Kaleb Michaud

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.

Objectives: Postmenopausal women with RA experience worsening functional decline, independent of disease activity. Estrogen replacement therapy (ERT) has been proposed to mitigate musculoskeletal deterioration, but its role in RA remains unclear. This study investigated the association between ERT use and physical function in postmenopausal women with RA. Methods: This longitudinal study analysed data from ‘Forward, the National Databank for Rheumatic Diseases’ (2000–22). Postmenopausal women with RA who initiated ERT were matched 1:1 to non-users based on menopause year or ERT initiation. The primary outcome was physical function, assessed using the HAQ. Generalized estimating equations (GEE) were used to evaluate the association between ERT and HAQ scores, adjusting for demographics, reproductive history, RA duration, comorbidities and medication use. Sensitivity analyses with propensity score matching were conducted. Results: A total of 8246 women were included, with 4123 ERT users matched to non-users. ERT use was associated with modestly improved HAQ scores (β = −0.02, 95% CI −0.03, −0.01; P < 0.001). Later menopause correlated with better function (β = −0.008 per year after menopause, 95% CI −0.03, −0.01; P < 0.001). Women initiating ERT within 5 years of menopause demonstrated greater benefits. Sensitivity analyses using propensity score adjustment confirmed these findings and revealed additional improvements in patient-reported outcomes. Conclusion: ERT use was modestly associated with improved physical function and other patient-reported outcomes in postmenopausal women with RA, with the greatest benefits seen in early postmenopausal initiation. No excess crude rates of cardiovascular or cancer events were observed. Further research is needed to determine the clinical implications of ERT in RA management.

Objective: This study describes baseline demographics, clinical characteristics and treatments of patients diagnosed with systemic lupus erythematosus (SLE) at the time of registration in the registries of the Lupus Federated Data Network (LupusNet). Methods: Data were collected from five SLE registries in four global regions: APLC (Asia Pacific), FORWARD (North America), RELESSER (Europe), GLADEL 2.0 and Almenara (Latin America). LupusNet uses a federated data network approach and a privacy-by-design method, where only aggregated results are shared. Demographics, disease activity (based on Physician Global Assessment (PGA) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores), accumulated damage (Systemic Lupus International Collaborating Clinics Damage Index) and treatment use data were mapped and harmonised using the Observational Medical Outcomes Partnership Common Data Model V.5.4. Results: A total of 10 370 patients were included in the analysis; of those, 3908 patients were in Asia Pacific, 3066 in North America, 1806 in Europe and 1590 in Latin America. The majority of patients were female (91%); the median (IQR) duration from SLE diagnosis to registry entry ranged from 5 (1–12) to 12 (6–19) years. Heterogeneity in disease activity was observed across registries based on mean (SD) SLEDAI-2K total (3.0 (4.1)−7.0 (7.4)) and PGA (0.4 (0.5)−1.2 (1.0)) scores. Across registries, SLE features most common were related to serologic activity (low complement and increased DNA binding (19%–47%)); other common clinical features included proteinuria and arthritis (4%–37%). Cataracts (4%–9%) were the most common characteristic related to accumulated damage. Glucocorticoids, antimalarials and immunosuppressants were the most commonly used treatments, with variations in their proportions observed across registries. Conclusions: These findings demonstrate significant heterogeneity in clinical characteristics and treatment patterns across the registries in LupusNet. By recognising regional differences, findings from LupusNet may help guide treatment approaches in SLE and optimise patient outcomes.

