Systemic Lupus Erythematosus Disease Research Articles

Valuing Health Gain from Composite Response Endpoints for Multisystem Diseases

ObjectivesThis study aimed to demonstrate how to estimate the value of health gain after patients with a multisystem disease achieve a condition-specific composite response endpoint. MethodsData from patients treated in routine practice with an exemplar multisystem disease (systemic lupus erythematosus) were extracted from a national register (British Isles Lupus Assessment Group Biologics Register). Two bespoke composite response endpoints (Major Clinical Response and Improvement) were developed in advance of this study. Difference-in-differences regression compared health utility values (3-level version of EQ-5D; UK tariff) over 6 months for responders and nonresponders. Bootstrapped regression estimated the incremental quality-adjusted life-years (QALYs), probability of QALY gain after achieving the response criteria, and population monetary benefit of response. ResultsWithin the sample (n = 171), 18.2% achieved Major Clinical Response and 49.1% achieved Improvement at 6 months. Incremental health utility values were 0.0923 for Major Clinical Response and 0.0454 for Improvement. Expected incremental QALY gain at 6 months was 0.020 for Major Clinical Response and 0.012 for Improvement. Probability of QALY gain after achieving the response criteria was 77.6% for Major Clinical Response and 72.7% for Improvement. Population monetary benefit of response was £1 106 458 for Major Clinical Response and £649 134 for Improvement. ConclusionsBespoke composite response endpoints are becoming more common to measure treatment response for multisystem diseases in trials and observational studies. Health technology assessment agencies face a growing challenge to establish whether these endpoints correspond with improved health gain. Health utility values can generate this evidence to enhance the usefulness of composite response endpoints for health technology assessment, decision making, and economic evaluation.

Systemic lupus erythematosus and cardiovascular disease.

The prognosis in systemic lupus erythematosus (SLE) has improved due to better treatment and care, but cardiovascular disease (CVD) still remains an important clinical problem, since the risk of CVD in SLE is much higher than among controls. Atherosclerosis is the main cause of CVD in the general population, and in SLE, increased atherosclerosis, especially the prevalence of atherosclerotic plaques, has been demonstrated. Atherosclerosis is an inflammatory condition, where immunity plays an important role. Interestingly, oxidized low-density lipoprotein, defective clearance of dead cells, and inflammation, with a pro-inflammatory T-cell profile are characteristics of both atherosclerosis and SLE. In addition to atherosclerosis as an underlying cause of CVD in SLE, there are also other non-mutually exclusive mechanisms, and the most important of these are antiphospholipid antibodies (aPL) leading to the antiphospholipid antibody syndrome with both arterial and venous thrombosis. aPL can cause direct pro-inflammatory and prothrombotic effects on endothelial and other cells and also interfere with the coagulation, for example, by inhibiting annexin A5 from its antithrombotic and protective effects. Antibodies against phosphorylcholine (anti-PC) and other small lipid-related epitopes, sometimes called natural antibodies, are negatively associated with CVD and atherosclerosis in SLE. Taken together, a combination of traditional risk factors such as hypertension and dyslipidemia, and nontraditional ones, especially aPL, inflammation, and low anti-PC are implicated in the increased risk of CVD in SLE. Close monitoring of both traditional risk factors and nontraditional ones, including treatment of disease manifestations, not lest renal disease in SLE, is warranted.

Peroxisome proliferator activated receptor-γ agonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus

ObjectivesPremature cardiovascular events in systemic lupus erythematosus (SLE) contribute to morbidity and mortality, with no effective preventive strategies described to date. Immune dysregulation and metabolic disturbances appear to play prominent...

Timing and Predictors of Incident Cardiovascular Disease in Systemic Lupus Erythematosus: Risk Occurs Early and Highlights Racial Disparities.

