dsDNA Antibodies Research Articles

12238 A Case Of Drug-induced Vasculitis

Abstract Disclosure: C. Javier: None. M.H. Horani: None. Title: A Case of Drug-Induced VasculitisChristian Javier, DOMohamad Horani, MD Introduction: Graves’ disease is commonly managed with thionamides. These have rare but serious complications of drug-induced lupus-like syndrome and vasculitis. In patients who present with rheumatologic and inflammatory findings, it is important to consider the possibility of these complications . Case Presentation: We present a 30-year-old female with Graves disease, asthma, and hypertension with concerns for cough, body aches, fatigue, bilateral flank pain, erythema, itching and burning of the hands, in the setting of recent spontaneous miscarriage. She was diagnosed with Graves’ nearly 2 years ago and was started on methimazole, but discontinued due to adverse effects of the medication. She was then started on PTU. The patient had a seizure, and head CT revealed a left-sided 4 cm brain mass in the left frontal lobe. The patient was admitted to the ICU, intubated, and started on IV Decadron. Further imaging showed multiple enlarged lymph nodes in the axilla, mediastinum, and hilum. Her brain mass was biopsied showing acute inflammation with early acute necrosis and multifocal fibrinous vascular necrosis, which has been reported in ANCA vasculitis. She had undetectable TSH (0.35-5.0) and free T4 of 1.54 (4.87-11.72). She was also found to have proteinuria and AKI. At this point, PTU-induced vasculitis and drug-induced lupus were suspected and PTU was discontinued. She was found to have low complement levels (C3 40, C4 6.1), elevated p-ANCA (>1:1280), ANA (1:640), anti-histone IgG (2.3) dsDNA (1:160), SSB La antibodies (70), anti-Smith antibodies (319), anti-RNP antibodies (146). Renal biopsy is pending. After discontinuation of PTU and administration of IV steroids, her symptoms largely resolved and she was extubated and stable for discharge. Conclusion: In patients being treated for Graves’ disease with PTU, there are rare but life-threatening complications associated with this medication including lupus-like state or vasculitis with elevated ANCA antibodies. Common presenting symptoms of drug-induced vasculitis include fever, joint pains, myalgias, skin lesions, glomerulonephritis, cerebral angiitis, and pulmonary hemorrhage. The onset of vasculitis can occur at any time after starting medication, with one study showing an average onset of 36 months after initiation of therapy. Other case reports have demonstrated positive serologies for ANA and anti DS-DNA antibodies in those with PTU-induced lupus. Drug induced lupus can also occur in patients taking PTU, with kidney and CNS involvement being more uncommon. In those with p-ANCA associated vasculitis secondary to PTU, anti-GBM, antiphospholipid, and antinuclear antibodies can also be present. Presentation: 6/1/2024

Genetic susceptibility and clinical features of CYP2D6 associated with systemic lupus erythematosus in a Chinese population.

This study aims to explore possible susceptibility genes and clinical features for systemic lupus erythematosus (SLE) patients in a Chinese population. Expanding on the results of a prior single-center observational study involving 60 systemic lupus erythematosus patients, a subsequent single-center prospective observational study was conducted on SLE patients undergoing treatment at Nanfang Hospital Affiliated to Southern Medical University from 2021 to 2023. The identification process for drug-related target genes entailed an extensive search across PharmGKB (https://www.pharmgkb.org/), the Clinical Pharmacogenetics Implementation Consortium (CPIC),and PubMed literature databases, to pinpoint common drugs and target single nucleotide polymorphisms(SNPs)for SLE. Blood samples were individually collected and genotyped using MassARRAY® high-throughput nucleic acid mass spectrometry. Genotype frequency differences were assessed through Chi-square tests against both the larger East Asian population as well as kidney transplant recipients. Data collection relied on electronic medical records, encompassing demographic details(age, gender),medication regimens(hormones, NSAIDs, hydroxychloroquine, DMARDs, biologic agents, stomach medications, calcitriol, etc.),laboratory indicators(RF, Anti-CCP antibody, ESR, CRP, anti-ANA antibodies, dsDNA antibodies, anti-SM antibodies, S m. RNP antibodies, A LT, ALB, CR, UA, WBC, PLT, HGB, Ca, K, Glu, CHOL, TG, LDL-C, HDL-C) and lupus activity scores(SLEDAI-2K). Possible disease susceptibility genes were categorized, and SPSS26 software facilitated statistical analyses. The research encompassed a total of 137 SLE patients along with 50 SNPs. After conducting statistical analyses, it emerged that there existed significant disparities in CYP2D6 gene (rs1065852) distribution when compared against allele mutation rates within both East Asian populations (p < .05) and kidney transplant patients(p < .05). Wild-type gene (GG) constituted 14% of cases while mutant gene (GA + AA) constituted 86%. Allele mutation rate (A63.6%) was significantly higher among SLE patients (RR = 0.802; p = .0355). Furthermore, the variant rs1065852 genotype (GA + AA) demonstrated significant associations with lower CRP levels, higher HGB levels, and higher HDL-C levels (p < 0 0.05). The metabolic enzyme CYP2D6 may be used as susceptibility gene for predicting systemic lupus erythematosus and are correlated with CRP and other indicators.

