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1.
Artigo em Inglês | MEDLINE | ID: mdl-39404817

RESUMO

OBJECTIVES: To evaluate urinary activated leucocyte cell adhesion molecule (ALCAM) and CD6 as predictors of lupus nephritis (LN) progression or disease resolution across a 1-year study. METHODS: Serum and urine samples from biopsy proven LN subjects (n = 122) were prospectively collected over the course of a year at 3- or 6-month intervals (weeks 0, 12, 26, and 52) across multiple study sites and assessed for soluble ALCAM and CD6 levels. Urine creatinine from the same urine sample was used to normalize the levels of urinary ALCAM and urinary CD6. Measured levels of serum and urine ALCAM and CD6 were then analyzed against disease metrics cross-sectionally and longitudinally. RESULTS: Cross-sectional analysis at baseline revealed that urinary ALCAM significantly correlated with urine protein creatinine ratio (UPCR), renal SLEDAI, and the Physician Global Assessment (PGA), and negatively correlated with serum C3 and C4. Receiver operating characteristic (ROC) curve analysis demonstrated that urinary ALCAM is a predictor of LN with an area under the curve (AUC) of 0.97, compared with urinary CD6 with an AUC of 0.71. Importantly, the change in urinary ALCAM over a 3-month period distinguished between non-responders and responders at week 52. CONCLUSION: Urinary ALCAM is reflective of changes in LN and may be predictive of response status.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38530774

RESUMO

OBJECTIVE: Lupus nephritis (LN) can occur as an isolated component of disease activity or be accompanied by diverse extrarenal manifestations. Whether isolated renal disease is sufficient to decrease health related quality of life (HRQOL) remains unknown. This study compared Patient-Reported Outcomes Measurement Information System 29-Item (PROMIS-29) scores in LN patients with isolated renal disease to those with extrarenal symptoms to evaluate the burden of LN on HRQOL and inform future LN clinical trials incorporating HRQOL outcomes. METHODS: A total of 181 LN patients consecutively enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership completed PROMIS-29 questionnaires at the time of a clinically indicated renal biopsy. Raw PROMIS-29 scores were converted to standardized T scores. RESULTS: Seventy-five (41%) patients had extrarenal disease (mean age 34, 85% female) and 106 (59%) had isolated renal (mean age 36, 82% female). Rash (45%), arthritis (40%) and alopecia (40%) were the most common extrarenal manifestations. Compared with isolated renal, patients with extrarenal disease reported significantly worse pain interference, ability to participate in social roles, physical function, and fatigue. Patients with extrarenal disease had PROMIS-29 scores that significantly differed from the general population by > 0.5 SD of the reference mean in pain interference, physical function, and fatigue. Arthritis was most strongly associated with worse scores in these three domains. CONCLUSION: Most patients had isolated renal disease and extrarenal manifestations associated with worse HRQOL. These data highlight the importance of comprehensive disease management strategies that address both renal and extrarenal manifestations to improve overall patient outcomes.

3.
Clin Exp Rheumatol ; 42(5): 1115-1117, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38526001

RESUMO

OBJECTIVES: Lupus pericarditis affects 22% of patients with systemic lupus erythematosus (SLE), is associated with worse outcomes, and often requires immunosuppression. Rilonacept is an interleukin-1 receptor antagonist approved for the treatment of recurrent idiopathic pericarditis, but its efficacy in lupus pericarditis is unknown. Here, we report the efficacy of rilonacept in a case series of patients with lupus pericarditis. METHODS: We describe a case series of 4 patients with refractory lupus pericarditis treated with rilonacept in the Johns Hopkins Lupus Center. All patients met the 2012 SLICC criteria for SLE. Refractory lupus pericarditis was defined as recurring or persistent typical pericardial pain symptoms despite standard-of-care treatment including at least one immunosuppressant. RESULTS: Four patients with refractory pericarditis were included. All patients were women, age ranged 26-44 years, 2 patients reported White, 1 Black, and 1 Hispanic ethnicity. Extra-pericardial SLE manifestations were heterogeneous among patients. Only 1 of 3 patient had elevated CRP (not measured in one). Two patients were previously treated with anakinra with initial response, but pericarditis redeveloped in both. Rilonacept led to complete resolution of pericardial symptoms in 3 patients, and partial resolution (40%) in 1, within 2 weeks. CONCLUSIONS: Rilonacept successfully treated lupus pericarditis in this case series. Rilonacept should be considered for the treatment of lupus pericarditis.


