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1.
J Immunol ; 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38949522

RESUMEN

The Krebs cycle enzyme aconitate decarboxylase 1 (ACOD1) mediates itaconate synthesis in monocytes and macrophages. Previously, we reported that administration of 4-octyl itaconate to lupus-prone mice abrogated immune dysregulation and clinical features. In this study, we explore the role of the endogenous ACOD1/itaconate pathway in the development of TLR7-induced lupus (imiquimod [IMQ] model). We found that, in vitro, ACOD1 was induced in mouse bone marrow-derived macrophages and human monocyte-derived macrophages following TLR7 stimulation. This induction was partially dependent on type I IFN receptor signaling and on specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1-/-) displayed disruptions of the splenic architecture, increased serum levels of anti-dsDNA and proinflammatory cytokines, and enhanced kidney immune complex deposition and proteinuria, when compared with the IMQ-treated wild-type mice. Consistent with these results, Acod1-/- bone marrow-derived macrophages treated in vitro with IMQ showed higher proinflammatory features. Furthermore, itaconate serum levels in systemic lupus erythematosus patients were decreased compared with healthy individuals, in association with disease activity and specific perturbed cardiometabolic parameters. These findings suggest that the ACOD1/itaconate pathway plays important immunomodulatory and vasculoprotective roles in systemic lupus erythematosus, supporting the potential therapeutic role of itaconate analogs in autoimmune diseases.

2.
Arthritis Rheumatol ; 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38923259

RESUMEN

OBJECTIVE: Systemic lupus erythematosus (SLE) increases cardiovascular disease (CVD) risk, and this is not explained by traditional risk factors. Characterization of blood immunologic signatures that associate with subclinical CVD and predict its progression has been challenging and may help identify subgroups at risk. METHODS: Patients with SLE (n = 77) and healthy controls (HCs) (n = 27) underwent assessments of arterial stiffness, vascular wall inflammation, and coronary atherosclerosis burden with cardio-ankle vascular index (CAVI); fluorodeoxyglucose-positron emission tomography/computed tomography (CT) (target-to-background ratio [TBR]); and coronary CT angiography. Whole blood bulk RNA sequencing was performed in a subset of study participants (HC n = 10, SLE n = 20). In a partially overlapping subset (HC n = 24, SLE n = 64), serum inflammatory protein biomarkers were quantified with an Olink platform. RESULTS: CAVI, TBR, and noncalcified coronary plaque burden (NCB) were increased in patients with SLE compared to HCs. When comparing patients with SLE with high CAVI scores to those with low CAVI scores or to HCs, there was a down-regulation of genes in pathways involved in the cell cycle and differentially regulated pathways related to metabolism. Distinct serum proteins associated with increased CAVI (CCL23, colony-stimulating factor 1, latency-activating peptide transforming growth factor ß1, interleukin 33 [IL-33], CD8A, and IL-12B), NCB (monocyte chemotactic protein 4 and FMS-like tyrosine kinase 3 ligand [Flt3L]), and TBR (CD5, IL-1α, AXIN1, cystatin D [CST5], and tumor necrosis factor receptor superfamily 9; P < 0.05). CONCLUSION: Blood gene expression patterns and serum proteins that associate with worse vascular phenotypes suggest dysregulated immune and metabolic pathways linked to premature CVD. Cytokines and chemokines identified in associations with arterial stiffness, inflammation, and NCB in SLE may allow for characterization of new CVD biomarkers in lupus.

