Distinct transcriptome architectures underlying lupus establishment and exacerbation.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving multiple immune cells. To elucidate SLE pathogenesis, it is essential to understand the dysregulated gene expression pattern linked to various clinical statuses with a high cellular resolution. Here, we conducted a large-scale transcriptome study with 6,386 RNA sequencing data covering 27 immune cell types from 136 SLE and 89 healthy donors. We profiled two distinct cell-type-specific transcriptomic signatures: disease-state and disease-activity signatures, reflecting disease establishment and exacerbation, respectively. We then identified candidate biological processes unique to each signature. This study suggested the clinical value of disease-activity signatures, which were associated with organ involvement and therapeutic responses. However, disease-activity signatures were less enriched around SLE risk variants than disease-state signatures, suggesting that current genetic studies may not well capture clinically vital biology. Together, we identified comprehensive gene signatures of SLE, which will provide essential foundations for future genomic and genetic studies.

Using Computer Vision to Improve Endoscopic Disease Quantification in Therapeutic Clinical Trials of Ulcerative Colitis.

BACKGROUND & AIMS: Endoscopic assessment of ulcerative colitis (UC) typically reports only the maximum severity observed. Computer vision methods may better quantify mucosal injury detail, which varies among patients. METHODS: Endoscopic video from the UNIFI clinical trial (A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis) comparing ustekinumab and placebo for UC were processed in a computer vision analysis that spatially mapped Mayo Endoscopic Score (MES) to generate the Cumulative Disease Score (CDS). CDS was compared with the MES for differentiating ustekinumab vs placebo treatment response and agreement with symptomatic remission at week 44. Statistical power, effect, and estimated sample sizes for detecting endoscopic differences between treatments were calculated using both CDS and MES measures. Endoscopic video from a separate phase 2 clinical trial replication cohort was performed for validation of CDS performance. RESULTS: Among 748 induction and 348 maintenance patients, CDS was lower in ustekinumab vs placebo users at week 8 (141.9 vs 184.3; P < .0001) and week 44 (78.2 vs 151.5; P < .0001). CDS was correlated with the MES (P < .0001) and all clinical components of the partial Mayo score (P < .0001). Stratification by pretreatment CDS revealed ustekinumab was more effective than placebo (P < .0001) with increasing effect in severe vs mild disease (-85.0 vs -55.4; P < .0001). Compared with the MES, CDS was more sensitive to change, requiring 50% fewer participants to demonstrate endoscopic differences between ustekinumab and placebo (Hedges' g = 0.743 vs 0.460). CDS performance in the JAK-UC replication cohort was similar to UNIFI. CONCLUSIONS: As an automated and quantitative measure of global endoscopic disease severity, the CDS offers artificial intelligence enhancement of traditional MES capability to better evaluate UC in clinical trials and potentially practice.

An Elevated IL10 mRNA Combined with Lower TNFA mRNA Level in Active Rheumatoid Arthritis Peripheral Blood.

We aimed to investigate the expression of pro-inflammatory cytokine genes TNFA, IL6, IL12B, IL23, IL18 and immunoregulatory genes FOXP3, TGFB1, and IL10 in the peripheral blood of patients with rheumatoid arthritis (RA) at messenger ribonucleic acid (mRNA) level. The total RNA was isolated from peripheral blood samples. Real-time quantitative PCR was used to perform TaqMan-based assays to quantify mRNAs from 8 target genes. IL23A was upregulated (1.7-fold), whereas IL6 (5-fold), FOXP3 (4-fold), and IL12B (2.56-fold) were downregulated in patients compared to controls. In addition, we found a strong positive correlation between the expression of FOXP3 and TNFA and a moderate correlation between FOXP3 and TGFB1. These data showed the imbalance of the T helper (Th) 1/Th17/ T regulatory (Treg) axis at a systemic level in RA. In cases with active disease, the IL10 gene expression was approximately 2-fold higher; in contrast, the expression of FOXP3 was significantly decreased (3.38-fold). The main part of patients with higher disease activity expressed upregulation of IL10 and downregulation of TNFA. Different disease activity cohorts could be separated based on IL10, TNFA and IL12B expression combinations. In conclusion, our results showed that active disease is associated with an elevated IL10 and lower TNFA mRNA level in peripheral blood cells of RA patients.