Systemic lupus erythematosus (SLE) affects Black people 2 to 3 times more frequently than non-Black people and is associated with higher morbidity and mortality. In total, 4 studies with predominantly non-Black SLE cohorts highlighted that cardiovascular disease (CVD) is no longer primarily a late complication of SLE. This study assessed the timing and predictors of incident CVD in a predominantly Black population-based SLE cohort. Incident SLE cases from the population-based Georgia Lupus Registry were validated as having a CVD event through review of medical records and matching with the Georgia Hospital Discharge Database and the National Death Index. The surveillance period for an incident CVD event spanned a 15-year period, starting from 2 years prior to SLE diagnosis. Among 336 people with SLE, 253 (75%) were Black and 56 (17%) had an incident CVD event. The frequency of CVD events peaked in years 2 and 11 after SLE diagnosis. There was a 7-fold higher risk of incident CVD over the entire 15-year period; this risk was 19-fold higher in the first 12 years in Black people as compared to non-Black people with SLE. Black people with SLE (P < 0.001) and those with discoid rash (hazard ratio 3.2, 95% CI 1.4-7.1) had a higher risk of incident CVD events. The frequency of incident CVD events peaked in years 2 and 11 after SLE diagnosis. Being Black or having a discoid rash were strong predictors of an incident CVD event. Surveillance for CVD and preventive interventions, directed particularly toward Black people with recent SLE diagnoses, are needed to reduce racial disparities.

Characteristics and risk factors of severe coronary artery disease in systemic lupus erythematosus: A multicenter, Chinese Rheumatism Date Center database study.

Systemic lupus erythematosus (SLE) with severe coronary artery disease (CAD) is associated with increased mortality. This study aimed to assess the characteristics and risk factors of severe CAD in SLE. This multicenter, cross-sectional study enrolled consecutive patients with SLE included in the Chinese Rheumatism Date Center registry. Patients with severe CAD including angiography-confirmed stenosis ≥50% in the left main, ≥70% in other major coronary arteries, or myocardial infarction were classified into the CAD group. Patients without CAD were classified into the control group. Subgroups were stratified according to age (set as above and below 45 and 50 for men and women, respectively) and gender. Binary logistic regression analysis was performed to determine independent risk factors of severe CAD in SLE. Forty-three patients had severe CAD from a total of 3744 patients with SLE, 30 of whom were female; 35 belonged to the older age group and 8 belonged to the younger age group. In older patients, independent risk factors included age, 5 major CAD risk factors, SLE Disease Activity Index 2000 (SLEDAI-2K), hyperuricemia, and corticosteroid exposure. In younger patients, the risk factors were 5 major CAD risk factors and positive antiphospholipid antibody (APL). Male risk factors were age and 5 major CAD risk factors, whereas female risk factors were age, 5 major CAD risk factors, SLEDAI-2K, and positive APL. Three-vessel disease was most prevalent in patients with severe CAD. We recommend screening for severe CAD in patients with SLE with age- and gender-stratified risk factors.

Sex bias in systemic lupus erythematosus: a molecular insight.

Acknowledging sex differences in immune response is particularly important when we consider the differences between men and women in the incidence of disease. For example, over 80% of autoimmune disease occurs in women, whereas men have a higher incidence of solid tumors compared to women. In general women have stronger innate and adaptive immune responses than men, explaining their ability to clear viral and bacterial infections faster, but also contributing to their increased susceptibility to autoimmune disease. The autoimmune disease systemic lupus erythematosus (SLE) is the archetypical sexually dimorphic disease, with 90% of patients being women. Various mechanisms have been suggested to account for the female prevalence of SLE, including sex hormones, X-linked genes, and epigenetic regulation of gene expression. Here, we will discuss how these mechanisms contribute to pathobiology of SLE and how type I interferons work with them to augment sex specific disease pathogenesis in SLE.

Ramipril Improves Endothelial Function and Increases the Number of Endothelial Progenitor Cells in Patients With Systemic Lupus Erythematosus.