Mycophenolate Mofetil and New-Onset Systemic Lupus Erythematosus

Anti-double-stranded DNA (dsDNA) antibody has been reported to have a close relationship with systemic lupus erythematosus (SLE) flares and participates in the pathogenesis of lupus nephritis (LN) as well as causing damage to other organs. However, whether early use of mycophenolate mofetil (MMF) could prevent SLE flares is not clear. To assess the efficacy and safety of MMF plus prednisone and hydroxychloroquine sulfate compared with prednisone and hydroxychloroquine sulfate alone in patients with SLE. This investigator-initiated, multicenter, observer-blinded randomized clinical trial enrolled 130 participants aged 18 to 65 years and was conducted in 3 hospitals across China. Treatment-naive patients with newly diagnosed SLE, a high titer of anti-dsDNA antibody, and no major organ involvement were included. The study was started September 1, 2018, and the follow-up was completed September 30, 2021. Data were analyzed from December 1, 2021, to March 31, 2022. Patients were randomized 1:1 to receive oral prednisone (0.5 mg/kg/d) and hydroxychloroquine sulfate (5 mg/kg/d) (control group) or prednisone (0.5 mg/kg/d) and hydroxychloroquine sulfate (5 mg/kg/d) plus MMF (500 mg twice daily) (MMF group) for 96 weeks. The primary outcome was the proportion of patients presenting with flares according to the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Flare Index. The secondary outcomes included the proportion with lupus low disease activity state at week 96, 36-Item Short Form Health Survey scores before and after treatment, proportion of adverse events (AEs), and changes in SLEDAI-2000 scores and prednisone doses. Among 130 randomized patients (mean [SD] age, 34.5 [12.5] years; 112 [86.2%] women), 119 (91.5%) completed the follow-up. The risk of severe flare was significantly lower in the MMF group (7 of 65 [10.8%]) vs the control group (18 of 65 [27.7%]) (relative risk [RR], 0.39 [95% CI, 0.17-0.87]; P = .01). Additionally, 1 of 65 patients in the MMF group (1.5%) and 9 of 65 in the control group (13.8%) manifested LN (RR, 0.11 [95% CI, 0.01-0.85]; P = .008). Most common serious study drug-related AEs were infections (20 of 65 [30.8%] in the control group and 22 of 65 [33.8%] in the MMF group). The findings of this randomized clinical trial suggest that MMF may reduce the rate of severe flare and lower the incidence of LN in patients with new-onset SLE and a high titer of anti-dsDNA antibody without major organ involvement. Chinese Clinical Trial Registry: ChiCTR1800017540.

Abstract P180: Female mice with systemic lupus erythematosus produce antibodies to mitochondrial antigens and have impaired renal mitochondrial function

Patients with autoimmune disorders like systemic lupus erythematosus (SLE) are at significant risk for renal and cardiovascular mortality. The pathology of SLE is driven by a loss of immune tolerance with the subsequent production of autoantibodies (IgG), and our laboratory previously demonstrated a mechanistic role for autoantibodies in autoimmune mediated hypertension. While anti-double stranded DNA (dsDNA) antibodies are pathognomonic for SLE, a breadth of autoantibodies may contribute to disease pathology. The goal of this study is to identify autoantibodies that may contribute to the renal and cardiovascular consequences associated with SLE. To accomplish this goal, an antigen array was performed (University of Texas Southwestern Genomics &amp; Microarray Core Facility) using plasma samples collected from an established experimental mouse model of SLE (30 week old female NZBWF1, n=8) and healthy controls (30 week old female NZWLacJ, n=7). As anticipated, autoantibodies raised to nuclear antigens were prominently represented in the array and were significantly increased relative to control mice. This includes antibodies to dsDNA, ssRNA, chromatin, and histones (total) (p&lt;0.02). In addition, SLE mice produce antibodies to mitochondrial antigens including cardiolipin and cytochrome C (p&lt;0.02 vs control mice), critical components of the inner mitochondrial membrane and respiratory chain, respectively. In a separate study, renal mitochondrial function was tested using high resolution respirometry (Oroboros Instruments) in whole kidney homogenates from 30 week old female SLE (n=6) and control mice (n=5). Results show that coupled respiration, an estimation of oxidative phosphorylation, is significantly impaired at Complex I in kidneys from SLE mice compared to healthy controls (62±9 vs. 90±7 pmol/s/mg tissue, p&lt;0.05). Uncoupled respiration, an estimation of maximal electron transport, is also reduced in the kidneys of female SLE mice compared to controls (157±23 vs. 212±14 pmol/s/mg tissue, p=0.07). These data provide insight for new mechanistic pathways to pursue in understanding the underlying mechanisms promoting cardiovascular risk factors like hypertension during SLE.

CX-5461 ameliorates disease in lupus-prone mice by triggering B-cell ferroptosis via p53-SLC7A11-ALOX12 pathway

CX-5461, a first-in-class compound, is widely recognized as a selective inhibitor of RNA polymerase I. Recently, it has been reported to possess novel immunosuppressive properties with significant therapeutic effects in transplantation immune rejection. However, the potential use of CX-5461 for Systemic Lupus Erythematosus (SLE) treatment remains unknown. In this study, we elucidated the mechanism underlying the therapeutic efficacy of CX-5461 in lupus. Our findings demonstrated that CX-5461 selectively targets B cells and effectively reduces the proportions of B cells, germinal center B cells, and plasma cells in MRL/MPJ-Faslpr and Resiquimod (R848)-induced lupus mice. Molecular studies revealed that CX-5461 modulates CD36-Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4)-mediated glycerolipid metabolism in B cells, triggering ferroptosis through the p53- Solute Carrier Family 7 Member 11 (SLC7A11)- Arachidonate 12-Lipoxygenase (ALOX12) pathway, thereby decreasing IgG and Anti-Double-Stranded Deoxyribonucleic Acid (dsDNA) antibody levels and attenuating lupus. Collectively, these results suggest that CX-5461 holds promise as an effective candidate for targeted therapy against lupus.