Hyperactivation and enhanced cytotoxicity of reduced CD8+ gamma delta T cells in the intestine of patients with Crohn's disease correlates with disease activity.

BACKGROUND AND AIMS: We aimed to investigate the immune characteristics of intestinal CD8+ gamma delta T (CD8+ γδ T) cells in Crohn's disease (CD) and their correlation with disease activity. METHODS: The study cohorts included 21 CD patients and 21 healthy individuals. CD8+ γδ T cells were isolated from human ileal mucosa for detection by flow cytometry. The activation or inhibition status of cells was detected by detecting the expression of activation marker HLA-DR and the immunosuppressive molecule PD-1 on cells. The cytotoxicity of cells was assessed by detecting the expression of cytotoxic molecules (Perforin, Granzyme B, and TRAIL) in cells. Ratios of investigated cells were calculated as prediction factors by receiver operating characteristic curve (ROC) analysis. RESULTS: The study revealed a reduction in intestinal CD8+ γδT cells among active CD patients, with a more pronounced reduction observed in moderately active patients compared to mildly active patients. Moreover, active CD patients exhibited heightened activation levels in their intestinal CD8+ γδT cells, whereas the activation was comparatively weakened in moderately active patients compared with mildly active patients. Additionally, the cytotoxicity of intestinal CD8+ γδT cells was enhanced solely in mildly active patients, while it was impaired in moderately active patients compared with mildly active patients. Furthermore, HLA-DR+ CD8+ γδT cell ratio, CD8+ γδT ratio, and CD8+ γδT count were identified as indicators in the diagnosis of active CD. Meanwhile, the ratios of Granzyme B+ CD8+ γδT cell and Perforin+ CD8+ γδT cell were identified as indicators that distinguish mildly moderately active CD cases. CONCLUSIONS: Intestinal CD8+ γδT was reduced in active CD patients, but their activation and cytotoxicity were enhanced. However, with increased disease activity, intestinal CD8+ γδ T cells became dysfunctional. CD-specific perturbations observed in various phenotypic markers in CD8+ γδ T cells can be used as indicators to assist in diagnosing CD patients.

Targeted metabolomics combined with machine learning to identify and validate new biomarkers for early SLE diagnosis and disease activity.

BACKGROUND: The early diagnosis of systemic lupus erythematosus (SLE) and the assessment of disease activity progression remain a great challenge. Targeted metabolomics has great potential to identify new biomarkers of SLE. METHODS: Serum from 44 healthy participants and 89 SLE patients were analyzed using HM400 high-throughput targeted metabolomics. Machine learning (ML) with seven learning models and trained the model several times iteratively selected the two best prediction model in a competitive way, which were independent validated by enzyme-linked immunosorbent (ELISA) with 90 SLE patients. RESULTS: In this study, 146 differential metabolites, most of them organic acids, amino acids, and bile acids, were detected between patients with initial SLE and healthy participants, and 8 potential biomarkers were found by intersection of ML and statistics (area under the curve [AUC] > 0.95) showing a significant positive correlation with clinical indicators. In addition, we identified and validated 2 potential biomarkers for SLE classification (P < 0.05, AUC > 0.775; N-Methyl-L-glutamic acid, L-2-aminobutyric acid) showing a significant correlation with the SLE Disease Activity Index. These differential metabolites were mainly involved in metabolic pathways, amino acid biosynthesis, 2-oxocarboxylic acid metabolism and other pathways. CONCLUSION: This study indicated that the tricarboxylic acid cycle might be associated with SLE drug therapy. We identified 8 diagnostic models biomarkers and 2 biomarkers that could be used to identify initial SLE and distinguish different activity degree, which will promote the development of new tools for the diagnosis and evaluation of SLE.

