inhibitors, with few cases of local skin candidiasis. [34][6][7,8,37]

In integrated safety analyses of GUS, three cases of opportunistic infections were observed in the DISCOVER-2 trial (after week 52), with an otherwise consistent safety profile compared to the placebo-controlled period and no cases of active Tbc.[52]

Long-term safety of PsA patients in the UPA trial program (comparing UPA 15mg OD [n=907] to ADA 40mg Q2W [n=429] treated patients, data for UPA 30mg OD not reported; low RoB) showed higher rates for UPA for serious infections (exposure adjusted event rate, EAER [95% CI]: 3.9 [3.1, 4.9] vs. 1.4 [0.8, 2.5]), opportunistic infections (0.5 [0.2, 0.9] vs 0) and herpes zoster rates (3.6 [2.8, 4.6] vs. 0.4 [0.1, 1.1]). Of note, 29 of 93 (31.2%) COVID-19 infections occurring in UPA-treated patients were serious [vs. ADA: 4/37 (10.8%)] with 6 (6.5%) fatal cases for UPA treated vs. none in ADA-treated patients. No cases of active tuberculosis occurred in both groups.[53]
An analysis of influenza occurrence in the TOFA trial program (low RoB) showed numerically increased rates of influenza infections in TOFA 5mg BID (5/347, 196.2 PY, IR 2.51, 95% CI: 0.81-5.85) and TOFA 10mg BID (5/344, 192.2 PY, IR 2.56, 95% CI: 0.83-5.97) treated patients compared to ADA 40mg BID (no event).[54]

### Observational studies

Investigation of incidence of tuberculosis (Tb activation, Tb development or Tb reactivation) in the secukinumab trial database (low RoB) on 2523 PsA patients with in total 4943 patient years did not find cases of active Tb during the program.[55] A Slovenian cohort study (low RoB) found similar Tb incidence rates in PsA patients receiving TNF treatment compared to the general population of non-endemic countries with 2 cases occurring in 413 patients (1849 PY; standardised incidence rate: 5.8 [0.3, 112]).[56]

An observational study (low RoB) of PsA and SpA patients in four Nordic registers (DANBIO, ROB-FIN, NOR-DMARD and ARTIS/SRQ) compared TNFi to SEC-treated patients to assess the differences in risk of hospitalized infections. Although not powered to investigate the PsA subpopulation separately, a trend towards a higher risk for hospitalized infections in SEC treated patients (IR [95% CI]: 5.6; 4.1, 7.5; reference) compared to TNFi (aHR [95% CI]: adalimumab: 0.59 [0.34, 1.03]; etanercept: 0.59 [0.28, 1.20]; golimumab (0.57 [0.28, 1.20]; infliximab: 0.88 [0.54, 1.42]) was observed.[57]

A claims database study (high RoB) also compared the risk of hospitalized infections in Pso and PsA patients receiving DMARD therapy, comparing ustekinumab to TNFi and IL17i as well as apremilast. Lower rates of hospitalizations due to infection were observed for ustekinumab (reference) treated patients compared to the other therapies in the overall comparison, with a similar trend found in the sensitivity analysis investigating PsA patients only (aHR [95% CI]: ADA 1.67 [0.55, 5.07], APR 1.72 [0.68, 4.30], CZP 1.28 [0.74, 2.20], ETN 1.41 [0.40, 4.98], GOL 1.62 [0.18, 14.41], INF 2.89 [1.26, 6.63], IXE 15.05 [4.27-53.04] and SEC 1.93 [0.97-3.87].[58] Another claims database study (high RoB) compared the risk for infections requiring hospitalisation between TNF, IL17 or IL12/23 inhibition in PsA and Pso patients. No statistical difference was observed in serious infection for PsA patients between the different modes of action (aHR [95% CI]: IL-17 vs. TNF 0.73 [0.36, 1.45]; IL-12/23 vs TNF 0.59 [0.38, 0.92]; IL-17 vs. IL12/23 1.01 [0.53, 1.92]).[59]

A matched case-control study from the DANBIO registry (unclear RoB) compared the risk for serious infections in patients starting bDMARD treatment. Controls were randomly selected (matched by sex, age and postal-code) from the general population without PsA. In twelve months 89/2429 (3.7%, HR 3.4, 95% CI: 2.7, 4.3) of PsA patients experienced a serious infection versus 262/24288 (1.1%) of matched controls (reference). Patients with comorbidities (one: HR 5.3 [3.4, 8.2]); two or more: (HR 4.9 [2.5, 9.6]) compared to PsA patients without comorbidities (HR 2.5 [1.8, 3.5]) were at higher risk, as well as patients receiving GC treatment (HR 5.3 [3.3, 8.5] vs. no GC use: HR 2.9 [2.2, 3.9]).[60]

The PsABio study was an observational post-marketing surveillance study (high RoB), investigating ustekinumab (n=494) and TNFi (n=557) treatment in patients receiving these treatments as first, second or third-line therapy. The choice of the bDMARD was made by the treating rheumatologist. UST users showed numerically lower numbers of SAEs (UST: 31/494, 6.3%, [4.3, 8.8] vs. TNFi: 40/557, 7.2% [5.2, 9.7]). Exposure-adjusted incidence rates showed a higher risk for the occurrence of infections in TNFi vs. UST-treated patients (EAIR not reported). Rates of serious or opportunistic infections were similar (UST: 6/494, 1.2% [0.4, 2.6] vs. TNFi: 5/557, 0.9% [0.3, 2.1]).[61]

### Major adverse cardiovascular events & arterial thrombotic events

### Randomized controlled trials and long-term extension studies

During the placebo controlled period of the SELECT PsA trials, in SELECT PsA 1, no MACE occurred in the UPA treatment arms, one in the placebo and two in the ADA arm.[18] In SELECT PsA 2, one MACE occurred in UPA 15mg OD treated patients (compared to none in the PBO and UPA 30mg OD arm).[12] No MACE was seen in either the DEUC or the BREP phase 2 trial.[11][10]

