Lupus Science & Medicine最新文献

Objective: To evaluate the efficacy of mepacrine (MC) as an add-on therapy in patients with SLE unresponsive to hydroxychloroquine (HCQ)-containing regimens at 6 months after MC introduction.

Methods: Observational study using routine clinical care data of patients from the Lupus-Cruces cohort. All of them received therapy with HCQ and prednisone at baseline. Two groups of initial therapy were compared: single therapy (ST; HCQ + prednisone) and multiple therapy (MT; additional immunosuppressives or biologics). Achieving the definition of remission in SLE (DORIS) at 6 months was the main outcome. Prednisone tapering and MC side effects and discontinuation were also analysed. A logistic regression was performed in search of clinical predictors of response.

Results: 106 different episodes were included (ST=56, MT=50). The mean SLE Disease Activity Index (SLEDAI) at baseline was 6.7, with a mean prednisone dose of 6 mg/day. DORIS remission at 6 months was 71% for the complete cohort (ST 79% vs MT 62%, p=0.06). SLEDAI reduction at 6 months was similar in both groups (mean 4.6 points in the ST group vs 5 in the MT group, p=0.5). The reduction at 6 months was also similar (mean 1.75 mg/day in the ST group vs 1.69 mg/day in the MT group, p=0.9). The most frequent reason for MC discontinuation was improvement (45%). Adverse effects were reported in 17% patients.

Conclusions: MC is a useful therapy in mild-moderate active SLE. Using MC as the first drug after the failure of glucocorticoids and HCQ is the best option; however, the addition of MC to a multidrug regimen can also be of help.

Introduction: Accurate assessment of disease activity in SLE is crucial but challenging due to its varied clinical manifestations and severity. Current tools like the SLE Disease Activity Index (SLEDAI) have limitations, including unvalidated cut-off points, low sensitivity to certain severe features and an overemphasis on serological markers. There is a need for improved definitions of disease activity.

Methods: We analysed data from 1463 patients with SLE in the prospective, multicentre RELESSER-PROS cohort (39 Spanish hospitals) over five annual visits. A panel of lupus experts used the Delphi method to develop new definitions for moderate disease activity state (MODAS) and severe disease activity state (SEDAS). These incorporated clinical SLEDAI (cSLEDAI), selected severe non-SLEDAI manifestations (eg, neuropsychiatric involvement, proteinuria, severe haematological features) and the Physician Global Assessment. We compared the predictive performance of MODAS/SEDAS with SLEDAI for mortality, organ damage, severe flares, hospitalisations and health-related quality of life, using receiver operating characteristics curves.

Results: At baseline, 20% of patients met MODAS criteria and 24.6% SEDAS criteria, versus 10.5% and 3.0%, respectively, by SLEDAI. MODAS/SEDAS reclassified 19.9% of patients considered mild by SLEDAI, and 53.3% of moderate cases. MODAS/SEDAS showed modest but consistent improvement in predictive accuracy for damage (area under the curve 0.570 vs 0.550), flares (0.609 vs 0.564) and hospitalisations (0.609 vs 0.565). These definitions were associated with worse outcomes and demonstrated a dose-response relationship, although the overall predictive ability remained moderate.

Conclusion: MODAS and SEDAS offer an alternative framework for defining moderate and severe SLE activity, with modest but consistent improvements in predictive performance compared with SLEDAI. By integrating cSLEDAI, key severe features and physician judgement, they improve prognostic performance and support a severity-based approach to clinical management and research. Their clinical utility remains preliminary, and further external validation is required before routine implementation.

Background: Follicular helper T (TFH) cells play a crucial role in the dysregulated antibody responses in SLE. Circulating TFH17 (cTFH17) subsets are elevated in active lupus, and their frequency is associated with increased disease activity and autoantibody levels, indicating their potential role in disease development by promoting B-cell and autoantibody production. However, how activated cTFH17 cells drive B cell dysregulation for autoantibody production in SLE remains incompletely understood.

Objective: To investigate the phenotypic function of interleukin (IL)-17A-producing cTFH cells in subjects with SLE, explore their association with clinical parameters and inflammatory markers and demonstrate potential contributions to B cell-mediated autoantibody production METHODS: Forty subjects with SLE were enrolled to characterise and phenotype cTFH or circulating peripheral helper T cell subsets, based on molecule surface expression and intracellular cytokine production by flow cytometry. The correlations of cTFH17 or cTFH17.1 cells with disease activity, anti-double-stranded DNA (dsDNA) autoantibodies and inflammatory cytokines were analysed. The interactions of cTFH17 cells with autoreactive B cell responses were studied in co-culture assays. The proliferation and inducible T cell costimulator (ICOS) upregulation were detected in cTFH17 cells, while autoantibody-secreting cell differentiation and autoantibody production were detected in B cells.