CLADIN- CLADribine and INnate immune response in multiple sclerosis - A phase IV prospective study.

Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS), but its mechanism of action and its effects on innate immune responses in unknown. This study is a prospective Phase IV study of 41 patients with RRMS, and aims to investigate the mechanism of action of cladribine on peripheral monocytes, and its impact on the P2X7 receptor. There was a significant reduction in monocyte count in vivo at week 1 post cladribine administration, and the subset of cells being most impacted were the CD14lo CD16+ 'non-classical' monocytes. Of the 14 cytokines measured in serum, CCL2 levels increased at week 1. In vitro, cladrabine induced a reduction in P2X7R pore as well as channel activity. This study demonstrates a novel mechanism of action for cladribine. It calls for studying potential benefits of cladribine in progressive forms of MS and other neurodegenerative diseases where innate immune related inflammation is implicated in disease pathogenesis.

First validation of the childhood lupus low disease activity state (cLLDAS) definition in a real-life longitudinal cSLE cohort.

OBJECTIVES: To validate the childhood lupus low disease activity state (cLLDAS) definition in cSLE by describing differences in time to reach first adult LLDAS (aLLDAS) versus cLLDAS. Secondly, to analyse positive and negative predictors for maintaining cLLDAS for at least 50% of follow-up time (cLLDAS-50) and for the occurrence of damage. METHODS: Prospective longitudinal data from a cSLE cohort were analysed. Used definitions were: aLLDAS according to Franklyn, cLLDAS by cSLE treat-to-target (T2T) Task Force, disease activity score by SLEDAI -2 K and damage by SLICC damage index. RESULTS: Fifty cSLE patients were studied, with a median follow-up of 3.1 years. Each patient reached aLLDAS and cLLDAS at least once. Mean time to reach first aLLDAS/cLLDAS was 8.2/9.0 months, respectively. For 22/42 patients the mean steroid-dose related delay to reach first cLLDAS was 6.2 months. 58% of patients were able to maintain cLLDAS-50. Time to first cLLDAS (OR 0.8, p = 0.013) and higher number of flares (OR 0.374, p = 0.03) were negative predictors to maintain cLLDAS-50. Damage occurred in 34% of patients (23.5% steroid-related), in 64.7% within one year after diagnosis. African/Afro-Caribbean ethnicity, neuropsychiatric involvement and ever use of a biologic were significant predictors for damage. CONCLUSION: Time to reach cLLDAS in cSLE differs from time to (a)LLDAS, which validates the new cLLDAS definition. Attaining cLLDAS-50 was difficult in real-life. This cohort shows the high risk for early damage in cSLE. T2T with earlier focus on steroid-tapering and starting steroid-sparing drugs seems important to prevent (steroid-related) damage in cSLE.

Proteomic profile of extracellular vesicles from plasma and CSF of multiple sclerosis patients reveals disease activity-associated EAAT2.

