Subchronic intranasal lipopolysaccharide exposure induces pulmonary autoimmunity and glomerulonephritis in NZBWF1 mice.

Lupus, a systemic autoimmune disease shaped by gene-environment interplay, often progresses to endstage renal failure. While subchronic systemic exposure to bacterial lipopolysaccharide (LPS) triggers autoimmunity and glomerulonephritis in lupus-prone mice, it is unknown if inhaling LPS, which is common in certain occupations, can similarly trigger lupus. Here we determined how subchronic intranasal (IN) LPS instillation influences autoimmunity and glomerulonephritis development in lupusprone NZBWF1 female mice. Briefly, mice were IN-instilled with vehicle or E. coli LPS (0.8 µg/g) twice weekly for 5 wk, followed by necropsy. For systemic comparison, additional cohorts of mice were injected with LPS intraperitoneally (IP) using identical doses/timing. Lungs were assessed for inflammatory and autoimmune responses and then related to systemic autoimmunity and glomerulonephritis. IN/LPS exposure induced in the lung: i) leukocyte infiltration, ii)mRNA signatures for cytokines, chemokines, IFN-regulated, and cell death-related genes, iii) ectopic lymphoid tissue formation, and iv)diverse IgM and IgG autoantibodies (AAbs). Pulmonary effects coincided with enlarged spleens, elevated plasma IgG AAbs, and inflamed IgG-containing kidney glomeruli. In contrast, IP/LPS treatment induced systemic autoimmunity and glomerulonephritis without pulmonary manifestations. Taken together, these preclinical findings suggest the lung could serve as a critical nexus for triggering autoimmunity by respirable LPS in genetically predisposed individuals.

Inhibition of GRK2 ameliorates the pristane-induced mouse SLE model by suppressing plasma cells differentiation.

Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by diverse clinical manifestations and organ damage. Despite its elusive etiology, dysregulated subsets and functions of B cells are pivotal in SLE pathogenesis. Peoniflorin-6'-O-benzene sulfonate (CP-25), an esterification modification of Paeoniflorin, exhibits potent anti-inflammatory and immunomodulatory properties in autoimmune diseases (AID). However, the involvement of CP-25 and its target, GRK2, in SLE development has not been explored. In this study, we demonstrate that both genetic deficiency and pharmacological inhibition of GRK2 attenuate autoantibodies production, reduce systemic inflammation, and mitigate histopathological alterations in the spleen and kidney in the pristane-induced mouse SLE model. Importantly, our findings highlight that both genetic deficiency and pharmacological inhibition of GRK2 suppress plasma cells generation and restore dysregulated B-cell subsets by modulating two crucial transcription factors, Blimp1 and IRF4. Collectively, targeting GRK2 with CP-25 emerges as a promising therapeutic approach for SLE.

Environmental triggers of autoimmunity: The association between bisphenol analogues and systemic lupus erythematosus.

The aim of this research was to examine the correlation between the exposure to bisphenol analogues (BPs), such as bisphenol A (BPA), bisphenol F (BPF), and bisphenol S (BPS), and the risk of developing systemic lupus erythematosus (SLE). Ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was utilized to measure the levels of BPA, BPF, and BPS in the urine of 168 female participants diagnosed with SLE and 175 female participants who were deemed healthy controls. Logistic regression models were utilized to assess the connections between levels of bisphenol and the risk of SLE. The findings indicated that levels of BPA and BPF in the urine of individuals with SLE were markedly elevated compared to those in the control group. Higher exposure to BPA and BPF exhibited positive dose-response relationships with increased SLE risk. No significant associations were identified between BPS and the risk of SLE. These findings suggest exposure to BPA and BPF may be implicated as novel environmental triggers in the development of autoimmunity such as SLE. The significantly increased levels of these bisphenol analogues detected in SLE patients versus healthy controls, along with the associations between higher exposures and elevated SLE risk, which offers crucial hints for comprehending how endocrine-disrupting substances contribute to the genesis of autoimmune illnesses. Further research using robust longitudinal assessments of bisphenol analogue exposures is warranted to corroborate these epidemiological findings. Overall, this study highlights potential environmental risk factors for SLE while calling for additional investigation into the impact of bisphenol exposures on autoimmunity development.