Assuntos
Lúpus Eritematoso Sistêmico , Pericardite , Proteínas Recombinantes de Fusão , Humanos , Feminino , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Adulto , Proteínas Recombinantes de Fusão/uso terapêutico , Pericardite/tratamento farmacológico , Pericardite/etiologia , Resultado do Tratamento , Imunossupressores/uso terapêutico
4.
Curr Opin Rheumatol ; 35(2): 61-67, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36695053

RESUMO

PURPOSE OF REVIEW: Autoantibodies are cornerstone biomarkers in systemic lupus erythematosus (SLE), an autoimmune disease characterized by autoantibody-mediated tissue damage. Autoantibodies can inform about disease susceptibility, clinical course, outcomes and the cause of SLE. Identifying pathogenic autoantibodies in SLE, however, remains a significant challenge. This review summarizes recent advances in the field of autoantibodies in SLE. RECENT FINDINGS: High-throughput technologies and innovative hypothesis have been applied to identify autoantibodies linked to pathogenic pathways in SLE. This work has led to the discovery of functional autoantibodies targeting key components is SLE pathogenesis (e.g. DNase1L3, cytokines, extracellular immunoregulatory receptors), as well as the identification of endogenous retroelements and interferon-induced proteins as sources of autoantigens in SLE. Others have reinvigorated the study of mitochondria, which has antigenic parallels with bacteria, as a trigger of autoantibodies in SLE, and identified faecal IgA to nuclear antigens as potential biomarkers linking gut permeability and microbial translocation in SLE pathogenesis. Recent studies showed that levels of autoantibodies against dsDNA, C1q, chromatin, Sm and ribosomal P may serve as biomarkers of proliferative lupus nephritis, and identified novel autoantibodies to several unique species of Ro52 overexpressed by SLE neutrophils. SUMMARY: Autoantibodies hold promise as biomarkers of pathogenic mechanisms in SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Autoanticorpos , Autoantígenos , Biomarcadores
5.
Rheumatology (Oxford) ; 61(6): 2483-2493, 2022 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-34664621

RESUMO

OBJECTIVES: Pure membranous (class V) LN is considered a less aggressive phenotype, but tissue fibrosis and chronic kidney disease may still develop. This study aimed to elucidate the prognostic value of a history of class switch in pure membranous LN. METHODS: We included LN patients with at least two clinically indicated kidney biopsies. New onset of end stage kidney disease (ESKD) was defined as estimated glomerular filtration rate <15 ml/min/1.73 m2, initiation of dialysis or kidney transplantation. RESULTS: Among 220 patients (542 biopsies), 199 (90%) were female, and 118 (54%) were African American, 59 (27%) Caucasian, with median age of 28 years at the first kidney biopsy. Patients with pure class V in a first biopsy converted to proliferative LN in 41% of cases. Pure class V in a repeat biopsy was preceded by proliferative LN in 52%. Trajectory analysis of up to four repeat biopsies revealed that ISN class switch may happen at any time, even after multiple biopsies with the same class. New onset ESKD was observed within 2 years in 5/56 (9%) patients with pure class V in a repeat biopsy. All five patients had proliferative LN in the first biopsy (log rank P = 0.024). CONCLUSIONS: The conversion from proliferative to membranous (and vice-versa) is frequent in SLE. It can occur at any time in the course of disease, limiting the prognostic value of the first biopsy. Evidence of prior proliferative LN is key as it is associated with higher risk of ESKD in non-proliferative LN.


