Sign o’ the Times: PAISLEY Study Hits the High Notes in Lupus Management

Emerging data supporting TYK2 inhibition in active systemic lupus erythematosus (SLE) has been presented through the phase II PAISLEY study by Mosca et al published in Lupus Science & Medicine.1 In this 48-week, double-blind, randomized controlled trial, 363 adults with moderate–to–severe active SLE were assigned to placebo (n = 90) or deucravacitinib at doses of 3 mg twice daily (n=91), 6 mg twice daily (n=93), or 12 mg once daily (n = 89), in addition to standard background therapy.

Eligibility required fulfillment of SLICC classification criteria, seropositivity for ANA, anti-dsDNA and/or anti-Sm antibodies, and active disease with musculoskeletal and/or mucocutaneous involvement. Concomitant corticosteroids, antimalarials, and immunosuppressants were permitted, with a protocol-directed steroid taper.

The original primary endpoint (SRI-4 at week 32) and multiple secondary endpoints at week 48 were met in the 3 mg twice-daily group, with supportive signals at other doses. The current analysis focused on patient-reported outcomes (PROs) as exploratory endpoints.

PROS were assessed using a variety of quantitative tools. Pain was measured using an 11-point Numeric Rating Scale (NRS), fatigue via the PROMIS Fatigue 7a instrument, and health-related quality of life (HRQoL) using the 36-item Short Form Health Survey (SF-36). Clinically meaningful change thresholds were predefined: ≥1-point improvement in pain NRS, ≥4-point reduction in PROMIS Fatigue, and ≥2.5-point improvement in SF-36 physical or mental component scores.

At week 48, patients receiving deucravacitinib demonstrated greater mean reductions in pain scores (range, −2.2 to −2.3) than those on placebo (mean, −1.3). Fatigue scores improved by −5.9 to −7.3 points in the active arms versus −3.4 with placebo. Gains in SF-36 physical and mental component scores were also greater with deucravacitinib. Across all measures, a higher proportion of deucravacitinib-treated patients achieved clinically meaningful improvement.

Importantly, when results were stratified by composite clinical responder status (SRI-4 or BICLA), PRO improvements were found to be more common in responders but were also seen in some non-responders. Suggesting that symptom relief may occur independently of changes detected by standard disease activity indices.

The value of PROs in lupus research is increasingly recognized. Pain, fatigue, and impaired daily functioning are among the most disabling aspects of SLE yet have historically been secondary considerations in trial design. Our own research, published in The Journal of Rheumatology, demonstrated that certain subgroups have disproportionately worse baseline PROs, regardless of physician-assessed activity.2 These disparities risk obscuring unmet needs if PROs are not routinely measured and analysed.

PAISLEY adds to a growing body of evidence showing that interventions can deliver meaningful improvements in domains most important to patients, even when traditional endpoints are not met. This reinforces the argument for integrating PROs into core outcome sets for SLE and reporting them in stratified analyses to assess equity of benefit.

The past decade has seen incremental but important therapeutic advances in SLE, with approvals for belimumab, anifrolumab, and voclosporin. Each has targeted a specific pathogenic pathway — B-cell survival factors, type I interferon receptor signalling, and calcineurin activation, respectively. Deucravacitinib represents a further diversification, selectively inhibiting TYK2-mediated signalling of type I interferons, IL-12, and IL-23.

An oral, targeted therapy with a favorable selectivity profile would have clear advantages in patient convenience and potentially in tolerability. PAISLEY’s demonstration of broad PRO improvement aligns with recent trials such as TULIP-2 (anifrolumab) and AURORA (voclosporin), which have also begun to elevate the prominence of PROs in their assessments.

It should be noted that this was a post hoc analysis and thus not powered for formal statistical inference. The trial enrolled a moderate–severe population, limiting generalisability to milder phenotypes. Finally, PROs are inherently subjective and may be influenced by recall bias. Ongoing phase III studies will be critical to validating the efficacy, safety, and tolerability of deucravacitinib in a larger and more diverse SLE population. Inclusion of PROs as secondary endpoints, and ideally analysis by demographic and clinical subgroups, will be essential to fully understanding its clinical value.

In summary. PAISLEY strengthens the rationale for TYK2 inhibition as a novel therapeutic strategy in SLE and illustrates the importance of PROs in capturing treatment benefit. By showing that meaningful improvements in pain, fatigue, and HRQoL can occur independently of composite clinical response, it challenges us to broaden our definition of therapeutic success. If these findings are confirmed in phase III trials, deucravacitinib could represent both a mechanistic advance and a step toward more patient-centred lupus care — a true “sign of the times” for the field.

References

1. Mosca M, Arnaud L, Askanase A, et al. Deucravacitinib, an oral, selective, allosteric, tyrosine kinase 2 inhibitor, in patients with active SLE: efficacy on patient-reported outcomes in a phase II randomised trial. Lupus Sci Med. 2025; 1;12(1):e001517. doi: 10.1136/lupus-2025-001517.

2. Arnold J, Carter LM, Yusof MY, et al. DISCOVERY AND VALIDATION OF A NEW CLASSIFICATION OF ANA-RMDS THAT BETTER PREDICT LONG-TERM OUTCOMES COMPARED TO LEGACY DIAGNOSES. J Rheumatol. 2025 (52) No. Suppl 1, pp. 15-16. The Journal of Rheumatology.