De novo Connective Tissue Disorders as Immune-related Adverse Events.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment through blocking immunoregulatory pathways, resulting in augmented antitumor responses. However, ICIs can cause inflammatory autoimmune toxicities, known as immune-related adverse events (irAEs). Common rheumatic irAEs include inflammatory arthritis, polymyalgia rheumatica-like symptoms, and myositis. Fewer cases of de novo connective tissue disease as irAEs have been described and have mainly presented with cutaneous manifestations of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Treatments include glucocorticoids and steroid-sparing agents such as hydroxychloroquine, mycophenolate mofetil, and methotrexate with improvement of symptoms. In this review, the authors discuss immune-related SLE and SSc and their management.

Drug-induced lupus erythematosus in childhood: Case-based review.

BACKGROUND: Drug-induced lupus erythematosus (DILE) is the development of lupus-like syndrome following a drug exposure. DILE has been reported less frequently among children than adults. METHODS: In this study, we present four children with DILE and similar published cases through a systematic literature review. RESULTS: We report four children (three girls and one boy) who developed DILE associated with the use of topiramate, doxycycline, etanercept, and ethosuximide. Three of them were positive for anti-histone antibodies. In all patients, the drug was discontinued and symptoms resolved completely. The literature review revealed 48 articles describing 61 children with DILE. In the evaluation of 65 patients (our 4 patients and 61 patients from the literature), the most frequently reported drugs associated with DILE were ethosuximide (n = 13) and minocycline (n = 12). Fever (n = 33), arthralgia (n = 31), rash (n = 30), and arthritis (n = 29) were the most common clinical manifestations. Antinuclear antibody (ANA) was positive in 93.5% of patients and anti-histone antibodies were detected in 72.2% of the patients. As for treatment, the responsible drug was discontinued in all patients, and corticosteroids were initiated in 53.3%. Improvement was achieved in 92.0% of patients. CONCLUSION: For children presenting with SLE features, proper drug history is crucial since DILE may be more frequent than anticipated. An association of the relevant drug with the symptoms, and resolution of symptoms on drug withdrawal provides evidence for the diagnosis of DILE.

Methyl-supplemented nutrition delays the development of autoimmune disease in pristane-induced murine lupus.

The aetiology and progression of systemic lupus erythematosus (SLE) resulted from a complex sequence of events generated both from genetic and epigenetic processes. In the current research, the effect of methyl-supplemented nutrition on the development of SLE was studied in the pristane-induced mouse model of the disease. The results clearly demonstrated decreased anti-dsDNA antibody and proteinuria levels, modulation of cytokines and protected renal structures in the group of treated mice. An additional increase in the DNA methylation of mouse B lymphocytes was also observed. The beneficial effect of the diet is due to the methyl-containing micronutrients with possible anti-inflammatory and immunomodulating effects on cell proliferation and gene expression. Since these components are responsible for maintaining the physiological methylation level of DNA, the results point to the central role of methylation processes in environmentally triggered lupus. As nutrition represents one of the major epigenetic factors, these micronutrients may be considered novel agents with significant therapeutic outcomes.

Initiation of belimumab with higher daily prednisolone is effective for rapid glucocorticoid reduction: A 96-week retrospective study.