IRAK4 is an immunological checkpoint in neuropsychiatric systemic lupus erythematosus

The search for dementia treatments, including treatments for neuropsychiatric lupus (NPSLE), has not yet uncovered useful therapeutic targets that mitigate underlying inflammation. Currently, NPSLE’s limited treatment options are often accompanied by severe toxicity. Blocking toll-like receptor (TLR) and IL-1 receptor signal transduction by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4) offers a new pathway for intervention. Using a pre-clinical NPSLE model, we compare lupus-like B6.MRL-Faslpr (MRL) mice with B6.MRL-Faslpr-IRAK4 kinase-dead (MRL-IRAK4-KD) mice, which are were less prone to ‘general’ lupus-like symptoms. We demonstrate that lupus-prone mice with a mutation in the kinase domain of IRAK4 no longer display typical lupus hallmarks such as splenomegaly, inflammation, production of hormones, and anti-double-stranded (ds)DNA antibody. water maze behavioral testing, which measures contextual associative learning, revealed that mice without functional IRAK4 displayed a recovery in memory acquisition deficits. RNA-seq approach revealed that cytokine and hormone signaling converge on the JAK/STAT pathways in the mouse hippocampus. Ultimately, the targets identified in this work may result in broad clinical value that can fill the significant scientific and therapeutic gaps precluding development of cures for dementia.

Phenotypic subgroup in serologically active clinically quiescent systemic lupus erythematosus: A cluster analysis based on CSTAR cohort

Serologically active clinically quiescent (SACQ) is a state within systemic lupus erythematosus (SLE) characterized by elevated serologic markers without clinical activity. The heterogeneity in SACQ patients poses challenges in disease management. This multicenter prospective study aimed to identify distinct SACQ subgroups and assess their utility in predicting organ damage. SACQ was defined as a sustained period of at least 6months with persistent serologic activity, marked by positive anti-double-stranded DNA (dsDNA) antibodies and/or hypocomplementemia, and without clinical activity. Cluster analysis was employed, utilizing 16 independent components to delineate phenotypes. Among the 4,107 patients with SLE, 990 (24.1%) achieved SACQ within 2.0± 2.3 years on average. Over a total follow-up of 7,105.1 patient years, 340 (34.3%) experienced flares, and 134 (13.5%) developed organ damage. Three distinct SACQ subgroups were identified. Cluster 1 (n= 219, 22.1%) consisted predominantly of elderly males with a history of major organ involvement at SLE diagnosis, showing the highest risk of severe flares (16.4%) and organ damage (27.9%). Cluster 2 (n= 279, 28.2%) was characterized by milder disease and a lower risk of damage accrual (5.7%). Notably, 86 patients (30.8%) in cluster 2 successfully discontinued low-dose glucocorticoids, with 49 of them doing so without experiencing flares. Cluster 3 (n= 492, 49.7%) featured the highest proportion of lupus nephritis and a moderate risk of organ damage (11.8%), with male patients showing significantly higher risk of damage (hazard ratio [HR]= 4.51, 95% confidence interval [CI], 1.82-11.79). This study identified three distinct SACQ clusters, each with specific prognostic implications. This classification could enhance personalized management for SACQ patients. This work was funded by the National Key R&D Program (2021YFC2501300), the Beijing Municipal Science& Technology Commission (Z201100005520023), the CAMS Innovation Fund (2021-I2M-1-005), and National High-Level Hospital Clinical Research Funding (2022-PUMCH-D-009).

Development of clinical and laboratory biomarkers in an international cohort of 428 children with lupus nephritis.

Lupus nephritis (LN) is a very severe manifestation of lupus. There is no consensus on which treatment goals should be achieved to protect kidney function in children with LN. We retrospectively analyzed trends of commonly used laboratory biomarkers of 428 patients (≤ 18years old) with biopsy-proven LN class ≥ III. We compared data of patients who developed stable kidney remission from 6 to 24months with those who did not. Twenty-five percent of patients maintained kidney stable remission while 75% did not. More patients with stable kidney remission showed normal hemoglobin and erythrocyte sedimentation rate from 6 to 24months compared to the group without stable kidney remission. eGFR ≥ 90ml/min/1.73m2 at onset predicted the development of stable kidney remission (93.8%) compared to 64.7% in those without stable remission (P < 0.00001). At diagnosis, 5.9% and 20.2% of the patients showed no proteinuria in the group with and without stable kidney remission, respectively (P = 0.0001). dsDNA antibodies decreased from onset of treatment mainly during the first 3months in all groups, but more than 50% of all patients in both groups never normalized after 6months. Complement C3 and C4 increased mainly in the first 3months in all patients without any significant difference. Normal eGFR and the absence of proteinuria at onset were predictors of stable kidney remission. Significantly more children showed normal levels of Hb and erythrocyte sedimentation rate (ESR) from 6 to 24months in the group with stable kidney remission.