BACKGROUND AND OBJECTIVES: There is an urgent need to discover blood-based biomarkers of multiple sclerosis (MS) to better define the underlying biology of relapses and monitor disease progression. The main goal of this study is to search for candidate biomarkers of MS relapses associated with circulating extracellular vesicles (EVs), an emerging tool for biomarker discovery. METHODS: EVs, purified from unpaired plasma and CSF samples of RRMS patients by size-exclusion chromatography (SEC), underwent proteomic analysis to discover novel biomarkers associated with MS relapses. The candidate biomarkers of disease activity were detected by comparison approach between plasma- and CSF-EV proteomes associated with relapses. Among them, a selected potential biomarker was evaluated in a cohort of MS patients, using a novel and highly reproducible flow cytometry-based approach in order to detect low abundant EV subsets in a complex body fluid such as plasma. RESULTS: The proteomic profiles of both SEC-purified plasma EVs (from 6 patients in relapse and 5 patients in remission) and SEC-purified CSF EVs (from 4 patients in relapse and 3 patients in remission) revealed a set of proteins associated with MS relapses significant enriched in the synaptic transmission pathway. Among common proteins, excitatory amino-acid transporter 2, EAAT2, responsible for the majority of the glutamate uptake in CNS, was worthy of further investigation. By screening plasma samples from 110 MS patients, we found a significant association of plasma EV-carried EAAT2 protein (EV-EAAT2) with MS relapses, regardless of disease-modifying therapies. This finding was confirmed by investigating the presence of EV-EAAT2 in plasma samples collected longitudinally from 10 RRMS patients, during relapse and remission. Moreover, plasma EV-EAAT2 levels correlated positively with Expanded Disability Status Scale (EDSS) score in remitting MS patients but showed a negative correlation with age in patients with secondary progressive (SPMS). CONCLUSION: Our results emphaticize the usefulness of plasma EVs as a source of accessible biomarkers to remotely analyse the CNS status. Plasma EV-EAAT2 showed to be a promising biomarker for MS relapses. Further studies are required to assess the clinical relevance of this biomarker also for disability progression independent of relapse activity and transition from RRMS towards SPMS.

Lower body mass and lower adiposity are associated with differential responses to two treatment strategies for rheumatoid arthritis.

PURPOSE: To determine if body mass index (BMI) and adipokine levels identify rheumatoid arthritis (RA) patients most likely to benefit from initiation of tumour necrosis factor inhibitors (TNFi) after methotrexate inadequate response. METHODS: This is a secondary analysis of the Rheumatoid Arthritis Comparison of Active Treatments (RACAT) trial and the (TEAR) trial. Both studies compared treatment strategies starting with conventional disease-modifying anti-rheumatic drugs (DMARDs) (triple therapy) versus etanercept plus methotrexate. We compared response rates between TNFi and triple therapy among patients with different BMI. Adipokines were measured at enrolment and associations with treatment response were examined using regression, adjusting for age, sex, BMI and baseline disease activity. RESULTS: In RACAT (n=306), participants who were normal/underweight were more likely to benefit from TNFi versus triple therapy, with greater change in Disease Activity Score in 28 and greater ACR20 response (ACR 20: 64% vs 23%, p=0.001). In contrast, overweight/obese participants had similar response to TNFi versus triple therapy (p-for-interaction=0.001). Similarly, but modest patterns were observed in TEAR (n=601; ACR20: 67% vs 52%, p=0.05). In RACAT, adipokine scores consistent with lower adiposity also predicted greater response to TNFi (ACR20: 58% vs 37%, p=0.01) with better model fit compared with BMI alone. CONCLUSIONS: Lower BMI and evidence of lower adiposity based on adipokine profiles were associated with a superior response to TNFi compared with triple therapy. There was no difference between treatments among overweight/obese participants. The results support TNFi being a particularly important therapeutic among normal/underweight patients, with implications for clinical decisions and trial design.

Comorbidity clusters in patients with rheumatoid arthritis identify a patient phenotype with a favourable prognosis.

OBJECTIVES: We aimed to cluster patients with rheumatoid arthritis (RA) based on comorbidities and then examine the association between these clusters and RA disease activity and mortality. METHODS: In this population-based study, residents of an eight-county region with prevalent RA on 1 January 2015 were identified. Patients were followed for vital status until death, last contact or 31 December 2021. Diagnostic codes for 5 years before the prevalence date were used to define 55 comorbidities. Latent class analysis was used to cluster patients based on comorbidity patterns. Standardised mortality ratios were used to assess mortality. RESULTS: A total of 1643 patients with prevalent RA (72% female; 94% white; median age 64 years, median RA duration 7 years) were studied. Four clusters were identified. Cluster 1 (n=686) included patients with few comorbidities, and cluster 4 (n=134) included older patients with 10 or more comorbidities. Cluster 2 (n=200) included patients with five or more comorbidities and high prevalences of depression and obesity, while cluster 3 (n=623) included the remainder. RA disease activity and survival differed across the clusters, with cluster 1 demonstrating more remission and mortality comparable to the general population. CONCLUSIONS: More than 40% of patients with prevalent RA did not experience worse mortality than their peers without RA. The cluster with the worst prognosis (<10% of patients with prevalent RA) was older, had more comorbidities and had less disease-modifying antirheumatic drug and biological use compared with the other clusters. Comorbidity patterns may hold the key to moving beyond a one-size-fits-all perspective of RA prognosis.