OBJECTIVES: For appropriate glucocorticoid (GC) reduction, we investigated the optimal strategy including baseline factors that could reduce GC more than 50% with 96 weeks of belimumab. METHODS: This is a retrospective cohort study of Kakogawa Central City hospital from 2019 to 2023. We identified SLE patients who were receiving 200 mg of belimumab weekly by subcutaneous injection for 96 weeks. The background at baseline, trends in clinical indicators, and factors involved in GC reduction were statistically analyzed. Finally, univariate and multivariate logistic analyses were carried out to identify baseline factors associated ≥50% GC reduction at 96 weeks. RESULTS: Forty-seven patients were enrolled, with a median daily prednisolone of 5 mg. Almost 90% of them received concomitant immunosuppressants and/or hydroxychloroquine. Serological indices, daily GC dose, and SLEDAI-2K scores showed significant improvement in 96 weeks. At baseline, a significant negative correlation has been shown between the daily dose of GC and the duration from onset or last flare, as well as C4 levels. At 96 weeks, GC reduction rate and SLEDAI-2K scores were negatively correlated with duration from onset or last flare to initiation of belimumab. Mycophenolate mofetil use was significantly frequent in patients with lupus nephritis (LN), which also correlated with the frequency of past flares. In addition, LN presence was associated with higher SLEDAI-2K scores at 96 weeks, and baseline SLEDAI-2K ≥10 was associated with significantly higher GC dose at 96 weeks. Univariate analysis of the factor contributing to achieving ≥50% GC reduction at 96 weeks has pointed shorter disease duration and higher daily GC dose at baseline as significant variables. Finally, we performed a multivariate analysis by combining above two items with age, which extracted the higher daily GC dose at baseline as a significant variable (OR (95% CI) 1.25 (1.00 to 1.56), p = .047). CONCLUSIONS: Our study showed that a delay in belimumab initiation led to higher SLEDAI-2K score and difficulty in achieving a 50% GC reduction at 96 weeks. Since GC-related adverse events increase with long-term administration of GC though with small daily doses, we proposed here that belimumab should be started in combination with higher daily prednisolone.

Identification of new risk factors for hydroxychloroquine and chloroquine retinopathy in systemic lupus erythematosus patients.

BACKGROUND: Long-term hydroxychloroquine (HCQ) or chloroquine (CQ) intake causes retinal toxicity in 0.3-8 % of patients with rheumatic diseases. Numerous risk factors have been described, eg, daily dose by weight, treatment duration, chronic kidney disease, concurrent tamoxifen therapy and pre-existing retinal or macular disease. However, those factors cannot explain the entire risk of developing antimalarial retinopathy. OBJECTIVE: This study was undertaken to identify new risk factors associated with HCQ or CQ retinopathy (QRNP) in systemic lupus erythematosus (SLE) patients. METHODS: This case-control (1:2) study compared SLE patients with QRNP (cases) to those without (controls). Controls were matched for sex and known QRNP risk factors: HCQ and/or CQ treatment duration (±1 year) and age (±5 year) at SLE diagnosis. RESULTS: Forty-eight cases were compared to 96 SLE controls. Multivariable logistic-regression analysis retained the following as independent determinants significantly associated with QRNP: concomitant selective serotonin-reuptake inhibitor (SSRI) or serotonin- and norepinephrine-reuptake inhibitor (SNRI) intake (OR [95 % confidence interval] 6.6 [1.2 to 40.9]; p < 0.01); antiphospholipid syndrome (OR=8.9 [2.2 to 41.4] p < 0.01); blood hydroxychloroquine/desethylchloroquine concentration ([HCQ]/[DCQ]) ratio <7.2 (OR 8.4 [2.7 to 30.8]; p < 0.01) or skin phototype ≥4 (OR 5.5 [1.4 to 26.5]; p = 0.02), but not daily HCQ dose, blood [HCQ] or body mass index. CONCLUSION: The results of this case-control study identified blood [HCQ]/[DCQ] ratio, concurrent SSRI/SNRI therapy, skin phototype ≥4 and antiphospholipid syndrome as new risk factors for QRNP.

Predictors and prognostic factors influencing outcomes of anti-CD20 monoclonal antibodies in systemic lupus erythematosus: A systematic review update.