Background: Older age is a risk factor for serious infection (SI) associated with biologic or targeted synthetic DMARDs (b/tsDMARDs) use in rheumatoid arthritis (RA). Among older adults with RA, one-third are diagnosed at ⩾60 years (late-onset RA, LORA), while others are diagnosed earlier (young-onset RA, YORA). LORA is characterized by a more acute onset and heightened inflammatory burden due to age-related immune dysregulation. Whether RA onset age independently affects infection risk with b/tsDMARDs remains unclear. Objective: Evaluate SI risk in older adults with RA initiating b/tsDMARDs, stratified by RA onset age: LORA versus YORA. Design: Retrospective cohort study using prospectively collected registry data. Methods: From FORWARD, the National Databank for Rheumatic Diseases (2001–2019), we identified RA patients aged ⩾60 years who initiated (1) anti–TNF then (2) subsequent non-TNF b/tsDMARDs. Patients were categorized as LORA versus YORA and matched using kernel-based propensity scores. SI was defined as an infection requiring hospitalization, intravenous antibiotics, or death. Multivariable Cox models estimated the risk of SI in LORA versus YORA. Results: Among 1379 LORA and 2727 weighted YORA patients initiating anti-TNF therapy, the crude incidence of SI was 28.2 and 20.5 per 1000 person-years. In adjusted models, LORA was not associated with increased anti-TNF-related SI risk compared to YORA (HR 0.82, 95% CI 0.63–1.02). Among 198 LORA and 675 weighted YORA patients subsequently initiating non-TNF b/tsDMARDs, the crude incidence of SI was 17.3 versus 19.5 per 1000 person-years. In adjusted models, LORA was not associated with increased non-TNF related SI risk (aHR 0.81, 95% CI 0.31–2.12). Across cohorts, older age was independently associated with increased SI risk. For anti-TNF, prior SI and recent long-term glucocorticoid use, and for non-TNF, HAQ disability were also associated with SI. Conclusion: Age at RA onset was not independently associated with SI risk following b/tsDMARD initiation. Risk stratification should prioritize functional status and treatment history.

Objective: Despite advances in rheumatoid arthritis (RA) treatment, a considerable proportion of patients exhibit refractory disease, prompting the need for a comprehensive understanding of refractory RA. We aimed to analyze the burden and patient experiences associated with initiation of a third biologic or targeted synthetic disease‐modifying antirheumatic drugs (b/tsDMARDs) (BT3‐RA) in a large observational cohort. Methods: Data were obtained from participants with RA in the FORWARD Databank from 1999 to 2019. Participants, stratified into BT3‐RA and a comparator BT1‐RA (first initiation of a b/tsDMARD) cohorts, were matched based on key demographic and disease‐specific parameters. Demographics, patient‐reported outcomes (PROs), comorbidities, and health care interactions were assessed at initiation of first advanced therapy and at the time of meeting BT3‐RA criteria. Results: After matching, 1,384 participants were included in the study (692 each for BT3‐RA and BT1‐RA). The BT3‐RA cohort had worse PROs, greater comorbidity burden, and lower health satisfaction than BT1‐RA controls. Those with BT3‐RA had significantly higher odds of having a greater number of rheumatology visits in the previous six months than controls (>4 visits, 0–2 visit reference, odd ratio [OR] 3.8 [95% confidence interval (CI) 2.7–5.4], P < 0.001; 3–4 visits, 0–2 visit reference, OR 1.9 [95% CI 1.5–2.5]; P < 0.001). Those with BT3‐RA also had higher odds of concomitant glucocorticoid use (OR 1.5 [95% CI 1.2–2.0], P < 0.001) and gastrointestinal disorders (OR 1.5 [95% CI 1.1–1.9], P < 0.01). Conclusion: Exposure to three advanced RA therapies was associated with significant disease burden and unmet health care needs. These findings underscore the importance of well‐defined refractory criteria and the need for further investigation into this RA phenotype to identify targeted treatment strategies and ultimately improve outcomes. image