Assuntos
Glomerulonefrite Membranosa , Falência Renal Crônica , Nefrite Lúpica , Biópsia , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/patologia , Humanos , Rim/patologia , Falência Renal Crônica/complicações , Nefrite Lúpica/complicações , Nefrite Lúpica/patologia , Masculino , Estudos Retrospectivos
6.
Rheumatology (Oxford) ; 61(11): 4335-4343, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-35212719

RESUMO

OBJECTIVE: Delayed detection of LN associates with worse outcomes. There are conflicting recommendations regarding a threshold level of proteinuria at which biopsy will likely yield actionable management. This study addressed the association of urine protein:creatinine ratios (UPCR) with clinical characteristics and investigated the incidence of proliferative and membranous histology in patients with a UPCR between 0.5 and 1. METHODS: A total of 275 SLE patients (113 first biopsy, 162 repeat) were enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership across 15 US sites at the time of a clinically indicated renal biopsy. Patients were followed for 1 year. RESULTS: At biopsy, 54 patients had UPCR <1 and 221 had UPCR ≥1. Independent of UPCR or biopsy number, a majority (92%) of patients had class III, IV, V or mixed histology. Moreover, patients with UPCR <1 and class III, IV, V, or mixed had a median activity index of 4.5 and chronicity index of 3, yet 39% of these patients had an inactive sediment. Neither anti-dsDNA nor low complement distinguished class I or II from III, IV, V or mixed in patients with UPCR <1. Of 29 patients with baseline UPCR <1 and class III, IV, V or mixed, 23 (79%) had a UPCR <0.5 at 1 year. CONCLUSION: In this prospective study, three-quarters of patients with UPCR <1 had histology showing class III, IV, V or mixed with accompanying activity and chronicity despite an inactive sediment or normal serologies. These data support renal biopsy at thresholds lower than a UPCR of 1.


Assuntos
Nefrite Lúpica , Humanos , Estudos Prospectivos , Incidência , Proteinúria/diagnóstico , Testes de Função Renal , Rim/patologia
7.
Lupus ; 31(11): 1367-1372, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35775881

RESUMO

OBJECTIVE: Proteinuria is the clinical expression of lupus nephritis and despite recent advances in the therapeutic armamentarium for lupus nephritis, morbidity and mortality rates remain high. Therefore, the identification of factors that predict lupus nephritis is paramount in preventing damage accrual and disease progression. Lipoprotein (a) (Lp[a]) is a primarily genetically inherited plasma lipoprotein with pro-thrombotic and pro-atherosclerotic effects. Elevated Lp(a) has been observed at early stages of renal impairment in the general population and is associated with the development of chronic kidney disease. However, little is known about renal implications of Lp(a) in SLE. Thus, we evaluated Lp(a) and atherosclerotic events, thrombotic events, renal disease, and disease activity in patients with SLE. METHODS: SLE patients fulfilling the revised American College of Rheumatology (ACR) or SLICC classification criteria with a measurement of Lp(a) were included in the analysis. A cutoff of 125 nmol/L was chosen based on expert opinion. Chi-square test was used to compare the differences between patient characteristics and Lp(a) levels. Logistic regression or linear regression were used, where appropriate, to assess the association between Lp(a) values and the measured outcomes. RESULTS: Lp(a) levels from 562 patients were analyzed. There was an association between elevated Lp(a) and a history of proteinuria (OR 1.58, p-value = 0.02). This association remained significant following adjustment for age, sex, race, low C3, and elevated anti-dsDNA (OR = 1.55, p-value = 0.04). There was also an association with eGFR < 60 (p = 0.02). Patients with elevated Lp(a) had higher physician global activity (p = 0.01) and erythrocyte sediment rate (p = 0.03). CONCLUSION: Elevated Lp(a) was associated with proteinuria, independent of known factors associated with lupus proteinuria, as well as reduced eGFR and physician global activity. Our findings highlight the potential role of Lp(a) as a noninvasive biomarker for early renal disease in SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Insuficiência Renal , Biomarcadores , Humanos , Rim/fisiologia , Lipoproteína(a) , Proteinúria/etiologia
9.
J Autoimmun ; 96: 1-13, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30448290