3.
medRxiv ; 2024 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-38605883

RESUMEN

Objective: The Krebs cycle enzyme Aconitate Decarboxylase 1 (ACOD1) mediates itaconate synthesis in myeloid cells.. Previously, we reported that administration of 4-octyl itaconate abrogated lupus phenotype in mice. Here, we explore the role of the endogenous ACOD1/itaconate pathway in the development of murine lupus as well as their relevance in premature cardiovascular damage in SLE. Methods: We characterized Acod1 protein expression in bone marrow-derived macrophages and human monocyte-derived macrophages, following a TLR7 agonist (imiquimod, IMQ). Wild type and Acod1-/- mice were exposed to topical IMQ for 5 weeks to induce an SLE phenotype and immune dysregulation was quantified. Itaconate serum levels were quantified in SLE patients and associated to cardiometabolic parameters and disease activity. Results: ACOD1 was induced in mouse bone marrow-derived macrophages (BMDM) and human monocyte-derived macrophages following in vitro TLR7 stimulation. This induction was partially dependent on type I Interferon receptor signaling and specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1-/-) displayed disruptions of the splenic architecture, increased serum anti-dsDNA and proinflammatory cytokine levels, enhanced kidney immune complex deposition and proteinuria, when compared to the IMQ-treated WT mice. Consistent with these results, Acod1-/- BMDM exposed to IMQ showed higher proinflammatory features in vitro. Itaconate levels were decreased in SLE serum compared to healthy control sera, in association with specific perturbed cardiometabolic parameters and subclinical vascular disease. Conclusion: These findings suggest that the ACOD1/itaconate pathway plays important immunomodulatory and vasculoprotective roles in SLE, supporting the potential therapeutic role of itaconate analogs in autoimmune diseases.

4.
Ann Rheum Dis ; 83(8): 1034-1047, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38527764

RESUMEN

OBJECTIVES: Inflammatory cytokines that signal through the Janus kinases-signal transducer and activator of transcription (JAK-STAT) pathway, especially interferons (IFNs), are implicated in Sjögren's disease (SjD). Although inhibition of JAKs is effective in other autoimmune diseases, a systematic investigation of IFN-JAK-STAT signalling and the effect of JAK inhibitor (JAKi) therapy in SjD-affected human tissues has not been fully investigated. METHODS: Human minor salivary glands (MSGs) and peripheral blood mononuclear cells (PBMCs) were investigated using bulk or single-cell (sc) RNA sequencing (RNAseq), immunofluorescence (IF) microscopy and flow cytometry. Ex vivo culture assays on PBMCs and primary salivary gland epithelial cell (pSGEC) lines were performed to model changes in target tissues before and after JAKi. RESULTS: RNAseq and IF showed activated JAK-STAT pathway in SjD MSGs. Elevated IFN-stimulated gene (ISGs) expression associated with clinical variables (eg, focus scores, anti-SSA positivity). scRNAseq of MSGs exhibited cell type-specific upregulation of JAK-STAT and ISGs; PBMCs showed similar trends, including markedly upregulated ISGs in monocytes. Ex vivo studies showed elevated basal pSTAT levels in SjD MSGs and PBMCs that were corrected with JAKi. SjD-derived pSGECs exhibited higher basal ISG expressions and exaggerated responses to IFN-ß, which were normalised by JAKi without cytotoxicity. CONCLUSIONS: SjD patients' tissues exhibit increased expression of ISGs and activation of the JAK-STAT pathway in a cell type-dependent manner. JAKi normalises this aberrant signalling at the tissue level and in PBMCs, suggesting a putative viable therapy for SjD, targeting both glandular and extraglandular symptoms. Predicated on these data, a phase Ib/IIa randomised controlled trial to treat SjD with tofacitinib was initiated.


Asunto(s)
Inhibidores de las Cinasas Janus , Quinasas Janus , Leucocitos Mononucleares , Factores de Transcripción STAT , Glándulas Salivales Menores , Transducción de Señal , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/tratamiento farmacológico , Síndrome de Sjögren/inmunología , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , Transducción de Señal/efectos de los fármacos , Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Glándulas Salivales Menores/inmunología , Femenino , Interferones , Piperidinas/farmacología , Piperidinas/uso terapéutico , Persona de Mediana Edad , Masculino , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Adulto , Inflamación , Pirroles/farmacología , Pirroles/uso terapéutico , Células Epiteliales/efectos de los fármacos
5.
Rheumatology (Oxford) ; 63(1): 8-15, 2024 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-37341643