During the long-term safety period comparing UPA 15mg OD (n=907) to ADA 40mg Q2W (n=429) rates of (adjudicated) MACE were similar between both groups (EAER: 0.3 [0.1, 0.6] vs. 0.3 [0.1, 1.0]).[53,62]
Analysis of the long-term safety data of PsA patients treated with tofacitinib (high RoB) showed 1/347 cases of arterial thromboembolisms in the TOFA 5mg BID arm (IR: 0.5, 95% CI: 0.01-2.78), and 2/106 in the ADA arm (IR 2.16, 95% CI: 0.26-7.82) and no event in the TOFA 10mg BID arm.[63]

No signal for MACE was identified in KEEPSAKE 1 & 2, investigating risankizumab.[8,37] and in the integrated safety analyses of guselkumab.[52]

### Observational studies

Two investigations of claims data (high RoB) found no increased risk of myocardial infarction or MACE in patients receiving bDMARD therapy compared to patients receiving conventional DMARDs, GC or apremilast.[64][65] A cohort study using the French health insurance and hospital discharge database found an increased risk of MACE in bDMARD naïve patients without previous cardiovascular disease initiating IL12/23i therapy (aHR 2.0 [1.3, 3.0]) or IL17i therapy (aHR 1.9 [1.2, 3.0]) compared to TNFi (reference). No increased risk was found when comparing TNFi to apremilast (aHR 1.3, [0.8, 2.2]), while other tsDMARDs were not studied.[64] A study from Hong Kong (conference abstract, RoB not assessed) did not find bDMARD treatment to be associated with occurrence of MACE, but it was associated with elevated acute-phase reactants over time (aHR 1.16 [1.11, 1.21], p<0.001), as well as with steroid usage (aHR 1.93 [1.04, 3.57], p=0.036).[65]

In the UST arm of the PsABio study (see details above), two myocardial infarctions and one cardiac arrest occurred, compared to three myocardial infarctions in the TNFi arm.[61]

### Venous thromboembolisms

Comparing UPA 15mg OD [n=907] to ADA 40mg Q2W [n=429] rates of (adjudicated) VTE were similar for both groups (VTE: UPA: 0.2 [0.1, 0.5] vs. ADA: 0.2 [0, 0.8]) in patients receiving UPA.[53,62] No VTE was observed in the DEUC and BREP phase 2 trial.[11][10]

Analysis of the long-term safety data of PsA patients treated with tofacitinib 5mg BID or 10mg BID (high RoB) showed low event rates, with one VTE (deep vein thrombosis, IR 0.51, 95% CI 0.01, 2.83) occurring in the TOFA 10mg BID (1/344, 197.2 PY) arm (vs. none in the ADA [92.6 PY] and TOFA 5mg BID arm [201.1 PY]) during the active-controlled period. VTEs were experienced by patients who had baseline cardiovascular or VTE risk factors [63]

### Malignancies

### Randomized controlled trials and long-term extension studies

During the placebo-controlled period of SELECT-PsA 1, five malignancies (excluding non-melanoma skin cancer) were observed: one in the UPA 15mg OD arm (neuroendocrine carcinoma), one in the UPA 30mg OD arm (malignant lung neoplasm) and three in the ADA 40mg Q2W arm (colon cancer, ovarian cancer, uterine cancer), with none in the placebo arm.[18] In the placebo controlled period of the SELECT-PsA 2 trial, malignancies observed in each of the UPA arms were: one prostate cancer, one rectal cancer in UPA 15mg OD (n=2); one rectal adenocarcinoma and one ovarian/endometrial cancer in the UPA 30mg OD arm (n=2), compared to none in the placebo arm.[12] In the UPA long term extension, rates of malignancies (excluding non-melanoma skin cancer) were similar (UPA 15mg OD: 0.6 [0.3, 1.1] vs. ADA 40mg Q2W: 0.4 [0.1, 1.1]), with higher age (Hazard ratio, HR (95% CI): 3.1 [1.7, 5.8]) and BMI (HR 1.1, [1.003, 1.15]), being significant predictors for development of malignancies in patients receiving UPA 15mg OD.[53,66] Rates of non-melanoma skin cancer were numerically higher (UPA: 0.8 [0.4, 1.3] vs. ADA: 0.2 [0, 0.8]) for UPA treated patients. One basal cell carcinoma occurred in the BREP 60mg OD arm compared to no events in the other arms.[10]

In the phase 2 trial investigating BREP, one malignancy was observed (uterine leiomyoma) in the BREP 60mg OD arm compared to no events in the other treatment arms.[10] No malignancy occurred during the 16 weeks of the DEUC phase 2 trial.[11]

An analysis of malignancy occurrence during SEC treatment in the SEC trial database showed a cumulative incidence of 51/4902 malignancies in PsA patients (exposure adjusted incidence rate per 100 patient years: 1.04, 95% CI: 0.77, 1.37), with non-melanoma skin cancer (basal cell carcinoma [n=15] and squamous cell carcinoma [n=2]) being the most prevalent. The incidence rate was in line with the expected rate of the general
population (SEER database, standardised IR 1.16 (95% CI 0.80-1.62).[67] No signal for an increased risk for malignancies was found in the integrated safety analysis of GUS.[52]

### Observational studies

No difference in the occurrence of malignancies between UST and TNFi treated patients was observed in the PsABio study.[61]