RESUMO

Systemic lupus erythematosus (SLE) is a worldwide chronic autoimmune disease which may affect every organ and tissue. Genetic predisposition, environmental triggers, and the hormonal milieu, interplay in disease development and activity. Clinical manifestations and the pattern of organ involvement are widely heterogenous, reflecting the complex mosaic of disrupted molecular pathways converging into the SLE clinical phenotype. The SLE complex pathogenesis involves multiple cellular components of the innate and immune systems, presence of autoantibodies and immunocomplexes, engagement of the complement system, dysregulation of several cytokines including type I interferons, and disruption of the clearance of nucleic acids after cell death. Use of immunomodulators and immunosuppression has altered the natural course of SLE. In addition, morbidity and mortality in SLE not only derive from direct immune mediated tissue damage but also from SLE and treatment associated complications such as accelerated coronary artery disease and increased infection risk. Here, we review the diagnostic approach as well as the etiopathogenetic rationale and clinical evidence for the management of SLE. This includes 1) lifestyle changes such as avoidance of ultraviolet light; 2) prevention of comorbidities including coronary artery disease, osteoporosis, infections, and drug toxicities; 3) use of immunomodulators (i.e. hydroxychloroquine and vitamin D); and 4) immunosuppressants and targeted therapy. We also review new upcoming agents and regimens currently under study.


Assuntos
Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/diagnóstico , Vitamina D/uso terapêutico , Animais , Humanos , Estilo de Vida , Lúpus Eritematoso Sistêmico/terapia , Terapia de Alvo Molecular , Raios Ultravioleta
10.
J Proteome Res ; 16(1): 355-365, 2017 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-27700100

RESUMO

Proteolysis of autoantigens can alter normal MHC class II antigen processing and has been implicated in the induction of autoimmune diseases. Many autoantigens are substrates for the protease granzyme B (GrB), but the mechanistic significance of this association is unknown. Peptidylarginine deiminase 4 (PAD4) is a frequent target of autoantibodies in patients with rheumatoid arthritis (RA) and a substrate for GrB. RA is strongly associated with specific MHC class II alleles, and elevated levels of GrB and PAD4 are found in the joints of RA patients, suggesting that GrB may alter the presentation of PAD4 by RA-associated class II alleles. In this study, complementary proteomic and immunologic approaches were utilized to define the effects of GrB cleavage on the structure, processing, and immunogenicity of PAD4. Hydrogen-deuterium exchange and a cell-free MHC class II antigen processing system revealed that proteolysis of PAD4 by GrB induced discrete structural changes in PAD4 that promoted enhanced presentation of several immunogenic peptides capable of stimulating PAD4-specific CD4+ T cells from patients with RA. This work demonstrates the existence of PAD4-specific T cells in patients with RA and supports a mechanistic role for GrB in enhancing the presentation of autoantigenic CD4+ T cell epitopes.


Assuntos
Artrite Reumatoide/imunologia , Autoantígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Granzimas/imunologia , Hidrolases/imunologia , Idoso , Sequência de Aminoácidos , Apresentação de Antígeno , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Autoanticorpos/biossíntese , Autoantígenos/química , Autoantígenos/genética , Sítios de Ligação , Linfócitos T CD4-Positivos/patologia , Estudos de Casos e Controles , Medição da Troca de Deutério , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Expressão Gênica , Granzimas/química , Granzimas/genética , Humanos , Hidrolases/química , Hidrolases/genética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteína-Arginina Desiminase do Tipo 4 , Desiminases de Arginina em Proteínas , Proteólise , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Especificidade por Substrato
11.
BMC Bioinformatics ; 16: 293, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26373409