Results: The frequencies of cTFH17 and cTFH17.1 cells were significantly elevated in subjects with SLE compared with healthy controls, particularly in those with active disease. These cells exhibited increased activation, as indicated by the expression of ICOS and CD40L. The frequency of activated cTFH17 or cTFH17.1 cells correlated positively with SLE disease activity index 2000 (SLEDAI-2K) scores but not with anti-dsDNA antibody levels. Profiling of inflammatory cytokines revealed the elevated levels of IL-6, IL-8 and IL-17A in individuals with SLE. However, the increased levels of these cytokines did not correlate with the frequency of cTFH17 cells nor SLEDAI-2K scores. In cTFH17-B cell co-cultures, proliferation and activation of cTFH17 cells were detected. There, B cells differentiated into antibody-secreting cells, which secreted anti-DNA autoantibodies.

Conclusion: cTFH17 cells were significantly expanded and activated in subjects with active SLE, showing a positive correlation with clinical activity. Functionally, cTFH17-B cell interactions enhanced plasma cell generation and autoantibody production. These findings suggest that cTFH17 cells play a key role in SLE pathogenesis.

Objective: To estimate the incidence of herpes zoster (HZ) and the incremental healthcare resource utilisation (HRU) and costs associated with HZ among adults with systemic lupus erythematosus (SLE).

Methods: This retrospective cohort study included insured patients from 2015 to 2022. HZ incidence rates were estimated among patients with SLE, SLE without other immunocompromising conditions (ICC) (SLE only) and no ICC. Adjusted incidence rate ratios (aIRRs) and 95% confidence intervals (CIs) comparing the SLE and SLE only cohorts versus the no ICC cohort were estimated using Poisson regression. All-cause HRU and costs were compared between patients with SLE and HZ (SLE+/HZ+) and propensity score matched patients with SLE without HZ (SLE+/HZ-).

Results: The incidence rates of HZ in the SLE (n=60 430), SLE only (n=21 206) and no ICC (n=1 000 000) cohorts were 19.72, 14.03 and 5.64 per 1000 patient-years, respectively (aIRR 1.89, 95% CI 1.79 to 2.00, and aIRR 1.54, 95% CI 1.40 to 1.69). Mean all-cause per-patient costs were significantly higher in the SLE+/HZ+ versus SLE+/HZ- cohorts during the first 1 month (n=2126 and n=8504, respectively; cost difference $1349, 95% CI $722 to 1977) and 3 months (n=1968 and n=7872; $1558, 95% CI $108 to 3007).

Conclusions: Patients with SLE had a significantly higher incidence of HZ compared with adults without ICC. Patients with SLE who developed HZ incurred significantly higher all-cause costs than those who did not. These data support considering HZ vaccination for patients with SLE.

Objective: Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological diagnosis that can be associated with SLE. The clinical presentation, risk factors and outcomes of PRES in patients with SLE remain insufficiently described.

Methods: We conducted a multicentre cohort study at the Mayo Clinic and performed a systematic literature review (SLR) of patients with incident PRES and SLE. We described the clinical features, treatments and outcomes. Across both the cohort study and SLR, we assessed neurological sequelae, recurrence and survival. Within the cohort study, we examined PRES risk factors and discontinuation of antiseizure medications (ASMs). We used logistic regression to evaluate factors associated with neurological sequelae and Cox regression to assess predictors of recurrence. Kaplan-Meier methods estimated the rates of recurrence, survival and ASMs discontinuation.

Results: 550 cases (53 from the cohort study) were included, of whom 92% were female. Across both cohort and SLR, the most common symptom was seizure, occurring in 80%. PRES was the first manifestation of SLE in 13% of cases. In the adjusted analysis, older age was associated with neurological sequelae (OR 1.63 per 10-year increase; 95% CI 1.12 to 2.39). After 5 years of follow-up, 11.5% (95% CI 2.3 to 19.9%) of patients had a recurrent PRES episode. 30-day and 180-day survival following PRES was observed in 96.3% (95% CI 93.5 to 99.1%) and 93.7% (95% CI 89.8 to 97.7%) patients, respectively. In the Mayo Clinic cohort, 81% of PRES cases were attributed to hypertension in the context of lupus nephritis (LN), and by the fifth year of follow-up, 78.1% (95% CI 58.7 to 88.4%) of patients had discontinued ASMs.