In a British cohort study (high RoB) the incidence of cancer was found to be comparable in PsA patients receiving TNFi treatment compared to the general population (standardised incidence rate 0.94; 95% CI: 0.65, 1.34), however an increased risk for non-melanoma skin cancer was observed (standardised incidence rate 2.12; 95% CI: 1.19, 3.50). Also an increased all-cause mortality (standardised mortality rate 1.56; CI: 1.12, 2.11) and increased risk of death from coronary heart disease (standardised mortality rate 2.42; 95% CI: 1.11, 4.59) was found.[68] No increased risk for development of solid cancer was found in a large Nordic cohort study (unclear RoB) comparing PsA patients exposed to TNFi treatment with bDMARD naïve PsA patients (aHR (95% CI): 1.0 [0.9, 1.2] and 0.8 [0.7, 1.0] for comparison with the Nordic clinical rheumatology registers and the national patient registers, respectively).[69] A similar analysis (low RoB) investigating hematologic malignancies did not find an increased risk for PsA patients receiving TNFi therapy compared to bDMARD naïve patients (incidence rate ratio: 0.96 [0.68, 1.35] and 0.84 [0.64, 1.10], respectively). However, an increased risk of hematologic malignancies compared to the general population was observed (incidence rate ratio: 1.35 [1.17, 1.55]).[70]

### BKZAdverse events of special interest

### Randomized controlled trials and long-term extension studies

In EXCEED, new cases of IBD were more frequent in the SEC arm compared to ADA (two cases vs. none). [16]

In the PBO-controlled period (until week 16) of the phase 2 trial investigating DEUC, acne was reported in 2/70 (2.9%) patients receiving DEUC 6mg OD and 1/67 (1.5%) in the 12mg OD arm – compared to none in the placebo group. Also, acneiform dermatitis was reported in 2/70 (2.9%), 2/67 (3%) in DEUC 6mg/12mg OD treated patients compared to none in the PBO arm.[11]

In the DISCOVER-1 and -2 trials, similar rates of suicidal ideation in GUS-treated patients, compared to placebo were observed, with no events occurring in the studies investigating BKZ and TIL.[6-9,34,36,37,40] In COSMOS, one patient in the guselkumab arm experienced two events of conversion disorder, which resolved after discontinuation of GUS. Another patient with a previous history of a suicidal attempt did report depressive symptoms after receiving guselkumab – the study drug was discontinued, and no further follow-up occurred.[36] Trials investigating brodalumab (AMVISION 1 and 2) were terminated early following a sponsor's decision due to events of suicidal ideation and behaviour observed in the study programme.[41]

In the integrated safety analyses of GUS no cases of IBD or anaphylactic reactions were observed.[52] No risk for MACE or malignancies was observed in the placebo and long-term extension period for apremilast-treated patients.[71] Also, investigation of long-term safety from the UST PsA trial database did not reveal any new signal regarding the safety of MACE, malignancies or Tb.[72]

### Observational studies

An US claims database analysis (high RoB, n=30426, 60497 PY) investigating the incidence of anxiety and depression disorder found especially users of corticosteroids (as an adjunctive therapy) to be at higher risk for depression (aHR 1.5 [1.1, 2.0]) and a trend regarding anxiety (aHR 1.3 [0.9, 1.9]) with no signal for other DMARDs including bDMARDs and apremilast investigated.[71]

Another US claims database study (high RoB) investigated the impact of TNFi treatment on development of liver disease (cirrhosis or non-alcoholic fatty liver disease) and found a higher risk in the overall cohort (including patients with rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease), with a trend towards higher rates of liver disease also in the PsA subcohort (TNFi vs. no TNFi use: aHR 1.25, [0.88, 1.76]).[73]
Discussion

The aim of this SLR was to summarise the evidence regarding efficacy and safety of pharmacological therapies of PsA since the elaboration of the 2019 EULAR PsA management recommendations.

Similar to other SLRs, also this SLR has strengths and limitations. Data of trials included were not pooled through meta-analyses, due to high heterogeneity of the trials. Instead, the data was reported descriptively, avoiding (indirect) meta-analytic comparisons between drugs. On the other hand, the literature was fully searched in a systematic manner using pre-defined criteria. Though 10% of articles were screened in duplicate, each article was analysed for risk of bias and quality; and the data synthesis was descriptive which avoids over-interpretation.

Evidence on the efficacy of csDMARDs and especially methotrexate was confirmed with clinically meaningful improvements of disease activity observed in the COMPLETE-PsA and GO-DACT trials but is still based on comparisons to other treatment regimens and not to placebo. Combination of MTX with leflunomide provided significantly better efficacy results than MTX monotherapy, however with substantially higher rates of adverse events.[19]

The efficacy of other meanwhile well-established therapies was confirmed and furthermore expanded with trials investigating the efficacy of IL-17 inhibition on specific musculoskeletal domains which showed significant differences compared to placebo treatment for axial disease (MAXIMISE),[14] and synovitis (ULTIMATE),[13] as well as the efficacy of golimumab in combination with MTX (versus MTX monotherapy) on dactylitis (GO-DACT).[15] Several recent trials utilised more stringent and clinically meaningful efficacy outcomes than the commonly used ACR20% response as a (co-)primary efficacy endpoint (ACR50% response at week 16/24).[9,17,31,40] Non-inferiority of ustekinumab monotherapy compared to ustekinumab + MTX combination therapy was shown in the MUST study.[30] Head-to-head comparisons of IL-17i (secukinumab [EXCEED], ixekizumab [SPIRIT-H2H]) compared to TNFi (adalimumab) showed comparable ACR response rates, but better skin responses in IL-17i treated patients.[16,31] Two observational studies found higher rates of hospitalised infections in IL-17i-treated patients (compared to TNFi) [57][58], while another study did not show an increased risk.[59] No benefit of therapeutic drug monitoring was seen in infliximab-treated PsA patients.[48][47] Studies investigating molecules targeting the p19 subunit of IL-23 (guselkumab, risankizumab, tildrakizumab) as well as new molecules inhibiting IL-17A (izokibep) and IL-17A/F (bimekizumab),[42,43][44][9][40] showed superior efficacy when compared to placebo across many disease domains (including arthritis, enthesitis, dactylitis, skin and nail disease) as well as improvement of physical function,[6-8][7][36][38,39][6] Fungal infections occurred more frequently in patients receiving IL-17i compared to placebo and TNFi treatment. Only very few cases of fungal infections were observed in IL23-p19i treated patients.[34][6][7,8,37]

