RESUMO
Myasthenia gravis (MG) is an autoantibody-mediated neuromuscular disease with an unpredictable clinical course. Serum free light chains (FLCs) have risen as a promising biomarker for MG, but their role in different subtypes of MG and in predicting disease progression is still uncharted. We investigated plasma from 58 generalized MG patients during post-thymectomy follow-up to determine κ and λ FLC and κ/λ ratio. In a subcohort of 30 patients, we examined the expression of 92 proteins associated with immuno-oncology using Olink. We further studied the ability of FLCs or proteomic markers to differentiate disease severity. Patients with late-onset MG (LOMG) displayed significantly higher mean κ/λ ratio than patients with early-onset MG (P = 0.004). Inducible T-cell co-stimulator ligand (ICOSLG), matrix metalloproteinase 7 (MMP7), hepatocyte growth factor (HGF), and arginase 1 (ARG1) were differentially expressed in MG patients compared to healthy controls. There were no significant associations between clinical outcomes and FLCs or the assayed proteins. In conclusion, an elevated κ/λ ratio suggests long-lasting aberrant clonal plasma cell function in LOMG. Immuno-oncology-related proteomic analysis showed alterations in immunoregulatory pathways. Our findings pinpoint the FLC ratio as a biomarker for LOMG and call for further investigation of the immunoregulatory pathways in MG.
Assuntos
Miastenia Gravis , Proteômica , Humanos , Miastenia Gravis/diagnóstico , Cadeias Leves de Imunoglobulina , Biomarcadores , Autoanticorpos , Cadeias kappa de Imunoglobulina , Cadeias lambda de ImunoglobulinaRESUMO
The ability of thymic histopathology to predict the long-term impact of thymectomy in non-thymomatous myasthenia gravis (NTMG) is mainly uncharted. We applied digital pathology to quantitatively characterize differences of thymic histology between early-onset (EOMG) and late-onset MG (LOMG) and to investigate the role of thymic changes for thymectomy outcomes in MG. We analyzed 83 thymic H&E slides from thymectomized NTMG patients, of which 69 had EOMG and 14 LOMG, using digital pathology open-access software QuPath. We compared the results to the retrospectively assessed clinical outcome at two years after thymectomy and at the last follow-up visit where complete stable remission and minimal use of medication were primary outcomes. The automated annotation pipeline was an effective and reliable way to analyze thymic H&E samples compared to manual annotation with mean intraclass correlation of 0.80. The ratio of thymic tissue to stroma and fat was increased in EOMG compared to LOMG (p = 8.7e-07), whereas no difference was observed in the ratio of medulla to cortex between these subtypes. AChRAb seropositivity correlated with the number of ectopic germinal centers (eGC; p = 0.00067) but not with other histological areas. Patients with an increased number of eGCs had better post-thymectomy outcomes at two years after thymectomy (p = 0.0035) and at the last follow-up (p = 0.0267). ROC analysis showed that eGC area predicts thymectomy outcome in EOMG with an AUC of 0.79. Digital pathology can thus help in providing a predictive tool to the clinician, the eGC number, to guide the post-thymectomy treatment decisions in EOMG patients.
Assuntos
Miastenia Gravis , Timectomia , Centro Germinativo/patologia , Humanos , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/patologia , Miastenia Gravis/cirurgia , Prognóstico , Estudos Retrospectivos , Timectomia/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Gelsolin amyloidosis (AGel amyloidosis) is a hereditary form of systemic amyloidosis featuring ophthalmological, neurological and cutaneous symptoms. Previous studies based mainly on patients' self-reporting have indicated that hearing impairment might also be related to the disease, considering the progressive cranial neuropathy characteristic for AGel amyloidosis. In order to deepen the knowledge of possible AGel amyloidosis-related hearing problems, a clinical study consisting of the Speech, Spatial and Qualities of Hearing Scale (SSQ) questionnaire, clinical examination, automated pure-tone audiometry and a speech-in-noise test was designed. RESULTS: Of the total 46 patients included in the study, eighteen (39%) had self-reported hearing loss. The mean scores in the SSQ were 8.2, 8.3 and 8.6 for the Speech, Spatial and Qualities subscales, respectively. In audiometry, the mean pure tone average (PTA) was 17.1 (SD 12.2) and 17.1 (SD 12.3) dB HL for the right and left ears, respectively, with no difference to gender- and age-matched, otologically normal reference values. The average speech reception threshold in noise (SRT) was - 8.2 (SD 1.5) and - 8.0 (SD 1.7) dB SNR for the right and left ears, respectively, which did not differ from a control group with a comparable range in PTA thresholds. CONCLUSION: Although a significant proportion of AGel amyloidosis patients experience subjective difficulties in hearing there seems to be no peripheral or central hearing impairment at least in patients up to the age of 60 years.
