RESUMO
Blood- and marrow-derived stem cells (BMDSCs) provide disease-ameliorating effects for cardiovascular and autoimmune diseases. Microchimerism from donor BMDSCs has been reported in several recipient tissues. We hypothesized that this finding suggests a potential use of BMDSCs in the treatment of salivary dysfunctions. We investigated the presence of Y chromosome-positive cells in salivary gland biopsies of 5 females who had received a marrow or blood stem cell transplant from male donors. One to 16 years after transplantation, all recipients exhibited scattered Y chromosome-positive cells in the acini, ducts, and stroma of their salivary glands (mean of 1.01%). Potentially, these cells can be markers of transplantation tolerance, contribute to neoplastic epithelial tissues, or engraft at sites of injury. In addition, transplantation of BMDSCs could be used for treatment of Sjögren's syndrome and salivary glands damaged by therapeutic irradiation for cancers of the head and neck.
Assuntos
Transplante de Medula Óssea , Quimerismo , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco de Sangue Periférico , Glândulas Salivares/metabolismo , Adulto , Biomarcadores/metabolismo , Biópsia , Cromossomos Humanos Y/metabolismo , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Ductos Salivares/citologia , Ductos Salivares/metabolismo , Doenças das Glândulas Salivares/terapia , Glândulas Salivares/citologia , Células Estromais/citologia , Células Estromais/metabolismoRESUMO
West Nile Virus (WNV) is a neurotropic flavivirus that can cause debilitating diseases, such as encephalitis, meningitis, or flaccid paralysis. We report the safety, pharmacokinetics, and immunogenicity of a recombinant humanized monoclonal antibody (MGAWN1) targeting the E protein of WNV in a phase 1 study, the first to be performed on humans. A single intravenous infusion of saline or of MGAWN1 at escalating doses (0.3, 1, 3, 10, or 30 mg/kg of body weight) was administered to 40 healthy volunteers (30 receiving MGAWN1; 10 receiving placebo). Subjects were evaluated on days 0, 1, 3, 7, 14, 21, 28, 42, 56, 91, 120, and 180 by clinical assessments, clinical laboratory studies, electrocardiograms (ECGs), and pharmacokinetic and immunogenicity assays. All 40 subjects tolerated the infusion of the study drug, and 39 subjects completed the study. One serious adverse event of schizophrenia occurred in the 0.3-mg/kg cohort. One grade 3 neutropenia occurred in the 3-mg/kg cohort. Six MGAWN1-treated subjects experienced 11 drug-related adverse events, including diarrhea (1 subject), chest discomfort (1), oral herpes (1), rhinitis (1), neutropenia (2), leukopenia (1), dizziness (1), headache (2), and somnolence (1). In the 30-mg/kg cohort, MGAWN1 had a half-life of 26.7 days and a maximum concentration in serum (C(max)) of 953 microg/ml. This study suggests that single infusions of MGAWN1 up to 30 mg/kg appear to be safe and well tolerated in healthy subjects. The C(max) of 953 microg/ml exceeds the target level in serum estimated from hamster studies by 28-fold and should provide excess WNV neutralizing activity and penetration into the brain and cerebrospinal fluid (CSF). Further evaluation of MGAWN1 for the treatment of West Nile virus infections is warranted.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Antivirais/efeitos adversos , Vírus do Nilo Ocidental/imunologia , Adulto , Animais , Anticorpos Anti-Idiotípicos/biossíntese , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Cricetinae , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacocinética , Febre do Nilo Ocidental/terapia , Adulto JovemRESUMO
In a phase-1 study, siplizumab, a humanized anti-CD2 monoclonal antibody, was administered (0.012 or 0.04 mg/kg) to 10 pediatric patients with > or = grade-II newly diagnosed, non-steroid-refractory aGvHD after BMT or PBSCT. SAEs and other AEs including infections, and GvHD staging changes (overall, skin, liver, gut) were evaluated over 364 days. Patients reported a total of 121 AEs (19 grade-3, 5 grade-4 0.012 mg/kg group; 17 grade-3, 17 grade-4 0.04 mg/kg group) and 14 SAEs (five grade-3, three grade-4, 0.012 mg/kg group; three grade-3, 0.04 mg/kg group); 15 AEs in five patients and four SAEs in three patients (fever, PTLD, adenoviral infection, and EBV lymphoma) were considered siplizumab-related. Six deaths occurred (study days 17-267); two were considered siplizumab-related: one from EBV-associated PTLD (0.012 mg/kg) and one from adenoviral infection (0.04 mg/kg); the other four deaths could potentially be attributed in part to study drug Three patients (one, 0.012 mg/kg group; two, 0.04 mg/kg group) developed PTLD. By study day 12, GvHD grade decreased in 3/5 and 2/5 patients in the 0.012 and 0.04 mg/kg groups, respectively; remission (grade 0) occurred in one patient in each group. Four of five patients (0.012 mg/kg group) and one of four patients (0.04 mg/kg group) achieved grade 0 GvHD during the first 100 study days (55.6% response). While treatment with siplizumab was associated with improvement of GvHD and remission in some pediatric patients, the overall high morbidity, mortality, and occurrence of PTLD is of safety concern, not warranting further development of siplizumab for the treatment of aGvHD in children.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Doença Aguda , Adolescente , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Humanos , MasculinoRESUMO
PURPOSE: Radiotherapy is commonly used to treat a majority of patients with head and neck cancers. The long-term radiation-induced reduction of saliva output significantly contributes to the posttreatment morbidity experienced by these patients. The purpose of this study was to test the ability of the stable-free radical Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), an established radioprotector, to prevent radiation-induced salivary hypofunction in mice. EXPERIMENTAL DESIGN: The heads of C3H mice were exposed to a range of single radiation doses with or without an i.p. injection of 275 mg/kg Tempol 10 min before treatment. Salivary gland output was assessed 8 weeks postirradiation. RESULTS: Radiation caused a dose-dependent reduction in salivary flow in this model. Tempol treatment alone significantly reduced radiation-induced salivary hypofunction. The combination of Tempol with mouth/nose shielding showed essentially complete radiation protection at 15 Gy and approximately 75% protection at 17.5 Gy. CONCLUSIONS: This study demonstrates for the first time that significant radioprotection of the salivary glands is possible with Tempol in C3H mice.
Assuntos
Antioxidantes/uso terapêutico , Óxidos N-Cíclicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/radioterapia , Glândulas Salivares/efeitos da radiação , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C3H , Protetores contra Radiação/farmacologia , Radioterapia/efeitos adversos , Glândulas Salivares/efeitos dos fármacos , Marcadores de SpinRESUMO
Female nonobese diabetic (NOD) mice develop spontaneous autoimmune sialadenitis and loss of salivary flow, and are a widely used model of Sjögren's syndrome. We examined the feasibility of local salivary gland immunomodulatory gene delivery to alter these sequelae in NOD mice. We constructed recombinant adeno-associated virus (rAAV) vectors encoding either human interleukin 10 (rAAVhIL-10) or beta-galactosidase (rAAVLacZ, control vector). Mice received rAAVhIL-10 or rAAVLacZ by retrograde submandibular ductal instillation either at age 8 weeks (early, before onset of sialadenitis), or at 16 weeks (late, after onset of sialadenitis). As a systemic treatment control, separate mice received intramuscular delivery of rAAVhIL-10 at each time point. Both submandibular and intramuscular delivery of vector led to low circulating levels of hIL-10. After submandibular administration of rAAVhIL-10, salivary flow rates at 20 weeks for both the early and late treatment groups were significantly higher than for both rAAVLacZ-administered and untreated mice. Systemic delivery of rAAVhIL-10 led to improved salivary flow in the late treatment group. Inflammatory infiltrates in submandibular glands, however, were significantly reduced only in mice receiving rAAVhIL-10 locally in the salivary gland compared with mice receiving this vector intramuscularly, or rAAVLacZ or no treatment. In addition, after submandibular rAAVhIL-10 delivery, NOD mice exhibited significantly lower blood glucose, and higher serum insulin, levels than all other groups, indicating some systemic benefit of this treatment. These studies show that expression of hIL-10 by rAAV vectors can have disease-modifying effects in the salivary glands of NOD mice, and suggest that local immunomodulatory gene transfer may be useful for managing the salivary gland pathology in Sjögren's syndrome.