RCTs on novel targeted synthetic DMARDs (brepocitinib [JAK1/TYK2], deucravacitinib [TYK2], upadacitinib [JAK1/2]) showed significantly higher response rates compared to placebo treatment, [10][11][12] as well as superiority of UPA 30mg (but not 15mg) compared to adalimumab 40mg Q2W on the expense of more adverse events.[18,33]

In regard to safety, higher event rates in upadactinib-treated patients of serious infections (including serious and fatal COVID-19 infections), opportunistic infections, and herpes zoster rates were observed, compared to adalimumab, while rates of MACE and VTEs were similar.[53] Also, decreases of haemoglobin levels were higher in upadactinib-treated patients, while they increased on adalimumab.[12] Increased rates of acne and acneiform rashes were reported in deucravacitinib-treated patients.[11]

No trial investigating the efficacy of glucocorticoids was identified, however observational studies provided evidence of increased adverse event rates (MACE, serious infections, anxiety and depression) in patients treated with systemic glucocorticoids.[74][65]

Trials on strategic tapering (using a T2T approach) were reassuring, showing the potential of successful treatment withdrawal while maintaining disease control,[21] but abrupt treatment cessation led to an elevated risk of disease flares.[50]
Results of the safety analysis also highlighted the importance of comorbidities in PsA patients, with higher risks of serious infections especially in patients with one or more comorbidities compared to patients without comorbidities,[60] a higher risk for VTEs in patients with cardiovascular or VTE risk factors.[63] While not associated with any DMARD therapy, an increased risk for non-melanoma skin cancer in PsA patients was observed, as well as an increased all-cause mortality and death from coronary heart disease.[68]

This systematic literature research provided the taskforce with the evolved evidence since 2018 for the 2023 update of the EULAR recommendations on pharmacological management of PsA.

**Acknowledgments and affiliations**

**Contributors**

All authors contributed and finally approved the current manuscript.

**Funding**

The European Alliance of Associations for Rheumatology (EULAR) funded this literature review

**Data Availability Statement**

All data relevant to the study are included in the article or uploaded as online supplementary information. Detailed data of all included studies are also available in the public domain.

**Patient and Public Involvement statement**

The steering committee on this project involved a PPI representative (HB), member of the EULAR Standing Committee of People with Arthritis/Rheumatism in Europe, who contributed during all task force meetings, especially to take patient perspectives into account and refine research questions.

**Competing interests**

Andreas Kerschbaumer, Speakers bureau, Consultancy: AbbVie, Amgen, Galapagos, Janssen, Eli Lilly, MSD, Novartis, Pfizer and UCB

Josef S. Smolen: research grants from Abbvie, Astra-Zeneca, Lilly, Galapagos; Royalties from Elsevier (textbook); consulting fees from Abbvie, Galapagos/Gilead, Novartis-Sandoz, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly; Honoraria from Samsung, Lilly, R-Pharma, Chugai, MSD Janssen, Novartis-Sandoz; participation in advisory board from Astra-Zeneca.

Ricardo J. O. Ferreira, research grants: Medac, Lilly; Consulting fees: Sanofi.

Heidi Bertheussen, none

Xenofon Baraliakos: Scientific grants: Abbvie, MSD, Novartis. Consultancies, honoraria and advisory board member for Abbvie, Amgen, Celltrion, Chugai, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche, Sandoz, UCB. Membership on an entity's Board of Directors or advisory committees: ASAS President, EULAR President Elect.

Daniel Aletaha, research grants: Galapagos, Lilly; Consulting fees: Abbvie, Gilead, Janssen, Lilly, Merck, Novartis, Sanofi.

Dennis McGonagle, research grants: Janssen, Abbvie, Lilly, Novartis. UCB, BMS, Moonlake; consulting fees: Janssen, Abbvie, Lilly, Novartis. UCB, BMS, Moonlake, Celgene; honoraria: Janssen, Abbvie, Lilly, Novartis. UCB, BMS, Moonlake; support to attending meetings: Novartis Janssen.

Désirée van der Heijde: consulting fees AbbVie, Argenx, Bayer, BMS, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Novartis, Pfizer, Takeda, UCB Pharma. Director of Imaging Rheumatology bv. Associate editor
Annals Rheumatic Diseases, editorial board member Journal of Rheumatology and RMD Open, Advisor Assessment Axial Spondyloarthritis international Society.

Iain B. McInnes, Honoraria/consultation fees & grants/research supports: Abbvie, Amgen, BMS, Causeway Therapeutics, Cabaletta, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi, UCB, Evelo, Compugen, AstraZeneca, Moonlake; Non Exec Roles: NHS GGC Board Member, Evelo Board of Directors, Versus Arthritis Trustee Status; Stock or Stock Options: Evelo, Cabaletta, Compugen, Causeway Therapeutics, Dextera.

Bente Appel Esbensen, none

Kevin Winthrop, Research: BMS, Pfizer; Consulting: Pfizer, AbbVie, Union Chimique Belge (UCB), Eli Lilly & Company, Galapagos, GlaxoSmithKline (GSK), Roche, Gilead, BMS, Regeneron, Sanofi, AstraZeneca, Novartis,

Wolf-Henning Boehncke, Honoraria: Abbvie, Almirall, BMS, Janssen, Leo, Eli Lilly, Novartis, UCB; Expert testimony: Novartis; Participation on a Data Safety Monitoring Board or Advisory Board: Abbvie, Almirall, BMS, Janssen, Leo, Eli Lilly, Novartis, UCB