Assuntos
Neuropatias Amiloides Familiares , Gelsolina , Neuropatias Amiloides Familiares/genética , Audiometria de Tons Puros , Audição , Humanos , Pessoa de Meia-Idade , RuídoRESUMO
BACKGROUND: The effect of comorbidities on the prognosis of myasthenia gravis (MG) remains unclear. In particular, the role of other autoimmune diseases (AD) is controversial. METHODS: In this retrospective single-center cohort study, we investigated 154 consecutive generalized thymectomized MG patients, with a mean follow-up time of 8.6 (±5.0) years post-thymectomy. Comorbidities diagnosed at any timepoint were retrieved from medical records and Charlson comorbidity index (CCI) scores were calculated. Patients were categorized into subgroups MG alone (n = 45) and MG with any comorbidity (n = 109); the latter was further categorized into MG with other ADs (n = 33) and MG with non-AD comorbidities (n = 76). The endpoints analyzed were complete stable remission (CSR), minimal need for medications, and need for in-hospital treatments. RESULTS: CSR was more frequent in MG alone than in MG with any comorbidity group (26.7% vs 8.3%, p = 0.004). Minimal need for medication was reached more often in the MG alone than in the MG with non-AD comorbidities group (p = 0.047). Need for in-hospital treatments was lower in the MG alone group than in MG patients with any comorbidity (p = 0.046). Logistic regression analysis revealed that lower CCI scores increased the likelihood of CSR (p = 0.033). Lower CCI scores were more prevalent both in patients with minimal need for medication and in patients who did not need in-hospital treatments (p < 0.001). CONCLUSIONS: Patients with generalized MG and comorbidities have a poorer prognosis than patients with MG alone during almost 9 years follow-up after thymectomy. AD comorbidities appeared not to translate into a higher risk compared to other comorbidities.
Assuntos
Miastenia Gravis , Timectomia , Estudos de Coortes , Comorbidade , Humanos , Miastenia Gravis/complicações , Miastenia Gravis/epidemiologia , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
INTRODUCTION: Finnish gelsolin amyloidosis (AGel amyloidosis) is an inherited systemic amyloidosis with well-known ophthalmological, neurological and cutaneous symptoms. Additionally, cardiomyopathies, conduction disorders and need of cardiac pacemakers occur in some patients. This study focuses on electrocardiographic (ECG) findings in AGel amyloidosis and their relation to cardiac magnetic resonance (CMR) changes. We also assessed whether ECG abnormalities were associated with pacemaker implantation and mortality. MATERIALS AND METHODS: In this cohort study, 51 genetically verified AGel amyloidosis patients (mean age 66 years) without cardiac pacemakers underwent 12-lead ECG and CMR imaging with contrast agent in 2017. Patients were followed-up for 3 years. RESULTS: Conduction disturbances were found in 22 patients (43%). Nine (18%) presented with first-degree atrioventricular block, six (12%) with left anterior hemiblock, seven (14%) with left or right bundle branch block and two (4%) with non-specific intraventricular conduction delay. Low QRS voltage was present in two (4%) patients. Late gadolinium enhancement (LGE) concentrating on the interventricular septum and inferior parts of the heart was present in 19 (86%) patients with conduction abnormalities. During the follow-up, only one patient received a pacemaker, and one patient died. DISCUSSION: Conduction disorders and septal LGE are common in AGel amyloidosis, whereas other ECG and CMR findings typically observed in most common cardiac amyloidosis types were rare. Septal pathology seen in CMR may interfere with the cardiac conduction system in AGel amyloidosis, explaining conduction disorders, although pacemaker therapy is rarely required.