Endothelial dysfunction and reduced number of endothelial progenitor cells (EPCs) in peripheral blood are contributing factors to cardiovascular disease in systemic lupus erythematosus (SLE) patients. Endothelial progenitor cell proliferation is regulated by vascular endothelial growth factor (VEGF). Angiotensin-converting enzyme inhibitors reduce cardiovascular mortality in patients with coronary heart disease. This was a randomized trial including 37 female SLE patients without cardiovascular risk factors allocated into 2 groups: 19 patients received ramipril 10 mg/d for 12 weeks (IG) and 18 patients maintained without ramipril (CG). Endothelial function was assessed by brachial artery ultrasound measuring flow-mediated dilation, and EPCs were quantified by flow cytometry and cell culture, at baseline and after 12 weeks. Serum VEGF levels were measured by enzyme-linked immunosorbent assay. Statistical analysis was intention to treat. p < 0.05 was considered significant. After 12 weeks, higher flow-mediated dilation (6.17% vs. 11.14%, p < 0.001) was observed in IG, without change in CG (5.37% vs. 5.02%, p = 0.630). Higher number of EPC colony-forming units was also observed in IG (21.3 ± 10.4 vs. 31.6 ± 8.5, p < 0.001), without difference in CG ( p = 0.714). No difference was found in EPCs evaluated by flow cytometry. Vascular endothelial growth factor level increased after 12 weeks in IG ( p = 0.048), with no difference in CG ( p = 0.661). Ramipril improved endothelial function and increased the numbers of EPCs evaluated by cell culture and VEGF levels in SLE patients without cardiovascular risk factors. These data suggest that angiotensin-converting enzyme inhibitor bring an extra benefit beyond the hypotensive action and should be considered as a preferred antihypertensive drug in SLE patients.

Global characterization of megakaryocytes in bone marrow, peripheral blood, and cord blood by single-cell RNA sequencing.

Megakaryocytes (MK) are mainly derived from bone marrow and are mainly involved in platelet production. Studies have shown that MK derived from bone marrow may have immune function, and that MK from peripheral blood are associated with prostate cancer. Single-cell transcriptome sequencing can help us better understand the heterogeneity and potential function of MK cell populations in bone marrow (BM), peripheral Blood (PB), and cord blood (CB) of healthy and diseased people.We integrated more than 1.2 million single-cell transcriptome data from 132 samples of PB, BM, and CB from healthy individuals and patients from different dataset. We examined the MK (including MK and product of MK) by single-cell RNA sequencing data analysis methods and identification of MK-related protein expression by the Human Protein atlas. We investigate the relationship between the MK subtype and Non-Small Cell Lung Cancer (NSCLC) in 77 non-cancer and 402 NSCLC. We found that MK were widely distributed and the amount of MK in peripheral blood was more than that in bone marrow and there were specificity MK subtypes in peripheral blood. We found classical MK1 with typical MK characteristics and non-classical MK2 closely related to immunity which was the most common subtype in bone marrow and cord blood. Classical MK1 was closely related to Non-Small Cell Lung Cancer (NSCLC) and can be used as a diagnostic marker. MK2 may have potential adaptive immune function and play a role in tumor NSCLC and autoimmune diseases Systemic Lupus Erythematosus. MK have 14 subtypes and are widely distributed in PB, CB, and BM. MK subtypes are closely related to immunity and have potential to be a diagnostic indicator of NSCLC.

OP0039 RISK OF ARRHYTHMIA AMONG NEW USERS OF HYDROXYCHLOROQUINE: A LONGITUDINAL POPULATION-BASED COHORT STUDY ON NEWLY DIAGNOSED RHEUMATOID ARTHRITIS AND SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS

BackgroundPrevious findings on hydroxychloroquine (HCQ) use and the risk of arrhythmia are contradictory and low-level evidence-based results. Additional research is required to evaluate the safety profile of HCQ to arrhythmia in managing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).ObjectivesTo assess the association between HCQ initiation and risk of incident arrhythmia among newly diagnosed RA and SLE patients.MethodsAll patients with incident RA or SLE and no arrhythmic events or anti-arrhythmic medications and no HCQ use prior to disease index date in British Columbia, Canada, between January 1997 and March 2015 were identified using administrative databases. HCQ initiator and HCQ non-initiator groups were identified and matched 1:1 by propensity scores using baseline confounders on demographics including presence of RA or SLE disease and duration of disease prior to the index date of HCQ initiators or non-initiators, comorbidities, other medications, and healthcare utilization. Matching was done within the same calendar year to account for a potential secular trend in HCQ use and risk of arrhythmia. Outcomes were any new arrhythmias, atrial fibrillation, abnormal electrocardiogram including prolonged QT syndrome and conduction disorder, and other unspecified arrhythmias during follow-up. We used Cox proportional hazard models with death as a competing event to assess the association of HCQ initiation and the outcomes.ResultsWe identified 11,518 HCQ initiators (10,655 RA and 863 SLE patients, mean ± SD age 55.9 ± 15.1 years, 76.1% female) and 11,518 HCQ non-initiators (10,639 RA and 879 SLE patients, mean ± SD age 56.0 ± 16.2 years, 76.4% female) after 1:1 propensity score matching. Over the mean follow-up of eight years, there were 1,610 and 1,646 incident arrhythmias in the HCQ initiator and non-initiator groups, respectively. The crude incidence rates of arrhythmia were 17.5, and 18.1 per 1,000 person-years, respectively. Cumulative risk of incident arrhythmia remained similar for both groups. (Figure 1). Adjusted hazard ratio (aHR) of incident arrhythmia from the Cox proportional hazard model for HCQ initiators was 0.99 (95% CI: 0.92-1.06) compared to non-initiators (Table 1). The corresponding aHRs for HCQ initiators in subtypes of arrhythmia – atrial fibrillation, abnormal electrocardiogram, and other unspecified arrhythmias were 0.95 (95% CI: 0.84-1.06), 1.04 (95% CI: 0.87-1.26), and 0.96 (95% CI: 0.86-1.08), respectively.Table 1.Incident arrhythmias of any type among RA and SLE patients initiating HCQ prescription compared with HCQ non-initiatorsHCQ initiatorHCQ non-initiatorParticipants (number)11,51811,518Mean follow-up (years)8.007.89Events (number)1,6101,646Crude incidence rate per 1000 person-years17.4818.12Unadjusted HR (95% CI)0.98 (0.91-1.05)1.00 (reference)Adjusted# HR (95% CI)0.99 (0.92-1.06)1.00 (reference)Abbreviations: HCQ, hydroxychloroquine; HR, hazard ratio.#The multivariable Cox proportional hazard model was adjusted for baseline confounders on demographics, comorbidities, medications, and healthcare utilization.Figure 1.Cumulative risk of incident arrhythmias for HCQ initiators and non-initiators over the follow-up time.ConclusionThere is no increased risk of any type of arrhythmia among new users of HCQ in RA and SLE patients. We believe the results of this large cohort study will add to the confidence with which HCQ can be used in RA and SLE management.Disclosure of InterestsNone declared.

Influence of Autoantibodies to Estradiol and Progesterone on the Blood Serum Hormones Concentrations in Postmenopausal Healthy Women and Breast Cancer Patients

Background: It is known that antibodies to steroid hormones are associated with some human diseases (systemic lupus erythematosus, thrombosis, recurrent pregnancy loss, autoimmune dermatitis et al.). There were no any data about action of specific autoantibodies on the sex hormones in hormone-dependent cancer patients. Objectives: The purpose of this study was to investigate the probable links between estradiol (Es) and progesterone (Pg) levels and autoantibodies of A-class specific to these hormones (IgA-Es and IgA-Pg) in the blood serum of healthy women and breast cancer patients. Patients and Methods: There were examined 521 nearly diagnosed breast carcinoma patients from Regional Clinical Oncology Dispensary (Kemerovo, Russian Federation) and 143 healthy women from Kemerovo (Russian Federation). The serum concentration of Es and Pg were analyzed by competitive immunoassay using specific monoclonal antibodies. The serum IgA-Pg and IgA-Es were analyzed by solid-phase non-competitive immunoassay using Pg and Es conjugated with bovine serum albumin as adsorbed antigens. The data analysis was performed using software STATISTICA 8.0 (Stat Soft Inc., USA).Results: We discovered that low ratios Pg/Es&lt;4.3 were associated with breast cancer. Personal IgA-Pg/IgA-Es ratios negatively correlated with Es levels and positively correlated with Pg levels and Pg/Es ratios in compared groups. The influence of IgA-Pg/IgA-Es ratio on the hormones levels and their ratio in heathy women was more strong than in breast cancer patients. Conclusions: Our clinical results correspond to the known experimental data about influence of specific antibodies on the levels of steroid hormones in immunized animals. Human autoantibodies to Es and Pg could stimulate or inhibit promotion of carcinogenesis by influence on Pg/Es ratio depending on individual IgA-Pg/IgA-Es ratio.