Assuntos
Dependovirus/genética , Técnicas de Transferência de Genes , Interleucina-10/genética , Síndrome de Sjogren/terapia , Animais , Linhagem Celular , DNA Complementar/metabolismo , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Humanos , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Glândulas Salivares/metabolismo , Fatores de TempoRESUMO
OBJECTIVES: To examine the frequency of central nervous system (CNS) disease in primary Sjogrens syndrome (pSS) and indicate ways in which cerebral magnetic resonance imaging (MRI) may help determine the significance of CNS involvement. METHODS: The current review was based on a Medline (Pubmed) literature search through May 2003, focused on Sjogrens syndrome, other vasculitides, multiple sclerosis (MS), specific MRI techniques, and MRI findings with regard to the above-mentioned diseases. Additional literature was identified in the reference sections of articles listed in Medline. RESULTS: Severe CNS manifestations reminiscent of MS have been described in pSS patients. Moreover, the prevalence of nonfocal neuropsychological abnormalities has been found to be elevated in some pSS patient populations. MRI studies suggest discrete cerebral tissue damage even in neurologically asymptomatic patients. However, small white matter lesions are nonspecific and may be related to age or cerebrovascular risk factors such as hypertension. A large controlled study, complementing established T2-weighted MRI with fluid-attenuated inversion recovery (FLAIR) to achieve high sensitivity in lesion detection, could indicate the disease specificity of white matter lesions in pSS. Newer MR techniques, such as spectroscopy and magnetization transfer imaging, applied, for example, in MS and systemic lupus erythematosus (SLE) to evaluate CNS tissue injury, could help determine the extent and mechanisms of macroscopic and microscopic CNS lesions in pSS. CONCLUSIONS: Future controlled studies will be necessary to more precisely estimate the prevalence of CNS lesions in pSS, specifically of discrete white matter abnormalities. Newer MRI techniques have the potential to provide information on the severity and pathophysiological mechanisms of CNS tissue damage.
Assuntos
Encéfalo/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla/complicações , Síndrome de Sjogren/complicações , Humanos , MEDLINE , Esclerose Múltipla/patologia , Síndrome de Sjogren/patologiaRESUMO
Saliva is essential for the preservation of oral-pharyngeal health, and disorders of salivary physiology are associated with numerous oral and pharyngeal problems, particularly in older people. Although salivary function is remarkably intact in healthy aging, medical problems, medications, and head and neck radiotherapy can cause salivary dysfunction and complaints of xerostomia among older people. Sjögren's syndrome, an autoimmune exocrinopathy, is the most common medical disease associated with salivary dysfunction. Medications with anticholinergic side effects will impair salivary output, and head and neck radiotherapy for cancer will cause permanent destruction of salivary glands. Treatments for salivary problems are based upon establishing a diagnosis, protecting oral and pharyngeal health, stimulating remaining glands, and replacing lost salivary fluids.
Assuntos
Xerostomia , Fatores Etários , Idoso , Humanos , Glândulas Salivares/fisiopatologia , Xerostomia/epidemiologia , Xerostomia/etiologia , Xerostomia/terapiaRESUMO
OBJECTIVE: The purpose of this study was to determine whether systolic and diastolic blood pressures are associated with salivary flow, dry mouth, or dry eye symptoms in patients with primary Sjögren's syndrome as compared with xerostomic control subjects. STUDY DESIGN: One hundred forty consecutive patients seen at the Sjögren's Syndrome Clinic were categorized retrospectively with various classification schemes: (1) subjective dry mouth; (2) subjective dry eye; (3) European criteria; and (4) international criteria. Data collection included age, gender, systolic blood pressure, diastolic blood pressure, salivary flow rate, focus score, Schirmer's test, and laboratory findings, including antinuclear antibodies, anti-SSA, anti-SSB, IgG, IgA, IgM, erythrocyte sedimentation rate, and rheumatoid factor. RESULTS: No meaningful associations of salivary flow rates with systolic or diastolic blood pressures were found in patients with Sjögren's syndrome or in xerostomic control subjects. An inverse correlation was seen between salivary flow and elevated diastolic blood pressure in xerostomic control subjects only. CONCLUSION: Elevated blood pressure was not related to saliva flow in patients with Sjögren's syndrome.
Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/fisiopatologia , Saliva/metabolismo , Síndrome de Sjogren/fisiopatologia , Adulto , Anticorpos Antinucleares/análise , Sedimentação Sanguínea , Distribuição de Qui-Quadrado , Diástole , Feminino , Humanos , Imunoglobulina A Secretora/análise , Imunoglobulina G/análise , Imunoglobulina M/análise , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fator Reumatoide/análise , Taxa Secretória/fisiologia , Síndrome de Sjogren/classificação , Estatística como Assunto , Sístole , Xeroftalmia/classificação , Xeroftalmia/fisiopatologia , Xerostomia/classificação , Xerostomia/fisiopatologiaRESUMO
OBJECTIVE: We sought to investigate the prevalence of Candida carriage and the relationships between salivary flow rates and oral Candida load in patients with Sjögren's syndrome (SS). METHODS: The oral Candida load of patients with SS was evaluated by culturing oral rinse (swish and spit) samples. Culture, Gram stain, and wet-mount test results were reported. RESULTS: One hundred three patients (96 women) met European criteria for SS (91 with primary SS and 12 with secondary SS). The mean age (95% confidence interval) was 55 years (range, 51-57 years). Oral rinse cultures were positive in 77% of subjects. The total stimulated salivary flow rate was inversely correlated with oral Candida load (r = -0.47; P =.0001). The oral rinse samples yielded gram-positive results in 38% of patients with SS, and the Fungi-Fluor assay (wet mount) results were positive in 49%. CONCLUSIONS: The prevalence of Candida carriage varies according to the methods used to determine the presence of the organism and is similar to that reported in the literature. A low stimulated salivary flow rate-not a low unstimulated flow rate-was associated with Candida carriage.
Assuntos
Candida/crescimento & desenvolvimento , Candidíase Bucal/microbiologia , Síndrome de Sjogren/microbiologia , Candida/classificação , Candida albicans/crescimento & desenvolvimento , Candida glabrata/crescimento & desenvolvimento , Candida tropicalis/crescimento & desenvolvimento , Candidíase Bucal/fisiopatologia , Contagem de Colônia Microbiana , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Saliva/metabolismo , Saliva/microbiologia , Taxa Secretória/fisiologia , Síndrome de Sjogren/fisiopatologia , Estatísticas não ParamétricasRESUMO
OBJECTIVE: To provide a single source for the best available estimates of the US prevalence of and number of individuals affected by arthritis overall, rheumatoid arthritis, juvenile arthritis, the spondylarthritides, systemic lupus erythematosus, systemic sclerosis, and Sjögren's syndrome. A companion article (part II) addresses additional conditions. METHODS: The National Arthritis Data Workgroup reviewed published analyses from available national surveys, such as the National Health and Nutrition Examination Survey and the National Health Interview Survey (NHIS). For analysis of overall arthritis, we used the NHIS. Because data based on national population samples are unavailable for most specific rheumatic conditions, we derived estimates from published studies of smaller, defined populations. For specific conditions, the best available prevalence estimates were applied to the corresponding 2005 US population estimates from the Census Bureau, to estimate the number affected with each condition. RESULTS: More than 21% of US adults (46.4 million persons) were found to have self-reported doctor-diagnosed arthritis. We estimated that rheumatoid arthritis affects 1.3 million adults (down from the estimate of 2.1 million for 1995), juvenile arthritis affects 294,000 children, spondylarthritides affect from 0.6 million to 2.4 million adults, systemic lupus erythematosus affects from 161,000 to 322,000 adults, systemic sclerosis affects 49,000 adults, and primary Sjögren's syndrome affects from 0.4 million to 3.1 million adults. CONCLUSION: Arthritis and other rheumatic conditions continue to be a large and growing public health problem. Estimates for many specific rheumatic conditions rely on a few, small studies of uncertain generalizability to the US population. This report provides the best available prevalence estimates for the US, but for most specific conditions, more studies generalizable to the US or addressing understudied populations are needed.