BACKGROUND: Anti-C20 monoclonal antibodies (MAb), such as rituximab, are commonly used for the treatment of patients with severe or refractory systemic lupus erythematosus (SLE) but clinical outcomes are highly variable. We aimed to provide an update of a systematic review of predictive and prognostic factors of anti-CD20 MAb treatment in SLE. METHODS: A systematic literature search was undertaken to identify predictive and prognostic factors of clinical response following treatment with anti-CD20 therapies in SLE patients. Studies examining rituximab published prior to 2015 were excluded. Risk of bias was assessed for randomized controlled trials (RCTs) using the Cochrane Collaboration (RoB2) tool for RCTs and the Quality In Prognosis Studies Tool (QUIPS) for cohort studies. A narrative synthesis of the evidence was undertaken and quality of evidence (QoE) was assessed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: From 850 studies identified, 17 studies met the inclusion criteria. A further 8 studies were identified and included through search updates. There were two post-hoc analyses of RCTs of rituximab, one RCT of ocrelizumab and one of obinutuzumab; and 16 cohort studies examining rituximab treatment. The overall QoE was low or very low. There was wide heterogeneity in definitions of clinical disease activity and outcome measures, non-standardized laboratory cut-offs, failure to account for confounders and multiple subgroup analyses of differing outcomes. B cell depletion as well as novel biomarkers, such as S100 proteins, FCGR genotype, anti-vimentin and anti-drug antibodies showed some evidence of prognostic value but QoE was limited due to moderate to high risk of bias, early phase of investigation and imprecision of results. CONCLUSION: There has been no validation of previously identified prognostic factors to guide outcome in anti-CD20 treated lupus patients. Hypothesis-driven studies of several novel markers however, demonstrate prognostic value and require replication and validation to support their use in routine clinical practice. PROSPERO REGISTRATION NUMBER: CRD42020220339.

COVID vaccine-induced lupus nephritis: Case report and review of the literature.

Vaccines offer an effective strategy to prevent infectious diseases with minimal adverse effects. On rare occasions, vaccination can disrupt the immune response leading to induction of autoimmune diseases. We describe a case of new-onset lupus nephritis following COVID-19 vaccination with the first dose of the Pfizer vaccine. Her symptoms and lab values improved with steroids, hydroxychloroquine, and mycophenolate mofetil.

Does baricitinib reduce disease activity in patients with systemic lupus erythematosus? A systematic review and meta-analysis of randomized controlled trials.

Baricitinib is a selective Janus kinase inhibitor that has recently been approved for treating certain autoimmune disorders. This meta-analysis pooled the conflicting results from all published randomized controlled trials (RCTs) about the efficacy and safety of baricitinib in patients with systemic lupus erythematosus (SLE). We systemically searched four electronic databases. RCTs comparing baricitinib versus placebo were included. Our outcomes were pooled as the risk ratio (RR) in the random effects model. Our primary outcome was the proportion of patients who achieved a SLE Responder Index-4 (SRI-4) response. A total of three RCTs, comprising 1849 patients, were included. Baricitinib 4 mg was associated with a significantly higher proportion of patients who attained SRI-4 response at week 24 (RR = 1.19, 95% CI [1.05, 1.35], P < 0.01). However, this did not reach statistical significance with baricitinib 4 mg at week 52 and baricitinib 2 mg at both week 24 and week 52 (RR = 1.13, 95% CI [0.96, 1.34], P = 0.15; RR = 1.09, 95% CI [0.96, 1.24], P = 0.20; RR = 1.05, 95% CI [0.92, 1.19], P = 0.50, respectively). The risk for serious infections was higher in the baricitinib 4 mg group (RR = 2.23, 95% CI [1.13, 4.37], P = 0.02). Baricitinib 2 mg did not show any clinical benefit. In contrast, baricitinib 4 mg might have the potential to reduce SLE disease activity; however, further research is required to evaluate its long-term efficacy. Until higher-quality evidence is developed, the benefits and risks of baricitinib should be considered before initiating its therapy. Key Points • Baricitinib is a selective Janus kinase inhibitor that has recently been approved for treating certain autoimmune disorders; however, its efficacy in patients with systemic lupus erythematosus (SLE) is still inconclusive. • In our meta-analysis, baricitinib 2 mg did not show any clinical benefit. In contrast, baricitinib 4 mg significantly reduced SLE activity in terms of SRI-4 response at week 24. However, this did not reach statistical significance at week 52. • Further studies are required to investigate the long-term efficacy of baricitinib 4 mg in patients with SLE.

Belimumab and antimalarials combined against renal flares in patients treated for extra-renal systemic lupus erythematosus: results from 4 phase III clinical trials.