Single-cell multi-omics analysis reveals IFN-driven alterations in T lymphocytes and natural killer cells in systemic lupus erythematosus.

Background: The characterisation of the peripheral immune system in the autoimmune disease systemic lupus erythematosus (SLE) at the single-cell level has been limited by the reduced sensitivity of current whole-transcriptomic technologies. Here we employ a targeted single-cell multi-omics approach, combining protein and mRNA quantification, to generate a high-resolution map of the T lymphocyte and natural killer (NK) cell populations in blood from SLE patients. Methods: We designed a custom panel to quantify the transcription of 534 genes in parallel with the expression of 51 surface protein targets using the BD Rhapsody AbSeq single-cell system. We applied this technology to profile 20,656 T and NK cells isolated from peripheral blood from an SLE patient with a type I interferon (IFN)-induced gene expression signature (IFN hi), and an age- and sex- matched IFN low SLE patient and healthy donor. Results: We confirmed the presence of a rare cytotoxic CD4 + T cell (CTL) subset, which was exclusively present in the IFN hi patient. Furthermore, we identified additional alterations consistent with increased immune activation in this patient, most notably a shift towards terminally differentiated CD57 + CD8 + T cell and CD16 + NK dim phenotypes, and the presence of a subset of recently-activated naïve CD4 + T cells. Conclusions: Our results identify IFN-driven changes in the composition and phenotype of T and NK cells that are consistent with a systemic immune activation within the IFN hi patient, and underscore the added resolving power of this multi-omics approach to identify rare immune subsets. Consequently, we were able to find evidence for novel cellular peripheral biomarkers of SLE disease activity, including a subpopulation of CD57 + CD4 + CTLs.

Genotype Triad for HOTAIR rs10783618, LINC-ROR rs1942347, and MALAT1 rs3200401 as Molecular Markers in Systemic Lupus Erythematous.

Accumulating evidence supports the implication of long non-coding RNAs (lncRNAs) in autoimmune diseases, including systemic lupus erythematosus (SLE). LncRNA variants could impact the development and/or outcome of the disease with variable diagnostic/prognostic utility in the clinic. We aimed to explore the contribution of HOTAIR (rs10783618), LINC-ROR (rs1942347), and MALAT1 (rs3200401) variants to SLE susceptibility and/or severity in 163 SLE patients and age-/sex-matched controls using real-time TaqMan allelic discrimination PCR. HOTAIR rs10783618*C/C was associated with a 77% increased risk of SLE (OR = 1.77, 95%CI = 1.09–2.87, p = 0.020) under the recessive model. Similarly, MALAT1 rs3200401*T/T carriers were three times more likely to develop SLE (OR = 2.89, 95%CI = 1.42–5.90) under the recessive model. While the rs3200401*T/C genotype was associated with a 49–57% decreased risk of SLE under codominant (OR = 0.51, 95%CI = 0.31–0.82, p < 0.001) and over-dominant (OR = 0.43, 95%CI = 0.27–0.68, p < 0.001) models. LINC-ROR rs1942347*A/A patients were more likely to have a positive family history of SLE. At the same time, HOTAIR rs10783618*C/C was associated with a higher frequency of arthritis (p = 0.001) and the presence of oral ulcers (p = 0.002), while patients carrying rs10783618*T/T genotype were more likely to develop hair loss (p < 0.001), weight loss (p = 0.001), and neurological symptoms (p = 0.003). In conclusion, the studied lncRNAs, HOTAIR, and MALAT1 gene polymorphisms confer susceptibility for SLE, providing a potential theoretical basis for their clinical translation in SLE disease.

Key Molecules of Triglycerides Pathway Metabolism Are Disturbed in Patients With Systemic Lupus Erythematosus.