#2889 Multiple renal tumors as an atypical clinical manifestation of granulomatosis with polyangiitis

Abstract Background and Aims Granulomatosis with polyangiitis (GPA) is a systemic small- vessel vasculitis associated with antineutrophilic cytoplasmic antibody (ANCA), in which kidney involvement often occurs. In some cases the course of vasculitis with kidney involvement is atypical, what complicates the diagnostic process and makes appropriate treatment difficult. Finding nodular masses in the kidneys always causes an oncological concern, while in the differential diagnosis a systemic vasculitis is rarely taken into account, what may lead to an unnecessary nephrectomy. Method We present a case of granulomatosis with polyangiitis (GPA) who presented with multiple tumors in the kidneys and adrenal gland. Results 29-year-old man experienced a sudden disease onset, at the age of 18 years, when due to peripheral oedema, nephrotic grade proteinuria (13.7 g/24 h), hematuria and presence of renal failure markers (serum creatinine 3.4 mg/dL), he was admitted to hospital. A suggestion of a rapidly progressive glomerulonephritis (RPGN) was put forward and a renal biopsy was performed (in the histopathological examination of the kidney, pauci-immune crescentic necrotizing glomerulonephritis was revealed). A treatment with plasmaphereses, high glucocorticosteroid doses and cyclophosphamide pulses was instituted. Haemodialysis therapy was also applied temporarily. ANCA and anti-glomerular basement membrane (GBM) antibodies were determined to give negative results. As a result of the remission-inducing treatment, an improvement of the renal function was obtained (serum creatinine 1.6-1.9 mg/dL). In spite of the remission-maintaining treatment with mycophenolate mofetil (MMF) and oral prednisone, after 10 years again a dramatic renal function impairment occurred, with a necessity of institution of a long-term haemodialysis therapy. Furthermore, on abdominal ultrasound examination multiple focal lesions were found in both kidneys, which rendered a kidney transplantation procedure in the patient impossible. In order to extend the diagnostic procedures, a magnetic resonance imaging (MRI) of the abdominal cavity without contrast agent administration was carried out (in both kidneys disseminated focal lesions were described: non-homogeneous, with moderately enhanced signal on T2-weighted images in the central part, without signs of water diffusion restriction; in the left kidney, of 23 x 22 mm and 19 x 15 mm dimensions; in the right kidney, of 30 x 32 mm, 26 x 22 mm and 22 x 18 mm dimensions. The picture of the lesions was unspecific and atypical. In the differential diagnosis granulomas could not have been ruled out, while disseminated proliferative lesions were less likely. Besides that, in both kidneys cysts of up to 7 mm diameters were present. In the lateral limb of the left adrenal gland a focal lesion was visible, of 23 x 14 mm dimensions, of a structure identical to that of the foci in both kidneys). On high-resolution computed tomography (HRCT) of the chest at the same time, small ground glass areas were found in the lungs. On positron emission tomography/computed tomography (PET/CT) no changes were visualised, suggesting presence of a metabolically active proliferative process. Tests for ANCA, antinuclear antibodies (ANA), anti- double-stranded DNA (dsDNA) antibodies, anti- GBM antibodies were again performed and gave negative results. He was diagnosed with granulomatosis with polyangiitis without ANCA and treated with corticosteroid and intravenous rituximab (4x 787 mg). Three months later, follow-up showed reduced mass lesions in the kidney and adrenal gland by MRI. Conclusion The case highlights the atypical clinical presentation of vasculitis and the significance of considering this possibility in differential diagnosis when confronting mass lesions present in the kidney.

Humoral Immunity Abnormalities in Advanced Maternal-Age Women With Recurrent Spontaneous Abortion: A Single Center Study

To determine the humoral immunity in advanced maternal-age women with recurrent spontaneous abortion (RSA). A retrospective study was performed between January 2022 and October 2023 in the Department of Reproductive Immunity of Shanghai First Maternity and Infant Hospital. Women with RSA were recruited and multiple autoantibodies were tested. Multivariate logistic regression was performed to compare the associations between different age groups (20 to 34 years old in the low maternal-age group and 35 to 45 years in the advanced maternal-age group) and multiple autoantibodies, while controlling for three confounding factors, including body mass index (BMI), previous history of live birth, and the number of spontaneous abortions. Then, we investigated the differences in the humoral immunity of advanced maternal-age RSA women and low maternal-age RSA women. A total of 4009 women with RSA were covered in the study. Among them, 1158 women were in the advanced maternal-age group and 2851 women were in the low maternal-age group. The prevalence of antiphospholipid syndrome, systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, and undifferentiated connective tissue disease was 15.6% and 14.1%, 0.0% and 0.1%, 0.9% and 0.9%, 0.3% and 0.0%, and 23.7% and 22.6% in the advanced maternal-age group and low maternal-age group, respectively, showing no statistical difference between the two groups. The positive rates of antiphospholipid antibodies (aPLs), antinuclear antibody (ANA), extractable nuclear antigen (ENA) antibody, anti-double stranded DNA (dsDNA) antibody, anti single-stranded DNA (ssDAN) antibody, antibodies against alpha-fodrin (AAA), and thyroid autoimmunity (TAI) were 19.1% and 19.5%, 6.6% and 6.6%, 9.2% and 10.5%, 2.0% and 2.0%, 2.2% and 1.2%, 5.1% and 4.9%, and 17.8% and 16.8%, respectively. No differences were observed between the two groups. 1.6% of the women in the advanced maternal-age group tested positive for lupus anticoagulant (LA), while 2.7% of the women in the low maternal-age group were LA positive, with the differences being statistically significant (odds ratio=0.36, 95% confidence interval: 0.17-0.78). In the 4008 RSA patients, the cumulative cases tested positive for the three antibodies of the aPLs spectrum were 778, of which 520 cases were positive for anti-β2 glycoprotein Ⅰ antibodies (β2GPⅠ Ab)-IgG/IgM, 58 were positive for aCL-IgG/IgM, 73 were positive for LA, 105 were positive for both β2GPⅠ Ab-IgG/IgM and aCL-IgG/IgM, 17 were positive for both β2GPⅠ Ab-IgG/IgM and LA, 2 were positive for both aCL-IgG/IgM and LA, and 3 were positive for all three antibodies. Our study did not find a difference in humoral immunity between RSA women of advanced maternal age and those of low maternal age.

