RESUMO
OBJECTIVES: We aimed to estimate the risk of HCQ retinopathy and its risk factors among incident users in the community. METHODS: Using the Rochester Epidemiology Project, a record-linkage system, a cohort of incident users of HCQ was identified from 27 counties in the American upper Midwest. HCQ retinopathy was defined based on characteristic paracentral automated 10-2 visual field (10-2 AVF) defects and parafoveal retinal photoreceptor layer changes on spectral domain optical coherence tomography. Cumulative incidence rates were estimated adjusting for competing risk of death. Risk factors for HCQ retinopathy were examined using Cox models. RESULTS: The study included 634 incident HCQ users (mean age at initial HCQ use was 53.7 years, 79% females, 91% white). Most common indications for HCQ were RA (57%) and SLE (19%). The average follow-up length was 7.6 years. Eleven patients developed HCQ retinopathy (91% females, 91% white). The majority used HCQ for RA (91%). The cumulative incidence rate at year 5 was 0%, which increased to 3.9% (95% CI 2.0, 7.4) by 10 years. Taking an HCQ dose ≥5 mg/kg was associated with a hazard ratio (HR) of 3.59 (95% CI 1.09, 11.84) compared with lower doses. There was a 48% increase [HR 1.48 (95% CI 1.03, 2.14)] in the risk of HCQ retinopathy for each 100 g of HCQ cumulative dose. CONCLUSION: The risk of HCQ retinopathy at 10 years of use is lower compared with previous prevalence-based estimations. A dose ≥5 mg/kg was associated with higher HCQ retinopathy risk.
Assuntos
Antirreumáticos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Doenças Retinianas , Antirreumáticos/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Masculino , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/epidemiologia , Tomografia de Coerência Óptica/métodosRESUMO
Previous studies in patients with Raynaud's phenomenon (RP) have found an association between microvascular abnormalities assessed by nail fold capillaroscopy and macrovascular peripheral endothelial dysfunction (PED), but the association between RP and nitric oxide related (NO) microvascular PED is not yet established. We performed a retrospective cross-sectional analysis of patients who were referred to Mayo Clinic between 2006 and 2014 for routine cardiovascular evaluation and who underwent evaluation of Reactive Hyperemia Peripheral Arterial Tonometry (index <2 consistent with PED). Identification of the presence of RP was determined by retrospective chart review. Six hundred sixty six individuals were included in this study (mean age 51.9 ± 13.5 years, 411 (61.3%) women), 637 (95.1%) individuals did not have RP (control group), and 29 (4.3%) had secondary RP. Only 4 patients had primary RP and were thus excluded from the final analyses. In a multivariate analysis adjusting for age, sex, smoking status, and use of statins we found a significant association between secondary RP and microvascular PED in all patients (Odds ratio: 2.45; 95% confidence interval 1.13-5.34; P = 0.0236) that remained significant in women after stratifying by sex. Secondary RP is associated with microvascular PED, detected using a non-invasive NO-dependent method. Early detection of microvascular PED could help in identifying individuals with secondary RP who are at risk for developing connective tissue disease as well as CVD.
Assuntos
Endotélio Vascular/fisiopatologia , Microcirculação , Microvasos/fisiopatologia , Doença de Raynaud/fisiopatologia , Extremidade Superior/irrigação sanguínea , Adulto , Idoso , Estudos Transversais , Endotélio Vascular/metabolismo , Feminino , Humanos , Hiperemia/fisiopatologia , Masculino , Manometria , Microvasos/metabolismo , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Doença de Raynaud/diagnóstico , Doença de Raynaud/metabolismo , Estudos RetrospectivosRESUMO
Gout is a painful inflammatory arthropathy caused by crystallization of monosodium urate within the joints. We present the case of a patient with primary gout who had positive results of joint aspiration and synovial biopsy for monosodium urate crystals in the third metacarpophalangeal joint but false-negative results of dual-energy computed tomography.