Risk of flare and damage accrual after tapering glucocorticoids in modified serologically active clinically quiescent patients with systemic lupus erythematosus: a multinational observational cohort study.

OBJECTIVES: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE). METHODS: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred. RESULTS: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day. CONCLUSIONS: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients.

Autoreactive B cells remain active despite clinical disease control in rheumatoid arthritis.

BACKGROUND: Autoimmune diseases (AIDs) are frequently hallmarked by the presence of autoreactive B cell responses which are involved in disease pathogenesis. However, the dynamics of such responses and their relation to clinical disease activity in humans is poorly understood. Rheumatoid arthritis (RA), a prototypic chronic AID, is hallmarked by B cell responses directed against citrullinated proteins. OBJECTIVE: To determine the relation between the activity of the anti-citrullinated protein antibody (ACPA) B cell response and clinical disease activity in ACPA+ patients with RA. METHODS: Expression of B cell activation markers by ACPA+, tetanus toxoid (TT)+ and ACPA- memory B cells (MBCs) from peripheral blood of ACPA+ RA patients receiving different treatments was analyzed by flow cytometry. Results were correlated to clinical disease activity. RESULTS: Compared to TT+ and ACPA- MBCs, ACPA+ MBCs displayed a highly activated phenotype as evidenced by increased expression of Ki-67, CD86, CD80, CD19 and CD20 and reduced expression of CD32. The activated phenotype of ACPA+ MBCs did not associate with clinical disease activity in a cross-sectional analysis of RA patients treated with various therapeutic agents. Also, in a longitudinal analysis of patients treated with Janus kinase (JAK) inhibitors, ACPA+ MBCs retained their activated phenotype despite effective control of inflammation and clinical disease. CONCLUSION: ACPA+ MBCs remain active despite clinical disease control in patients with RA across a range of interventions. This persistent activity indicates the absence of immunological remission and might explain why ACPA+ patients rarely reach sustained drug-free remission and frequently flare upon drug tapering.

Treatment decisions in axial spondyloarthritis daily clinical practice are more than treat-to-target.

OBJECTIVE: 'Treat-to-target principles' are advised for axial spondyloarthritis (axSpA), although a clear target is not yet defined and targets do not always reflect inflammation. Treat-to-target use and motives for treatment choices in clinics are unknown. Therefore, we studied the presence of residual disease activity according physician's opinion, patient's opinion and composite indices and compared them to the subsequent treatment decisions. METHODS: This cross-sectional multicentre study included 249 patients with a clinical diagnosis of axSpA ≥6 months. Remission and low disease activity according to the BASDAI (<1.9 and <3.5, respectively) and physician's and patient's opinion were assessed. Questionnaires included patient-reported outcomes and patients and physicians completed questions regarding treatment decisions. RESULTS: A total of 115/249 (46%) patients were in remission according to the physician and 37% (n = 43) of these patients reached remission according to the BASDAI. In 51/83 (60%) of the patients with residual disease activity according to the physician and a BASDAI >3.5 the treatment was left unchanged, either because of low disease activity as rated by the physician [n = 15 (29%)] or because of a combination of low disease activity with non-inflammatory complaints or comorbidities [n = 11 (25%)]. Retrospective treat-to-target evaluations showed that treatments were most frequently intensified in patients with arthritis or inflammatory back pain and less often in patients with other (non-inflammatory) musculoskeletal comorbidities. CONCLUSION: This study shows that physicians do not always strictly apply treat-to-target in case of residual disease activity in axSpA. Usually, they accept low disease activity as satisfactory.