Receipt of rheumatology care and lupus-specific labs among young adults with systemic lupus erythematosus: A US Medicare retention in care cohort study.

In systemic lupus erythematosus, poor disease outcomes occur in young adults, patients identifying as Black or Hispanic, and socioeconomically disadvantaged patients. These identities and social factors differentially shape care access and quality that contribute to lupus health disparities in the US. Thus, our objective was to measure markers of care access and quality, including rheumatology visits (longitudinal care retention) and lupus-specific serology testing, by race and ethnicity, neighborhood disadvantage, and geographic context. This cohort study used a geo-linked 20% national sample of young adult Medicare beneficiaries (ages 18-35) with lupus-coded encounters and a 1-year assessment period. Retention in lupus care required a rheumatology visit in each 6-month period, and serology testing required ≥1 complement or dsDNA antibody test within the year. Multivariable logistic regression models were fit for visit-based retention and serology testing to determine associations with race and ethnicity, neighborhood disadvantage, and geography. Among 1,036 young adults with lupus, 39% saw a rheumatologist every 6months and 28% had serology testing. White beneficiaries from the least disadvantaged quintile of neighborhoods had higher visit-based retention than other beneficiaries (64% vs 30%-60%). Serology testing decreased with increasing neighborhood disadvantage quintile (aOR 0.80; 95% CI 0.71, 0.90) and in the Midwest (aOR 0.46; 0.30, 0.71). Disparities in care, measured by rheumatology visits and serology testing, exist by neighborhood disadvantage, race and ethnicity, and region among young adults with lupus, despite uniform Medicare coverage. Findings support evaluating lupus care quality measures and their impact on US lupus outcomes.

Racial Differences in Plasma Microbial Translocation and Plasma Microbiome, Implications in Systemic Lupus Erythematosus Disease Pathogenesis.

Black groups have increased prevalence and accelerated pathogenicity of systemic lupus erythematosus (SLE) compared to other ethnic/racial groups. The microbiome and systemic microbial translocation are considered contributing factors to SLE disease pathogenesis. However, racial differences in the plasma microbiome and microbial translocation in lupus remain unknown. In the current study, we investigated plasma levels of microbial translocation (lipopolysaccharide [LPS] and zonulin) and the plasma microbiome using microbial 16S RNA sequencing of Black and White patients with SLE and Black and White healthy controls. Plasma microbial translocation was increased in Black patients versus in White patients and in patients with SLE versus healthy controls regardless of race. Compared to sex, age, and disease status, race had the strongest association with plasma microbiome differences. Black groups (Black controls and Black patients) had lower α-diversity than White groups (White controls and White patients) and more distinct β-diversity. Black and White patients demonstrated differences in plasma bacterial presence, including Staphylococcus and Burkholderia. Compared to White patients, Black patients had higher SLE Disease Activity Index (SLEDAI) scores and urinary protein levels as well as a trend for increased anti-double-stranded DNA (dsDNA) antibody levels consistent with the known increased severity of lupus in Black patients overall. Certain plasma bacteria at the genus level were identified that were associated with the SLEDAI score, urinary protein, and anti-dsDNA antibody levels. This study reveals racial differences in both quality and quantity of plasma microbial translocation and identified specific plasma microbiome differences associated with SLE disease pathogenesis. Thus, this study may provide new insights into future potential microbiome therapies on SLE pathogenesis.

Clinical algorithm model based on cfDNA to predict SLE disease activity.

Circulating cell-free DNA (cfDNA) has been widely used as a new liquid-biopsy marker. Dysregulation of cfDNA has been found in patients with systemic lupus erythematosus (SLE). However, the detailed association between cfDNA and SLE has not been thoroughly studied. Plasma samples were collected from 88 patients with active SLE and 39 patients with inactive SLE. The cfDNA concentration was determined, and the length and distribution of cfDNA fragments were verified. cfDNA concentrations were significantly higher in patients with active SLE than in patients with inactive SLE (0.4 [0.18-0.897] ng/µL vs 0.249 [0.144-0.431] ng/µL; p = .043). cfDNA fragments were enriched in the ranges of 153-198 bp and 300-599 bp. cfDNA concentrations were associated with the reduction of the anti-double-stranded DNA (dsDNA) antibodies titer (r = -0.301, p = .034). The presence of anti-U1 ribonucleoprotein (p = .012), anti-Sjogren syndrome A (p = .024), anti-dsDNA (p = .0208), and anti-nucleosome antibodies (p = .0382) might associate to the variation of cfDNA concentration. Reduced cfDNA concentration was associated with renal damage in active SLE patients (0.31 [0.11-0.73] ng/µL vs 0.65 [0.27-1.53] ng/µL; p = .009). The Active index, a combination model including cfDNA concentration and other clinical indices, had an area of 0.886 under the receiver operating characteristics curve for distinguishing active SLE. The Active index was positively correlated with the SLE disease activity index score (r = 0.6724, p < .0001). Through systematic stratified analysis and clinical algorithm model, this study found that plasma cfDNA concentration is closely related to SLE disease severity, which has guiding significance for the future clinical application of cfDNA in SLE.