RESUMO

BACKGROUND: This work seeks to develop a methodology for identifying reliable biomarkers of disease activity, progression and outcome through the identification of significant associations between high-throughput flow cytometry (FC) data and interstitial lung disease (ILD) - a systemic sclerosis (SSc, or scleroderma) clinical phenotype which is the leading cause of morbidity and mortality in SSc. A specific aim of the work involves developing a clinically useful screening tool that could yield accurate assessments of disease state such as the risk or presence of SSc-ILD, the activity of lung involvement and the likelihood to respond to therapeutic intervention. Ultimately this instrument could facilitate a refined stratification of SSc patients into clinically relevant subsets at the time of diagnosis and subsequently during the course of the disease and thus help in preventing bad outcomes from disease progression or unnecessary treatment side effects. The methods utilized in the work involve: (1) clinical and peripheral blood flow cytometry data (Immune Response In Scleroderma, IRIS) from consented patients followed at the Johns Hopkins Scleroderma Center. (2) machine learning (Conditional Random Forests - CRF) coupled with Gene Set Enrichment Analysis (GSEA) to identify subsets of FC variables that are highly effective in classifying ILD patients; and (3) stochastic simulation to design, train and validate ILD risk screening tools. RESULTS: Our hybrid analysis approach (CRF-GSEA) proved successful in predicting SSc patient ILD status with a high degree of success (>82% correct classification in validation; 79 patients in the training data set, 40 patients in the validation data set). CONCLUSIONS: IRIS flow cytometry data provides useful information in assessing the ILD status of SSc patients. Our new approach combining Conditional Random Forests and Gene Set Enrichment Analysis was successful in identifying a subset of flow cytometry variables to create a screening tool that proved effective in correctly identifying ILD patients in the training and validation data sets. From a somewhat broader perspective, the identification of subsets of flow cytometry variables that exhibit coordinated movement (i.e., multi-variable up or down regulation) may lead to insights into possible effector pathways and thereby improve the state of knowledge of systemic sclerosis pathogenesis.


Assuntos
Biomarcadores/análise , Citometria de Fluxo/métodos , Doenças Pulmonares Intersticiais/diagnóstico , Escleroderma Sistêmico/diagnóstico , Estudos de Coortes , Progressão da Doença , Humanos , Doenças Pulmonares Intersticiais/metabolismo , Aprendizado de Máquina , Fenótipo , Curva ROC , Escleroderma Sistêmico/metabolismo , Máquina de Vetores de Suporte
12.
Arthritis Care Res (Hoboken) ; 76(10): 1396-1399, 2024 10.
Artigo em Inglês | MEDLINE | ID: mdl-38831658

RESUMO

OBJECTIVE: Having a low complement level is associated with clinical systemic lupus erythematosus (SLE) disease activity and future organ damage. We studied the association of hydroxychloroquine (HCQ) whole blood levels with changes in complement level. METHODS: We performed two analyses on data prospectively collected from an SLE cohort. In the first (a "new starts on HCQ" analysis), we compared changes in complement level between those starting HCQ and those not starting it. The second analysis evaluated the association between HCQ whole blood levels and low complement level in all cohort visits using conditional logistic regression. RESULTS: In the "new starts on HCQ" analysis, a higher percentage of patients starting HCQ (as reflected in HCQ blood levels >50) experienced a normalization of C4 level compared to those not starting HCQ (23 of 57 [40%] vs. 9 of 56 [13%]; P = 0.011), as well as a significantly greater increase in both C3 and C4 level (P = 0.048 and P = 0.017, respectively). In the "all cohort visits" analysis, there was a statistically significant higher probability of having normal C4 levels in visits with higher HCQ whole blood levels (odds ratio 1.8-2.6 depending on the levels). This relationship was most pronounced for whole blood HCQ levels of 200 ng/mL or more. CONCLUSION: We observed significant improvement in complement levels when HCQ was started and among those with higher whole blood levels of HCQ, particularly with respect to C4. Modulating the pathogenic mechanisms that lead to complement consumption may be one mode by which HCQ prevents poor outcomes in SLE.