BackgroundElevated triglycerides or triglyceride-rich lipoproteins are an additional cause of cardiovascular (CV) disease. Given that patients with systemic lupus erythematosus (SLE) have a high prevalence of premature CV disease and show an altered lipid profile, our objective was to study whether three molecules that play a central role in the triglyceride metabolism: apolipoprotein C-III (ApoC3), angiopoietin-like protein 4 (ANGPLT4), and lipoprotein lipase (LPL) differ between SLE patients and controls, and how they are related to disease characteristics, including disease damage.MethodsCross-sectional study that included 347 women, 185 of them diagnosed with SLE and 162 age-matched controls. ANGPTL4, ApoC3 and LPL, and standard lipid profiles were analyzed in SLE patients and controls. A multivariable analysis was performed to assess whether ANGPTL4, ApoC3 and LPL molecules differ between patients and controls and to study their relationship with SLE disease damage.ResultsAfter fully multivariable analysis that included classic CV risk factors, and the modifications that the disease itself produces over the lipid profile, it was found that ApoC3 was significantly lower (beta coef. -1.2 [95%CI -1.6- -0.8) mg/dl, <0.001), and ANGPTL4 (beta coef. 63 [95%CI 35-90] ng/ml, <0.001) and LPL (beta coef. 79 [95%CI 30-128] ng/ml, p=0.002) significantly higher in patients with SLE compared to controls. Disease damage score was significantly and independently associated with higher serum levels of LPL (beta coef. 23 [95%CI 10-35] ng/ml, p=0.001). Mediation analysis suggested that the relationship between disease damage and LPL was direct and not mediated by ApoC3 or ANGPLT4.ConclusionThe ApoC3, ANGPLT4 and LPL axis is disrupted in patients with SLE. Disease damage explains this disturbance.

Significance of hyperferritinemia as a diagnostic and prognostic biomarker

Ferritin is a complex protein composite (iron protein) that plays the role of the main intracellular iron depot in humans and animals, consisting of the protein apoferritin and the ferric atom in the composition of phosphate hydroxide. The reference value of ferritin in women is 200 μg/l, in men – 300 μg/l. Ferritin is a marker of total body iron stores, and low levels are specific for iron deficiency. Ferritin is also involved in immune processes and has both pro-inflammatory and immunosuppressive activity. Hyperferritinemia is a nonspecific symptom that occurs in a number of immunoinflammatory, infectious diseases, as well as during body iron stores overload. Hyperferritinemia is a criterion sign of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis, systemic lupus erythematosus and Kawasaki disease, as well as a predictive biomarker of adult-onset Still's disease. High ferritin levels occur in catastrophic antiphospholipid syndrome, as well as in infectious pathologies such as septic shock and COVID-19, including multisystem inflammatory syndrome associated with COVID-19. Ferritin concentration is an important parameter for assessing the activity and prognosis of the disease, which allows a rational approach to the choice of therapy in these patients.

Single-cell multi-omics analysis reveals IFN-driven alterations in T lymphocytes and natural killer cells in systemic lupus erythematosus

Background: The characterisation of the peripheral immune system in the autoimmune disease systemic lupus erythematosus (SLE) at the single-cell level has been limited by the reduced sensitivity of current whole-transcriptomic technologies. Here we employ a targeted single-cell multi-omics approach, combining protein and mRNA quantification, to generate a high-resolution map of the T lymphocyte and natural killer (NK) cell populations in blood from SLE patients. Methods: We designed a custom panel to quantify the transcription of 534 genes in parallel with the expression of 51 surface protein targets using the BD Rhapsody AbSeq single-cell system. We applied this technology to profile 20,656 T and NK cells isolated from peripheral blood from an SLE patient with a type I interferon (IFN)-induced gene expression signature (IFN hi), and an age- and sex- matched IFN low SLE patient and healthy donor. Results: We confirmed the presence of a rare cytotoxic CD4 + T cell (CTL) subset, which was exclusively present in the IFN hi patient. Furthermore, we identified additional alterations consistent with increased immune activation in this patient, most notably a shift towards terminally differentiated CD57 + CD8 + T cell and CD16 + NK dim phenotypes, and the presence of a subset of recently-activated naïve CD4 + T cells. Conclusions: Our results identify IFN-driven changes in the composition and phenotype of T and NK cells that are consistent with a systemic immune activation within the IFN hi patient, and underscore the added resolving power of this multi-omics approach to identify rare immune subsets. Consequently, we were able to find evidence for novel cellular peripheral biomarkers of SLE disease activity, including a subpopulation of CD57 + CD4 + CTLs.