Right ventricular-pulmonary arterial coupling ratio derived from 3-dimensional echocardiography predicts outcomes in systemic lupus erythematosus-associated pulmonary arterial hypertension patients.

Systemic lupus erythematosus (SLE) is a complex autoimmune connective tissue disease (CTD) that is an important cause of devastating pulmonary arterial hypertension (PAH), and persistent progression of PAH can lead to right heart failure, predicting a poor prognosis for SLE patients. Right ventricular-pulmonary arterial (RV-PA) coupling with echocardiography has been demonstrated to be a noninvasive alternative method for evaluating PAH patients' predictive outcomes. Whether the ratio of right ventricular stroke volume (RVSV) to right ventricular end-systolic volume (RVESV) measured by three-dimensional echocardiography (3DE) is a new index of RV-PA coupling has not been discussed as a new predictor for the clinical outcome of systemic lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH). From June 2019 to February 2023, 46 consecutive patients with SLE-PAH were enrolled prospectively, and their clinical data and echocardiographs were studied and analyzed. The control group consisted of 30 healthy subjects matched for age, sex, and body surface area (BSA). The main endpoints of this study were a composite of all-cause mortality and adverse clinical events. Baseline clinical characteristics and echocardiographic assessments were analyzed. During a median of 24months (IQR 18-31), 16 of 46 SLE-PAH patients (34.7%) experienced endpoint-related events. At baseline, patients who experienced mortality or adverse events had a worse WHO functional class (WHO FC) and lower anti-double-stranded DNA (dsDNA) antibody levels. The right ventricular (RV) systolic dysfunction in SLE-PAH subjects was significantly worse than that in the healthy control group, especially in SLE-PAH patients in the endpoint event group. Compared to controls, patients with SLE-PAH had a lower RVSV/RVESV ratio. In the group comparison, patients who had experienced an endpoint event had a sequentially worse ratio (1.86 (1.65-2.3) versus 1.30 (1.09-1.46) versus 0.64 (0.59-0.67), p < .001). There were statistically significant associations between the RVSV/RVESV ratio to routine RV systolic function and clinical parameters. The RVSV/RVESV ratio was negatively correlated with the WHO FC (r = -0.621, p < .001) and positively correlated with the anti-dsDNA level. The ROC curve showed that the optimal cutoff for RVSV/RVESV < 0.712 determined a higher risk of poor prognosis. Kaplan‒Meier survival curves showed that an RVSV/RVESV ratio >0.712 was associated with more favorable long-term outcomes. The 3DE-derived SV/ESV ratio as a noninvasive alternative surrogate of RV-PA coupling was an eximious indicator for identifying endpoint events in SLE-PAH patients and can provide a diagnostic basis for clinical intervention.

Clinical characteristics and prognostic value of autoantibody profile in children with monogenic lupus.

To report the frequency of selected autoantibodies and their associations with clinical features in Arab children with monogenic lupus. This study was retrospective single-center study of genetically confirmed monogenic lupus cases at childhood lupus clinic at King Faisal Specialist Hospital and Research Center, from June 1997 to July 2022. We excluded familial lupus without genetic testing and patients with insufficient data. Collected data comprised clinical and laboratory findings, including the autoantibody profile, which included the anti-double-stranded DNA (anti-dsDNA), anti-Smith, anti-Sjögren's-syndrome-related antigen A (anti-SSA), anti-Sjögren's-syndrome-related antigen B (anti-SSB), and antiphospholipid (APL) antibodies. Also, disease activity and accrual disease damage were collected at the last follow-up visit. This study enrolled 27 Arab patients (14 males) with a median age of 11 years (interquartile range 8.0~16 years), with 63% having early-onset disease. The consanguinity rate and family history of lupus were high (74.1% and 55.6%, respectively). The most frequent clinical features were hematological (96.3%), fever (81.5%), mucocutaneous lesions (85.2%), and renal (66.7%). The frequency of the APL antibodies was 59.3%, anti-dsDNA was 55.6%, and anti-Smith and anti-SSA were 48.2% and 44.4%, respectively. Moreover, dsDNA antibodies were significantly associated with musculoskeletal complaints (p<0.05). Likewise, both anti-Smith and anti-SSA antibodies were linked to failure to thrive and recurrent infections in the univariate analysis (p<0.05). Our study reveals autoantibody frequencies and their association with clinical and prognostic in a substantial monogenic lupus cohort. Distinct clinical manifestations and prognosis association with certain autoantibodies support the idea that monogenic lupus is a distinctive form of lupus. Larger studies needed to validate these findings.

Comparative analysis of contemporary anti-double stranded DNA antibody assays for systemic lupus erythematosus.