Assuntos
Gota/diagnóstico por imagem , Articulação Metacarpofalângica/diagnóstico por imagem , Líquido Sinovial/metabolismo , Tomografia Computadorizada por Raios X/métodos , Ácido Úrico/metabolismo , Alopurinol/administração & dosagem , Artralgia/diagnóstico por imagem , Artralgia/etiologia , Artralgia/metabolismo , Biópsia , Reações Falso-Negativas , Gota/tratamento farmacológico , Gota/metabolismo , Supressores da Gota/administração & dosagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos TestesRESUMO
BACKGROUND: Anti-phosphatidylserine prothrombin antibodies (aPSPT) are reported to be highly associated with the lupus anticoagulant (LAC) in established antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) cohorts. Further, aPSPT has been suggested to be a useful surrogate LAC marker. However, validation studies replicating this relationship in an all-comer study population in the diagnostic clinical setting are lacking. OBJECTIVES: To determine the sensitivity and specificity of aPSPT to the LAC in an all-comer population undergoing evaluation for suspected APS. METHODS: An assembled cross-sectional cohort from June 2017 to December 2018 undergoing APS evaluations across all medical specialties were reviewed for LAC, aPSPT, anti-cardiolipin (aCL), and anti-ß2 glycoprotein-1 (ß2GP1). Sensitivities, specificities, and negative and positive predictive values were calculated. RESULTS AND CONCLUSIONS: A cohort of 166 eligible patients was identified. Seventy-one percent were female, 89% White, 15% with SLE, and 21% with APS. The aPSPT was found to be the most specific to the LAC. Specificity of IgG aPSPT was 100% (96%-100%) and IgM aPSPT was 97% (91%-100%) to the LAC. Corresponding positive predictive value for IgG aPSPT was 100% (89%-100%) and IgM aPSPT was 95% (84%-99%). In contrast, the sensitivities of aPSPT to the LAC were less robust, only in the 40%-50% range. The findings validate previously reported findings and lends extension to an all-comer population. These findings corroborate aPSPT as a potentially useful clinical marker of the LAC.
Assuntos
Síndrome Antifosfolipídica , Lúpus Eritematoso Sistêmico , Anticorpos Anticardiolipina , Biomarcadores , Estudos Transversais , Feminino , Humanos , Imunoglobulina G , Imunoglobulina M , Inibidor de Coagulação do Lúpus , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Fosfatidilserinas , ProtrombinaRESUMO
OBJECTIVE: Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN. METHODS: Two hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C). Podocyte cell line gene expression was measured by real-time PCR. RESULTS: Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P = 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. CONCLUSION: Systemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN.
Assuntos
Interferon Tipo I , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Anticorpos Antinucleares , Humanos , Lectinas Tipo C , Nefrite Lúpica/patologia , Glicoproteínas de Membrana , Receptores ImunológicosRESUMO
BACKGROUND: We performed expression quantitative trait locus (eQTL) analysis in single classical (CL) and non-classical (NCL) monocytes from patients with systemic lupus erythematosus (SLE) to quantify the impact of well-established genetic risk alleles on transcription at single-cell resolution. METHODS: Single-cell gene expression was quantified using qPCR in purified monocyte subpopulations (CD14++CD16- CL and CD14dimCD16+ NCL) from SLE patients. Novel analysis methods were used to control for the within-person correlations observed, and eQTLs were compared between cell types and risk alleles. RESULTS: The SLE-risk alleles demonstrated significantly more eQTLs in NCLs as compared to CLs (p = 0.0004). There were 18 eQTLs exclusive to NCL cells, 5 eQTLs exclusive to CL cells, and only one shared eQTL, supporting large differences in the impact of the risk alleles between these monocyte subsets. The SPP1 and TNFAIP3 loci were associated with the greatest number of transcripts. Patterns of shared influence in which different SNPs impacted the same transcript also differed between monocyte subsets, with greater evidence for synergy in NCL cells. IRF1 expression demonstrated an on/off pattern, in which expression was zero in all of the monocytes studied from some individuals, and this pattern was associated with a number of SLE risk alleles. We observed corroborating evidence of this IRF1 expression pattern in public data sets. CONCLUSIONS: We document multiple SLE-risk allele eQTLs in single monocytes which differ greatly between CL and NCL subsets. These data support the importance of the SPP1 and TNFAIP3 risk variants and the IRF1 transcript in SLE patient monocyte function.