Effect of Systemic Diseases on Periodontal Microbiome. A Literature Review. Part III

Periodontitis is defined as a chronic inflammatory disease and is mainly caused by a dysbiosis of the periodontal microbiome. Many systemic diseases have been linked to periodontal disease, and the alteration of the microbiome plays a major role in the pathogenesis. Diabetes has been highly associated with the increased risk of periodontal disease, as it provides a hyperglycemic microenvironment that heavily influences the periodontal microbiome by reducing its diversity and favoring disease associated bacteria. Rheumatoid arthritis has also been associated with periodontitis, with many studies indicating microbial shifts in affected individuals without reaching a consensus on the precise nature of dysbiosis. Contradictory and limited number of studies focusing on the effect of other diseases (systemic lupus erythematosus, human immunodeficiency virus, leucocyte adhesion deficiency, liver diseases) on the periodontal microbiome have been also conducted, and many of them have shown distinct microbial shifts in affected individuals.

Sensitivity to Iron‐Mediated Pro‐Inflammatory Signaling in NZBWF1 Mice, a Model of Systemic Lupus Erythematosus

IntroductionThe autoimmune disease systemic lupus erythematosus predominantly affects women and can lead to lupus nephritis (LN) as a common and severe complication in approximately 50% of patients. The F1 hybrid of New Zealand Black (NZB) X New Zealand White (NZW) mice (NZBWF1) is a well‐established mouse model to study LN. Our previous data indicated that the onset of albuminuria in female 34‐week NZBWF1 mice was associated with renal iron accumulation, and iron may contribute to renal injury. This study tests the hypothesis that 34‐week NZBWF1 lupus mice are sensitized to iron's injurious and pro‐inflammatory effects compared to 8‐week normal NZBWF1 mice. As a means to differentiate effects of age as opposed to development of lupus, parallel experiments were performed in 8 and 34‐week‐old NZW mice as healthy controls.Methods and ResultsFemale 8‐week (pre‐autoimmune) and 34‐week NZBWF1 (autoimmune, pre‐albuminuric) mice together with age‐matched healthy control NZW mice underwent 24 h urine collection to confirm non‐albuminuric status. Mice were then were injected i.v. with a single dose of iron‐sucrose (2 mg elemental iron) or vehicle (saline) and sacrificed 24 h later. Plasma blood urea nitrogen (BUN) was measured to determine renal health, SRY‐Box Transcription Factor 9 (SOX‐9)‐ positive cells were quantified in kidney sections as an early tubular injury marker, and plasma monocyte chemoattractant protein‐1 (MCP‐1) was measured by ELISA as an inflammatory marker. Lupus (NZBWF1) and control mice (NZW) were compared within strains by age (8‐week vs. 34‐week) and treatment (Vehicle vs. Treatment). All statistical analyses were done by 2‐way ANOVA (n=7‐12/group), and post‐hoc testing was done using Bonferroni. Iron‐sucrose treatment significantly increased plasma MCP‐1 concentrations in the NZBWF1 and the control NZW mice (PTreatment &lt; 0.01). There was no significant effect of age on this effect for NZW mice (PTreatment*Age = 0.2); however, in NZBWF1 mice, the iron‐sucrose induced increase in MCP‐1 was significantly greater in 34‐week compared to 8‐week mice (PTreatment*Age &lt; 0.05; P&lt;0.05 by posthoc test). BUN was significantly increased with age in both strains (PAge&lt;0.05), but there was no significant effect of iron‐sucrose (PTreatment&gt;0.05). The numbers of SOX‐9+ tubular cells increased in the 34‐week NZBWF1 mice compared to 8‐week mice (Page&lt;0.05), consistent with early stages of renal injury, but iron sucrose treatment did not show any significant effect (PTreatment= 0.9).ConclusionOur data suggest that at the autoimmune but pre‐albuminuric stage, 34‐week NZBWF1 mice show increased pro‐inflammatory responsiveness to iron‐mediated stress. Further studies to determine whether the enhanced pro‐inflammatory effects of iron contribute to pathology in lupus nephritis are ongoing.

