Jack Arnold, MBBS, MRCP, PhD, is a NIHR Academic Clinical Lecturer in Rheumatology at the University of Leeds and Leeds Teaching Hospitals NHS Trust. His research focuses on therapeutic precision in systemic autoimmune rheumatic diseases, particularly systemic lupus erythematosus (SLE) and related connective-tissue disorders.

Jack Arnold, MBBS, MRCP, PhD

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 

 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 

, demonstrated that certain subgroups have disproportionately worse baseline PROs, regardless of physician-assessed activity.

 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.

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. 

 2025; 1;12(1):e001517. doi: 10.1136/lupus-2025-001517. 

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. 

 2025 (52) No. Suppl 1, pp. 15-16. The Journal of Rheumatology.

Articles

The phase II PAISLEY study evaluated the efficacy of deucravacitinib, a TYK2 inhibitor, in patients with moderate-to-severe active systemic lupus erythematosus (SLE). The trial demonstrated significant improvements in patient-reported outcomes (PROs) such as pain, fatigue, and health-related quality of life, even when traditional clinical endpoints were not met. These findings highlight the importance of integrating PROs into SLE research to capture meaningful treatment benefits. Deucravacitinib's potential as a novel therapeutic strategy in SLE is reinforced, pending further validation in phase III trials.

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

 is becoming an increasingly important weapon in the rheumatologist’s and nephrologist’s arsenal for managing lupus nephritis, since initial efficacy was demonstrated in the original AURORA program. That pivotal trial showed that combining voclosporin with mycophenolate mofetil and low-dose glucocorticoids resulted in rapid and sustained reductions in proteinuria, alongside significantly higher complete renal response (CRR) rates at 52 weeks post-induction. These compelling findings led to voclosporin’s inclusion in key treatment guidelines, such as those from the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR), and the Kidney Disease: Improving Global Outcomes (KDIGO) initiative.

Despite this progress, concerns lingered about the long-term renal safety profile of voclosporin. As a calcineurin inhibitor, voclosporin shares a drug class with older agents such as tacrolimus known for their nephrotoxic potential, especially when administered at high doses or over extended periods. This has bred some caution, underscoring the need for detailed data on how voclosporin affects renal architecture beyond the initial treatment phase.

Enter AURORA 2, the follow-up study designed to shed light on voclosporin’s safety over a medium to longer term timeframe. In this analysis by Rovin et al, renal biopsies obtained at baseline were compared with repeat biopsies performed 18 months into treatment, involving 16 patients treated with voclosporin and 10 controls drawn from the original AURORA cohort. The 2 groups were largely comparable demographically, with a notable 60% of participants of Hispanic descent. Interestingly, the voclosporin group had a higher proportion of patients with class IV nephritis (81.3% versus 30%), reflecting a potentially more severe baseline disease burden.

Adverse events prompted early discontinuation in 2 control patients and 1 voclosporin treated patient. Histological endpoints in median activity and chronicity indices, according to the revised National Institutes of Health criteria, showed no significant differences between groups either at baseline or after 18 months. Furthermore, semiquantitative evaluations of vascular and tubular lesions revealed no emerging trends suggestive of voclosporin-induced nephrotoxicity.

The authors conclude that voclosporin, when administered over an 18-month period, does not appear to increase nephrotoxicity or accelerate the progression of pre-existing kidney damage. This provides reassurance for clinicians aiming to balance efficacy and safety in treating lupus nephritis, particularly given the drug’s mechanistic overlap with earlier calcineurin inhibitors.

Nonetheless, several caveats limit the generalisability of these findings. The relatively small sample size limits the robustness and generalizability of the conclusions, and there may be selection bias as patients who poorly tolerated the drug in the initial AURORA trial likely did not continue into this extension study. Moreover, the underrepresentation of patients of African and South Asian ancestry, a demographic with a high burden of lupus nephritis, limits the applicability of these results to some of the highest-risk populations. Finally, while 18 months marks an important milestone, longer-term follow-up is imperative to fully characterize voclosporin’s renal safety profile.