Conclusions: In this cohort, most of the incident PRES episodes were preceded by hypertension and occurred in patients with LN. Although short-term and long-term prognoses are favourable, older patients more frequently experienced neurological sequelae.

Objective: Delivery of a small for gestational age (SGA) infant is a common pregnancy complication among women with SLE. Although disease activity and autoantibodies such as anti-Smith and anti-ribonucleoprotein associate with SGA, underlying pathological mechanisms remain unclear and reliable predictors are lacking. To address this, we applied a proteomic approach to identify proteins associated with SGA in SLE.

Methods: Plasma samples were collected repeatedly during pregnancy, at delivery and from placental intervillous blood in women with SLE (n=83) and healthy controls (n=67) enrolled in the prospective SLE-Placenta study. Postpartum samples (≥6 months) from a subset of women with SLE (n=19) served as non-pregnant controls. Mass spectrometry was performed on a discovery cohort comprising six healthy uncomplicated pregnancies, eight uncomplicated SLE pregnancies and eight SLE pregnancies complicated by SGA (SLE-SGA). Differential protein abundance analysis was performed in R. Candidate proteins were quantified by ELISA in the full cohort.

Results: Discovery proteomics identified four proteins with increased abundance in SLE-SGA compared with uncomplicated SLE pregnancies: endostatin (P _adj =0.0003), angiogenin (P _adj =0.03), insulin-like growth factor-binding protein 5 (P _adj =0.03) and complement factor H-related protein 5 (P _adj =0.004). In the full cohort, ELISA quantification did not confirm increased levels of these proteins in SLE-SGA but suggested elevated levels of the angiogenesis-related proteins endostatin and angiogenin in women with SLE who later developed pre-eclampsia. Endostatin levels were consistently higher in SLE compared with controls across all trimesters (p≤0.0001). Endostatin, but not angiogenin, was enriched in placental blood.

Conclusion: Our study did not validate the differentially abundant proteins as markers for SLE-SGA but suggested a link between the antiangiogenic and proangiogenic proteins, endostatin and angiogenin, respectively, and pre-eclampsia in SLE. Given the consistent elevation of endostatin throughout pregnancy in SLE compared with controls, its potential effects on placental development in SLE warrant further investigation.

The Lupus Research Alliance formed the Lupus Accelerating Breakthroughs Consortium (Lupus ABC) in 2023 as a public-private partnership with investigators, pharmaceutical companies, the Food and Drug Administration, National Institutes of Health, patient-focused non-profits and professional societies with the goals of developing initiatives to accelerate lupus drug development in a precompetitive setting, and ensuring that perspectives of people with lived experience of lupus are included into the drug development process. Patient-reported outcome (PRO) measures are a top area of focus for the Lupus ABC. To support future work in the area of PROs, a public meeting was held on 16-17 October 2024 with the objectives of (1) assessing the current state of PROs used in lupus clinical trials, (2) developing a roadmap to advance the use of PROs in lupus clinical trials and (3) identifying and setting priorities for efforts to be pursued by a Lupus ABC PRO Working Group. After a series of presentations, small groups addressed what PRO domains to measure, the questionnaire burden for trial participants, how PROs should be selected for trials and what efforts are needed to advance use of PROs in lupus clinical trials.Meeting participants concluded that although PROs are being collected in most lupus clinical trials, they may be underused as primary or secondary/exploratory endpoints. A strong desire to change the focus in trials from disease activity and signs to include PROs, as a way of highlighting patients' voices, was noted. The group concluded that the specific steps needed are to identify PRO measures appropriate for the target populations of interest, incorporate PROs into endpoints for regulatory decision-making, ensure PRO data are publicly available and accessible to researchers and involve people living with lupus in selection of PRO domains, measures and trial design. For these actions, collaborations among industry, researchers, regulators, payors and patients are needed.

Objectives: Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Significant morbidity and early mortality necessitate early intervention. This study harnessed SLE-associated immune dysregulation to create a Lupus Classification Risk Index (LCRII) and Lupus Disease Activity Immune Index (LDAII) that identified individuals at risk for SLE classification and disease activity.

Methods: The LCRII was developed from 84 military personnel who developed classified SLE (≥4 American College of Rheumatology criteria) versus matched healthy controls, which was confirmed in 56 lupus blood relatives who developed SLE versus 154 matched unaffected relatives and 77 unrelated controls. The LDAII was informed by SLE patient visits with low (n=132) or active (n=179) disease and 48 matched controls. Data from blood samples assessed for circulating SLE-associated autoantibody specificities and soluble immune mediators informed the LCRII and LDAII. Random forest modelling guided the selection of informative analytes.