OBJECTIVES: To determine the effect of antimalarial agents (AMA) and different doses and pharmaceutical forms of belimumab on preventing renal flares in patients with SLE treated for extra-renal disease. METHODS: We pooled data from the BLISS-52, BLISS-76, BLISS-SC and BLISS-Northeast Asia trials of belimumab (n = 3225), that included patients with active SLE yet no severe ongoing nephritis. Participants were allocated to receive intravenous belimumab 1 mg/kg, intravenous belimumab 10 mg/kg, subcutaneous belimumab 200 mg, or placebo in addition to standard therapy. We estimated hazards of renal flare development throughout the study follow-up (52-76 weeks) using Cox regression analysis. RESULTS: In total, 192 patients developed a renal flare after a median of 197 days. Compared with placebo, the risk of renal flares was lower among patients receiving intravenous belimumab 10 mg/kg (HR: 0.62; 95% CI: 0.41, 0.92; P = 0.018) and intravenous belimumab 1 mg/kg (HR: 0.42; 95% CI: 0.22, 0.79; P = 0.007), while no significant association was found for subcutaneous belimumab 200 mg. AMA use yielded a lower hazard of renal flares (HR: 0.66; 95% CI: 0.55, 0.78; P < 0.001). The protection conferred was enhanced when belimumab and AMA were co-administered; the lowest flare rate was observed for the combination intravenous belimumab 1 mg/kg and AMA (18.5 cases per 1000 person-years). CONCLUSIONS: The protection conferred from belimumab against renal flare development in patients treated for extra-renal SLE appears enhanced when belimumab was administered along with AMA. The prominent effect of low-dose belimumab warrants investigation of the efficacy of intermediate belimumab doses. CLINICAL TRIAL IDENTIFICATION: BLISS-52: NCT00424476; BLISS-76: NCT00410384; BLISS-SC: NCT01484496; BLISS-NEA: NCT01345253.

Efficacy and safety of intravenous belimumab in a subgroup of South Korean patients with systemic lupus erythematosus enrolled into a Phase 3, randomized, placebo-controlled trial in North East Asia.

AIM: This post hoc analysis evaluated the efficacy and safety of intravenous belimumab 10 mg/kg in the South Korean subgroup of patients with systemic lupus erythematosus (SLE) enrolled in the North East Asia (NEA) study (GSK Study BEL113750; NCT01345253). METHODS: NEA was a double-blind, placebo-controlled, randomized Phase 3 trial. Patients with active, autoantibody-positive SLE were randomized 2:1 to belimumab or placebo plus standard therapy administered on Days 0, 14, and 28, and then every 28 days up to Week 48. The primary efficacy endpoint in this analysis was SLE Responder Index 4 (SRI-4) response rate at Week 52, defined as the proportion of patients achieving a ≥4-point reduction in Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score, no worsening (<0.3 increase from baseline) in Physician Global Assessment, no new British Isles Lupus Assessment Group (BILAG) A domain and <2 new BILAG B domain scores. RESULTS: Among 100 South Korean patients enrolled in NEA, 54/66 (81.8%) belimumab- and 24/34 (70.6%) placebo-treated patients completed the double-blind phase. Significantly more belimumab- than placebo-treated patients achieved SRI-4 response at Week 52 (n = 35/66, 53.0% vs. n = 8/34, 23.5%; odds ratio [OR; 95% confidence interval (CI)]: 3.67 [1.45, 9.28]; p = .0061). The proportion of patients experiencing ≥1 adverse event was similar between groups (belimumab: n = 60/66, 90.9% vs. placebo: n = 31/34, 91.2%). No new safety signals emerged in this subgroup analysis. CONCLUSION: Belimumab was efficacious for the treatment of SLE and well tolerated among the South Korean subgroup of patients from the NEA study.

Methylprednisolone pulse-enhanced neutrophil extracellular trap formation in mice with imiquimod-induced lupus-like disease, resulting in ischaemia of the femoral head cartilage.