Epidemiology of interstitial lung disease in systemic lupus erythematosus in France: A nation-wide population-based study over 10 years.

Background and objectiveData regarding interstitial lung disease (ILD) in the setting of systemic lupus erythematosus (SLE) are limited. We used a nationwide database to determine the incidence and the prevalence of ILD in SLE.MethodsCharacteristics of all SLE inpatients admitted between 2011 and 2012 in France were analysed through the French medico‐administrative database. Features associated with the presence of ILD were studied. Cox hazard model was used to measure the impact of ILD on survival from the first stay to 2020. The incidence of ILD in SLE was estimated by analysing the onset of ILD from 2013 to 2020 in SLE patients who had no evidence of ILD in 2013.ResultsBetween 2011 and 2012, 10,460 SLE patients had at least one hospital stay and could be traced until 2020. Among them, 134 (1.2%) had an ILD diagnosed at baseline. The frequency of ILD in SLE was higher in patients who had an associated autoimmune disease such as Sjögren's syndrome or systemic sclerosis (29.9% vs. 5.9%, p < 0.0001). ILD was associated with an increased risk of death in SLE in the multivariable analysis (hazard ratio [95% CI] 1.992 [1.420–2.794]; p < 0.0001). Among the 31,029 SLE patients with no evidence of ILD at baseline, ILD occurred in 795 (2.6%) between 2013 and 2020. The incidence rate of ILD in SLE was 10.26 for 1000 patient‐years [95% CI: 10.24–10.28].ConclusionIn SLE, ILD is exceedingly rare, often associated with another systemic autoimmune disorder and appears as a major risk factor for death.

Assessment of left ventricular systolic synchrony by peak strain dispersion in patients with systemic lupus erythematosus.

The aim of the study was to investigate the clinical value of the peak strain dispersion (PSD) in evaluating left ventricular (LV) systolic synchrony in patients with systemic lupus erythematosus (SLE). 58 SLE patients without cardiovascular diseases and 60 healthy subjects were enrolled in the study. Both groups were examined by transthoracic two-dimensional echocardiography. Traditional parameters were measured by conventional echocardiography. Two-dimensional speckle tracking imaging (2D-STI) was used to analyze the PSD and LV global longitudinal strain (LVGLS). Related ultrasound and blood test results were analyzed and compared. The PSD was significantly higher in SLE patients than in controls (p<0.05). The LVGLS was significantly lower in SLE patients than in controls (p<0.05). The PSD was negatively correlated with the LVGLS. LV systolic synchrony is impaired in patients with SLE disease. The PSD can be used as a new reliable index to evaluate LV systolic synchrony.

Neurology of Rheumatic Diseases

This review examines the neurologic complications of several rheumatic diseases, including rheumatoid arthritis, seronegative spondyloarthritis, systemic lupus erythematosus, scleroderma and related diseases, vasculitis, spinal osteoarthritis and spondylosis, and primary Sjögren syndrome. Tables describe the categories of neurologic complications of lupus, the prevalence of neurologic manifestations among patients with lupus, distribution of nerve involvement among patients with mononeuritis multiplex caused by microscopic polyangiitis, sensitivity of combined superficial peroneal nerve and peroneus brevis muscle in patients with suspected vasculitis, sites of central nervous system involvement among patients with parenchymal neuro-Behçet syndrome, and localization of cervical radiculopathy. Figures include a radiograph of a patient with rheumatoid arthritis, magnetic resonance imaging showing diffuse pachymeningeal enhancement and the cervical patient with lupus, and photographs of a muscle biopsy of a patient with vasculitis nephropathy and anterior ischemic optic neuropathy secondary to temporal arteritis. This review contains 5 figures, 6 tables, and 77 references Keywords: Rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, scleroderma, vasculitis, spinal osteoarthritis, spondylosis, Sjögren syndrome, neurologic deficit, radiculopathy, Sciatica