Assuntos
Lúpus Eritematoso Sistêmico , Locos de Características Quantitativas , Alelos , Predisposição Genética para Doença/genética , Humanos , Lúpus Eritematoso Sistêmico/genética , Monócitos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genéticaRESUMO
OBJECTIVE: To estimate the annual incidence and prevalence of and frequency of mortality associated with antiphospholipid syndrome (APS). METHODS: An inception cohort of patients with incident APS in 2000-2015 from a geographically well-defined population was identified based on comprehensive individual medical records review. All cases met the 2006 Sydney criteria for APS (primary definition) or had a diagnosis of APS confirmed by physician consensus (secondary definition). Levels of lupus anticoagulant, IgM and IgG anticardiolipin antibodies, and anti-ß2-glycoprotein I antibodies were tested in a centralized laboratory. Incidence rates were age- and sex-adjusted to the 2010 US white population. Prevalence estimates were obtained from the incidence rates, assuming that there was no increased mortality associated with APS and that migration in or out of the area was independent of disease status. RESULTS: Among this cohort in 2000-2015, 33 cases of incident APS, as defined by the Sydney criteria, were identified (mean age of patients 54.2 years; 55% female, 97% white). The annual incidence of APS in adults ages ≥18 years was 2.1 (95% confidence interval [95% CI] 1.4-2.8) per 100,000 population. Incidence rates were similar in both sexes. The estimated prevalence of APS was 50 (95% CI 42-58) per 100,000 population, and was similar in both sexes. Six patients (18%) had a concurrent diagnosis of systemic lupus erythematosus. The most frequent clinical manifestation was deep vein thrombosis. The overall frequency of mortality among patients with APS was not significantly different from that in the general population (standardized mortality ratio 1.61, 95% CI 0.74-3.05). CONCLUSION: APS occurred in ~2 persons per 100,000 population per year. The estimated prevalence was 50 per 100,000 population. Overall mortality was not notably different from that observed in the general population.
Assuntos
Síndrome Antifosfolipídica/epidemiologia , Adulto , Anticorpos Anticardiolipina/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Austrália/epidemiologia , Autoanticorpos/sangue , Feminino , Humanos , Imunoglobulina M/sangue , Incidência , Inibidor de Coagulação do Lúpus/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Prevalência , Trombose Venosa/sangue , Trombose Venosa/epidemiologia , Trombose Venosa/imunologia , Adulto Jovem , beta 2-Glicoproteína I/imunologiaRESUMO
OBJECTIVE: Type I interferon (IFN) is important to systemic lupus erythematosus (SLE) pathogenesis, but it is not clear how chronic elevations in IFN alter immune function. We compared cytokine responses after whole blood stimulation with Toll-like receptor (TLR) agonists in high- and low-IFN SLE patient subgroups. METHODS: SLE patients and nonautoimmune controls were recruited, and SLE patients were categorized as either high or low IFN. Whole blood was dispensed into tubes coated with lipopolysaccharide (LPS), oligonucleotides with cytosine-guanine repeats, Resiquimod, IFN-α, and IFN-α + LPS. Cytokine production in patient sera and after whole blood TLR stimulation was measured by multiplex assay, and type I IFN was assessed using a functional assay. RESULTS: Circulating plasmacytoid dendritic cell numbers were specifically reduced in high-IFN SLE patients and not in low-IFN SLE patients. In serum, we observed that the correlations between cytokines in serum differed to a much greater degree between the high- and low-IFN groups (P < 0.0001) than the absolute cytokine levels differed between these same groups. In stimulated conditions, the high-IFN patients had less cytokine production in response to TLR ligation than the low-IFN SLE patients. LPS produced the most diverse response, and a number of interactions between type I IFN and LPS were observed. CONCLUSION: We find striking differences in resting and stimulated cytokine patterns in high- vs. low-IFN SLE patients, which supports the biological importance of these patient subsets. These data could inform personalized treatment approaches and the pathogenesis of SLE flare following infection.