Assuntos
Doenças Reumáticas/epidemiologia , Adolescente , Adulto , Idoso , Artrite Juvenil/epidemiologia , Artrite Reumatoide/epidemiologia , Dor nas Costas/epidemiologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Pessoa de Meia-Idade , Cervicalgia/epidemiologia , Prevalência , Escleroderma Sistêmico/epidemiologia , Síndrome de Sjogren/epidemiologia , Espondilartrite/epidemiologia , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: Recent clinical trials suggest that etanercept is ineffective in controlling Sjögren's syndrome (SS). To address the hypothesis that tumor necrosis factor blockade can result in increased levels of interferon-alpha (IFNalpha) and BAFF, we quantified those mediators in plasma from etanercept- and placebo-treated SS patients. METHODS: We studied plasma samples from 20 patients with SS treated with etanercept (25 mg twice weekly) or placebo in a 12-week, randomized, double-blind clinical trial. In addition, we studied plasma samples from 29 healthy controls. IFNalpha activity was determined by reporter cell assay, and BAFF levels were determined by enzyme-linked immunosorbent assay. RESULTS: Baseline IFNalpha plasma activity and BAFF levels were increased in SS patients compared with healthy controls (mean +/- SD IFNalpha plasma activity score 4.43 +/- 2.60 versus 2.08 +/- 0.91; P < 0.0001) (mean +/- SD BAFF level 0.83 +/- 0.27 ng/ml versus 0.60 +/- 0.15 ng/ml; P = 0.008). A significant increase in IFNalpha activity was detected after 12 weeks of treatment in the etanercept group, but not in the placebo group (P = 0.04 and P = 0.58, respectively). Furthermore, a statistically significant increase in BAFF levels was noted in patients receiving etanercept, but not in those receiving placebo (P = 0.01 and P = 0.56, respectively). In vitro culture of control peripheral blood mononuclear cells with etanercept resulted in a dose-dependent increase in the expression of IFNalpha and the IFNalpha-inducible genes IFN-induced protein with tetratricopeptide repeats 1 and BAFF. CONCLUSION: IFNalpha activity and BAFF levels are elevated in the plasma of patients with SS compared with healthy controls. Etanercept treatment exacerbates IFNalpha and BAFF overexpression, providing a possible explanation for the lack of efficacy of this agent in SS.
Assuntos
Antirreumáticos/uso terapêutico , Imunoglobulina G/uso terapêutico , Interferon-alfa/metabolismo , Receptores do Fator de Necrose Tumoral/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/metabolismo , Antirreumáticos/farmacologia , Autoanticorpos/sangue , Fator Ativador de Células B/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Método Duplo-Cego , Etanercepte , Humanos , Imunoglobulina G/metabolismo , Imunoglobulina G/farmacologia , Imunoglobulina M/metabolismo , Interferon-alfa/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: To determine which centromere proteins are recognized in Sjögren's syndrome (SS) and whether antibodies recognizing centromere proteins (CENP) B and CENP C identify a specific serologic subset. METHODS: Sera from 47 patients with SS, 12 xerostomic controls without SS, and 12 healthy controls were studied. All 47 patients met San Diego criteria for SS. Of these, 45 patients had primary SS and 2 had secondary SS with CREST. Sera were analyzed by immunoprecipitation of [35S] methionine-labeled Ro 52, La, and CENP B and C generated by coupled in vitro transcription/translation. Human salivary gland cells were also lysed and immunoprecipitated to determine antibody status against Ro 60. Serological and clinical profiles of patients recognizing CENP were defined. Proportions of sera recognizing CENP B, CENP C, Ro, or La across the 3 groups were compared using Fisher's exact test. RESULTS: Twenty-eight of 45 primary SS patients (62%) recognized Ro 52, and 24 patients (53%) recognized La. Ten of these 45 (22%) sera recognized CENP B or C. Furthermore, 7 of these 10 recognized exclusively CENP C; these 7 (100%) all tested positive for antibodies to both Ro 52 and La. This was in contrast to the group of SS patients that did not recognize CENP C alone, in whom anti-Ro 52 antibodies were found in 21 of 38 (55%; p = 0.034), and antibodies to La in 17 (45%; p = 0.01). Five of 7 CENP C positive sera were also positive for Ro 60. One of 3 patients with antibodies to CENP B also had antibodies to Ro 52, while none of these 3 had antibodies to La. Only patients with antibodies to CENP B showed a centromere pattern on immunofluorescence staining. CONCLUSION: Antibodies to both CENP B and CENP C occur in SS. In a subset representing 15% of SS patients studied, these anticentromere antibodies recognize exclusively CENP C, and were uniformly associated with antibodies to Ro 52 and La.