RESUMEN

OBJECTIVES: Late-onset SLE is usually milder and associated with lower frequency of LN and neuropsychiatric manifestations. The diagnosis of NPSLE is especially challenging in older patients because of increased incidence of neurological comorbidities. We performed a systematic review and meta-analysis to evaluate the differences in NPSLE manifestations in early-onset (<50-year-old) vs late-onset (≥50-year-old) SLE patients. METHODS: A literature search was performed using the PubMed, Web of Science and Cochrane Library databases. Studies available in English (1959-2022) including a late-onset SLE comparison group and evaluating the frequency of NPSLE were eligible. A forest plot was used to compare odds ratios (95% CI) of incidence and manifestations of NPSLE by age groups. Study heterogeneity was assessed using I2 statistics. RESULTS: A total of 44 studies, including 17 865 early-onset and 2970 late-onset SLE patients, fulfilled our eligibility criteria. CNS involvement was reported in 3326 patients. Cumulative NPSLE frequency was higher in the early-onset group than in the late-onset group (OR: 1.41, 95% CI: 1.24, 1.59, P < 0.0001). In early-onset SLE patients, seizures (OR: 1.68, 95% CI: 1.27, 2.22) and psychosis (OR: 1.72, 95% CI: 1.23, 2.41) were more common than in late-onset SLE patients (P values, 0.0003 and 0.0014, respectively). Peripheral neuropathy was more commonly reported in the late-onset SLE group than in the early-onset SLE group (OR: 0.64, 95% CI: 0.47, 0.86, P = 0.004). CONCLUSION: Our meta-analysis revealed that the frequencies of overall NPSLE, seizures, and psychosis were less common in late-onset SLE patients than in early-onset SLE patients. In contrast, peripheral neuropathy was more common in the late-onset SLE group.


Asunto(s)
Lupus Eritematoso Sistémico , Vasculitis por Lupus del Sistema Nervioso Central , Enfermedades del Sistema Nervioso Periférico , Trastornos Psicóticos , Humanos , Anciano , Persona de Mediana Edad , Vasculitis por Lupus del Sistema Nervioso Central/epidemiología , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico , Lupus Eritematoso Sistémico/complicaciones , Trastornos Psicóticos/etiología , Convulsiones
6.
medRxiv ; 2023 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-37662351

RESUMEN

Objectives: Inflammatory cytokines that signal through the JAK- STAT pathway, especially interferons (IFNs), are implicated in Sjögren's Disease (SjD). Although inhibition of JAKs is effective in other autoimmune diseases, a systematic investigation of IFN-JAK-STAT signaling and effect of JAK inhibitor (JAKi) therapy in SjD-affected human tissues has not been reported. Methods: Human minor salivary glands (MSGs) and peripheral blood mononuclear cells (PBMCs) were investigated using bulk or single cell (sc) RNA sequencing (RNAseq), immunofluorescence microscopy (IF), and flow cytometry. Ex vivo culture assays on PBMCs and primary salivary gland epithelial cell (pSGEC) lines were performed to model changes in target tissues before and after JAKi. Results: RNAseq and IF showed activated JAK-STAT pathway in SjD MSGs. Elevated IFN-stimulated gene (ISGs) expression associated with clinical variables (e.g., focus scores, anti-SSA positivity). scRNAseq of MSGs exhibited cell-type specific upregulation of JAK-STAT and ISGs; PBMCs showed similar trends, including markedly upregulated ISGs in monocytes. Ex vivo studies showed elevated basal pSTAT levels in SjD MSGs and PBMCs that were corrected with JAKi. SjD-derived pSGECs exhibited higher basal ISG expressions and exaggerated responses to IFNß, which were normalized by JAKi without cytotoxicity. Conclusions: SjD patients' tissues exhibit increased expression of ISGs and activation of the JAK-STAT pathway in a cell type-dependent manner. JAKi normalizes this aberrant signaling at the tissue level and in PBMCs, suggesting a putative viable therapy for SjD, targeting both glandular and extraglandular symptoms. Predicated on these data, a Phase Ib/IIa randomized controlled trial to treat SjD with tofacitinib was initiated.