Assuntos
Neuropatias Amiloides Familiares , Gelsolina , Idoso , Estudos de Coortes , Meios de Contraste , Eletrocardiografia , Finlândia , Gadolínio , Gelsolina/genética , HumanosRESUMO
OBJECTIVES: We investigated long-term symptom control of myasthenia gravis following robotic-assisted thoracic surgery (RATS) versus video-assisted thoracic surgery (VATS) thymectomy in a retrospective single-centre cohort. METHODS: From 1999 to 2015, a total of 147 patients underwent thymectomy for myasthenia gravis. Demographic data, medications, operative details, hospital length of stay (LOS), procedure complications and follow-up data were collected by chart review. The Myasthenia Gravis Foundation of America classification was used to evaluate preoperative and postoperative myasthenia gravis status. The primary outcome was complete stable remission (CSR) status. RESULTS: Of the 147 patients, 86 (59%) patients underwent VATS thymectomy and 61 (42%) patients underwent RATS thymectomy. There was no operative mortality. The median follow-up was 12 years in the VATS group [interquartile range (IQR) 9-14 years] and 5 years in the RATS group (IQR 3-6 years) (P = 0.001). Two patients in the VATS (2%) and 2 patients (3%) in the RATS group had Clavien-Dindo grade 3 complications. The median LOS was 3 days in the VATS group (IQR 2-4 days) and 2 days in the RATS group (IQR 2-3 days) (P = 0.013). The rate of CSR was 18% (14/65) in the VATS group compared to 26% (16/44) in the RATS group (P = 0.06). Younger age, RATS approach and preoperative medical remission were independently predictive of CSR by Cox regression analysis. CONCLUSIONS: Patients who underwent RATS thymectomy and were younger or medically remitted before surgery were more likely to achieve CSR. Both methods yield excellent perioperative outcome.
Assuntos
Previsões , Miastenia Gravis/cirurgia , Indução de Remissão/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Cirurgia Torácica Vídeoassistida/métodos , Timectomia/métodos , Adulto , Idoso , Feminino , Seguimentos , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Hereditary gelsolin (AGel) amyloidosis is an autosomal dominantly inherited systemic amyloidosis that manifests with the characteristic triad of progressive ophthalmological, neurological and dermatological signs and symptoms. The National Finnish Gelsolin Amyloidosis Registry (FIN-GAR) was founded in 2013 to collect clinical data on patients with AGel amyloidosis, including altogether approximately one third of the Finnish patients. We aim to deepen knowledge on the disease burden and life span of the patients using data from the updated FIN-GAR registry. We sent an updated questionnaire concerning the symptoms and signs, symptomatic treatments and subjective perception on disease progression to 240 members of the Finnish Amyloidosis Association (SAMY). We analyzed the lifespan of 478 patients using the relative survival (RS) framework. RESULTS: The updated FIN-GAR registry includes 261 patients. Symptoms and signs corresponding to the classical triad of ophthalmological (dry eyes in 93%; corneal lattice amyloidosis in 89%), neurological (numbness, tingling and other paresthesias in 75%; facial paresis in 67%), and dermatological (drooping eyelids in 86%; cutis laxa in 84%) manifestations were highly prevalent. Cardiac arrhythmias were reported by 15% of the patients and 5% had a cardiac pacemaker installed. Proteinuria was reported by 13% and renal failure by 5% of the patients. A total of 65% of the patients had undergone a skin or soft tissue surgery, 26% carpal tunnel surgery and 24% at least unilateral cataract surgery. As regards life span, relative survival estimates exceeded 1 for males and females until the age group of 70-74 years, for which it was 0.96. CONCLUSIONS: AGel amyloidosis causes a wide variety of ophthalmological, neurological, cutaneous, and oral symptoms that together with repeated surgeries cause a clinically significant disease burden. Severe renal and cardiac manifestations are rare as compared to other systemic amyloidoses, explaining in part the finding that AGel amyloidosis does not shorten the life span of the patients at least for the first 75 years.
