Precision medicine and patient perspectives in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease (AID) with diverse clinical presentations and complex immunopathogenesis. Its chronic and variable course necessitates regular monitoring, yet optimal biomarkers for assessing disease activity are lacking. Neuropsychiatric SLE (NPSLE) is generally considered a severe manifestation but remains less well understood. Patients often experience fatigue, pain, and reduced health-related quality of life (HRQoL), which are not well captured by current clinical instruments. Since the early 21st century, most clinical trials in SLE have failed, leaving the treatment landscape behind other rheumatic diseases.

The overall aim of this thesis is to contribute to optimised surveillance and treatment evaluation, and to identify drug targets in patients with SLE, with a particular focus on NPSLE.

Paper I investigated psychometric properties of patient-reported experience of full health state (FHS) using the EQ-5D health questionnaire in two successful phase III randomised clinical trials (RCTs) of belimumab in SLE, i.e., BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384). FHS distinguished belimumab from placebo and responders from non-responders in this large SLE population (N=1665) from week 36 through week 52.

Paper II further explored whether EQ-5D FHS after trial intervention was associated with prevention of subsequent organ damage progression during nearly eight years of open-label extension follow-up (NCT00724867; NCT00712933) in a subset of the same patients as in Paper I (N=973). FHS heralded a reduced hazard of accruing organ damage after adjustments (HR: 0.60; 95% CI: 0.38-0.96), suggesting its potential as a useful PROM in SLE studies. This also supports optimising its HRQoL dimensions as a relevant treatment target in patients with SLE, alongside clinical and laboratory parameters.

Paper III investigated the transcriptome, expression quantitative trait loci (eQTLs), and levels of cytokines and autoantibodies in peripheral blood of 350 SLE patients from the European cross-sectional PRECISESADS cohort (NTC02890121). We replicated 18 gene modules of apparent relevance in the SLE patients by splitting the cohort into a discovery (60%) and a replication (40%) set, and we further validated 11 of those in 1760 SLE patients from two RCTs of tabalumab, ILLUMINATE-1 (NCT01196091) and ILLUMINATE-2 (NCT01205438). We assessed their dysregulation in comparison to 497 healthy controls (HC), corroborating the roles of interferon (IFN) and lymphocyte signalling, plasma cells, and inflammation in SLE. eQTL analysis revealed an association between rs7918733 T > C and reduced expression of CTSL, leading us to speculate that carriers of this polymorphism might exhibit a less favourable response to the proteasome inhibitor bortezomib, known for modulating CTSL expression.

Paper IV explored potential serum biomarkers for diagnosis and disease activity in 422 patients with SLE compared with 546 HC or 1223 patients with AIDs from the PRECISESADS project. CCL8 and CXCL13 levels were elevated in patients with active SLE, but not in those with inactive SLE, compared to HC. These levels were also higher in SLE patients compared to those with AIDs. The chemokine levels correlated, albeit weakly, with SLE Disease Activity Index 2000 (SLEDAI-2K) scores, suggesting their potential as biomarkers in SLE upon further validation.

Paper V examined the whole-blood transcriptome of 26 patients with active central nervous system (CNS) lupus, comparing them to 38 patients with active non-neuropsychiatric SLE and 497 HC from the PRECISESADS project. We identified gene dysregulation patterns related to innate and adaptive lymphoid immunity in active CNS lupus, stratifying the patients into two subgroups. One subgroup showed prominent upregulation of the IFN gene module and a greater anticipated response to type I IFN inhibition with anifrolumab (73% versus 20% of patients) based on in silico druggability analysis, advancing precision medicine in NPSLE.