Lupus activity and outcomes in lupus patients undergoing maintenance dialysis.

OBJECTIVES: Lupus activity has long been considered to decline after initiation of maintenance dialysis (MD). This assumption is based on limited historical data. We aimed to describe the natural history of lupus in patients undergoing MD. METHODS: We assembled a national retrospective cohort of lupus patients who started dialysis between 2008 and 2011, included in the REIN registry with a 5-year follow-up. We analysed healthcare consumption from the National Health Data System. We evaluated the proportion of patients 'off-treatment' (i.e. receiving 0-5 mg/d of corticosteroids, without any immunosuppressive therapy) after the start of MD. We describe the cumulative incidences of non-severe and severe lupus flares, cardiovascular events, severe infections, kidney transplantation and survival. RESULTS: We included 137 patients (121 females and 16 males), with a median age of 42 years. The proportion of patients 'off-treatment' at dialysis initiation was 67.7% (95% CI: 61.8, 73.8%), and increased to 76.0% (95% CI: 73.3, 78.8) at 1 year and 83.4% (95% CI: 81.0, 85.9%) at 3 years, with a lower proportion in younger patients. Lupus flares mainly occurred in the first year after MD initiation, and at 12 months 51.6% of patients had presented a non-severe lupus flare and 11.6% a severe lupus flare. In addition, 42.2% (95% CI: 32.9, 50.3%) and 23.7% (95% CI: 16.0, 30.7%) of patients at 12 months had been hospitalized for cardiovascular events or infections, respectively. CONCLUSION: The proportion of lupus patients off-treatment increases after MD initiation, but non-severe and severe lupus flares continue to occur, mainly during the first year. This calls for the continued follow-up of lupus patients by lupus specialists after dialysis initiation.

Subtherapeutic hydroxychloroquine concentration is associated with increased disease activity and greater organ damage in lupus.

OBJECTIVE: To investigate the effects of the serum HCQ concentration on clinical manifestations, disease activity and organ damage in a longitudinal cohort of SLE patients. METHODS: The 338 SLE patients were assessed with respect to their demographic data, clinical and laboratory findings, Physician's Global Assessment (PGA), adjusted mean SLEDAI-2000 (AMS) and SLICC Damage Index (SDI) annually for 5 consecutive years. Patients were divided into two groups according to their serum HCQ concentration at baseline: subtherapeutic (<500 ng/ml) and therapeutic (≥500 ng/ml) groups. The impact of the HCQ concentration on the clinical outcomes was evaluated in a longitudinal analysis using a generalized estimating equation (GEE). RESULTS: Of the 338 patients, 287 (84.9%) were in the subtherapeutic group at baseline. This group had a higher incidence of newly developed LN (P = 0.036) and had been prescribed higher mean and cumulative doses of prednisolone (P = 0.003 and P = 0.013, respectively) than the therapeutic group. In multivariable analyses based on GEE, the subtherapeutic group had a higher AMS score (ß = 1.398, 95% CI 0.607, 2.189; P < 0.001), higher PGA score (ß = 0.328, 95% CI 0.215, 0.441; P < 0.001) and higher SDI score (ß = 0.366, 95% CI 0.061, 0.671; P = 0.019) across all 5 years. CONCLUSION: The subtherapeutic HCQ concentration was associated with the development of new-onset LN, and had significant associations with disease activity and cumulative organ damage in SLE patients over time.

Does remission in systemic lupus erythematosus according to the 2021 DORIS definition match the treating rheumatologist's judgement?