Elevated double-stranded DNA (dsDNA) antibody levels in blood serum are considered a disease-specific marker in systemic lupus erythematosus (SLE), correlate with disease activity and the incidence of lupus nephritis, and can be detected in up to 86% of all SLE cases. Despite the high clinical relevance, the variety of dsDNA antibody testing methods with heterogenous performance in clinical use remains challenging. This study is the first to prospectively investigate the performance of two of today's most commonly applied anti-dsDNA testing methods head-to-head under real-world conditions, as well as their correlation with other clinical and serological disease parameters in SLE patients. In this prospective study, all SLE patients undergoing treatment at the Department of Rheumatology at the University Hospital Bonn within a 13-months period (n=41) and control patients without connective-tissue disease (n=51) were consecutively enrolled and examined. For all study participants' serum samples both anti-dsDNA-NcX enzyme-linked immunoassay testing EUROIMMUN, Luebeck, Germany) and the fluorescence immunoassay ELiA dsDNA (Thermo Fisher Scientific, Waltham, USA) were performed. In addition, demographic data, further laboratory values and disease activity parameters were recorded. Clinical disease activity was assessed by SLEDAI-2K. Both assays showed high specificity (anti-dsDNA-NcX ELISA: 0.9, ELiA dsDNA: 0.959), but there were notable differences in sensitivity (anti-dsDNA-NcX ELISA: 0.51, ELiA dsDNA: 0.38). Pearsons's correlation yielded a positive correlation between anti-dsDNA concentrations and CRP concentrations for the anti-dsDNA-NcX ELISA (R=0.22; p=0.038) and a mild-to-moderate inverse correlation between concentrations of anti-dsDNA and complement C4 for the ELiA dsDNA test (R=-0.22; p=0.045) when SLE and control patients were considered together. Other than, no significant correlation between anti-dsDNA concentrations and clinical or laboratory findings was found for either test procedure. Both anti-dsDNA antibody assays represent reliable examination methods with high specificity for the diagnosis of SLE that fulfill EULAR/ACR requirements. However, the anti-dsDNA-NcX ELISA showed superior sensitivity and significant correlation with disease activity (as measured by CRP concentrations).

Serum 25(OH)D levels are associated with disease activity and renal involvement in initial-onset childhood systemic lupus erythematosus.

Vitamin D deficiency is common in patients with systemic lupus erythematosus (SLE) and may affect their disease activity and severity. This study aims to assess the vitamin D status in patients with initial-onset SLE during childhood and its association with the clinical and laboratory markers of disease activity. This is a retrospective study that includes 168 patients with initial-onset SLE during childhood and 109 healthy children as controls. Clinical and laboratory data were recorded. The area under the curve (AUC) method was used to evaluate the efficacy of double-stranded deoxyribonucleic acid (dsDNA), lower 25(OH)D and complement 3 (C3) alone and in combination to diagnose the presence of renal damage in children with SLE. Compared with the controls (25.53 ± 7.02 ng/ml), patients with initial-onset SLE during childhood have lower serum 25(OH)D levels (18.63 ± 5.32 ng/ml) (P < 0.05). Among patients with initial-onset SLE during childhood, SLEDAI-2K scores are significantly higher in the vitamin D insufficiency (median = 14.5) and vitamin D deficiency (median = 14.0) groups than in the vitamin D sufficiency group (median = 9.0) (P < 0.05). Patients with initial-onset SLE during childhood with lower 25(OH)D levels are more likely to have lupus nephritis (LN) and a higher SDI score (P < 0.05). Compared with patients with other types of LN (16.69 ± 3.90 ng/ml), patients with type V LN have lower levels of 25(OH)D (12.27 ± 3.53 ng/ml) (P < 0.05). The AUC was 0.803 when dsDNA antibody, 25(OH)D level and C3 were used in combination to diagnose LN in patients with SLE. Vitamin D deficiency and insufficiency are closely related to an increase in SLEDAI and SDI scores. Significant decrease in vitamin D level is a risk factor for LN.

CD19/BCMA CAR-T Cell Therapy for Refractory Systemic Lupus Erythematosus - Safety and Preliminary Efficacy Data from a Phase I Clinical Study

