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1.
Artigo em Inglês | MEDLINE | ID: mdl-31754025

RESUMO

Neutrophil dysregulation is implicated in the pathogenesis of systemic lupus erythematosus (SLE). SLE is characterized by elevated levels of a pathogenic neutrophil subset known as low-density granulocytes (LDGs). The origin and phenotypic, functional, and pathogenic heterogeneity of LDGs remain to be systematically determined. Transcriptomics and epigenetic assessment of lupus LDGs, autologous normal-density neutrophils, and healthy control neutrophils was performed by bulk and single-cell RNA sequencing and assay for transposase-accessible chromatin sequencing. Functional readouts were compared among neutrophil subsets. SLE LDGs display significant transcriptional and epigenetic heterogeneity and comprise 2 subpopulations of intermediate-mature and immature neutrophils, with different degrees of chromatin accessibility and differences in transcription factor motif analysis. Differences in neutrophil extracellular trap (NET) formation, oxidized mitochondrial DNA release, chemotaxis, phagocytosis, degranulation, ability to harm the endothelium, and responses to type I interferon (IFN) stimulation are evident among LDG subsets. Compared with other immune cell subsets, LDGs display the highest expression of IFN-inducible genes. Distinct LDG subsets correlate with specific clinical features of lupus and with the presence and severity of coronary artery disease. Phenotypic, functional, and pathogenic neutrophil heterogeneity are prevalent in SLE and may promote immune dysregulation and prominent vascular damage characteristic of this disease.

2.
Ann Rheum Dis ; 78(9): 1151-1159, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31383717

RESUMO

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.

3.
Arthritis Rheumatol ; 71(9): 1400-1412, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385462

RESUMO

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.

4.
Front Immunol ; 10: 1327, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249572

RESUMO

Pulmonary involvement in primary Sjögren's syndrome (pSS) is an understudied entity with important clinical implications. Its prevalence has been reported in up to 20% of pSS patients. Pulmonary manifestations of pSS are diverse with involvement of airway and/or lung parenchyma. Histopathology of lung lesions suggests a predominance of submucosal mononuclear cell infiltration consisting predominantly of CD4+ T cells. Current understanding of the pathophysiology of lung disease in pSS suggests a similar process driving the pulmonary process as those in the salivary glands, with epithelial cells playing a critical role in the initiation, maintenance, and symptomatology of the disease. Clinical manifestations of lung involvement in pSS are as varied as the underlying pathology and can be vague and non-specific, thus delaying diagnosis. Management options depend on the underlying pathology but are generally limited due to lack of systematic randomized controlled trials. This review helps summarize our current understanding of lung involvement in pSS.

5.
Ann Rheum Dis ; 78(7): 957-966, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31040119

RESUMO

OBJECTIVES: The presence of proinflammatory low-density granulocytes (LDG) has been demonstrated in autoimmune and infectious diseases. Recently, regulatory neutrophilic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) were identified in systemic lupus erythematosus (SLE). Because LDG and PMN-MDSC share a similar phenotype with contrasting functional effects, we explored these cells in a cohort of patients with SLE. METHODS: LDG and normal-density granulocytes (NDG) were isolated from fresh blood of healthy donors (HD) and patients with SLE. Associations between LDG and clinical manifestations were analysed. Multicolor flow cytometry and confocal imaging were performed to immunophenotype the cells. The ability of LDG and NDG to suppress T cell function and induce cytokine production was quantified. RESULTS: LDG prevalence was elevated in SLE versus HD, associated with the interferon (IFN) 21-gene signature and disease activity. Also, the LDG-to-lymphocyte ratio associated better with SLE disease activity index than neutrophil-to-lymphocyte ratio. SLE LDG exhibited significantly heightened surface expression of various activation markers and also of lectin-like oxidised low-density lipoprotein receptor-1, previously described to be associated with PMN-MDSC. Supernatants from SLE LDG did not restrict HD CD4+ T cell proliferation in an arginase-dependent manner, suggesting LDG are not immunosuppressive. SLE LDG supernatants induced proinflammatory cytokine production (IFN gamma, tumour necrosis factor alpha and lymphotoxin alpha) from CD4+ T cells. CONCLUSIONS: Based on our results, SLE LDG display an activated phenotype, exert proinflammatory effects on T cells and do not exhibit MDSC function. These results support the concept that LDG represent a distinct proinflammatory subset in SLE with pathogenic potential, at least in part, through their ability to activate type 1 helper responses.