Assuntos
Autoanticorpos/imunologia , Proteínas Cromossômicas não Histona/imunologia , Síndrome de Sjogren/imunologia , Anticorpos Antinucleares/imunologia , Autoantígenos , Humanos , Aparelho Lacrimal/imunologia , Pessoa de Meia-Idade , Ribonucleoproteínas/imunologia , Glândulas Salivares/imunologia , Antígeno SS-BRESUMO
OBJECTIVE: To determine the prevalence and severity of focal lymphocytic sialadenitis in minor salivary glands of healthy, asymptomatic individuals, in whom Sjögren's syndrome (SS) has been excluded. METHODS: Charts of 54 healthy volunteers who had salivary gland biopsies at the National Institutes of Health from January 1992 to August 1998 were reviewed. The healthy volunteers served as control subjects in various studies of salivary dysfunction. Significant medical conditions including SS were excluded. A biopsy with a focus score (FS) >1 was regarded as positive. Descriptive statistics were used to summarize the population's characteristics. RESULTS: The frequency of focal lymphocytic infiltration in the healthy volunteers was about 15% (8 of 54). None of these individuals had subjective xerostomia or dry eyes. The positive FS ranged from 2 to 6. FS did not correlate with age, smoking, serologic findings, or salivary flow in these patients. CONCLUSION: Lymphocytic infiltration in minor salivary glands is not uncommon among individuals without a history of salivary gland dysfunction. This finding is in agreement with the result of a previous autopsy survey study, indicating that focal sialadenitis may occur in the absence of SS.
Assuntos
Glândulas Salivares Menores/patologia , Sialadenite/epidemiologia , Sialadenite/patologia , Adulto , Biópsia , Doença Crônica , Feminino , Humanos , Masculino , PrevalênciaRESUMO
OBJECTIVE: To investigate the relationships between concentrations of sex hormones and measures of disease activity in patients with primary Sjögren's Syndrome (pSS). METHODS: Fifty-four women were evaluated: 39 patients (age, Q1,Q3: 57.0 yrs; 46, 66) diagnosed with pSS and 15 patients (49.0 yrs; 45, 60) who did not meet diagnostic criteria for pSS. The following measures of disease activity were assessed: serological data [antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum immunoglobulin levels (IgG, IgA, IgM), serum protein, anti-SSA, and anti-SSB], labial minor salivary gland focus score, salivary flow rates, and objective measures of eye dryness (fluorescein corneal staining and unstimulated Schirmer's I test). Spearman correlations were calculated between these indices of disease activity and serum levels of sex hormones: dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione, testosterone, dihydrotestosterone (DHT), estrone, estradiol, and sex hormone binding globulin (SHBG). RESULTS: Numerous differences were noted between cases and controls with disease activity measures. All median values of sex steroid hormones were within the range of normal for pSS cases. Positive correlations were noted between testosterone and ESR (r = 0.36, p = 0.03), testosterone and serum protein (r = 0.37, p = 0.05), and testosterone and focus score (r = 0.44, p = 0.007). Negative correlations were present between SHBG and anti-SSA (r = -0.33, p = 0.05), SHBG and anti-SSB (r = -0.43, p = 0.009), and DHT and CRP (r = -0.41, p = 0.05). No correlations were noted between estrogens and measures of pSS disease activity. CONCLUSION: Higher levels of disease activity (ESR, serum protein, and focus score) were associated with higher concentrations of testosterone. No correlation between disease activity and estrogens was found.
Assuntos
Hormônios Esteroides Gonadais/sangue , Síndrome de Sjogren/sangue , Androstenodiona/sangue , Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/sangue , Di-Hidrotestosterona/sangue , Estradiol/sangue , Estrona/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangueRESUMO
OBJECTIVE: To investigate risk factors for positive minor salivary gland biopsy results in Sjögren's syndrome (SS) and dry mouth patients. METHODS: A total of 289 patients with dry mouth symptoms were evaluated. Potential risk factors for positive minor salivary gland biopsy results (>1 focus of lymphocytes) were studied in 2 phases. In phase 1, predictor variable candidates were identified for the test study (phase 2). Odds ratios were calculated for predictor variables. RESULTS: IgG, IgA, keratoconjunctivitis sicca, and sex, identified as the best predictor variables from phase 1 data, were included in a logistic regression model using phase 2 data. Only IgG demonstrated association with biopsy results (chi(2) = 20.4, P = 0.0001). An elevated IgG level (>1,482 mg/dl) had a high specificity (97% and 97%), high positive predictive value (PPV) (97% and 97%), but poor sensitivity (40% and 45%) in predicting positive biopsy results and SS, respectively. CONCLUSION: Elevated serum IgG levels best predicted a positive biopsy result and SS with high PPV and specificities.