7.
Open Forum Infect Dis ; 10(8): ofad410, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37564740

RESUMEN

Paecilomyces variotii is an opportunistic mold that causes pulmonary infections in immunosuppressed humans that are often treated with triazole therapy. Lupus nephritis is a major cause of progressive kidney disease in patients with systemic lupus erythematosus, often requiring cyclophosphamide-based therapies. Triazole-cyclophosphamide co-administration is challenging as triazoles increase cyclophosphamide concentrations, which can worsen cyclophosphamide toxicity. We describe herein a patient with Paecilomyces variotii pneumonia and concomitant lupus nephritis who was successfully treated with posaconazole and echinocandin-bridged interruptions to allow for cyclophosphamide therapy. This regimen was well-tolerated without cyclophosphamide toxicity and achieved improvements in both fungal pneumonia and renal function.

8.
Genes Immun ; 24(4): 200-206, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37488248

RESUMEN

Childhood-onset systemic lupus erythematosus (cSLE) patients are unique, with hallmarks of Mendelian disorders (early-onset and severe disease) and thus are an ideal population for genetic investigation of SLE. In this study, we use the transmission disequilibrium test (TDT), a family-based genetic association analysis that employs robust methodology, to analyze whole genome sequencing data. We aim to identify novel genetic associations in an ancestrally diverse, international cSLE cohort. Forty-two cSLE patients and 84 unaffected parents from 3 countries underwent whole genome sequencing. First, we performed TDT with single nucleotide variant (SNV)-based (common variants) using PLINK 1.9, and gene-based (rare variants) analyses using Efficient and Parallelizable Association Container Toolbox (EPACTS) and rare variant TDT (rvTDT), which applies multiple gene-based burden tests adapted for TDT, including the burden of rare variants test. Applying the GWAS standard threshold (5.0 × 10-8) to common variants, our SNV-based analysis did not return any genome-wide significant SNVs. The rare variant gene-based TDT analysis identified many novel genes significantly enriched in cSLE patients, including HNRNPUL2, a DNA repair protein, and DNAH11, a ciliary movement protein, among others. Our approach identifies several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort.


Asunto(s)
Desequilibrio de Ligamiento , Lupus Eritematoso Sistémico , Estudio de Asociación del Genoma Completo , Genoma Humano , Edad de Inicio , Lupus Eritematoso Sistémico/genética , Humanos , Masculino , Femenino , Niño , Adolescente , Variación Genética
9.
J Investig Med High Impact Case Rep ; 11: 23247096231171251, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37132021

RESUMEN

Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive skin fibrosis. It has 2 main clinical subtypes-diffuse cutaneous scleroderma and limited cutaneous scleroderma. Non-cirrhotic portal hypertension (NCPH) is defined as presence of elevated portal vein pressures without cirrhosis. It is often a manifestation of an underlying systemic disease. On histopathology, NCPH may be found to be secondary to multiple abnormalities such as nodular regenerative hyperplasia (NRH) and obliterative portal venopathy. There have been reports of NCPH in patients with both subtypes of SSc secondary to NRH. However, simultaneous presence of obliterative portal venopathy has not been reported. We present a case of NCPH due to NRH and obliterative portal venopathy as a presenting sign of limited cutaneous scleroderma. The patient was initially found to have pancytopenia and splenomegaly and was erroneously labeled as cirrhosis. She underwent workup to rule out leukemia, which was negative. She was referred to our clinic and diagnosed with NCPH. Due to pancytopenia, she could not be started on immunosuppressive therapy for her SSc. Our case describes the presence of these unique pathological findings in the liver and highlights the importance of an aggressive search for an underlying condition in all patients diagnosed with NCPH.