6.
Arthritis Rheumatol ; 71(7): 1135-1140, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30597768

RESUMO

OBJECTIVE: Autoreactive IgE antibodies have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We hypothesize that omalizumab, a monoclonal antibody binding IgE, may improve SLE activity by reducing type I interferon (IFN) production by hampering plasmacytoid dendritic cells and basophil activation. This study was undertaken to assess the safety, tolerability, and clinical efficacy of omalizumab in mild to moderate SLE. METHODS: Sixteen subjects with SLE and a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥4 and elevated autoreactive IgE antibody levels were randomized to receive omalizumab or placebo (2:1) for 16 weeks, followed by 16 weeks of open-label treatment and a 4-week washout period. The SLEDAI-2K score, British Isles Lupus Assessment Group index (BILAG 2004) score, and physician's global assessment of disease activity were recorded at each visit. The type I IFN-induced gene signature was determined using quantitative polymerase chain reaction. RESULTS: Omalizumab was well tolerated with no allergic reactions, and mostly mild adverse events comparable to those experienced with placebo treatment. SLEDAI-2K scores improved in the omalizumab group compared to the placebo group at week 16 (P = 0.038), as well as during the open-label phase in subjects initially receiving placebo (P = 0.02). No worsening in BILAG scores or the physician's global assessment was detected. There was a trend toward a reduction in IFN gene signature in subjects treated with omalizumab (P = 0.11), especially in subjects with a high baseline IFN signature (P = 0.052). CONCLUSION: Our findings indicate that omalizumab is well tolerated in SLE and is associated with improvement in disease activity. Larger randomized clinical trials will be needed to assess the efficacy of omalizumab in patients with SLE.

7.
Complement Ther Med ; 41: 111-117, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30477826

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with widespread inflammation and tissue damage. It is more common and severe among Blacks, Hispanics, and Asians; with higher incidence in women. While the goals of medical treatment are to prevent flares and reduce organ damage, up to 50% of patients perceive their health to be suboptimal with unaddressed needs including fatigue and pain. Recent SLE treatment guidelines focus on improving quality of life. Yoga has shown improvements in quality-of-life and fatigue in various diagnoses. While there is growing evidence that yoga therapy may help osteoarthritis and rheumatoid arthritis symptoms, there is only one reference in the literature related to SLE. METHODS/SETTING: An adjunct study was undertaken to evaluate adapting the Yoga as Self Care for Arthritis in Minority Communities study for a bilingual population living with SLE in the Washington, DC area. Informants included 7 patients enrolled onto the study, and 3 yoga instructors living with SLE. Qualitative methods included journals and semi-structured interviews. RESULTS: Enrolling patients clarified revisions for intake questionnaires, and symptoms that may impact class participation. Participants demonstrated increased balance, body awareness, and tolerated a faster-paced yoga class when compared to those in the parent study. Yoga instructors' recommendations included modifying yoga based on energy levels and frequent changes in physical ability. CONCLUSION: This paper shares perspectives from various informants and affirms the feasibility of progressing to a larger study. It summarizes our findings and recommendations towards creating a randomized controlled trial, as there are currently none in the literature.

8.
Arthritis Rheumatol ; 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30225865

RESUMO

OBJECTIVE: Endpoints currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. The objective of this investigation was to identify short-term endpoints that predict long-term kidney outcomes for use in clinical trials. METHODS: A database of 944 LN patients was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36 month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). Hazard Index Tools (HITs) to predict risk for each outcome were derived using multivariable analysis with Cox proportional hazards regression. RESULTS: Among 550 eligible subjects 54 CKD, 55 SKI and 22 RRT events occurred. Variables in the final CKD HIT were prediction period CKD status, 12-month proteinuria and12-month serum creatinine (SCr). The SKI HIT included prediction period CKD status, ISN Class, 12-month proteinuria, 12-month SCr, race and an interaction between ISN Class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria and 12-month SCr. Each HIT validated well internally (c-indices 0.84-0.92) and in an independent LN cohort (c-indices 0.83-0.92). CONCLUSION: HITs, derived from short-term kidney responses to treatment correlate with long-term kidney outcomes, and now must be validated as surrogate endpoints for LN clinical trials. This article is protected by copyright. All rights reserved.

9.
Autoimmun Rev ; 17(10): 990-1001, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30103044

RESUMO

Patients with Systemic Lupus Erythematosus (SLE) pose a unique dilemma pertaining to immunization against common pathogens. SLE patients are usually not immunized with vaccines based on the fear of either precipitating infection in this immunosuppressed patient population (with live vaccines) or aggravating autoimmunity and hence lupus flares (with any vaccines). However, elevated vulnerability to infection makes patients with SLE precisely the population that needs protection from vaccine-preventable diseases. A summary of guidelines from the Centers for Disease Control and Prevention, professional societies, review articles and expert opinions regarding use of individual vaccines applicable to adults with SLE is presented in this review.


Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Vacinas/efeitos adversos , Adjuvantes Imunológicos/efeitos adversos , Adulto , Estudos Clínicos como Assunto , Humanos , Hospedeiro Imunocomprometido , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Guias de Prática Clínica como Assunto , Vacinação , Vacinas/administração & dosagem , Vacinas/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos
10.
J Leukoc Biol ; 104(3): 499-514, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29999544

RESUMO

In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.

11.
Rheum Dis Clin North Am ; 44(3): 393-404, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30001782

RESUMO

Sarcopenia refers to the age-related loss of muscle mass, muscle strength, and physical function. With an increase in the number and proportion of elderly in the population, sarcopenia is a growing global health concern due to its impact on morbidity, mortality, and health care expenditure. Despite its clinical importance, sarcopenia remains underrecognized and poorly managed in routine clinical practice. This is, in part, due to a lack of available diagnostic testing and uniform diagnostic criteria. This article provides the general practitioner or rheumatologist an overview of the pathophysiology, diagnosis, and management of this complex and critical entity.


Assuntos
Administração dos Cuidados ao Paciente/métodos , Reumatologia/métodos , Sarcopenia , Idoso , Erros de Diagnóstico/prevenção & controle , Humanos , Determinação de Necessidades de Cuidados de Saúde , Sarcopenia/diagnóstico , Sarcopenia/imunologia , Sarcopenia/fisiopatologia , Sarcopenia/terapia
12.
Nat Commun ; 9(1): 1758, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29717110

RESUMO

Although the aetiology of systemic lupus erythematosus (SLE) is unclear, dysregulated B cell responses have been implicated. Here we show that an unusual CD11chiT-bet+ B cell subset, with a unique expression profile including chemokine receptors consistent with migration to target tissues, is expanded in SLE patients, present in nephrotic kidney, enriched for autoreactive specificities and correlates with defined clinical manifestations. IL-21 can potently induce CD11chiT-bet+ B cells and promote the differentiation of these cells into Ig-secreting autoreactive plasma cells. While murine studies have identified a role for T-bet-expressing B cells in autoimmunity, this study describes and exemplifies the importance of CD11chiT-bet+ B cells in human SLE.

13.
JCI Insight ; 3(8)2018 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-29669944

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with enhanced risk of atherosclerotic cardiovascular disease not explained by Framingham risk score (FRS). Immune dysregulation associated to a distinct subset of lupus proinflammatory neutrophils (low density granulocytes; LDGs) may play key roles in conferring enhanced CV risk. This study assessed if lupus LDGs are associated with in vivo vascular dysfunction and inflammation and coronary plaque. METHODS: SLE subjects and healthy controls underwent multimodal phenotyping of vascular disease by quantifying vascular inflammation (18F-fluorodeoxyglucose-PET/CT [18F-FDG-PET/CT]), arterial dysfunction (EndoPAT and cardio-ankle vascular index), and coronary plaque burden (coronary CT angiography). LDGs were quantified by flow cytometry. Cholesterol efflux capacity was measured in high-density lipoprotein-exposed (HDL-exposed) radioactively labeled cell lines. Whole blood RNA sequencing was performed to assess associations between transcriptomic profiles and vascular phenotype. RESULTS: Vascular inflammation, arterial stiffness, and noncalcified plaque burden (NCB) were increased in SLE compared with controls even after adjustment for traditional risk factors. In SLE, NCB directly associated with LDGs and associated negatively with cholesterol efflux capacity in fully adjusted models. A neutrophil gene signature reflective of the most upregulated genes in lupus LDGs associated with vascular inflammation and NCB. CONCLUSION: Individuals with SLE demonstrate vascular inflammation, arterial dysfunction, and NCB, which may explain the higher reported risk for acute coronary syndromes. The association of LDGs and neutrophil genes with vascular disease supports the hypothesis that distinct neutrophil subsets contribute to vascular damage and unstable coronary plaque in SLE. Results also support previous observations that neutrophils may disrupt HDL function and thereby promote atherogenesis. TRIAL REGISTRATION: Clinicaltrials.gov NCT00001372FUNDING. Intramural Research Program NIAMS/NIH (ZIA AR041199) and Lupus Research Institute.