RESUMO
BACKGROUND: Neuromyelitis optica (NMO) is often associated with other clinical or serological markers of non-organ-specific autoimmunity. OBJECTIVE: To evaluate the relationship between NMO spectrum disorders (NMOSDs), including NMO, longitudinally extensive transverse myelitis, and recurrent optic neuritis, and autoimmune disease. We concentrated on the association with systemic lupus erythematosus (SLE), Sjögren syndrome (SS), or serological evidence of these disorders, which commonly is a source of diagnostic confusion. DESIGN: Retrospective blinded serological survey. SETTING: Mayo Clinic College of Medicine, Rochester, and Centre Hospitalier Régional Universitaire de Lille. METHODS: Group 1 included 153 US patients with NMOSDs (78 with NMO and 75 with longitudinally extensive transverse myelitis) and 33 control subjects with SS/SLE. Group 2 included 30 French patients with SS/SLE, 14 with NMOSDs (6 with NMO, 6 with longitudinally extensive transverse myelitis, and 2 with recurrent optic neuritis), 16 without NMOSDs, and 4 with NMO without SS/SLE. RESULTS: For group 1, NMO-IgG was detected in 66.7%, antinuclear antibodies in 43.8%, and Sjögren syndrome A (SSA) antibodies in 15.7% of patients with NMO and longitudinally extensive transverse myelitis. Five NMO-IgG-seropositive patients with NMOSDs had coexisting SLE, SS, or both. Antinuclear antibodies and SSA antibodies were more frequent in NMO-IgG-seropositive patients than in NMO-IgG-seronegative patients (P= .001). For group 2, NMO-IgG was detected in 5 of 14 patients (35.7%) with NMOSDs and SS/SLE and in 2 of 4 patients (50.0%) with NMO without SS/SLE (P= .59). We detected NMO-IgG only in patients with NMOSDs and not in 49 controls with SS/SLE but without optic neuritis or myelitis from the 2 cohorts (P= .01). CONCLUSION: Neuromyelitis optica spectrum disorders with seropositive findings for NMO-IgG occurring with SS/SLE or non-organ-specific autoantibodies is an indication of coexisting NMO rather than a vasculopathic or other complication of SS/SLE.
Assuntos
Doenças Autoimunes do Sistema Nervoso/imunologia , Neuromielite Óptica/imunologia , Anticorpos Antinucleares/análise , Antígenos Nucleares/imunologia , Autoanticorpos/análise , Autoanticorpos/imunologia , Biomarcadores , Estudos de Coortes , Técnica Indireta de Fluorescência para Anticorpo , França , Humanos , Técnicas Imunoenzimáticas , Imunoglobulina G/imunologia , Testes Imunológicos , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/imunologia , Estudos Retrospectivos , Síndrome de Sjogren/imunologia , Estados UnidosRESUMO
Antiphospholipid (aPL) antibodies have historically been postulated to cause a poorly understood inflammatory myelitis. Neuromyelitis optica spectrum disorder (NMOSD) causes an inflammatory longitudinally extensive transverse myelitis (LETM). In 2004, aquaporin-4 immunoglobulin G (AQP4-IgG) was first reported as a highly specific (>99%) serum diagnostic biomarker of NMOSD, distinguishing it from other disorders (eg, multiple sclerosis). We sought to assess the frequency of AQP4-IgG (and thus NMOSD diagnosis) in LETM with aPL antibodies. We searched Mayo Clinic records (from January 1, 1996, through December 31, 2014) for patients with (1) LETM and (2) aPL or ß2-glycoprotein I antibodies and (3) a serum sample available. AQP4-IgG was evaluated in the 24 included patients and in 20 controls with aPL antibodies but without myelitis. Seropositivity for AQP4-IgG was confirmed in 11 of 24 patients with LETM (46%), confirming an AQP4-IgG-seropositive NMOSD diagnosis rather than aPL-associated LETM. Six of 11 AQP4-IgG-seropositive patients (54%) were initially diagnosed as having aPL/lupus-associated myelitis. Recurrent LETM was exclusive to AQP4-IgG-seropositive patients (P=.003). Alternative diagnoses assigned to the remaining 13 AQP4-IgG-seronegative patients included idiopathic transverse myelitis (n=5), seronegative NMOSD (n=2), spinal cord infarct attributed to aPL antibodies (n=2), spinal cord sarcoidosis (n=1), varicella-zoster virus myelitis (n=1), postinfectious myelitis (n=1), and multiple sclerosis (n=1). All 20 controls were seronegative for AQP4-IgG. Clotting disorders occurred in 36% of patients (4 of 11) with LETM with both aPL antibodies and AQP4-IgG. AQP4-IgG should be tested in all patients with LETM and aPL antibodies because AQP4-IgG-seropositive NMOSD accounts for almost half of all cases. Clotting disorders are common in patients with LETM with dual positivity for AQP4-IgG and aPL antibodies.