Asunto(s)
Hipertensión Portal , Pancitopenia , Esclerodermia Sistémica , Enfermedades Vasculares , Femenino , Humanos , Vena Porta/patología , Pancitopenia/etiología , Hipertensión Portal/etiología , Hipertensión Portal/complicaciones , Cirrosis Hepática/complicaciones , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico
10.
Cardiopulm Phys Ther J ; 34(1): 51-60, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36742346

RESUMEN

Purpose: Patients with systemic lupus erythematosus (SLE) experience excessive, debilitating fatigue with previously reported evidence of etiologically mediated cardiorespiratory impairments. Performance fatigability provides a precise characterization of fatigue as it can be quantified objectively as a function of time, frequency, and/or duration. Nevertheless, little consideration has been given to understanding performance fatigability and its physiological determinants in those with SLE. The purpose of this study was to characterize performance fatigability in patients with SLE, utilizing measures surrounding the anaerobic threshold, with emphasis on cardiorespiratory impairment as a potential mediating factor. Methods: This was a case-control study design. 44 physically inactive women, 26 with SLE and 18 controls, completed a treadmill cardiopulmonary exercise test to volitional exhaustion. Results: There were no significant differences in age (SLE 34.8(9.0) vs Control 36.9(7.3) yrs; p=0.422) between groups. BMI (SLE 27.1(5.4) vs Control 23.8(5.2) kg/m2; p=0.045) was significantly higher in the SLE vs Control group. Resting heart rate (SLE 68(16) vs Control 78(15) bpm; p=0.040) was significantly lower in the SLE compared to the Control group. The VO2 corresponding to the anaerobic threshold (AT-VO2), used to identify the onset of exercise-induced fatigue, was significantly lower in women with SLE than in controls (SLE 12.4(3.1) vs Control 16.4(2.2) ml/kg/min; p<0.001), as was AT-stage (SLE 2.5(0.90) vs Control 3.4(0.78); p=0.002). Additionally, Fatigue Severity Score (FSS) was highly and inversely correlated with AT-VO2 (rho=-0.615; p<0.001) and FSS was highly correlated with Functional Aerobic Impairment Index (FAI; rho=0.663; p<0.001). Conclusion: This study underscores severe performance fatigability in patients with SLE and its link to cardiorespiratory insufficiency. Physiological presentation of performance fatigability was observed during very low intensities of exercise, emphasizing the negative impact it may have on physical function in this population.

11.
Autoimmun Rev ; 22(4): 103297, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36781038

RESUMEN

BACKGROUND: Recent population-based cohort studies suggest that the incidence of systemic lupus erythematosus (SLE) is increased in patients with immune thrombocytopenic purpura (ITP). We performed a systematic review and meta-analysis to evaluate the development of SLE in patients with ITP. METHODS: Literature search was performed in PubMed, Web of Science and Cochrane Library for studies published prior to October 2022. Studies were included that reported development of SLE in ITP patients. Forest plot was used to detect overall SLE frequency in ITP and compare risk ratios for SLE development in different ITP subgroups. Study heterogeneity was assessed by using I2 statistics. RESULTS: 26 eligible studies comprising 14867 ITP patients were included in analysis. 311 ITP patients developed SLE during the follow-up period (range: 1.1-14 years) (2.09%, 95%CI: 1.87-2.33). Relative risk (RR) for developing SLE was significantly higher in female ITP patients (RR: 4.23, 95%CI: 2.52-7.12, p < 0.0001). Anti-nuclear antibody (ANA) was reported in 23 studies, there were 766/4377 ANA positive patients with ITP (17.5%). The risk of SLE development in ANA positive ITP patients was significant (RR: 26.29, 95%CI: 14.45-47.81, p < 0.0001). CONCLUSIONS: Our study suggests ITP patients are at high risk of developing SLE in future. Pooled data revealed that females and patients with a positive ANA titer are at a significantly high risk of developing SLE.