Assuntos
Antirreumáticos , Hidroxicloroquina , Lúpus Eritematoso Sistêmico , Hidroxicloroquina/uso terapêutico , Hidroxicloroquina/sangue , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/sangue , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Antirreumáticos/uso terapêutico , Estudos Prospectivos , Complemento C4/análise , Complemento C4/metabolismo , Complemento C3/análise , Complemento C3/metabolismo , Resultado do Tratamento
13.
Artigo em Inglês | MEDLINE | ID: mdl-39313480

RESUMO

OBJECTIVE: We evaluated the association of 25-hydroxyvitamin D (25(OH)D) levels with adverse pregnancy outcomes in systemic lupus erythematosus (SLE). METHODS: The Hopkins Lupus Cohort includes visits of pregnant patients, including assessment of 25(OH)D levels at each visit. We examined the relationship between 25(OH)D levels and adverse pregnancy outcomes (miscarriage, preterm delivery, and small for gestational age). We also used a time-to-event analysis to assess whether time-varying of 25(OH)D levels were associated with time to miscarriage or preterm delivery. RESULTS: In subgroups of patients defined by the average of 25(OH)D levels, we observed significantly different risks of miscarriage (P = 0.0045), preterm delivery (P = 0.0007), and the composite measure of all three adverse pregnancy outcomes (P = 0.011). The highest risks were observed among those with the lowest or highest levels of vitamin D. Nine of 10 pregnant patients with low vitamin D levels during the second trimester resulted in having a premature delivery. The time-to-event model confirmed the same U-shaped association after adjustment for SLE disease activity; however, the increased risk among those with highest levels of vitamin D was not statistically significant. Body mass index did not appear to be a confounding factor. CONCLUSION: Our study is not able to prove causation, but the results strongly suggest an association of 25(OH)D at both lower and higher levels with adverse pregnancy outcomes. We recommend the monitoring of maternal serum 25(OH)D levels during SLE pregnancies, aiming for the ideal range of 40 to 59 ng/mL.

14.
ACR Open Rheumatol ; 6(7): 429-439, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38698736

RESUMO

OBJECTIVE: T cells contribute to tissue injury in systemic sclerosis (SSc), yet the specific T cell subsets expanded in patients with SSc remain incompletely defined. Here we evaluated specific phenotypes and functions of peripheral helper T (Tph) and follicular helper T (Tfh) cells, which have been implicated in autoantibody production, and assessed their associations with clinical features in a well-characterized cohort of patients with SSc. METHODS: Mass cytometry of T cells from peripheral blood mononuclear cells of patients with SSc and controls were evaluated using t-distributed stochastic neighbor embedding visualization, biaxial gating, and marker expression levels. Findings were validated with flow cytometry and in vitro assays. RESULTS: The frequencies of PD-1highCXCR5+ Tfh cells and PD-1highCXCR5- Tph cells were similar in patients with SSc and controls. t-distributed stochastic neighbor embedding visualization (tSNE) revealed distinct populations within the PD-1highCXCR5- cells distinguished by expression of HLA-DR and inducible costimulator (ICOS). Among PD-1highCXCR5- cells, only the HLA-DR+ICOS- cell population was expanded in patients with SSc. Cytometric and RNA sequencing analyses indicated that these cells expressed cytotoxic rather than B cell helper features. HLA-DR+ICOS- PD-1highCXCR5- cells were less potent in inducing B cell plasmablast differentiation and antibody production than comparator T helper cell populations. HLA-DR+ICOS-PD-1highCXCR5- cells were significantly associated with the presence and severity of interstitial lung disease among patients with SSc. CONCLUSION: Among PD-1highCXCR5- T cells, a subset of HLA-DR+ICOS- cells with cytotoxic features is specifically expanded in patients with SSc and is significantly associated with interstitial lung disease severity. This potential cytotoxicity appearing in the CD4 T cell population can be evaluated as a prognostic disease biomarker in patients with SSc.