Assuntos
Aquaporina 4/imunologia , Imunoglobulina G/sangue , Neuromielite Óptica/diagnóstico , Adulto , Idoso , Anticorpos Antifosfolipídeos/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/sangue , Neuromielite Óptica/imunologiaRESUMO
A pathogenic hallmark of rheumatoid arthritis (RA) is persistent activation of self-reactive CD4(+) T cells. The cause of this aberrant activity remains elusive. We report here detection of autoantibodies against B7-H1, a recently described member of the B7 family, in 29% of patients with RA versus 4% of healthy donors. High-level expression of cell surface B7-H1 are found on activated human CD4(+), CD8(+), and CD45RO(+) T cells. Immobilized autoantibodies to B7-H1 are capable of costimulating the proliferation of CD4(+) T cells in vitro, and the presence of these autoantibodies correlates with active disease status. Using immobilized B7-H1 mAb's and programmed death 1Ig, we demonstrate that engagement of B7-H1 on CD4(+) T cells costimulates proliferation and secretion of IL-10, and subsequently leads to programmed cell death, accompanied with upregulated expression of TNF-related apoptosis-inducing ligand and activation of caspase-3. Taken together with our previous findings, these data indicate a bidirectional signaling role of B7-H1 in T cell costimulation and apoptosis and implicate B7-H1 autoantibodies as contributing to the progression of RA by inducing aberrant T cell responses.
Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos , Antígeno B7-1/imunologia , Proteínas Sanguíneas , Peptídeos , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais/metabolismo , Antígenos CD , Apoptose , Antígeno B7-H1 , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Divisão Celular , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-10/biossíntese , Antígenos Comuns de Leucócito/biossíntese , Masculino , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Linfócitos T/metabolismo , Fatores de TempoRESUMO
OBJECTIVE: Systemic lupus erythematosus (SLE) is frequently characterized by activation of the type I interferon (IFN) pathway. We previously observed that a missense single-nucleotide polymorphism (rs1049564) in the purine nucleoside phosphorylase (PNP) gene was associated with high levels of IFN in SLE. PNP is a key enzyme involved in purine metabolism. In this study, we performed functional follow-up of this polymorphism in human cells. METHODS: Type I IFN was measured in patient sera, using a reporter cell assay. Structural modeling of the PNP variant was performed using PyMOL software. PNP messenger RNA (mRNA) and protein levels and type I IFN-induced gene expression were measured in lymphoblastoid cell lines with known PNP rs1049564 genotypes. The cell cycle was assayed using flow cytometry. RESULTS: Structural modeling indicated no major disruption in folding related to rs1049564. We observed that homozygous rs1049564 TT lymphoblastoid cells had decreased PNP mRNA expression and protein levels, and that cells with the TT genotype had reduced PNP enzymatic activity even when the amount of PNP was controlled. Cells with the TT genotype had a 2-fold increase in S-phase block as compared with cells with the homozygous CC phenotype. The S-phase block could be pharmacologically reversed with hypoxanthine and adenosine, supporting the notion that relative PNP deficiency is the cause of the S-phase block. Type I IFN-induced transcripts were increased in a dose-response manner related to the rs1049564 T allele, at both baseline and after type I IFN stimulation. CONCLUSION: The PNP rs1049564 T allele is a loss-of-function variant that induces S-phase block and IFN pathway activation in lymphocytes. The S-phase block could be rescued in our in vitro experiments, suggesting the potential for personalized treatment.