Assuntos
Neuropatias Amiloides Familiares/mortalidade , Neuropatias Amiloides Familiares/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/mortalidade , Amiloidose/patologia , Amiloidose Familiar/mortalidade , Amiloidose Familiar/patologia , Criança , Distrofias Hereditárias da Córnea/mortalidade , Distrofias Hereditárias da Córnea/patologia , Efeitos Psicossociais da Doença , Progressão da Doença , Feminino , Finlândia , Gelsolina , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Adulto JovemRESUMO
Objectives: Previous clinical studies have shown frequent cardiac symptoms in patients with hereditary gelsolin (AGel) amyloidosis, possibly related to amyloid deposition in the heart and other internal organs. Previous studies on internal organ amyloid deposition in AGel amyloidosis have been based on small patient series. Methods: Paraffin-embedded tissue sections from 25 autopsied individuals (age at death 44.4-88.6 years) with AGel amyloidosis were stained with HE, Congo red and Herovici stains and immunohistochemistry against the low molecular weight gelsolin fraction was performed. The amount of amyloid was estimated semi-quantitatively. Results: AGel-based amyloid deposits were found in the myocardium and cardiac blood vessels in every patient. The deposits were mainly small and co-localized with regions with excess fibrosis in the myocardium. The lungs were positive for amyloid in 79%, renal parenchyma in 54% and renal blood vessels in 71% of the cases. The amount of myocardial, renal and hepatic amyloid correlated with age at death of the patients. Conclusions: We show the constant presence of AGel amyloid in the hearts of patients with AGel amyloidosis. Although the deposits were mainly small, the co-localization of amyloid with fibrosis may amplify the effect of pure amyloid deposition, possibly leading to clinical signs and symptoms.
Assuntos
Proteínas Amiloidogênicas/genética , Amiloidose/genética , Distrofias Hereditárias da Córnea/genética , Gelsolina/genética , Rim/metabolismo , Pulmão/metabolismo , Miocárdio/metabolismo , Idoso , Idoso de 80 Anos ou mais , Proteínas Amiloidogênicas/metabolismo , Amiloidose/metabolismo , Amiloidose/patologia , Autopsia , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Distrofias Hereditárias da Córnea/metabolismo , Distrofias Hereditárias da Córnea/patologia , Feminino , Gelsolina/metabolismo , Expressão Gênica , Humanos , Imuno-Histoquímica , Rim/irrigação sanguínea , Rim/patologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Miocárdio/patologiaRESUMO
Gelsolin (AGel) amyloidosis is a hereditary condition with common neurological effects. Myocardial involvement, especially strain, T1, or extracellular volume (ECV), in this disease has not been investigated before. Local myocardial effects and possible amyloid accumulation were the targets of interest in this study. Fifty patients with AGel amyloidosis were enrolled in the study. All patients underwent cardiovascular magnetic resonance imaging, including cine imaging, T1 mapping, tagging, and late gadolinium enhancement (LGE) imaging at 1.5 T. Results for volumetry, myocardial feature-tracking strain, rotation, torsion, native T1, ECV, and LGE were investigated. The population mean native T1 values in different segments of the left ventricle (LV) varied between 1003 and 1080 ms. Myocardial mean T1 was 1031 ± 37 ms. T1 was highest in the basal plane of the LV (1055 ± 40 ms), similarly to ECV (30.0% ± 4.4%). ECV correlated with native T1 in all LV segments (p < 0.005). Basal LGE was detected in 76% of patients, and mid-ventricular LGE in 32%. LV longitudinal strain was impaired (- 17.4% ± 2.6%), significantly decreasing apical rotation (p = 0.018) and concurrently myocardial torsion (p = 0.005). LV longitudinal strain correlated with mean T1 and ECV of different LV planes (p < 0.04; basal p < 0.01). Myocardial involvement in AGel amyloidosis is significant, but the effects are local, focusing on the basal plane of the LV.
Assuntos
Amiloidose/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Distrofias Hereditárias da Córnea/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Contração Miocárdica , Função Ventricular Esquerda , Amiloidose/genética , Amiloidose/patologia , Amiloidose/fisiopatologia , Fenômenos Biomecânicos , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Distrofias Hereditárias da Córnea/genética , Distrofias Hereditárias da Córnea/patologia , Distrofias Hereditárias da Córnea/fisiopatologia , Gelsolina/genética , Predisposição Genética para Doença , Humanos , Mutação , Miocárdio/patologia , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Sistema de Registros , Volume Sistólico , Função Ventricular DireitaRESUMO
Finnish gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominantly inherited systemic disorder with ophthalmologic, neurologic and dermatologic symptoms. Only the gelsolin (GSN) c.640G>A variant has been found in the Finnish patients thus far. The purpose of this study was to examine whether the Finnish patients have a common ancestor or whether multiple mutation events have occurred at c.640G, which is a known mutational hot spot. A total of 79 Finnish AGel amyloidosis families including 707 patients were first discovered by means of patient interviews, genealogic studies and civil and parish registers. From each family 1-2 index patients were chosen. Blood samples were available from 71 index patients representing 64 families. After quality control, SNP array genotype data were available from 68 patients from 62 nuclear families. All the index patients had the same c.640G>A variant (rs121909715). Genotyping was performed using the Illumina CoreExome SNP array. The homozygosity haplotype method was used to analyse shared haplotypes. Haplotype analysis identified a shared haplotype, common to all studied patients. This shared haplotype included 17 markers and was 361 kb in length (GRCh37 coordinates 9:124003326-124364349) and this level of haplotype sharing was found to occur highly unlikely by chance. This GSN haplotype ranked as the largest shared haplotype in the 68 patients in a genome-wide analysis of haplotype block lengths. These results provide strong evidence that although there is a known mutational hot spot at GSN c.640G, all of the studied 62 Finnish AGel amyloidosis families are genetically linked to a common ancestor.