OBJECTIVES: To assess agreement between the 2021 Definition Of Remission In SLE (DORIS) and physician-judged lupus activity. METHODS: A cross-sectional analysis was conducted of data from a Spanish prospective multicentre study of SLE patients. We applied the 2021 DORIS criteria and assessed whether remission status based on this definition agreed with remission as per physician clinical judgement and reasons for disagreement between them. RESULTS: Out of 508 patients [92% women; mean age (s.d.): 50.4 years (13.7)] studied, 267 (54.4%) met the criteria for 2021 DORIS remission. Based on physicians' judgement, 277 (55.9%) patients were classified as in remission or serologically active clinically quiescent (SACQ). The overall rate of agreement between these assessments was 81.2% (95% CI: 79.9, 82.9%) with a Cohen's kappa of 0.62 (0.55-0.69). Overall, 46 (9.1%) patients were classified as in remission/SACQ by rheumatologists but did not meet the 2021 DORIS criteria for remission. The main reasons for discrepancies were a clinical SLE Disease Activity Index (cSLEDAI) score >0 in 39 patients, a Physician Global Assessment score >0.5 in five patients, and prednisone >5 mg/day in another five patients. CONCLUSIONS: The 2021 DORIS remission is an achievable target in clinical practice. There is substantial agreement between the DORIS definition and physician-judged remission. The discordance was mainly due to physicians classifying some patients with ongoing mild disease activity as in remission. Thus, the standardized DORIS definition should be used to define the target in a treat-to-target strategy for the management of SLE.

Disease activity trajectories in juvenile dermatomyositis from childhood to adulthood.

OBJECTIVES: To assess whether there are identifiable subgroups of disease activity trajectory in a population of JDM patients-followed throughout childhood and into adulthood-and determine factors that predict those trajectory groupings. METHODS: This is a retrospective, longitudinal inception cohort of patients with idiopathic inflammatory myopathies, largely JDM. We sought to identify baseline factors that predict membership into different groups (latent classes) of disease activity trajectory. RESULTS: A total of 172 patients (64% females), with median age at diagnosis of 7.7 years, were analysed. We studied 4725 visits (1471 patient-years). We identified three latent classes of longitudinal disease activity, as measured by the modified DAS (DASm), with distinct class trajectories predicted by DASm at baseline, and by the changes of DASm from either baseline to 3 months or baseline to 6 months (early response to therapy). In the analysis in which DASm at baseline and the changes of DASm from baseline to 6 months are included as predictors, Class 1 (10%) has persistently high disease activity, Class 2 (34%) is characterized by moderate disease activity and Class 3 (56%) is characterized by individuals with a high early disease activity but an apparently good response to treatment and long-term low disease activity. CONCLUSION: High early disease activity, and treatment resistance in the first few months, predict a more chronic longitudinal course of JDM.

Pulmonary and extra-pulmonary effects of lung transplantation in an Italian cohort of patients with systemic sclerosis.

OBJECTIVES: Lung transplantation (LuTx) is a life-saving intervention for Systemic Sclerosis (SSc) patients with end-stage lung disease. The aim of this study was to evaluate patients' survival and LuTx outcomes on systemic disease manifestations. METHODS: A retrospective evaluation was conducted on SSc patients who underwent LuTx between 2010 and 2021. Outcomes assessed at baseline, 6, 12, and 24 months post-LuTx included skin involvement by modified Rodnan skin score (mRSS), global disease activity using a modified EUSTAR index (0-9 scale). Lung function rescue was evaluated by forced vital capacity (FVC). Patient survival was assessed by Kaplan-Meier analysis. RESULTS: 13 SSc patients were included, with a male/female ratio 9/4 and a median age of 48.7 years. Nine patients were affected by diffuse cutaneous scleroderma (dcSSc) and four by limited cutaneous scleroderma (lcSSc). FVC significantly increased from 56% of the predicted value at baseline to 78% at 2 years (p= 0.003). mRSS decreased from 7.4 ± 3.8-3.3 ± 2.5 in patients with dcSSc (p= 0.02). The modified EUSTAR index score decreased from 2.54 ± 1.8 at baseline to 0.49 ± 0.5 at 2 years (p= 0.02). Survival rate was 92.3% at 2 years, and 76.9% at 5 years. No unexpected adverse events were observed. CONCLUSIONS: In SSc patients undergoing LuTx, an excellent 2-year survival was observed, without any disease-related adverse events. Our study supports LuTx as a viable option in SSc patients with end-stage lung disease. Apart from expected recovery of lung function, LuTx was associated with improvement of mRSS and global systemic disease activity.