Assuntos
Glândulas Salivares Menores/patologia , Síndrome de Sjogren/patologia , Xerostomia/patologia , Adulto , Biópsia , Feminino , Humanos , Imunoglobulina G/sangue , Ceratoconjuntivite Seca/complicações , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To assess the safety and potential efficacy of etanercept in the treatment of Sjögren's syndrome (SS). METHODS: This pilot study was a 12-week randomized, double-blind, placebo-controlled trial of etanercept, with 14 subjects in each group. Patients received 25 mg of etanercept or placebo (vehicle) by twice-weekly subcutaneous injection. Patients met the American-European Consensus Group criteria for SS. The primary outcome required at least 20% improvement from baseline values for at least 2 of the following 3 domains: subjective or objective measures of dry mouth, subjective or objective measures of dry eyes, and IgG level or erythrocyte sedimentation rate (ESR). RESULTS: Of the 14 patients taking etanercept, 11 had primary SS and 3 had SS secondary to rheumatoid arthritis. Baseline measures did not differ between the 2 groups. Three etanercept-treated patients and 1 placebo-treated patient did not complete the trial. Five etanercept-treated patients and 3 placebo-treated patients showed improvement from baseline in the primary outcome variable at 12 weeks, but the difference was not statistically significant. There were no significant differences between the groups for changes in subjective measures of oral or ocular symptoms (by visual analog scale), the IgG level, Schirmer I test result, van Bijsterveld score, or salivary flow. At 12 weeks, the ESR had decreased in the etanercept group compared with baseline (P = 0.004); however, the mean reduction was only 18.6%. CONCLUSION: We found no evidence to suggest that treatment with etanercept at a dosage of 25 mg twice weekly for 12 weeks was clinically efficacious in SS. A larger trial will be necessary to definitively address the efficacy of etanercept in the treatment of SS.
Assuntos
Imunoglobulina G/uso terapêutico , Imunossupressores/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Artrite Reumatoide/complicações , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Etanercepte , Feminino , Humanos , Imunoglobulina G/administração & dosagem , Imunossupressores/administração & dosagem , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Placebos , Receptores do Fator de Necrose Tumoral/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico , Síndrome de Sjogren/etiologia , Falha de TratamentoRESUMO
PURPOSE: An undetermined number of patients with temporomandibular joint (TMJ) symptoms have been treated with intra-articular disc implants composed of Teflon ethylene/propylene or Teflon polytetrafluoroethylene and aluminum oxide (Proplast-Teflon; Vitek, Houston, TX). These implants have shown the potential to fragment in situ resulting in nonbiodegradable particles that stimulate a giant cell reaction and lead to degeneration of local structures, pain, and limitation of mandibular opening. We examined the possible relationship between TMJ implants and persistent pain, responses to sensory stimuli, quality of life, and systemic immune dysfunction. PATIENTS AND METHODS: This case series (32 patients) were referred from university-based orofacial pain centers and private practices from across the United States. Laboratory and clinical assessments evaluated orofacial pain symptoms, neurologic function, clinical signs and symptoms of rheumatologic disease, physical function, systemic measures of immune function, and behavioral measures. RESULTS: We found that TMJ implant patients appeared to have altered sensitivity to sensory stimuli, a higher number of tender points with a diagnosis of fibromyalgia, increased self-report of chemical sensitivity, higher psychologic distress and significantly lower functional ability. Systemic illness or autoimmune disease was not evident in this series of TMJ implant patients. CONCLUSIONS: Significant problems were noted on clinical assessment of TMJ implant patients. This is a US government work. There are no restrictions on its use.