In summary, AURORA 2 delivers encouraging early data suggesting that voclosporin’s safety profile holds steady beyond one year of treatment. This study represents the first double-blind investigation to directly address the long-term histopathologic impact of voclosporin and lays a valuable foundation for future research. As the rheumatology and nephrology communities continue to seek safer, more effective therapies for lupus nephritis, these findings light the way toward confident use of voclosporin, illuminating a path forward in managing lupus nephritis.

Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. 

. 2021  29;397(10289):2070-2080. doi: 10.1016/S0140-6736(21)00578-X. Erratum in: Lancet. 2021 May 29;397(10289):2048. doi: 10.1016/S0140-6736(21)01160-0. 

Saxena A, Ginzler EM, Gibson K, et al. Safety and Efficacy of Long-Term Voclosporin Treatment for Lupus Nephritis in the Phase 3 AURORA 2 Clinical Trial. 

 2024 Jan;76(1):59-67. doi: 10.1002/art.42657. Epub 2023 Sep 15. 

Voclosporin has emerged as a significant treatment for lupus nephritis, demonstrating efficacy in combination with mycophenolate mofetil and glucocorticoids. The AURORA 2 study evaluated its long-term safety, revealing no significant nephrotoxicity over 18 months. Despite promising results, limitations include a small sample size and underrepresentation of high-risk demographics, such as African and South Asian populations. These findings support voclosporin's continued use, but further research is needed to confirm its safety profile over longer periods and across diverse patient groups.

Shedding Light on Voclosporin for Lupus: AURORA 2 Finds No Increased Nephrotoxicity at 18 Months

Anxiety and depression are 2 of the most common conditions encountered by budding physicians irrespective of their primary specialty. Within rheumatology, these conditions can negatively impact the patient experience at several junctures. They can limit engagement with healthcare or treatment leading to later diagnosis, poor treatment adherence, and resultant poor disease control with associated negative sequelae. The clinical presentation of anxiety and depression can also overlap with features of active rheumatic disease, exacerbating the symptom burden experienced by patients.

 Within the paradigm of systemic lupus erythematosus (SLE), fatigue symptoms can be more prominent and can worsen with a coexistent diagnosis of depression.

 Furthermore, poorly treated depression and anxiety features can become a significant confounder when assessing outcome measures such as the Visual Analogue Scales (VAS), Short Form 36, FACIT-Fatigue, and other patient reported outcome scores.

A recent Chinese observational single center cross-sectional study assessed the impact of SLE disease activity on the prevalence of anxiety or depressive features.

 This study enrolled 325 patients over the age of 18 with SLE as defined by the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. Key exclusion criteria were a previous diagnosis of anxiety/depression or other psychiatric illness, major organ pathology, and those with a history of substance abuse. Depressive features were assessed using the Patient Health Questionnaire 9 (PHQ-9) and anxiety features were assessed using the 7 item General Anxiety Disorders Scale (GAD-7). SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI).

Within the 325 patients enrolled to the study, 61.5% had a PHQ-9 score compatible with significant depression and 54.4% had a GAD-7 score compatible with significant anxiety. Patients with significant depressive/anxiety features had significantly higher SLEDAI scores than their counterparts (p=0.001) and had significantly higher rates of musculoskeletal and neuropsychiatric involvement. This is concordant with previous work which has shown musculoskeletal features to be key drivers of the patient experience in SLE.

Key confounders were mostly similar between the anxiety/depression and non-anxiety/depression groups except for household income. Those with a low household income defined as >50,000 Renminbi (RMB) had higher rates of depression than those with a higher income (p=0.005).

The authors used receiver operating characteristic (ROC) curve analysis to assess the utility of SLEDAI as a predictor of depression or anxiety in SLE patients. The optimal cut-off of SLEDAI >8.5 demonstrated a sensitivity of 50.5% and specificity of 78.4% in predicting depression (AUC 0.660, p <0.001). This cut-off had a sensitivity of 54.2% and specificity of 78.4% in predicting significant anxiety (AUC 0.684, p <0.001).

There are several limitations to this study; the authors identify the lack of longitudinal data as a key factor. The lack of ethnic diversity within the cohort is another important consideration. As with most SLE research, the chosen disease activity score has several additional limitations. SLEDAI scores features such as arthritis, rash, and oral ulceration based on the presence or absence of these features. Therefore, a patient with a severe rash encompassing >50% of their body surface area scores the same as one with a mild malar rash. Additionally, a patient with 2 synovitic joints scores the same as one with 12 synovitic joints, despite their very different clinical presentation. Therefore, the use of an alternative measurement such as the British Isles Lupus Assessment Group (BILAG-2004) score might allow for greater fidelity when describing a patient’s individual symptom burden.