Assuntos
Ciclo Celular/genética , Interferon-alfa/fisiologia , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Purina-Núcleosídeo Fosforilase/genética , Alelos , Ciclo Celular/imunologia , Expressão Gênica , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Fenótipo , Purina-Núcleosídeo Fosforilase/sangue , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
OBJECTIVES: Important findings can be masked in gene expression studies of mixed cell populations. We examined single-cell gene expression in SLE patient monocytes in the context of clinical and immunological features. METHODS: Monocytes were purified from patients with SLE and controls, and individually isolated for single-cell gene expression measurement. A panel of monocyte-related transcripts were measured in individual classical (CL) and non-classical (NCL) monocytes. RESULTS: Analyses of both CL and NCL monocytes demonstrated that many genes had a lower expression rate in SLE monocytes than in controls. Unsupervised hierarchical clustering of the CL and NCL data sets demonstrated independent clusters of cells from the patients with SLE that were related to disease activity, type I interferon (IFN) and medication use. Thus, each of these factors exerted a different impact on monocyte gene expression that could be identified separately, and a number of genes correlated uniquely with disease activity. We found within-cell correlations between genes directly induced by type I IFN-induced and other non-IFN-induced genes, suggesting the downstream biological effects of type I IFN in individual human SLE monocytes which differed between CLs and NCLs. CONCLUSIONS: In summary, single-cell gene expression in monocytes was associated with a wide range of clinical and biological features in SLE, providing much greater detail and insight into the cellular biology underlying the disease than previous mixed-cell population studies.
RESUMO
OBJECTIVE: To characterize the epidemiology of mixed connective tissue disease (MCTD) from 1983 to 2014. METHODS: An inception cohort of patients with incident MCTD in 1985-2014 in Olmsted County, Minnesota was identified based on comprehensive individual medical record review. Diagnosis of MCTD required fulfillment of at least 1 of the 4 widely accepted diagnostic criteria without fulfillment of classification criteria for other connective tissue diseases. Data were collected on demographic characteristics, clinical presentation, laboratory investigations, and mortality. RESULTS: A total of 50 incident cases of MCTD were identified (mean age 48.1 years and 84% were female). The annual incidence of MCTD was 1.9 per 100,000 population. Raynaud's phenomenon was the most common initial symptoms (50%), followed by arthralgia (30%) and swollen hands (16%). The diagnosis was frequently delayed with the median time from first symptom to fulfillment of criteria of 3.6 years. At fulfillment of criteria, arthralgia was the most prevalent manifestation (86%), followed by Raynaud's phenomenon (80%), swollen hands (64%), leukopenia/lymphopenia (44%), and heartburn (38%). Evolution to other connective tissue occurred infrequently with a 10-year rate of evolution of 8.5% and 6.3% for systemic lupus erythematosus and systemic sclerosis, respectively. The overall mortality was not different from the general population with a standardized mortality ratio of 1.1 (95% confidence interval 0.4-2.6). CONCLUSION: This study was the first population-based study of MCTD to provide a complete picture of epidemiology and clinical characteristics of MCTD. MCTD occurred in about 2 persons per 100,000 per year. Evolution to other connective diseases occurred infrequently and the mortality was not affected.
Assuntos
Doença Mista do Tecido Conjuntivo/epidemiologia , Adulto , Artralgia/epidemiologia , Artralgia/etiologia , Estudos de Coortes , Edema/epidemiologia , Edema/etiologia , Feminino , Mãos , Azia/epidemiologia , Azia/etiologia , Humanos , Incidência , Leucopenia/epidemiologia , Leucopenia/etiologia , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Doença Mista do Tecido Conjuntivo/complicações , Doença de Raynaud/epidemiologia , Doença de Raynaud/etiologia , Fatores de TempoRESUMO
BACKGROUND: Antinuclear antibody (ANA)5 testing is routinely performed during evaluation of patients with a suspected connective tissue disease (CTD), yet the question of which method is most appropriate remains controversial. The purpose of this study was to evaluate the clinical utility of ANA testing by an enzyme immunoassay (EIA), an immunofluorescence assay (IFA), and a multiplex immunoassay (MIA) in a routine laboratory population. METHODS: Samples (n = 1000) were collected from specimens submitted for ANA testing by EIA (Bio-Rad). All samples were subsequently analyzed by IFA (Zeus) and MIA (Bio-Rad). The sample cohort was weighted to represent the routine testing population. Diagnostic information was obtained by chart review. RESULTS: For the diagnosis of a CTD, ROC curve analysis demonstrated no significant differences between IFA (area under the curve 0.81) and EIA (0.84) (P = 0.25), with overlay of a single point for the MIA. When normalized to a specificity of approximately 90%, the sensitivities of the MIA, EIA, and IFA were 67%, 67%, and 56%, respectively. By varying the clinical cutoff, the IFA could achieve the highest sensitivity of 94%; however, the corresponding specificity was only 43%. In contrast, a strongly positive EIA had a specificity of 97%, although, at this cutoff, the sensitivity was only 40%. CONCLUSIONS: Although the overall diagnostic performance of the IFA, EIA, and MIA were not statistically different, the clinical sensitivity and specificity varied dramatically based on the positive/negative cutoff. Knowledge about the performance characteristics of each method will significantly aid in the interpretation of ANA testing.