Jan W. Schoones, none

Dr. Gossec reports grants from AbbVie, Biogen, Lilly, Novartis, UCB, personal fees from AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, non-financial support from AbbVie, Amgen, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB, outside the submitted work.
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<table><caption>Table 1. Summary of studies in PsA published 2018-2022 and included for evaluation of efficacy.</caption><thead><tr><th>Intervention</th><th>Number of articles/abstracts</th><th>Therapeutic compound</th><th>Target</th><th>Reference</th></tr></thead><tbody><tr><td>csDMARDs, csDMARD combination versus other csDMARDs or placebo</td><td>1</td><td>Methotrexate + Leflunomide<br>Methotrexate + Placebo</td><td>dihydrofolate reductase / adenosine metabolism (AICAR); dihydroorotate dehydrogenase</td><td>[19]</td></tr><tr><td rowspan="6">bDMARD ± csDMARDs versus placebo</td><td>4</td><td>Secukinumab</td><td>IL-17A</td><td>[28][13][14][29]</td></tr><tr><td>3</td><td>Izokibep</td><td>IL-17A</td><td>[42,43][44]</td></tr><tr><td>2</td><td>Bimekizumab</td><td>IL-17A/F</td><td>[9][40]</td></tr><tr><td>1</td><td>Brodalumab</td><td>IL-17A receptor</td><td>[41]</td></tr><tr><td>4</td><td>Guselkumab</td><td>IL-23p19</td><td>[34][7][35][36]</td></tr><tr><td>4</td><td>Risankizumab</td><td>IL-23p19</td><td>[8][37][38,39]</td></tr><tr><td>1</td><td>Tildrakizumab</td><td>IL-23p19</td><td>[6]</td></tr><tr><td>bDMARD + csDMARD (combination therapy) versus bDMARD + placebo (monotherapy)</td><td>1</td><td>Ustekinumab + MTX vs. Ustekinumab + Placebo</td><td>IL-12/23; dihydrofolate reductase + purine metabolism (AICAR)</td><td>[30]</td></tr><tr><td>bDMARD + csDMARD (combination therapy) versus csDMARD + placebo (monotherapy)</td><td>1</td><td>Golimumab + MTX vs. Placebo + MTX</td><td>TNF; dihydrofolate reductase + purine metabolism (AICAR)</td><td>[15]</td></tr><tr><td rowspan="3">tsDMARDs ± csDMARDs versus placebo</td><td>1</td><td>Brepocitinib</td><td>JAK1, TYK2</td><td>[10]</td></tr><tr><td>1</td><td>Deucravacitinib</td><td>TYK2</td><td>[11]</td></tr><tr><td>1</td><td>Upadacitinib</td><td>JAK1, JAK2</td><td>[12]</td></tr><tr><td rowspan="2">bDMARDs versus other bDMARDs (head-to-head)</td><td>2</td><td>Secukinumab vs. Adalimumab</td><td>IL-17A vs. TNF</td><td>[16,32]</td></tr><tr><td>2</td><td>Ixekizumab vs. Adalimumab</td><td>IL-17A vs. TNF</td><td>[17][31]</td></tr><tr><td>tsDMARDs versus bDMARDs (head-to-head)</td><td>2</td><td>Upadacitinib vs. Adalimumab</td><td>JAK1, JAK2 vs. TNF</td><td>[18,33]</td></tr><tr><td>Strategic studies</td><td>3</td><td></td><td></td><td>[20][47][48]</td></tr><tr><td>csDMARD stopping</td><td>1</td><td>Methotrexate</td><td>dihydrofolate reductase + purine metabolism</td><td>[51]</td></tr><tr><td>bDMARD dose reduction and stopping</td><td>2</td><td>TNF</td><td>TNF</td><td>[21][49]</td></tr><tr><td>bDMARD stopping</td><td>1</td><td>Ixekizumab</td><td>IL-17A</td><td>[50]</td></tr></tbody></table>

AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; b, biologic; cs, conventional synthetic; DMARD, disease-modifying antirheumatic drug; IL, interleukin; JAK, Janus Kinase; MTX, methotrexate; TNF, tumour necrosis factor alpha; TNFi, tumour necrosis factor alpha inhibitor; JAK: Janus Kinase; RCT: randomised controlled trial; PDE4: phosphodiesterase 4; ts, targeted synthetic; wk, week;
<table><caption>Table 2: Summary of efficacy outcomes of studies in PsA published 2018-2022 and included for evaluation of efficacy.</caption><thead><tr><th>Disease domain</th><th>Abbreviation</th><th>Full form</th></tr></thead><tbody><tr><td rowspan="5">Composite scores</td><td>ACR response</td><td>American College of Rheumatology response definition</td></tr><tr><td>DAPSA</td><td>Disease Activity Index for Psoriatic Arthritis</td></tr><tr><td>DAS28-CRP</td><td>Disease Activity Score 28 (CRP)</td></tr><tr><td>MDA / VLDA</td><td>Minimal Disease Activity / Very Low Disease Activity</td></tr><tr><td>PASDAS</td><td>Psoriatic Arthritis Disease Activity Score</td></tr><tr><td rowspan="2">Peripheral arthritis</td><td>PsARC</td><td>Psoriatic Arthritis Response Criteria</td></tr><tr><td>SJC66</td><td>Swollen Joint Count 66</td></tr><tr><td rowspan="10">Patient reported outcomes &amp; Health related quality of life</td><td>TJC68</td><td>Tender Joint Count 68</td></tr><tr><td>EGA</td><td>Evaluator global assessment of disease activity</td></tr><tr><td>EQ5D</td><td>Euro Quality of Life five dimensions</td></tr><tr><td>FACIT-F</td><td>Functional Assessment of Chronic Illness Therapy-Fatigue</td></tr><tr><td>Pain</td><td>Patient global assessment of pain</td></tr><tr><td>PGA / PtGA</td><td>Patient global assessment of disease activity</td></tr><tr><td>PSAID</td><td>Psoriatic Arthritis Impact of Disease</td></tr><tr><td>SF36-MCS</td><td>Short Form 36 Mental Component Score</td></tr><tr><td>WPAI</td><td>Work Productivity and Activity Impairment</td></tr><tr><td rowspan="2">Physical function</td><td>HAQ-DI</td><td>Health Assessment Questionnaire Disability Index</td></tr><tr><td>SF36-PCS</td><td>Short Form 36 Physical Component Score</td></tr><tr><td rowspan="4">Skin / Nails</td><td>BSA</td><td>Body surface area</td></tr><tr><td>IGA</td><td>Investigator's Global Assessment Scale</td></tr><tr><td>NAPSI</td><td>Nail Psoriasis Severity Index</td></tr><tr><td>PASI</td><td>Psoriasis Area and Severity index</td></tr><tr><td rowspan="4">Enthesitis</td><td>LEI</td><td>Leeds Enthesitis Index</td></tr><tr><td>MASES</td><td>Maastrict AS Enthesis Score</td></tr><tr><td>SPARCC</td><td>Spondyloarthritis Research Consortium of Canada Index</td></tr><tr><td>-</td><td>Resolution of Enthesitis</td></tr><tr><td rowspan="3">Dactylitis</td><td>DSS</td><td>Dactylitis Severity Score</td></tr><tr><td>LDI</td><td>Leeds Dactylitis Index</td></tr><tr><td>-</td><td>Resolution of Dactylitis</td></tr><tr><td rowspan="5">Axial Disease</td><td>ASAS response</td><td>Assessment of SpondyloArthritis International Society response criteria</td></tr><tr><td>ASDAS</td><td>Ankylosing Spondylitis Disease Activity Score</td></tr><tr><td>BASDAI</td><td>Bath Ankylosing Spondylitis Disease Activity Index</td></tr><tr><td>BASFI</td><td>Bath Ankylosing Spondylitis Function Index</td></tr><tr><td>BASMI</td><td>Bath Ankylosing Spondylitis Metrology Index</td></tr><tr><td rowspan="2">Radiographic</td><td>mSvDHS</td><td>modified Sharp van der Heijde Score</td></tr><tr><td>-</td><td>Berlin MRI Score</td></tr></tbody></table>
<table><caption>**Table 3:** Efficacy outcomes of head-to-head studies comparing JAK inhibitors to biological DMARDs. Results of secondary efficacy outcomes are shown at the timepoint of the primary endpoint.</caption><thead><tr><th rowspan="2">Population</th><th rowspan="2">Study</th><th rowspan="2">RoB</th><th rowspan="2">Treatment</th><th rowspan="2">n</th><th rowspan="2">Primary Endpoint</th><th rowspan="2">Result (%)</th><th rowspan="2">Head-to-head comparison</th><th colspan="8">Endpoints at week 24</th></tr><tr><th>ACR 20 (%)</th><th>ACR 50 (%)</th><th>ACR 70 (%)</th><th>PASI90 (%)</th><th>MDA (%)</th><th>LEI=0 n/N (%)</th><th>LDI-B=0 n/N (%)</th><th>ΔHAQ-DI</th></tr></thead><tbody><tr><td rowspan="2">csDMARD-IR; bDMARD naive</td><td rowspan="2">Mease 2020 / Smolen 2020 (SPIRIT-H2H) [17,31]</td><td rowspan="2">High (assessor blinded)</td><td>IXE 80mg Q4W ± csDMARD</td><td>283</td><td rowspan="2">ACR50 + PASI100 at week 24</td><td>36.0%</td><td>S (met)</td><td>68.9%</td><td>50.5%</td><td>31.8%</td><td>71.7%</td><td>47.7%</td><td>95/159 (59.7%)</td><td>37/42 (88.1%)</td><td>NR</td></tr><tr><td>ADA 40mg Q2W ± csDMARD</td><td>283</td><td>27.9%</td><td>Reference</td><td>72.1%</td><td>46.6%</td><td>25.8%</td><td>55.8%</td><td>35.3%</td><td>81/147 (55.1%)</td><td>54/58 (93.1%)</td><td>NR</td></tr><tr><td rowspan="2">csDMARD-IR; bDMARD naive</td><td rowspan="2">McInnes 2020 (EXCEED) [16]</td><td rowspan="2">Low</td><td>SEC 300mg Q4W (mono)</td><td>426</td><td rowspan="2">ACR20 at week 52</td><td>67%</td><td>S (not met)</td><td>71%</td><td>43%</td><td>NR</td><td>63%</td><td>NR</td><td>119/234 (51%)</td><td>NR</td><td>-0.54</td></tr><tr><td>ADA 40mg Q2W (mono)</td><td>427</td><td>62%</td><td>Reference</td><td>64%</td><td>40%</td><td>NR</td><td>42%</td><td>NR</td><td>116/264 (44%)</td><td>NR</td><td>-0.51</td></tr><tr><td rowspan="4">csDMARD-IR; bDMARD naive</td><td rowspan="4">McInnes 2021 (SELECT PsA 1) [18]</td><td rowspan="4">Low</td><td>UPA 15mg OD ± csDMARD</td><td>429</td><td rowspan="4">ACR 20 at week 12</td><td>70.6%</td><td>NI (met) S (not met)</td><td>73.4%</td><td>52.4%</td><td>28.7%</td><td>41.6%</td><td>36.6%</td><td>145/270 (53.7%)</td><td>104/136 (76.5%)</td><td>-0.51</td></tr><tr><td>UPA 30mg OD ± csDMARD</td><td>423</td><td>78.5%</td><td>NI (met) S (met)</td><td>78.5%</td><td>60.5%</td><td>36.4%</td><td>48.1%</td><td>45.4%</td><td>154/267 (57.7%)</td><td>101/127 (79.5%)</td><td>-0.51</td></tr><tr><td>ADA 40mg Q2W ± csDMARD</td><td>429</td><td>65.0%</td><td>Reference</td><td>67.1%</td><td>44.3%</td><td>22.6%</td><td>45.0%</td><td>33.3%</td><td>125/265 (47.2%)</td><td>94/127 (74.0%)</td><td>-0.39</td></tr><tr><td>PBO ± csDMARD</td><td>423</td><td>36.2%</td><td>-</td><td>45.2%</td><td>18.9%</td><td>5.2%</td><td>16.6%</td><td>12.3%</td><td>78/241 (32.4%)</td><td>50/126 (39.7%)</td><td>-0.19</td></tr></tbody></table>