Background: Despite significant advances in the treatment of systemic lupus erythematosus (SLE), a subset of patients continue to experience severe progression of their disease despite multiple immunosuppressive and targeted therapies. Furthermore, to date, drug-free remission and seroconversion have been difficult to achieve in SLE. CD19 single-targeted chimeric antigen receptor (CAR) T-cell therapies have shown promising efficacy in SLE but have been unable to attack CD19-negative, long-lived plasma cells, which produce numerous antibodies.This trial aims to study the safety, tolerability and preliminary efficacy of deep B-cell clearance in patients with refractory SLE using autologous anti-CD19 and BCMA CAR-T cells. Method: The CAR product was manufactured by Shanghai YaKe Biotechnology Ltd. The clinical study was conducted in a dose-escalation format. T cells were enriched from patient's peripheral blood, transfected with lentiviral vectors and expanded. After lymphodepleting chemotherapy with cyclophosphamide/fludarabine (D-4 to D-2), patients receive a single infusion of 1-2x106 CD19 CAR-T cells and BCMA CAR-T cells per kilogram of body weight at D0. On the first day of chemotherapy initiation , all SLE-related immunosuppressants, biologics, etc. were discontinued except for a few patients who were maintained on low-dose prednisolone. Tolerability was assessed by monitoring cytokine release syndrome (CRS), immune-related effector cell neurotoxicity syndrome (ICANS), and infections. Initial efficacy was assessed by attainment of lupus low disease activity state (LLDAS), dsDNA antibody and ANA seroconversion, and discontinuation of all SLE-specific therapies. Results: As of July 31, 2023, 12 patients with refractory SLE were treated with CD19/BCMA CAR-T cells with a median follow-up of 118.5 (45-524) days. All patients had active severe SLE and had received glucocorticoids, hydroxychloroquine, tacrolimus, total glucosides of paeony, merti-macrolide, leflunomide, azathioprine, methotrexate, cyclophosphamide, immunoglobulin, rituximab, belimumab, and Tetracycline before treatment with CAR-T cells, which were standard treatments that were either ineffective or difficult to withdraw.3 patients received 1x10^6/kg of each of CD19 CAR-T cells and BCMA CAR-T cells, and 9 patients received 2x10^6/kg of each of CD19 CAR-T cells and BCMA CAR-T cells 2x10^6/kg. CAR-T cells were prepared successfully in all patients. BCMA CAR-T achieved expansion in all patients, while CD19 CAR-T did not expand in 1 patient, and expansion of CAR T cells preceded depletion of circulating B cells. All patients developed grade 1 CRS, which manifested as controllable fever, and no ICANS occurred. 11 patients (91.7%) developed grade 4 hematologic toxicity, and 1 patient (8.3%) developed grade 3 hematologic toxicity. Within 6 months of CAR-T treatment, 2 patients were infected with neocoronavirus, 1 patient developed gastrointestinal tract infection, and 1 patient developed pulmonary infection , and all of them recovered after treatment. The SLEDAI-2K score decreased in all patients, from a mean of 18.3 to 1.5. Low-level proteinuria persisted in some patients, possibly due to previously accumulated glomerular filtration impairment. All patients met LLDAS criteria and were able to successfully discontinue all SLE-related medications, including glucocorticoids. peripheral blood B cells recovered at approximately 3 months after CAR-T therapy. To date, no SLE flares have occurred. Conclusions: These data suggest that CD19/BCMA CAR-T cell therapy is well tolerated and can induce rapid and durable remission in severe refractory SLE.

Cerebral Microstructural and Microvascular Changes in Non-Neuropsychiatric Systemic Lupus Erythematosus: A Study Using Diffusion Kurtosis Imaging and 3D Pseudo-Continuous Arterial Spin Labeling.

The purpose of this study was to observe cerebral microstructure and microcirculation features, as well as changes in white matter (WM) and gray matter (GM) among patients with non-neuropsychiatric systemic lupus erythematosus (non-NPSLE). We compared 36 female patients with non-NPSLE and 20 age- and gender-matched healthy controls (HCs) who underwent 3.0T MRI imaging with diffusion kurtosis imaging (DKI) and 3D pseudo-continuous Arterial Spin Labeling (pCASL). Mean kurtosis (MK), mean kurtosis tensor (MKT), and cerebral blood flow (CBF) values were obtained from 25 brain regions, including WM and GM. We analyzed the correlation between imaging indicators and clinical data. When compared with HCs, patients with non-NPSLE had reduced MK and MKT values in regional WM, deep GM, and the left frontal lobe cortical GM, and increased CBF in the right parietal lobe WM and right semioval center (SOC). The MK and MKT values were weakly correlated with CBF in some regions, including WM and GM. Complement 3 (C3) and Complement 4 (C4) showed a weak positive correlation with MK and MKT in some regions, including WM and deep GM, while platelet (PLT) was positively correlated with MKT in the left frontal lobe WM; dsDNA antibody was correlated negatively with MK in the right occipital lobe WM; and erythrocyte sedimentation rate (ESR) was correlated negatively with CBF in the left SOC. Our findings revealed the presence of brain microstructural and microvascular abnormalities in non-NPSLE patients, indicating microstructural damage in the cortical GM, which was less commonly reported. We found DKI and pCASL useful in detecting early brain lesions, and MK was a more sensitive and beneficial indicator.

Multiple RNA-binding proteins associated with long interspersed element-1 encoded ORF1p are targeted by the autoimmune response in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a relatively common autoimmune disease characterized by the presence of autoantibodies against nucleic acids and proteins that associate with them, such as the ORF1p protein encoded by the long interspersed element-1 (LINE-1 or L1). Because well-known lupus autoantigens like RO60 associate with ORF1p in macromolecular assemblies, together with many other RNA-binding proteins, we tested whether these other proteins are also recognized by IgG autoantibodies in SLE patients. By ELISAs and immunoblots, we detected autoantibodies in the serum of SLE patients recognizing proteins encoded by LARP7, MOV10, ZCCHC3, MEPCE, YARS2, RPL18A, RPL27A, and H2BC17 (p&lt;0.05), but not CORO1B, DDX6, PABPC1, and PABPC4, and were mostly absent or low in healthy controls. The titers of antibodies against RO60, LARP7, MOV10, and MEPCE were higher (p&lt;0.05) in those patients who also had anti-ORF1p autoantibodies. These antibodies also correlated with dsDNA antibodies, the presence of arthritis, and higher levels of type I interferons. A cluster analysis revealed that all these autoantibodies collectively identified patients with more active disease. We conclude that patients with SLE have elevated IgG autoantibodies not only against the L1-encoded ORF1p, but also against 8 other proteins that co-localize with ORF1p in RNA-rich granules. These autoantibodies are higher in patients who have autoantibodies to ORF1p and together correlate with elevated type I interferon levels. Our findings are compatible with the notion that ORF1p-containing ribonucleoprotein granules are a target of the autoimmunity in SLE.