RESUMO
Systemic lupus erythematosus (SLE) rarely presents with a negative antinuclear antibody (ANA). Although antibodies to extractable nuclear antigens (ENA) are sometimes ordered despite a negative ANA, it is unclear if this contributes to the diagnosis of SLE or other forms of connective tissue disease (CTD). We reviewed 39 patients with anti-ENA antibodies despite a negative ANA during a 1-year period to determine the presence of SLE or other CTD. Several patients had clinical features suggestive of CTD, including 1 with possible SLE. A number of patients had neurologic disorders, especially peripheral neuropathy. In this study, the finding of anti-ENA despite negative ANA was associated with neurologic disorders and CTD. This may represent test bias or false-positive anti-ENA assays or false-negative ANA assays, or may imply immune-related mechanisms not previously described.
Assuntos
Anticorpos Antinucleares/análise , Anticorpos/análise , Antígenos Nucleares/imunologia , Autoimunidade/imunologia , Doenças do Tecido Conjuntivo/imunologia , Doenças do Sistema Nervoso/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Doenças do Tecido Conjuntivo/diagnóstico , Diagnóstico Diferencial , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Seguimentos , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/imunologia , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologiaRESUMO
Recurrent pericarditis is a debilitating condition that can be recalcitrant to conventional therapy with nonsteroidal anti-inflammatory agents, colchicine, and glucocorticoids. The aim of this study was to evaluate the therapeutic role of the recombinant interleukin-1 receptor antagonist anakinra in a series of adult patients with recurrent pericarditis refractory to conventional therapy. We retrospectively reviewed the medical records of 13 consecutive patients with treatment-refractory recurrent pericarditis who received anakinra for management of their disease. None of the patients had an identified systemic inflammatory rheumatic disease. The primary end points were symptom resolution and glucocorticoid discontinuation. Thirteen patients (10 women) treated with anakinra were followed for a median (range) of 16.8 months (1.3 to 24). All patients had chest pain. Total duration of symptoms before initiation of anakinra was 3 years (1.1 to 6.0). Pericardial thickening was detected by echocardiography in 9 patients (69%). All 13 patients (100%) experienced at least a partial and, most, a complete resolution of symptoms. Response to therapy was rapid, within 2 to 5 days. At last follow-up, 11 patients (84%) had successfully discontinued concomitant nonsteroidal anti-inflammatory agent, colchicine, and glucocorticoid therapy; 11 patients remained on anakinra at the end of the follow-up period. The only side effect was transient injection site reaction in 4 patients (31%). In conclusion, anakinra may be an effective alternative agent for the management of glucocorticoid-dependent recurrent pericarditis. Side effects were minor. A formal clinical trial to evaluate the usefulness of this agent should be considered.
Assuntos
Antirreumáticos/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Pericardite/tratamento farmacológico , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/efeitos adversos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pericardite/complicações , Pericardite/diagnóstico , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Echocardiographic-guided pericardiocentesis was found to be safe and efficacious in treating 11 patients with systemic lupus erythematosus who had hemodynamically significant pericardial effusions. These patients tended to present early in their disease course, and men were more often affected.