14.
Oral Dis ; 2018 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-29688608

RESUMO

Exosomes have emerged as novel nanovesicles that facilitate intracellular communication. The molecular content of exosomes is specific to their cell type of origin and reflective of the cells physiological status. Combined with their stability and accessibility in a variety of biofluids, exosomes may be used as biomarkers in a variety of diseases. Recent evidence suggests that exosomes have immunomodulatory functions that play a role in the severity and development of autoimmune disorders and cancers. This article focuses on the biomarker and therapeutic potential of exosomes for oral manifestation of autoimmune diseases and head and neck cancers.

15.
Artigo em Inglês | MEDLINE | ID: mdl-29693320

RESUMO

Systemic Lupus Erythematosus (SLE) predominantly affects women. Clinical phenotype and outcomes in SLE may vary by sex; complicated further by unique concerns depending on gender defined roles. Herein, we describe gender differences in disease specific quality of life (QOL) assessment scores using LupusPRO in a large International study. METHODS: Cross-sectional data from 1,803 SLE patients on demographics, self-identified gender status, LupusPRO and disease activity were analyzed. LupusPRO has two constructs: health-related QOL (HRQOL) and non-HRQOL. Disease activity and damage were evaluated using SELENA-SLEDAI and the SLICC/ACR-Damage Index (SDI), respectively. Non-parametric tests were used to compare QOL and disease activity by gender. RESULTS: 122 men and 1681 women with SLE participated. Mean age was similar by gender. Damage score was greater among men. Men fared worse on the non-HRQOL social support domain than women (p=0.02). When comparing disease and QOL among men and women aged ≤45 years, men were found to have greater damage and worse social support than women. However, women fared significantly worse on lupus symptoms, cognition and procreation domains with trends for worse functioning on physical health and pain-vitality domains. CONCLUSIONS: In the largest study of diverse SLE patients with a disease specific QOL tool, gender differences in QOL were observed on both HRQOL and non-HRQOL constructs. While men performed worse in the social support domain, women, especially those in the reproductive age group, fared worse on other domains. These observations may assist physicians in appropriately addressing QOL issues in a gender focused manner. This article is protected by copyright. All rights reserved.

16.
Ann Rheum Dis ; 77(6): 944-950, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29588275

RESUMO

OBJECTIVES: To assess if ubiquitinated proteins potentially present in neutrophil extracellular traps (NETs) can modify cellular responses and induce inflammatory mechanisms in patients with systemic lupus erythematosus (SLE) and healthy subjects. MATERIALS AND METHODS: We studied 74 subjects with SLE and 77 healthy controls. Neutrophils and low-density granulocytes were isolated, and NETs were induced. Ubiquitin content was quantified in NETs by western blot analysis, ELISA and immunofluorescence microscopy, while ubiquitination of NET proteins was assessed by immunoprecipitation. Monocyte-derived macrophages from SLE and controls were isolated and stimulated with NETs or ubiquitin. Calcium flux and cytokine synthesis were measured following these stimuli. RESULTS: NETs contain ubiquitinated proteins, with a lower expression of polyubiquitinated proteins in subjects with SLE than in controls. Myeloperoxidase (MPO) is present in ubiquitinated form in NETs. Patients with SLE develop antiubiquitinated MPO antibodies, and titres positively correlate with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (P<0.01), and negatively correlate with complement components (P<0.01). Stimulation of monocyte-derived macrophages with NETs or with ubiquitin led to enhanced calcium flux. In addition, stimulation with NETs led to enhanced cytokine (tumour necrosis factor-α and interleukin-10) production in macrophages from patients with SLE when compared with controls, which was hampered by inhibition of NET internalisation by macrophages. CONCLUSION: This is the first study to find ubiquitinated proteins in NETs, and evidence for adaptive immune responses directed towards ubiquitinated NET proteins in SLE. The distinct differences in ubiquitin species profile in NETs compared with healthy controls may contribute to dampened anti-inflammatory responses observed in SLE. These results also support a role for extracellular ubiquitin in inflammation in SLE.