OBJECTIVES: Methylprednisolone (mPSL) pulse therapy is an essential option for patients with active systemic lupus erythematosus, but there is a risk of adverse events related to microcirculation disorders, including idiopathic osteonecrosis of the femoral head (ONFH). Recent studies have revealed that excessive neutrophil extracellular traps (NETs) are involved in microcirculation disorders. This study aimed to demonstrate that mPSL pulse could induce NETs in lupus mice and identify the factors contributing to this induction. METHODS: Six mice with imiquimod (IMQ)-induced lupus-like disease and six normal mice were intraperitoneally injected with mPSL on days 39 to 41, and five mice with IMQ-induced lupus-like disease and six normal mice were injected with phosphate-buffered saline. Pathological examinations were conducted to evaluate the ischaemic state of the femoral head and tissue infiltration of NET-forming neutrophils. Proteome analysis was performed to extract plasma proteins specifically elevated in mPSL-administered mice with IMQ-induced lupus-like disease, and their effects on NET formation were assessed in vitro. RESULTS: Mice with IMQ-induced lupus-like disease that received mPSL pulse demonstrated ischaemia of the femoral head cartilage with tissue infiltration of NET-forming neutrophils. Proteome analysis suggested that prenylcysteine oxidase 1 (PCYOX1) played a role in this phenomenon. The reaction of PCYOX1-containing very low-density lipoproteins (VLDL) with its substrate farnesylcysteine (FC) induced NETs in vitro. The combined addition of IMQ and mPSL synergistically enhanced VLDL-plus-FC-induced NET formation. CONCLUSION: PCYOX1 and related factors are worthy of attention to understand the underlying mechanisms and create novel therapeutic strategies for mPSL-mediated microcirculation disorders, including ONFH.

In vivo ameliorative effects of vitamin E against hydralazine-induced lupus.

OBJECTIVE: In this study, we investigated the in vivo ameliorative effects of vitamin E in a hydralazine-induced lupus model, which closely resembles SLE in humans. We aim to shed light on its potential as a therapeutic agent for managing SLE. METHODS: Forty BALB/c mice were used in this study. Hydralazine hydrochloride was orally administered in a concentration of 25 mg/kg to the five mice groups once weekly for a period of 5 weeks to induce a lupus-like condition. The untreated group was the normal control group. To confirm the development of lupus, an ANA test was conducted. After the mice tested positive for ANA, drug treatments commenced. The negative control group did not receive any drug treatment. The treatments included prednisolone, methotrexate and vitamin E, all administered at a concentration of 25 mg/kg, with a higher dose of vitamin E (50 mg/kg) also administered. RESULTS: Notably, on day 35, after drug treatment, we observed that mice that received vitamin E at a dosage of 50 mg/kg (3.01±0.100) had a slight decrease in lymphocyte hydrogen peroxide radicals when compared with the group receiving 25 mg/kg of vitamin E (3.30±0.100) (p<0.05). This finding suggests that the scavenging potential of vitamin E is dose dependent. CONCLUSION: This study suggests that vitamin E supplementation, especially at a higher dose (50 mg/kg), holds promise in ameliorating lupus-like conditions. These findings warrant further exploration and may offer a potential avenue for improving the disease status of patients experiencing SLE.

Presumptive phenobarbital-induced systemic lupus erythematosus in a domestic dog.

CASE DESCRIPTION: We describe a case of presumptive acquired systemic lupus erythematosus secondary to phenobarbital administration in a dog, which resolved with withdrawal of the drug. CLINICAL FINDINGS: A 3.5 year-old poodle presented to a veterinary teaching hospital for Tier 1 idiopathic epilepsy and was treated with phenobarbital. The dog experienced fever, multiple cytopenias, and proteinuria in conjunction with a positive antinuclear antibody (ANA) titer. DIAGNOSTICS: Serial CBCs, urine protein : creatinine ratios, and sternal bone marrow aspirates were performed to evaluate improvement. TREATMENT AND OUTCOME: Phenobarbital was withdrawn and levetiracetam initiated. All abnormalities resolved with supportive care, without initiation of immunosuppressive drugs. All cytopenias and proteinuria resolved and ANA test results became negative within 3 months. The patient recovered and did well clinically. CLINICAL RELEVANCE: Systemic lupus erythematosus is a disease of multiple autoimmune syndromes occurring concurrently or sequentially in conjunction with the presence of circulating ANA. It has been well described in dogs as an idiopathic condition, but in human medicine may occur secondary to drug reactions (drug-associated lupus) including as a reaction to phenobarbital. The findings in our case are consistent with the criteria for drug-induced lupus in humans and we suggest it as the first report of phenobarbital-induced lupus in a dog.