15.
Arthritis Rheumatol ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38962936

RESUMO

OBJECTIVE: Autoantibodies are a hallmark of lupus nephritis (LN), but their association with LN classes and treatment response are not adequately known. In this study, we quantified circulating autoantibodies in the Accelerating Medicines Partnership LN longitudinal cohort to identify serological biomarkers of LN histologic classification and treatment response and how these biomarkers change over time based on treatment response. METHODS: Peripheral blood samples were collected from 279 patients with systemic lupus erythematosus undergoing diagnostic kidney biopsy based on proteinuria. Of these, 268 were diagnosed with LN. Thirteen autoantibody specificities were measured by bead-based assays (Bio-Rad Bioplex 2200) and anti-C1q by enzyme-linked immunosorbent assay at the time of biopsy (baseline) and at 3, 6, and 12 months after biopsy. Clinical response was determined at 12 months. RESULTS: Proliferative LN (International Society of Nephrology/Renal Pathology Society class III/IV±V, n = 160) was associated with higher concentrations of anti-C1q, anti-chromatin, anti-double-stranded DNA (dsDNA), and anti-ribosomal P autoantibodies compared to nonproliferative LN (classes I/II/V/VI, n = 108). Anti-C1q and-dsDNA were independently associated with proliferative LN. In proliferative LN, higher baseline anti-C1q levels predicted complete response (area under the curve [AUC] 0.72; P = 0.002) better than baseline proteinuria (AUC 0.59; P = 0.21). Furthermore, all autoantibody levels except for anti-La/SSB decreased over 12 months in patients with proliferative, but not membranous, LN with a complete response. CONCLUSION: Baseline levels of anti-C1q and anti-dsDNA may serve as noninvasive biomarkers of proliferative LN, and anti-C1q may predict complete response at the time of kidney biopsy. In addition, tracking autoantibodies over time may provide further insights into treatment response and pathogenic mechanisms in patients with proliferative LN.

16.
Arthritis Res Ther ; 26(1): 54, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38378664

RESUMO

BACKGROUND: Leveraging the Accelerating Medicines Partnership (AMP) Lupus Nephritis (LN) dataset, we evaluated longitudinal patterns, rates, and predictors of response to standard-of-care therapy in patients with lupus nephritis. METHODS: Patients from US academic medical centers with class III, IV, and/or V LN and a baseline urine protein/creatinine (UPCR) ratio ≥ 1.0 (n = 180) were eligible for this analysis. Complete response (CR) required the following: (1) UPCR < 0.5; (2) normal serum creatinine (≤ 1.3 mg/dL) or, if abnormal, ≤ 125% of baseline; and (3) prednisone ≤ 10 mg/day. Partial response (PR) required the following: (1) > 50% reduction in UPCR; (2) normal serum creatinine or, if abnormal, ≤ 125% of baseline; and (3) prednisone dose ≤ 15 mg/day. RESULTS: Response rates to the standard of care at week 52 were CR = 22.2%; PR = 21.7%; non-responder (NR) = 41.7%, and not determined (ND) = 14.4%. Only 8/180 (4.4%) patients had a week 12 CR sustained through week 52. Eighteen (10%) patients attained a week 12 PR or CR and sustained their responses through week 52 and 47 (26.1%) patients achieved sustained PR or CR at weeks 26 and 52. Week 52 CR or PR attainment was associated with baseline UPCR > 3 (ORadj = 3.71 [95%CI = 1.34-10.24]; p = 0.012), > 25% decrease in UPCR from baseline to week 12 (ORadj = 2.61 [95%CI = 1.07-6.41]; p = 0.036), lower chronicity index (ORadj = 1.33 per unit decrease [95%CI = 1.10-1.62]; p = 0.003), and positive anti-dsDNA antibody (ORadj = 2.61 [95%CI = 0.93-7.33]; p = 0.069). CONCLUSIONS: CR and PR rates at week 52 were consistent with the standard-of-care response rates observed in prospective registrational LN trials. Low sustained response rates underscore the need for more efficacious therapies and highlight how critically important it is to understand the molecular pathways associated with response and non-response.


Assuntos
Nefrite Lúpica , Humanos , Nefrite Lúpica/tratamento farmacológico , Imunossupressores/uso terapêutico , Estudos Prospectivos , Creatinina , Prednisona/uso terapêutico , Resultado do Tratamento , Indução de Remissão , Estudos Retrospectivos , Rim
17.
JCI Insight ; 9(2)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38258904

RESUMO

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.