17.
Med Res Arch ; 5(3)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29276769

RESUMO

Background: Infection is common cause of morbidity and mortality in systemic lupus erythematosus (SLE). Our objective was to determine incidence and types of infections, particularly opportunistic infections, in SLE patients receiving cyclophosphamide, and to identify contribution of variables like demographics, steroid, other immunosuppressives, white blood cell and absolute neutrophil count to infection risk. Patients and Methods: We did retrospective chart review of SLE patients in our institute over last 10 years, who received minimum six cyclophosphamide infusions. Types of infection, cumulative steroid dose, and maintenance medications were recorded. Statistical analyses were done using SAS software. Results: 87.1% of the 31 patients were female. Mean age was 37.9 years, 48.4% Hispanic, 25.8% African American, 6.4% Asian and 19.4% were Caucasian. No one was on pneumocystis jirovecii pneumonia (PJP) prophylaxis. There were 42 episodes of infection in 31 patients. Different infections were urinary tract infections (UTI), upper respiratory infections (URI), line sepsis, bacterial pneumonia, PJP, mucocutaneous infections and viral gastroenteritis. Infection frequency was significantly higher among Asians compared to Caucasians (p =0.0152). Infection rate was significantly higher during cyclophosphosphamide induction phase (65.9%) compared to maintenance phase (34.1%) (p value=0.0041). Infection rate was higher with higher cumulative steroid dose and in patients on quarterly cyclophosphamide infusion compared to those on oral azathioprine or mycophenolate mofetil. No association found among baseline white blood cell (WBC) or absolute neutrophil count (ANC) and infection rate. Conclusion: We found higher infection rates among Asians and in patients with higher cumulative steroid dose. Single incidence of PJP noted despite absence of prophylaxis. Quarterly cyclophosphamide was associated with higher infection rates. Larger prospective studies are needed to confirm our results.

18.
Front Immunol ; 8: 1200, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28993780

RESUMO

Autoantibodies directed against citrullinated epitopes of proteins are highly diagnostic of rheumatoid arthritis (RA), and elevated levels of protein citrullination can be found in the joints of patients with RA. Calcium-dependent peptidyl-arginine deiminases (PAD) are the enzymes responsible for citrullination. PAD2 and PAD4 are enriched in neutrophils and likely drive citrullination under inflammatory conditions. PADs may be released during NETosis or cell death, but the mechanisms responsible for PAD activity under physiological conditions have not been fully elucidated. To understand how PADs citrullinate extracellular proteins, we investigated the cellular localization and activity of PAD2 and PAD4, and we report that viable neutrophils from healthy donors have active PAD4 exposed on their surface and spontaneously secrete PAD2. Neutrophil activation by some stimulatory agents increased the levels of immunoreactive PAD4 on the cell surface, and some stimuli reduced PAD2 secretion. Our data indicate that live neutrophils have the inherent capacity to express active extracellular PADs. These novel pathways are distinguished from intracellular PAD activation during NETosis and calcium influx-mediated hypercitrullination. Our study implies that extracellular PADs may have a physiological role under non-pathogenic conditions as well as a pathological role in RA.

20.
Arthritis Rheumatol ; 69(9): 1832-1839, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28544690

RESUMO

OBJECTIVE: To identify a genetic cause of early-onset systemic lupus erythematosus (SLE) in a large consanguineous family from Turkey and to study the mechanisms of the disease. METHODS: We performed whole-exome sequencing and single-nucleotide polymorphism array genotyping in family members with and without SLE. Protein and gene expression, cytokine profile, neutrophil extracellular trap (NET) formation, and presence of low-density granulocytes were evaluated in patient primary cells and serum samples. RESULTS: We identified a novel, homozygous, loss-of-function mutation (p.Pro445Leufs*11) in the C1R gene. Using the Sanger method of DNA sequencing in 14 family members, we confirmed the presence of the mutation in 4 patients with SLE and in an asymptomatic 9-year-old girl. Complement levels were low in sera from patients with truncated C1r protein. Two siblings with SLE who were available for detailed evaluation exhibited strong type I interferon (IFN) inflammatory signatures despite their disease being clinically inactive at the time of sampling. The type I IFN transcriptional signature in the patients' blood correlated with disease expressivity, whereas the neutrophil signature in peripheral blood mononuclear cells was likely associated with disease severity. The female patient with SLE with the most severe phenotype presented with a stronger neutrophil signature, defined by enhanced NET formation and the presence of low-density granulocytes. Analysis of exome data for modifying alleles suggested enrichment of common SLE-associated variants in the more severely affected patients. Lupus-associated HLA alleles or HLA haplotypes were not shared among the 4 affected subjects. CONCLUSION: Our findings revealed a novel high-penetrance mutation in C1R as the cause of monogenic SLE. Disease expressivity in this family appears to be influenced by additional common and rare genetic variants.


Assuntos
Alelos , Complemento C1r/deficiência , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Complemento C1r/genética , Consanguinidade , Exoma , Feminino , Genótipo , Humanos , Interferon Tipo I/sangue , Leucócitos Mononucleares/citologia , Lúpus Eritematoso Sistêmico/sangue , Masculino , Neutrófilos/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Índice de Gravidade de Doença , Turquia
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