Lupus Low Disease Activity State and organ damage in relation to quality of life in systemic lupus erythematosus: a cohort study with up to 11 years of follow-up.

OBJECTIVES: Beyond prevention of organ damage, treatment goals in systemic lupus erythematosus (SLE) include optimisation of health-related quality of life (HRQoL). The Lupus Low Disease Activity State (LLDAS) has received increasing attention as a goal whenever remission cannot be achieved. How SLE disease activity, organ damage, and LLDAS attainment relate to patient-reported outcomes (PROs) is not fully explored, which formed the scope of this investigation. METHODS: We included 327 patients with SLE from a tertiary referral centre. Longitudinal registrations of disease activity using SLEDAI-2K and physician global assessment (PhGA), organ damage using the SLICC/ACR damage index (SDI), pharmacotherapies, EQ-5D-3L data, as well as visual analogue scale (VAS) scores for fatigue, pain, and overall SLE-related health state over a median follow-up time of 8.5 years were analysed. RESULTS: In the overall population, as well as subgroups of patients with recent-onset SLE and those with clinically active, autoantibody-positive disease, LLDAS attainment, lower PhGA, and lower clinical SLEDAI-2K scores were associated with favourable HRQoL by EQ-5D-3L and VAS assessments, while increasing SDI scores were associated with poor PROs yet not fatigue in the overall population. PROs were further enhanced by being in LLDAS sustainedly. In fully adjusted models of the entire study population, LLDAS attainment and lower disease activity were associated with favourable PROs, irrespective of SDI. CONCLUSION: In one of the longest to date observational studies, we demonstrated that low disease activity and being sustainedly in LLDAS were coupled with favourable HRQoL, pain, fatigue, and overall health experience, irrespective of organ damage.

Responsiveness and sensitivity of PROMs to change in disease activity status in early and established rheumatoid arthritis.

OBJECTIVES: To determine whether patient reported outcome measures (PROMs) capturing activity limitations, health impact, pain, fatigue and work ability are responsive and sensitive to changes in disease activity status in patients with early and established rheumatoid arthritis (RA). METHODS: All early RA patients (n = 557) from the tREACH-trial and established RA patients (n = 188) from the TARA-trial were included. Both studies were multicentre, single-blinded trials with a treat-to-target management approach. The following PROMs were studied: Health Assessment Questionnaire Disability Index(HAQ-DI), morning stiffness severity, EQ-5D, general health, 36-item short form(SF-36), joint pain, fatigue and productivity loss. Mean changes in PROMs between two consecutive visits were compared with changes in disease activity status(remission, low disease activity and active disease) using linear mixed models and standardised response means. Additionally, the proportion of individual observations that showed an expected PROM response to disease activity status alterations was calculated. RESULTS: HAQ-DI, morning stiffness severity, general health, EQ-5D and joint pain demonstrated responsiveness to improvement or worsening of disease activity status in both early and established RA. SF-36 physical and mental component scale, fatigue and productivity loss did not show this effect in both groups. Across nearly all PROMs, the magnitude of change and the proportion of individual observations that reflect a shift from and to active disease remained low. CONCLUSION: HAQ-DI, morning stiffness severity, EQ-5D, general health and joint pain are responsive to disease activity status alterations on a group level in both early and established RA. For the individual patient the responsiveness of these PROMs is poor. CLINICAL TRIAL REGISTRATION: tREACH trial (www.isrctn.com, ISRCTN26791028) and TARA trial (www.onderzoekmetmensen.nl, NTR2754).