Asunto(s)
Lupus Eritematoso Sistémico , Púrpura Trombocitopénica Idiopática , Femenino , Humanos , Anticuerpos Antinucleares , Incidencia , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/diagnóstico , Púrpura Trombocitopénica Idiopática/complicaciones , Púrpura Trombocitopénica Idiopática/epidemiología
14.
Kidney Int Rep ; 7(12): 2647-2656, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36506236

RESUMEN

Introduction: Proliferative lupus nephritis (LN) progresses to end-stage kidney disease (ESKD) in roughly 10% of the cases despite treatment. Other than achieving <0.8 g/24h proteinuria at 12 months after treatment, early biomarkers predicting ESKD or death are lacking. Recent studies encompassing not only LN have highlighted the central role of the alternative complement pathway (ACP), with or without histological evidence of thrombotic microangiopathy (TMA), as a key promotor of renal death. Methods: We assessed whether persistent isolated C3 hypocomplementemia (PI-LowC3), that is not accompanied by C4 hypocomplementemia, 6 months after kidney biopsy, is associated with an increased risk of death or ESKD in proliferative LN. Results: We retrospectively followed-up 197 patients with proliferative LN (51 with PI-LowC3) for a median of 4.5 years (interquartile-range: 1.9-9.0), 11 of whom died and 22 reached ESKD. After adjusting for age, gender, ethnicity, hypertension, mycophenolate, or cyclophosphamide use, PI-LowC3 was associated with a hazard ratio [HR] of the composite outcome ESKD or death of 2.46 (95% confidence interval [CI]: 1.22-4.99, P = 0.012). These results were confirmed even after controlling for time-varying estimated glomerular filtration rate (eGFR) measurements in joint longitudinal-survival multiple regression models. After accounting for the competing risk of death, PI-LowC3 patients showed a strikingly increased risk of ESKD (adjusted HR 3.41, 95% CI: 1.31-8.88, P = 0.012). Conclusion: Our findings support the use of PI-LowC3 as a low-cost readily available biomarker, allowing clinicians to modify treatment strategies early in the course of disease and offering a rationale for complement blockade trials in this particularly at-risk subgroup of LN patients.

15.
Lupus Sci Med ; 9(1)2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36220328

RESUMEN

OBJECTIVE: In patients with systemic lupus erythematosus (SLE), fatigue is a debilitating symptom with poorly understood pathophysiology. Cardiorespiratory dysfunction has been hypothesised as a contributor to SLE-fatigue. The purpose of this exploratory study was to examine changes in cardiorespiratory function, following an exercise training programme in women with SLE, together with patient reported outcomes and other pathophysiological measures that may underlie SLE-fatigue. METHODS: Sixteen women with SLE and fatigue (Fatigue Severity Scale (FSS) ≥3) were enrolled in a supervised aerobic exercise training programme of vigorous intensity. The primary outcome was time to reach anaerobic threshold (AT-Time) during a cardiopulmonary exercise test (CPET). Secondary outcomes included changes in the 10-minute walk test (10MWT), FSS scores and the Patient Reported Outcomes Measurement Information System (PROMIS-57) survey. Mitochondrial function was assessed by the oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) metabolic potential ratio. RESULTS: Following 12 weeks of exercise training, AT-Time increased by 93±82 (mean±SD) s (p<0.001), 10MWT increased by 84±66 m (p<0.001) and peak oxygen uptake (VO2) increased by 1.4±2.0 mL/kg/min (p=0.013). There were improvements in FSS score (-1.4±1.0, p<0.0001) and in most of the PROMIS-57 domains. The decrease in FSS scores correlated with an increase in the OCR/ECAR ratio (Pearson's correlation r=-0.59, p=0.03). A subset of subjects (9/15) had significant reduction in their Interferon Stimulated Genes (ISG) (p=0.007) accompanied by a significant increase in the OCR/ECAR ratio (p=0.013). CONCLUSIONS: Cardiorespiratory function was improved in concomitance with reductions in fatigue following a 12-week aerobic exercise programme. The reduction in fatigue scores correlated with improvements in mitochondrial function.


