Longitudinal Characterization of Nociplasticity in Systemic Lupus Erythematosus: A Nationwide Registry Study

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Abstract
Background: Nociplasticity is common in systemic lupus erythematosus (SLE), yet its longitudinal trajectory remain poorly characterized. Methods: Patients with SLE in the FORWARD Databank were classified as Minimal, Type 1, Type 2, or Mixed using the Polysymptomatic Distress Scale (PSD≥8) and the Systemic Lupus Activity Questionnaire (SLAQ) inflammatory domain score (≥2). Cross-sectional analyses (N=372) compared pain, function, disability, depression, organ damage, and medication use. Longitudinal analyses (n=301; median 3.7 years) characterized phenotype transitions using continuous-time Markov models and identified latent trajectory subgroups using joint group-based trajectory modeling (GBTM). Findings: At baseline, 29% were Minimal, 12% Type 1, 13% Type 2, and 47% Mixed. Functional impairment increased stepwise: SF-36 PCS worsened from 49.7 in Minimal to 30.0 in Mixed; PROMIS Pain Interference from 46.2 to 63.6 (both p<0.001). BILD organ damage was highest in Mixed (3.9 vs 2.6–2.9; p<0.001). Depression rose from 3% to 43% and opioid use reached 44% in Mixed. Longitudinally, Minimal and Mixed were persistent (mean duration 2.0 and 1.8 years; one-year retention 70%), while Type 1 and Type 2 were transient (∼0.5 years; retention 18% and 28%). Exit trajectories were asymmetric: Type 1 moved preferentially to Minimal (49% of exits), whereas Type 2 moved to Mixed (65%; p<0.001). Population-average PSD was nearly flat (+0.014 SD/year, p=0.07); opioid use declined to near zero in Minimal and Type 1 but remained high in Type 2 and Mixed. Joint GBTM identified four severity classes along a Minimal-to-Mixed diagonal, indicating that the two axes scale together longitudinally and that pure Type 1 and Type 2 are transient. Interpretation: Nociplastic phenotypes in SLE are persistent, severity-stratified, and associated with functional impairment, depression, cumulative damage, and sustained opioid burden. Type 1 and Type 2 are transient states with divergent exits: the former resolving, the latter progressing. Funding: Lupus Research Alliance Research in context: Evidence before this study: The Type 1 and Type 2 systemic lupus erythematosus (SLE) framework distinguishes inflammatory manifestations from symptoms associated with nociplastic pain and has provided a clinically meaningful approach to understanding the heterogeneity of SLE. Patient-reported instruments, including the polysymptomatic distress (PSD) scale combined with inflammatory symptom assessment, have enabled classification of these phenotypes in both research and clinical settings. A search of PubMed, Embase, and Web of Science (from database inception to June 01, 2026) using the terms “systemic lupus erythematosus”, “Type 1 SLE”, “Type 2 SLE”, “nociplastic pain”, “nociplasticity”, “polysymptomatic distress”, “trajectory”, and “transition”, together with screening of reference lists of relevant articles, identified studies describing cross-sectional phenotype distributions, intermittent and persistent Type 2 symptoms, and molecular differences between phenotypes. However, whether Type 1 and Type 2 phenotypes represent stable disease states or transient manifestations of a patient’s underlying longitudinal symptom trajectory is unknown. Added value of this study: This study analyzed prospectively collected patient-reported data from 301 SLE patients enrolled in the nationwide FORWARD registry over a median follow-up of 3.7 years to characterize the longitudinal behavior of Type 1 and Type 2 phenotypes. By combining continuous-time Markov modelling with group-based trajectory modelling, we distinguished threshold-defined phenotype transitions from underlying symptom trajectories. We found that Minimal and Mixed phenotypes were highly stable over time, whereas Type 1 and Type 2 phenotypes represented transient states with distinct transition patterns. Data-driven trajectories formed a stable severity continuum from Minimal to Mixed rather than persistent Type 1 and Type 2 classes. Higher nociplastic burden was also associated with sustained impairment in physical function, depression, medication burden, and opioid use. Implication of all the available evidence: These findings suggest that nociplastic symptom burden represents a persistent and clinically important component of SLE that is not fully captured by inflammatory disease activity alone. Routine assessment of nociplastic symptoms alongside inflammatory activity could improve longitudinal patient stratification and identify individuals who may benefit from combined immunomodulatory and symptom-directed management. Future studies should determine whether phenotype-informed treatment strategies improve long-term patient outcomes.

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