Assuntos
Nefrite Lúpica , Humanos , Nefrite Lúpica/tratamento farmacológico , Proteômica , Proteinúria , Inflamação , Agressão
18.
bioRxiv ; 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38293222

RESUMO

Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based pathologic immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation in patients with LN and to identify correlates of renal parameters and treatment response. Unbiased analysis identified 3 immunologically distinct groups of patients with LN that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells at baseline showed more severe disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized primarily by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive by immunophenotyping at enrollment but with chronic renal injuries. Main immune profiles could be distilled down to 5 simple cytometric parameters that recapitulate several of the associations, highlighting the potential for blood immune profiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.

19.
J Med Virol ; 85(11): 1925-34, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23983182

RESUMO

Viral infections have been associated with autoimmune connective tissue diseases. To evaluate whether active infection by Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus (HHV)-6, -7, -8, as well as parvovirus B19 (B19V) occur in patients with autoimmune connective tissue diseases, viral DNA loads were assessed in paired samples of serum and peripheral blood mononuclear cells (PBMCs) of 115 patients affected by different disorders, including systemic sclerosis, systemic, and discoid lupus erythematosus, rheumatoid arthritis, and dermatomyositis. Two additional groups, patients affected by inflammatory diseases (n=51) and healthy subjects (n=58) were studied as controls. The titers of anti-HHV-6 and anti-EBV antibodies were also evaluated. Cell-free HHV-6 serum viremia was detected in a significantly higher proportion of connective tissue diseases patients compared to controls (P<0.0002); a significant association between HHV-6 reactivation and the active disease state was found only for lupus erythematosus (P=0.021). By contrast, the rate of cell-free EBV viremia was similar in patients and controls groups. Cell-free CMV, HHV-8, and B19V viremia was not detected in any subject. Anti-HHV-6 and anti-EBV early antigen IgG titers were both significantly higher in autoimmune diseases patients as compared to healthy controls, although they were not associated with the presence of viremia. EBV, HHV-6, -7 prevalence and viral load in PBMCs of patients with connective tissue diseases and controls were similar. These data suggest that HHV-6 may act as a pathogenic factor predisposing patients to the development of autoimmune connective tissue diseases or, conversely, that these disorders may predispose patients to HHV-6 reactivation.


Assuntos
Doenças Autoimunes/complicações , Doenças do Tecido Conjuntivo/complicações , Herpesvirus Humano 6/fisiologia , Infecções por Roseolovirus/etiologia , Ativação Viral , Adulto , Idoso , Anticorpos Antivirais/sangue , Sangue/virologia , DNA Viral/sangue , Feminino , Humanos , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Carga Viral
20.
Lupus Sci Med ; 10(2)2023 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-38114267

RESUMO

OBJECTIVE: To assess the efficacy of anifrolumab, a type-1 interferon receptor subunit-1 monoclonal antibody, in treating refractory cutaneous lupus erythematosus (CLE) and lupus non-specific mucocutaneous manifestations in patients with systemic lupus erythematosus (SLE). METHODS: A case series comprising four SLE patients with refractory CLE received anifrolumab (300mg) as add-on therapy. Medical history, serological markers and images were collected. Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity (CLASI-A) was assessed at baseline and post-treatment visits. RESULTS: Patient 1: Anifrolumab effectively treated refractory chronic cutaneous lupus erythematosus with lupus panniculitis and calcinosis cutis.Patient 2: Anifrolumab demonstrated rapid improvement in generalised discoid lupus, achieving a substantial reduction in CLASI-A from 40 to 8.Patient 3: Switching from belimumab to anifrolumab led to notable improvement in photosensitivity and tumid lupus.Patient 4: Anifrolumab effectively managed refractory subacute cutaneous lupus erythematosus, resulting in remarkable cutaneous improvement and successful tapering of prednisone and mycophenolate mofetil. CONCLUSION: Anifrolumab demonstrates efficacy in treating refractory CLE subtypes and lupus non-specific mucocutaneous manifestations in SLE patients. Further studies are needed to establish response rates, optimal dosing, and long-term outcomes.


Assuntos
Lúpus Eritematoso Cutâneo , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Cutâneo/complicações , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Prednisona
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