Asunto(s)
Lupus Eritematoso Sistémico , Ejercicio Físico/fisiología , Fatiga/complicaciones , Fatiga/diagnóstico , Femenino , Humanos , Interferones , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/terapia , Oxígeno , Proyectos Piloto
16.
Lupus ; 31(14): 1706-1713, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36148853

RESUMEN

BACKGROUND: Cyclophosphamide (CYC) has known cytotoxic effects on ovarian reserve and has been linked to premature ovarian failure (POF) in systemic lupus erythematosus (SLE). The concurrent use of gonadotropin-releasing hormone agonists (GnRHas) is postulated to preserve ovarian function by reducing the number of follicles exposed to CYC, but there is paucity of data to establish its efficacy. We conducted a meta-analysis to summarize the effect of concurrent GnRHa use in persevering ovarian function and pregnancy. METHODS: English language databases of PubMed, Embase, and Cochrane were searched to include studies published between 2000 and 2021. Studies in females with rheumatic diseases receiving concurrent GnRHa and CYC therapy to evaluate ovarian preservation as defined by amenorrhea, follicle stimulating hormone (FSH), anti-mullerian hormone (AMH), or estradiol levels or successful pregnancy were included. We used a fixed effect, exact, Mantel-Haenszel approach to estimate the overall odds ratio (OR) and associated 95% confidence intervals (95% CIs). RESULTS: Seven studies with 218 female patients were included. The ovarian function was preserved in 125/132 (94.6%) of women who received GnRHa concurrently with CYC compared to 50/86 (58%) of women who did not receive GnRHa (OR = 10.3, CI = 4.83-36.29). The OR for pregnancy with GnRHa use = 2.94 (CI = 1.04-9.89). CONCLUSION: Our results based on limited published studies suggest that concurrent GnRHa use preserves ovarian function and increase odds of pregnancy. It can be considered for premenopausal SLE females receiving CYC. Long-term follow-up studies are needed to establish the efficacy and safety of GnRHa use for ovarian preservation.


Asunto(s)
Lupus Eritematoso Sistémico , Insuficiencia Ovárica Primaria , Embarazo , Humanos , Femenino , Hormona Liberadora de Gonadotropina , Lupus Eritematoso Sistémico/tratamiento farmacológico , Ciclofosfamida/efectos adversos , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/tratamiento farmacológico
17.
Ann Rheum Dis ; 2022 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-35914929

RESUMEN

OBJECTIVES: Premature 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 roles in the induction of vascular disease in SLE. The peroxisome proliferator activated receptor-gamma agonist pioglitazone (PGZ suppresses vascular damage and immune dysregulation in murine lupus and improves endothelial dysfunction in other inflammatory diseases. We hypothesised that PGZ could improve vascular dysfunction and cardiometabolic parameters in SLE. METHODS: Eighty SLE subjects with mild to severe disease activity were randomised to a sequence of PGZ followed by placebo for 3 months, or vice versa, in a double-blind, cross-over design with a 2-month wash-out period. Primary endpoints were parameters of endothelial function and arterial inflammation, measured by multimodal assessments. Additional outcome measures of disease activity, neutrophil dysregulation, metabolic disturbances and gene expression studies were performed. RESULTS: Seventy-two subjects completed the study. PGZ was associated with a significant reduction in Cardio-Ankle Vascular Index (a measure of arterial stiffness) compared with placebo. Various metabolic parameters improved with PGZ, including insulin resistance and lipoprotein profiles. Circulating neutrophil extracellular trap levels also significantly decreased with PGZ compared with placebo. Most adverse events experienced while on PGZ were mild and resolved with reduction in PGZ dose. CONCLUSION: PGZ was well tolerated and induced significant improvement in vascular stiffness and cardiometabolic parameters in SLE. The results suggest that PGZ should be further explored as a modulator of cardiovascular disease risk in SLE. TRIAL REGISTRATION NUMBER: NCT02338999.