 Exclusion of those with a pre-existing diagnosis of anxiety/depression in this study is understandable but given the widespread prevalence of these diagnoses, it may limit the generalizability of these findings in the rheumatology clinic.

This study does provide welcome data on an underappreciated and often poorly addressed feature of long term SLE management. The association between high disease activity and worsening depressive/anxiety features would seem obvious; however, this paper provides welcome quantitative evidence to the fact. Holistic care in SLE is critical and the mental health sequelae of high disease activity require addressing in a similar manner to the musculoskeletal or mucocutaneous features.

1. Arnaud L, Mertz P, Amoura Z, Voll RE, Schwarting A, Maurier F, et al. Patterns of fatigue and association with disease activity and clinical manifestations in systemic lupus erythematosus. Rheumatology [Internet]. 2021 Jun 18 [cited 2021 Jul 7];60(6):2672–7. Available from: https://pubmed.ncbi.nlm.nih.gov/33175957/

2. Figueiredo-Braga M, Cornaby C, Cortez A, Bernardes M, Terroso G, Figueiredo M, et al. Depression and anxiety in systemic lupus erythematosus: The crosstalk between immunological, clinical, and psychosocial factors. Medicine (Baltimore) [Internet]. 2018 Jul 1 [cited 2023 Jan 17];97(28). Available from: /pmc/articles/PMC6076116/

3. Meacock R, Dale N, Harrison MJ. The humanistic and economic burden of systemic lupus erythematosus: A systematic review [Internet]. Vol. 31, PharmacoEconomics. Springer; 2013 [cited 2021 Jul 2]. p. 49–61. Available from: https://link.springer.com/article/10.1007/s40273-012-0007-4

4. Liao J, Kang J, Li F, Li Q, Wang J, Tang Q, et al. A cross-sectional study on the association of anxiety and depression with the disease activity of systemic lupus erythematosus. BMC Psychiatry [Internet]. 2022 Dec 1 [cited 2022 Oct 6];22(1):591. Available from: https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-022-04236-z

5. Chaigne B, Chizzolini C, Perneger T, Trendelenburg M, Huynh-Do U, Dayer E, et al. Impact of disease activity on health-related quality of life in systemic lupus erythematosus - a cross-sectional analysis of the Swiss Systemic Lupus Erythematosus Cohort Study (SSCS). BMC Immunol [Internet]. 2017 Mar 28 [cited 2022 Mar 18];18(1). Available from: https://pubmed.ncbi.nlm.nih.gov/28351341/

6. Carter LM, Gordon C, Yee CS, Bruce I, Isenberg D, Skeoch S, et al. Easy-BILAG: a new tool for simplified recording of SLE disease activity using BILAG-2004 index. Rheumatology (Oxford) [Internet]. 2022 Oct 6 [cited 2023 Jan 17];61(10):4006. Available from: /pmc/articles/PMC9536795/

Anxiety and depression can limit engagement with healthcare or treatment leading to later diagnosis, poor treatment adherence, and poor disease control with associated negative sequelae. 

Quantifying the Association Between Anxiety and Depressive Features and High Disease Activity Scores in SLE 

Unfortunately, a substantial portion of pregnancies in lupus patients are complicated by an adverse pregnancy outcome (APO). This can include preterm delivery, intrauterine growth restriction and foetal mortality. Given the high prevalence of APOs in this group, there has been considerable interest in predicting those at the greatest risk of negative outcomes, to permit enhanced observation and intervention in these patients. The EUREKA algorithm was developed to predict obstetric risk in patients with different subsets of antiphospholipid antibodies and generated significant discourse.

 More recently, machine learning (ML) methodology has been applied by Fazzari et al to a large observational cohort (PROMISSE) to identify additional predictors of APO.

The PROMISSE cohort enrolled 385 pregnant women with mild to moderate SLE both with and without antiphospholipid antibody positivity. They collected data on pregnancy outcomes between 2003 and 2013 from 9 North American sites. Exclusion criteria included a daily prednisone dose >20mg, a urinary PCR >1000, serum creatinine >1.2 mg/dL, type 1 or 2 diabetes mellitus, or systemic hypertension.