<footnote>* p<0.05; ACR, American College of Rheumatology; ADA, adalimumab; bDMARD, biological DMARD; csDMARD, conventional synthetic disease-modifying antirheumatic drug; HAQ-DI, health assessment questionnaire-disability Index; LDI, Leeds Dactylitis Index; LEI, Leeds Enthesitis Index; IR, insufficient response; MTX, methotrexate; NI, non-inferiority; NR, Not Reported; OD, once daily; PASI, Psoriasis Area and Severity Index; S, superiority; UPA, upadacitinib; IXE: ixekizumab; SEC: secukinumab</footnote>
<table><caption>**Table 4:** Primary outcomes of studies investigating DMARD dose reduction and withdrawal.</caption><thead><tr><th>Study</th><th>RoB</th><th>Primary Outcome(s) [unit]</th><th>week</th><th>Treatment arm</th><th>n</th><th>Result</th><th>Difference / 95% CI / p-value</th></tr></thead><tbody><tr><td colspan="8" style="text-align: center; font-weight: bold;">bDMARD dose reduction & stopping</td></tr><tr><td rowspan="2">Michielsens 2022 [21]</td><td rowspan="2">High (open-label)</td><td rowspan="2">PASDAS≤3.2<br>Stopped DMARD usea<br>[n/%]</td><td rowspan="2">52</td><td>T2T TNFi with tapering</td><td>42</td><td>30 (71%)<br>15 (36%)<sup>a</sup></td><td rowspan="2">Difference: 8% (-14% to 30%)</td></tr><tr><td>T2T TNFi without tapering</td><td>22</td><td>16 (73%)<br>0 (0%)<sup>a</sup></td></tr><tr><td rowspan="2">Ruwaard 2023 [49]</td><td rowspan="2">High (open-label)</td><td rowspan="2">Sustained MDA<br>[n/%]</td><td rowspan="2">24</td><td>Etanercept interval prolongation</td><td>21</td><td>12 (57%)</td><td rowspan="2">Not reported</td></tr><tr><td>Etanercept continuation</td><td>20</td><td>14 (70%)</td></tr><tr><td colspan="8" style="text-align: center; font-weight: bold;">bDMARD stopping</td></tr><tr><td rowspan="2">Coates 2021 (SPIRIT-P3) [50]</td><td rowspan="2">Low</td><td rowspan="2">Time to relapse (loss of MDA) [weeks]</td><td rowspan="2">36 to 104</td><td>Placebo (Ixekizumab withdrawal)</td><td>79</td><td>22.3</td><td rowspan="2">95% CI: 16.1–28.3<br>P&lt;0.001</td></tr><tr><td>Ixekizumab continuation</td><td>79</td><td>NE<sup>b</sup></td></tr><tr><td colspan="8" style="text-align: center; font-weight: bold;">csDMARD stopping</td></tr><tr><td rowspan="2">Nash 2021 (OPAL Balance) [51]</td><td rowspan="2">Low</td><td rowspan="2">Change from baseline in<br>PASDAS and HAQ-DI<br>[LSM ± SE]</td><td rowspan="2">24</td><td>Placebo + Tofacitinib 5mg BID (MTX stopping)</td><td>90</td><td>0.23±0.08<br>0.04±0.03</td><td rowspan="2">Difference PASDAS: 0.09 (95% CI –0.13 to 0.31)<br>HAQ-DI: 0.03 (95% CI –0.05 to 0.10)</td></tr><tr><td>Tofacitinib 5mg BID + MTX (MTX continuation)</td><td>89</td><td>0.14±0.08<br>0.02±0.03</td></tr></tbody></table>

<footnote>a secondary outcome; b Not estimable, as <50% of patients experienced a relapse by the end of the study period.</footnote>