Results: An LCRII informed by 32 or 17 log-transformed/standardised mediators, weighted by their correlation to SLE-associated autoantibodies, differentiated pre-SLE individuals before reaching disease classification (area under the curve (AUC) ≥0.79, p<0.0001; effect size ≥1.1), even before the appearance of clinical criteria (AUC ≥0.74, p<0.0001; effect size ≥0.9). The LCRII-32, LCRII-17 and select mediators, MCP-3/CCL7, TNFRII, stem cell factor (SCF), IL-1α, IP-10/CXCL10 and TGF-β differentiated renal and serositis classification criteria (p<0.05). An LDAII informed by 26 or 13 log-transformed/standardised mediators, weighted by their correlation to SLE-associated autoantibodies or disease activity (hybrid Systemic Lupus Erythematosus Disease Activity Index; hSLEDAI), differentiated SLE patients with low (hSLEDAI <4) or active (hSLEDAI ≥4) disease (AUC >0.6, p ≤0.002, effect size ≥0.4), including clinical/serologic active versus quiescent disease (AUC ≥0.7, p<0.0001, effect size ≥0.6). The LDAII-26, LDAII-13 and select mediators MCP-1/CCL2, TNFRII, SCF, IL-2Rα, IL-10 and TGF-β differentiated renal and serositis manifestations.

Conclusions: We have conceptualised two immune mediator-informed indexes, the LCRII that predicts SLE from months to years before clinical presentation, and the LDAII that analogously predicts active disease in SLE to distinguish patients who would benefit from early intervention.

Objective: The question of sustained remission in SLE has been highlighted recently following data published on the use of chimeric antigen receptor-T cell therapy in SLE. With the review, we wanted to investigate the prevalence of sustained remission of 2 years or more in SLE with the current available treatments and to assess the predictive factors associated with this state.

Methods: A systematic review of Embase via Ovid and Medline via Ovid was performed. We considered articles of adult patients with SLE that report the prevalence and/or the predictive factors of sustained remission in SLE. We considered that the latter state is sustained if it was for 2 years or more.

Results: 20 studies were included for final review. The definition of remission was different between studies, and most authors considered different types of remission based on the serological activity and the current therapy. The prevalence of long-term remission was different across studies depending on the definition used. It ranged from 0.3% to 63%. Older age at diagnosis, lower disease activity at baseline and the absence of renal disease involvement were the most commonly found factors likely associated with sustained remission.

Conclusion: Long-term remission is an achievable state in SLE with current treatment. Studies report a striking heterogeneity in the current prevalences. This is likely to be caused by the lack of objective measures to confirm the state of sustained remission in SLE.

Background: Interstitial fibrosis in lupus nephritis (LN) is often infiltrated by immune cells but typically regarded as non-specific 'scar reaction'. This study aimed to investigate the relationship between inflammatory fibrosis and kidney disease progression in LN.

Methods: Interstitial fibrosis and tubular atrophy (IFTA) were scored in 124 LN kidney biopsies. Inflammation in areas of IFTA (i-IFTA) was graded 0-3 according to the Banff Classification of Allograft Pathology. Significant glomerular filtration rate (GFR) loss was defined as a decline of >15 mL/min at 3 years from biopsy. Immune cell phenotype was defined by serial immunohistochemistry (13-plex).

Results: IFTA was observed in 88/124 (71%) biopsies, and i-IFTA was identified in 76/88 (86%) cases. The distribution of i-IFTA grades was heterogeneous across all IFTA grades. In patients with moderate-to-severe IFTA (>25%), the degree of i-IFTA was associated with a higher risk of significant GFR loss: 0/1 (0%), 0/3 (%), 3/4 (75%) and 7/9 (78%) for i-IFTA grades 0, 1, 2 and 3, respectively (p=0.015). Multiplexed histology revealed that i-IFTA was mostly composed of CD163+ macrophages and CD4 T cells, followed by CD8 T cells and granulocytes.

Conclusion: I-IFTA is frequently observed in LN and is dominated by macrophages and T cells. For patients with baseline IFTA >25%, the degree of i-IFTA emerged as a predictor of GFR loss. These data support the routine scoring of i-IFTA in LN due to its prognostic implications and nominate i-IFTA as a potential therapeutic target.