Previous work in this cohort has linked increased levels of the complement activation products Bb and sC5b-9 to higher rates of APOs.

 More recently, Fazzari et al have applied several ML approaches to the PROMISSE cohort and compared these to logistic regression modelling to identify predictors of APO in SLE patients.

Approaches were trialled including least absolute shrinkage and selection operator (LASSO), random forest, neural network, support vector machines (SVM-RBF) gradient boosting, and SuperLearner. These were compared via area under the receiver operating characteristic (AUROC). Forty-one predictors assessed during routine care of patients with SLE were used to build these models.

Fazzari et al identified several risk factors for APO including high disease activity, lupus anticoagulant positivity, thrombocytopenia, and antihypertensive use. When comparing AUROC, the SuperLearner package had the numerically superior area under the curve (AUC) (0.78). However, this was not significantly different to LASSO, SVM-RBF, or random forest (AUC 0.77 in all cases).

Weaknesses of the PROMISSE cohort are its exclusion of high disease activity SLE patients and those with a systemic blood pressure of > 140/90mmHg. Additionally, the proportion of patients with APOs within the cohort was low (18.4%), likely in part related to the stringent exclusion criteria. A recent retrospective Portuguese study of which did not exclude high disease activity of lupus nephritis patients identified a far higher rate of APO (41.4%) in their SLE cohort.

 Indeed, Ntali et al recently demonstrated reduced APOs in SLE patients with low disease activity in a prospective observational study.

 Application of these models in a higher disease burden cohort would therefore be desirable.

This work demonstrates the utility of ML in aiding clinical risk stratification within a complex patient cohort. The utilization of standard clinical variables and comparison of several ML techniques are substantial strengths of this work. However, further validation in external cohorts is desirable. The application of ML methodology in risk stratification within SLE may provide better clarity in a heterogeneous patient cohort. Additionally, in the future, similar methodological approaches could be trialled across the autoimmune connective tissue disease spectrum to provide better prognostic information to patients at diagnosis, irrespective of their diagnostic label.

Pregnolato F, Gerosa M, Raimondo MG, Comerio C, Bartoli F, Lonati PA, et al. EUREKA algorithm predicts obstetric risk and response to treatment in women with different subsets of anti-phospholipid antibodies. Rheumatology (Oxford) [Internet]. 2021 Mar 1 [cited 2022 Oct 4];60(3):1114–24. Available from: https://pubmed.ncbi.nlm.nih.gov/32441742/

Fazzari MJ, Guerra MM, Salmon J, Kim MY. Adverse pregnancy outcomes in women with systemic lupus erythematosus: can we improve predictions with machine learning? Lupus Sci Med [Internet]. 2022 [cited 2022 Sep 21];9:769. Available from: http://lupus.bmj.com/

Kim MY, Guerra MM, Kaplowitz E, Laskin CA, Petri M, Branch DW, et al. Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies. Ann Rheum Dis [Internet]. 2018 Apr 1 [cited 2022 Oct 4];77(4):549–55. Available from: https://ard.bmj.com/content/77/4/549

Braga A, Barros T, Faria R, Marinho A, Carvalheira G, Rocha G, et al. Systemic lupus erythematosus and pregnancy: A retrospective single-center study of 215 pregnancies from Portugal. https://doi.org/101177/09612033211050340 [Internet]. 2021 Oct 24 [cited 2022 Oct 4];30(13):2165–75. Available from: https://journals.sagepub.com/doi/10.1177/09612033211050340?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed

Ntali S, Nikolopoulos D, Pantazi L, Emmanouilidou E, Papagoras C, Fanouriakis A, et al. Remission or low disease activity at pregnancy onset are linked to improved foetal outcomes in women with systemic lupus erythematosus: results from a prospective observational study. Clin Exp Rheumatol [Internet]. 2022 Aug 25 [cited 2022 Oct 4];40(9). Available from: https://pubmed.ncbi.nlm.nih.gov/35084312/

Findings demonstrate the utility of machine learning in aiding clinical risk stratification within a complex patient cohort. 