Assuntos
Artroplastia de Substituição/efeitos adversos , Dor Facial/etiologia , Prótese Articular/efeitos adversos , Qualidade de Vida , Transtornos da Articulação Temporomandibular/cirurgia , Articulação Temporomandibular/cirurgia , Adulto , Análise de Variância , Artroplastia de Substituição/psicologia , Doenças Autoimunes/etiologia , Exposição Ambiental , Feminino , Fibromialgia/etiologia , Humanos , Imunofenotipagem , Prótese Articular/psicologia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Politetrafluoretileno/efeitos adversos , Proplast/efeitos adversos , Amplitude de Movimento Articular , Estatísticas não Paramétricas , Articulação Temporomandibular/imunologia , Articulação Temporomandibular/fisiologia , Transtornos da Articulação Temporomandibular/psicologiaRESUMO
BACKGROUND: Adult bone marrow-derived (BMD) cells could be used to repair damaged organs and tissues, but the intrinsic plasticity of these cells has been questioned by results of in-vitro studies suggesting that such cells might fuse with other cells giving the appearance of differentiation. We aimed to determine whether fusion events are important in vivo. METHODS: To test whether BMD cells can colonise an epithelial tissue and differentiate there without fusion, we did in-situ hybridisation with Y and X chromosome probes labelled with 35-sulphur or digoxigenin, or labelled fluorescently. We did immunohistochemistry with anticytokeratin 13 along with fluorescence in-situ hybridisation to identify Y-chromosome positive buccal epithelial cells in cheek scrapings obtained from five females who had received either a bone-marrow transplant or an allogeneic mobilised peripheral-blood progenitor-cell transplant (enriched in CD34+ cells) from male donors. FINDINGS: When examined 4-6 years after male-to-female marrow-cell transplantation, all female recipients had Y-chromosome-positive buccal cells (0.8-12.7%). In more than 9700 cells studied, we detected only one XXXY-positive cell (0.01%) and one XXY cell (0.01%), both of which could have arisen when an XY cell fused with an XX cell. INTERPRETATION: Male BMD cells migrate into the cheek and differentiate into epithelial cells, an occurrence that does not depend on fusion of BMD cells to recipient cells. This finding might be an example of transdifferentiation of haemopoietic or stromal progenitor cells. Plasticity of BMD cells could be useful in regenerative medicine.
Assuntos
Células da Medula Óssea/citologia , Transplante de Medula Óssea/patologia , Diferenciação Celular/genética , Cromossomos Humanos X , Cromossomos Humanos Y , Células Epiteliais/citologia , Adulto , Fusão Celular , Movimento Celular/genética , Bochecha/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
OBJECTIVE: To screen for potential efficacy and assess feasibility and safety of dehydroepiandrosterone (DHEA) as a treatment for Sjögren's syndrome (SS). METHODS: A 24-week randomized, double-blinded, pilot trial of oral DHEA (200 mg/day) versus placebo was conducted. The primary comparison was to a hypothesized 20% placebo response rate. If 14 consecutive subjects on DHEA did not respond, a Phase III trial would be considered futile. A placebo group of 14 subjects was planned to verify placebo response rate and estimate sample size required for a definitive trial. Response criteria required 20% improvement in at least 2 of 3 domains. Analysis of covariance was used to adjust for baseline differences and for stratified randomization. Outcome measures included visual analog scale questionnaires for dry eye and dry mouth symptoms, lissamine green ocular dye staining and Schirmer I tests, stimulated salivary flow, IgG, and erythrocyte sedimentation rate (ESR). RESULTS: Randomization resulted in 14 DHEA and 14 placebo group subjects. At baseline, mean +/- SD for DHEA versus placebo groups were Schirmer I tests 4.5 +/- 4.5 versus 5.4 +/- 6.1 mm/5 minutes; Van Bijsterveld score 5.3 +/- 2.1 versus 5.5 +/- 2.2; unstimulated saliva 0.03 +/- 0.05 versus 0.04 +/- 0.10 ml/minute; IgG 1,699 +/- 749 versus 1,712 +/- 621 g/dl; and ESR 40 +/- 31 versus 44 +/- 28 mm/hour. Apart from changes over the trial in dry mouth symptoms, no significant differences were noted between the DHEA and placebo groups for dry eye symptoms, objective measures of ocular dryness, stimulated salivary flow; IgG, or ESR. Four DHEA and one placebo group patient dropped out because of adverse effects. Although 7 subjects met response criteria in the DHEA group, 5 met the criteria in the placebo group, and there was no significant difference between groups. CONCLUSION: DHEA showed no evidence of efficacy in SS. Without evidence for efficacy, patients with SS should avoid using unregulated DHEA supplements, since long-term adverse consequences of exposure to this hormone are unknown.