Paper VI explored novel autoantibodies in relation to global and organ-specific disease activity in SLE. Plasma samples from a discovery cohort of 196 SLE patients (NTC02890121) and an independent validation cohort of 30 SLE patients (NCT02890134) as well as 110 HC and 84 HC, respectively, matched for age and sex, all from the European PRECISESADS project, were screened for IgG and IgA seroreactivity against 1609 human proteins using the i-Ome Discovery protein microarray. We validated 89 IgG and 66 IgA differentially abundant autoantibodies. Of these, IgG anti-LIN28A and IgG anti-IRF5, as well as IgA anti- IRF5, were positively associated with high disease activity (SLEDAI-2K ≥10) and negatively associated with Lupus Low Disease Activity State (LLDAS). These autoantibodies were highly prevalent across patient subgroups with activity in various organ systems, including the nervous system. The multiple identified IgA autoantibodies highlight a potential role of mucosal immunity in SLE pathogenesis.

List of scientific papers

I. Julius Lindblom, Alvaro Gomez, Alexander Borg, Sharzad Emamikia, Dimitris Ladakis, Joaquin Matilla, Martin Pehr, Flordelyn Cobar, Yvonne Enman, Emelie Heintz, Malin Regardt, Ioannis Parodis. EQ-5D-3L full health state discriminates between drug and placebo in clinical trials of systemic lupus erythematosus. Rheumatology (Oxford). 2021 Oct 2;60(10):4703-4716. https://doi.org/10.1093/rheumatology/keab080

II. Julius Lindblom, Sture Zetterberg, Sharzad Emamikia, Alexander Borg, Gunilla von Perner, Yvonne Enman, Emelie Heintz, Malin Regardt, David Grannas, Alvaro Gomez, Ioannis Parodis. EQ-5D full health state after therapy heralds reduced hazard to accrue subsequent organ damage in systemic lupus erythematosus. Front Med (Lausanne). 2022 Dec 20;9:1092325. https://doi.org/10.3389/fmed.2022.1092325

III. Julius Lindblom, Daniel Toro-Domínguez, Elena Carnero-Montoro, Lorenzo Beretta, Maria Orietta Borghi, Jessica Castillo, Yvonne Enman, PRECISESADS Clinical Consortium, Chandra Mohan, Marta E Alarcón- Riquelme, Guillermo Barturen, Ioannis Parodis. Distinct gene dysregulation patterns herald precision medicine potentiality in systemic lupus erythematosus. J Autoimmun. 2023 Apr;136:103025. https://doi.org/10.1016/j.jaut.2023.103025

IV. Julius Lindblom, Lorenzo Beretta, Maria Orietta Borghi, PRECISESADS Clinical Consortium, Marta E Alarcón-Riquelme, Ioannis Parodis. Serum profiling identifies CCL8, CXCL13, and IL-1RA as markers of active disease in patients with systemic lupus erythematosus. Front Immunol. 2023 Nov 30;14:1257085. https://doi.org/10.3389/fimmu.2023.1257085

V. Julius Lindblom, Guillermo Barturen, Lorenzo Beretta, Daniel Toro- Domínguez, Elena Carnero-Montoro, Maria Orietta Borghi, Jessica Castillo, Ellen Iacobaeus, Yvonne Enman, PRECISESADS Clinical Consortium, Chandra Mohan, Marta E. Alarcón-Riquelme, Dionysis Nikolopoulos, Ioannis Parodis. Innate and adaptive lymphoid immunity dysregulation may guide symptom attribution and predict responses to targeted therapies in neuropsychiatric systemic lupus erythematosus. [Manuscript]

VI. Julius Lindblom, Dionysis Nikolopoulos, Denis Lagutkin, Helena Idborg, Lorenzo Beretta, Maria Orietta Borghi, PRECISESADS Clinical Consortium, Janique M. Peyper, Guillermo Barturen, Per-Johan Jakobsson, Marta E. Alarcón-Riquelme, Natalia Sherina, Ioannis Parodis IgG and IgA seroreactivity to protein antigens associates with disease activity and determines organ manifestations in systemic lupus erythematosus: implications for autoantibodies targeting LIN28A, HMGN5, IRF5, and TGIF1 in two independent cohorts. [Manuscript]