18.
Clin Rheumatol ; 41(11): 3299-3311, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35907971

RESUMEN

PURPOSE OF REVIEW: To describe root causes of health disparities by reviewing studies on incidence and outcomes of systemic lupus erythematosus (SLE) related to ethnic, race, gender, or socioeconomic differences and to propose solutions. RECENT FINDINGS: SLE outcomes have steadily improved over the past 40 years but are not uniformly distributed across various racial and ethnic groups. Belonging to racial and ethnic minority has been cited as a risk factor for more severe disease and poor outcome in SLE. Population-based registries have demonstrated that Black patients with SLE have significantly lower life expectancy compared to White patients. Lower socioeconomic status has been shown to be one of the strongest predictors of progression to end stage renal disease in lupus nephritis. An association between patient experiences of racial discrimination, increased SLE activity, and damage has also been described. The lack of representation of marginalized communities in lupus clinical trials further perpetuates these disparities. To that end, the goal of a rheumatology workforce that resembles the patients it treats has emerged as one of many solutions to current shortfalls in care. Disparities in SLE incidence, treatment, and outcomes have now been well established. The root causes of these disparities are multifactorial including genetic, epigenetic, and socioeconomic. The underrepresentation of marginalized communities in lupus clinical trials further worsen these disparities. Efforts have been made recently to address disparities in a more comprehensive manner, but systemic causes of disparities must be acknowledged and political will is required for a sustained positive change.


Asunto(s)
Lupus Eritematoso Sistémico , Nefritis Lúpica , Etnicidad , Humanos , Incidencia , Lupus Eritematoso Sistémico/complicaciones , Nefritis Lúpica/complicaciones , Grupos Minoritarios
20.
Rheumatol Int ; 42(11): 2003-2011, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-34727196

RESUMEN

The aims of the study were to (1) to characterize the breathing pattern and work of breathing during peak exercise in patients with SLE; (2) to examine the extent to which the breathing pattern and work of breathing impact the exercise capacity and fatigue. Forty-one women participated in the study (SLE: n = 23, median = 35, range = 21-57 years, control: n = 18, median = 38, range = 22-45 years). Each subject performed a treadmill cardiopulmonary exercise test (a modified Bruce treadmill protocol) ending with volitional exhaustion. Breathing mechanic was characterized by measures of expired minute volume (VE), tidal volume (Vt), respiratory rate (f), work of breathing, and cardiorespiratory fitness was quantified by measures of peak oxygen consumption (VO2) and time to exhaustion. Data presented as median and interquartile range (IQR). Women with SLE had lower Vt {1221 [488.8] mL/min vs. 1716 [453.1] mL; p = .006}, VE {58.9 [18.9] L/min vs 70 [28.1] L/min, p = 0.04} and increased breathing frequency {51.5 [10.8] vs 43.6 [37.8] bpm, p = 0.01} compared to the control group. The time to exhaustion and peak VO2 during the CPET were significantly reduced in those with SLE compared to controls {13.3 [10.2] vs 16.1 [2.2] min; p = 0.004}, {20 [6.1] mL/kg/min vs 26.6 [7] mL/kg/min p < 0.001}, respectively. Differences remained when the analyses were controlled for the observed differences in peak VO2. When the regression model adjusted for the peak VO2, it had been shown that Vt, WOB and f were explained variances in the fatigue severity by 64% [p < 0.001]. The decline in VE and Vt coupled with a decreased peak VO2, and work of breathing may have contributed to low cardiorespiratory fitness and fatigue in patients with systemic lupus erythematosus.


Asunto(s)
Tolerancia al Ejercicio , Lupus Eritematoso Sistémico , Adulto , Estudios de Casos y Controles , Prueba de Esfuerzo , Fatiga/complicaciones , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Persona de Mediana Edad , Consumo de Oxígeno , Respiración , Adulto Joven
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