<footnote>MDA: minimal disease activity; RoB: risk of bias; CI: confidence interval; DMARD: disease modifying anti-rheumatic drug; SE: standard error; HAQ-DI: Health Assessment Questionnaire Disability Index; PASDAS: Psoriatic Arthritis Disease Activity Score; MTX: methotrexate; BID: twice daily; TNFi: tumor necrosis factor alpha inhibitor; T2T: treat-to-target; MDA: minimal disease activity; RoB: risk of bias;</footnote>
<table><caption>**Table 5:** Safety outcomes of RCTs investigating targeted synthetic disease-modifying anti-rheumatic drugs.</caption><thead><tr><th>Population</th><th>Study</th><th>Risk of bias</th><th>Treatment</th><th>n</th><th>Safety endpoint (week)</th><th>Serious adverse event</th><th>Serious infectious event</th><th>Opportun-istic infection</th><th>Herpes zoster</th><th>Malignancy (other than NMSC)</th><th>Major adverse cardiovascular event</th><th>Venous thrombo-embolism</th></tr></thead><tbody><tr><td rowspan="4">csDMARD-IR; bDMARD naive</td><td rowspan="4">McInnes 2021 (SELECT PsA 1) [18]</td><td rowspan="4">Low</td><td>UPA 15mg OD ± csDMARD</td><td>429</td><td rowspan="4">24</td><td>14 (3.3)</td><td>5 (1.2)</td><td>1 (0.2)</td><td>4 (0.9)</td><td>1 (0.2)</td><td>0</td><td>0</td></tr><tr><td>UPA 30mg OD ± csDMARD</td><td>423</td><td>13 (3.1)</td><td>4 (0.9)</td><td>0</td><td>3 (0.7)</td><td>1 (0.2)</td><td>0</td><td>1 (0.2)</td></tr><tr><td>ADA 40mg Q2W ± csDMARD</td><td>429</td><td>16 (3.7)</td><td>3 (0.7)</td><td>0</td><td>0</td><td>3 (0.7)</td><td>2 (0.5)</td><td>2 (0.5)</td></tr><tr><td>PBO ± csDMARD</td><td>423</td><td>26 (6.1)</td><td>11 (2.6)</td><td>2 (0.5)</td><td>5 (1.2)</td><td>0</td><td>1 (0.2)</td><td>1 (0.2)</td></tr><tr><td rowspan="3">bDMARD-IR</td><td rowspan="3">Mease 2021 (SELECT PsA 2) [12]</td><td rowspan="3">low</td><td>UPA 15mg OD ± csDMARD</td><td>211</td><td rowspan="3">24</td><td>12 (5.7)</td><td>1 (0.5)</td><td>0</td><td>3 (1.4)</td><td>2 (0.9)</td><td>1 (0.5)</td><td>1 (0.5)</td></tr><tr><td>UPA 30mg OD ± csDMARD</td><td>218</td><td>18 (8.3)</td><td>6 (2.8)</td><td>2 (0.9)</td><td>8 (3.7)</td><td>2 (0.9)</td><td>0</td><td>0</td></tr><tr><td>PBO ± csDMARD</td><td>212</td><td>4 (1.9)</td><td>1 (0.5)</td><td>0</td><td>2 (0.9)</td><td>0</td><td>0</td><td>0</td></tr><tr><td rowspan="3">Mixed (NSAID / csDMARD / bDMARD-IR)</td><td rowspan="3">Mease 2022 (DEUC Phase 2) [11]</td><td rowspan="3">low</td><td>DEUC 6mg OD ± csDMARD</td><td>70</td><td rowspan="3">16</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>NR</td><td>0</td></tr><tr><td>DEUC 12mg OD ± csDMARD</td><td>67</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>NR</td><td>0</td></tr><tr><td>PBO ± csDMARD</td><td>66</td><td>1 (1.5)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>NR</td><td>1 (1.5)</td></tr><tr><td rowspan="4">Mixed (NSAID / csDMARD / bDMARD-IR)</td><td rowspan="4">Mease 2023 (BREP Phase 2) [10]</td><td rowspan="4">low</td><td>PBO ± csDMARD</td><td>67</td><td rowspan="4">16</td><td>1 (1.5)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>BREP 10mg OD ± csDMARD</td><td>31</td><td>0</td><td>0</td><td>0</td><td>1 (3.2)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>BREP 30mg OD ± csDMARD</td><td>60</td><td>3 (5.0)</td><td>2 (3.3)</td><td>0</td><td>1 (1.7)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>BREP 60mg OD ± csDMARD</td><td>59</td><td>1 (1.7)</td><td>0</td><td>0</td><td>0</td><td>2 (3.3)</td><td>0</td><td>0</td></tr></tbody></table>

ADA, adalimumab; bDMARD, biological DMARD; BREP: brepocitinib; csDMARD, conventional synthetic disease-modifying anti-rheumatic drug; DEUC: deucravacitinib; NSAID: non-steroidal anti-inflammatory drug; IR, insufficient response; OD, once daily; Q2W: every other week; UPA, upadacitinib; SAE: serious adverse event; SIE: serious infections event; OI: opportunistic infection; HZ: herpes zoster; NMSC: non-melanoma skin cancer; MACE: major adverse cardiac event; VTE: venous thromboembolism
Figure legends

<caption>Figure 1. PRISMA Flowchart of the efficacy and safety search of studies in PsA published 2018-2022.</caption>

<caption>Figure 2. Efficacy results of randomised controlled trials stratified by mode of action and disease domain.</caption>

Data from previous systematic literature research are also accounted for in this figure. *Different instruments used in studies. ACR, American College of Rheumatology Response; CD, cluster of differentiation; GUS, guselkumab; HAQ, Health Assessment Questionnaire Disability Index; IL, interleukin; JAK, Janus kinases; PASI, Psoriasis Area Severity Index; PDE4, phosphodiesterase-4; PsA-mSvdHS, Psoriatic Arthritis modified Sharp van der Heijde Score; RIS, risankizumab; TNF, tumour necrosis factor; UST, ustekinumab; IXE, ixekizumab; SEC, secukinumab; BKZ, bimekizumab; ADA, adalimumab; CTZ, certolizumab-pegol; ETA, etanercept; INF, infliximab; GOL: golimumab; TOFA, tofacitinib; UPA, upadacitinib; ABA, abatacept; APR, apremilast.

<figure><img src="image_3.png" /></figure>
<table><thead><tr><th rowspan="2">Target</th><th colspan="6">Disease Domain</th></tr><tr><th>Arthritis (ACR 70)</th><th>Physical function (HAQ)</th><th>Skin (PASI 75)</th><th>Enthesitis*</th><th>Dactylitis*</th><th>Radiographic damage (PzA-mSvdHS)</th></tr></thead><tbody><tr><td>TNF (ADA, CTZ, ETA, INF, GOL)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-17A (IXE, SEC)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-17A/F (BKZ)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-12/23 (UST)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-23-p19 (GUS, RIS)</td><td></td><td></td><td></td><td></td><td></td><td>GUS RIS</td></tr><tr><td>JAK (TOFA, UPA)</td><td></td><td></td><td></td><td>TOFA</td><td>UPA</td><td>TOFA</td></tr><tr><td>CD80/86 (ABA)</td><td></td><td></td><td></td><td></td><td></td><td>TOFA</td></tr><tr><td>PDE-4 (APR)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

<table><tr><td></td><td>Statistically superior compared to placebo (primary or secondary endpoints)</td><td></td><td>No difference compared to placebo</td></tr><tr><td></td><td>Superior compared to placebo; pre-specified post-hoc analysis</td><td></td><td>Not evaluated / reported</td></tr><tr><td></td><td>Not statistically different compared to placebo; numerically better results</td><td></td><td></td></tr></table>