Objective: Rheumatoid arthritis (RA) features sporadic symptoms that intensify during flares, significantly affecting the quality of life. This study aimed to (1) characterize flare frequency and severity, (2) assess if short‐term changes in patient‐reported outcomes (PROs) signal RA flares, and (3) examine the relationship between passive smartphone data and self‐reported flares. Methods: Participants from FORWARD Databank completed PROs in two phases: conditional (flare questions triggered by PRO changes) and fixed (biweekly flare assessments). Passive smartphone data, including mobility and communication patterns, were collected alongside PROs and flares (binary outcome). Adjusting for demographic and seasonal confounders, we assessed associations between smartphone data, PROs, and flares using logistic generalized estimating equation models, multivariate analyses with backward selection, and kappa statistics. Results: The study included 292 adults with RA. In the conditional phase, 71% reported greater than or equal to one flare over 441 days (2.9 per participant), while 76% reported flares in the fixed phase over 172 days (3.7 per participant). Flares were linked to worse PROs. Increased mobility and longer texts were associated with fewer flares, whereas slower reaction times and shorter texts were associated with more flares. Flares were less common in the summer. Lower mobility radius (odds ratio [OR] 0.88), younger age, workdays, and lower educational level were associated with flare in the conditional phase. Worse patient global (OR 1.25) and pain (OR 1.30) were associated with flaring in the fixed phase. Conclusion: Integrating PROs with passive smartphone data demonstrates novel associations with flare occurrence and highlights the potential for future predictive modeling. These findings suggest that, with further validation, personalized algorithms may one day support the earlier recognition of flares and improved disease management.

Objective: To quantify the degree of financial distress and identify its determinants in adults with rheumatoid arthritis (RA) given the frequent prolonged use of expensive disease‐modifying therapies. Methods: We identified adults enrolled in the FORWARD databank with either RA or noninflammatory musculoskeletal disease (NIMSKD) completing the Functional Assessment of Chronic Illness Therapy–Comprehensive Score for Financial Toxicity (FACIT‐COST) questionnaire. In this cross‐sectional study, FACIT‐COST was analyzed as a continuous (higher score indicates less financial distress) and binary variable (presence of financial distress with threshold P < 0.001). Assessed as a binary outcome, financial distress was more frequent in participants with RA than participants with NIMSKD (29% vs 15%; unadjusted P < 0.001). Differences in financial distress by diagnosis persisted following multivariable adjustment. Among those with RA, determinants identified in multivariable models included depression (adjusted odds ratio 1.12; 95% confidence interval 1.09–1.16) and disease severity. Conclusion: Financial distress is prevalent in adults with RA and appears to be greatest in those with comorbidities, specifically depression, identifying a potential area for intervention. Notably, expensive biologic or targeted synthetic disease‐modifying antirheumatic drugs were not associated with FACIT‐COST scores.

Objective: To characterize disease burden among adults with rheumatoid arthritis (RA) by both shared epitope (SE) and anticitrullinated protein antibody (ACPA) status, and to determine how their responses to abatacept, tumor necrosis inhibitors, and Janus kinase inhibitors may differ. Methods: Using data from 2 observational cohorts (FORWARD, Veterans Affairs RA [VARA]), individuals with RA were classified by SE/ACPA status. Outcomes included disease activity (Patient Activity Scale II [PAS-II], Routine Assessment of Patient Index Data 3 [RAPID3], Disease Activity Score in 28 joints), Rheumatic Disease Comorbidity Index (RDCI), lifetime disease-modifying antirheumatic drug (DMARD) exposure, and healthcare usage. Differences by SE/ACPA classification were determined with multiple linear regression. Response to DMARD initiation was assessed with linear regression for continuous measures of disease activity and logistic regression for achieving a change as large as the minimum clinically important difference. Results: A total of 3243 individuals were included (FORWARD, n = 917; VARA n = 2326). RDCI among ACPA-negative individuals was lower than in ACPA-positive individuals in both cohorts (β [95% CI]: FORWARD −0.35 [−0.65 to −0.05], P = 0.02; VARA −0.35 [−0.63 to −0.08], P = 0.01). In FORWARD, there were significant differences in disease burden, including lower disease activity (PAS-II −0.77 [−1.10 to −0.44], P < 0.001), lower healthcare usage (rheumatology visits −0.18 [−0.35 to 0.0], P = 0.046), and higher DMARD counts (0.43 [0.02 to 0.85], P = 0.04) among SE+/ACPA+ individuals. ACPA+ abatacept initiators were more likely to experience clinically important improvements in PAS-II and DAS28, but RAPID3 was not significantly associated with abatacept response. Conclusion: Our results highlight important differences in disease burden by SE/ACPA status and suggest that ACPA status, rather than correlative SE status, may be the stronger predictor of abatacept response among individuals with RA.