Assuntos
Amiloidose/genética , Distrofias Hereditárias da Córnea/genética , Efeito Fundador , Feminino , Finlândia , Gelsolina/genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Myasthenia gravis (MG) is the most common neuromuscular transmission disorder, causing weakness of skeletal muscles on exertion. The course of the disease is highly variable, symptoms and signs may change rapidly due to infection or pregnancy. MG is classified using serological, electrophysiological and pharmaceutical tools. A precise diagnosis allows for the choice of right treatment, predicts the course of disease and hence helps with the follow-up. In this review we present Finnish guidelines for diagnostics, treatment and follow-up of MG patients.
Assuntos
Miastenia Gravis/diagnóstico , Miastenia Gravis/terapia , Finlândia , Humanos , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: Doppler ultrasound (US) has been widely used to evaluate the cervical venous system of multiple sclerosis patients according to the hypothesis of chronic cerebrospinal venous insufficiency with contradictory results. Venous anatomy and pathology can be examined with less operator-dependent magnetic resonance imaging (MRI). Our aim is to assess the interobserver agreement in measuring internal jugular vein (IJV) cross-sectional area (CSA) in MR images and to explore the agreement between US and MRI in the detection of calibers of ≤0.3 cm2 in the IJV CSA in the prospective study. METHODS: Thirty-seven multiple sclerosis patients underwent MRI of the cervical venous system. Two independent neuroradiologists measured the CSA of IJV at the mid-thyroid level. Furthermore, the time from contrast enhancement of common carotid arteries to that of each IJV (transit time in seconds) was assessed, and recorded whether IJV or the vertebral plexus visualized first during the contrast passage. US examination had been performed earlier. RESULTS: Interobserver agreement for assessing IJV CSA in MR images was substantial: the measurements differed >0.5 cm2 between the examiners in only 5 IJVs (7%), Cohen's kappa 0.79. Transit times from common carotid artery to IJV varied between 5.1 and 14.1 sec. Fifteen patients had left-to-right asymmetry in the speed of IJV contrast filling. IJV CSA ≤ 0.3 cm2 was found in 51 IJVs on the basis of US. Ten of these IJVs (19.6%) showed IJV CSA ≤ 0.3 cm2 also in MRI. All IJVs defined as CSA ≤ 0.3 cm2 in MRI met this caliber criterion also in US. CONCLUSIONS: Interobserver agreement at the thyroid level of the IJV was good at MRI measurements. The US defines more IJVs as narrow (CSA ≤ 0.3 cm2) than MRI. The US measurements for IJV CSA are not comparable with these methods. The US seems too sensitive in terms of finding venous stenosis.
Assuntos
Veias Jugulares/diagnóstico por imagem , Angiografia por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Ultrassonografia Doppler , Adulto , Velocidade do Fluxo Sanguíneo , Estudos de Casos e Controles , Constrição Patológica , Feminino , Humanos , Veias Jugulares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/fisiopatologia , Variações Dependentes do Observador , Valor Preditivo dos Testes , Estudos Prospectivos , Fluxo Sanguíneo Regional , Reprodutibilidade dos Testes , Glândula Tireoide , Adulto JovemRESUMO
BACKGROUND: Finnish type of hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant disorder. Until recently, there has only been little knowledge of fatal complications of the disease and its possible impact on the patients' life span. METHODS: We identified 272 deceased patients based on patient interviews and genealogical data. After collecting their death certificates, we recorded the patients' underlying and immediate causes of death (CoD) and life span and compared them to the general Finnish population. We then calculated proportional mortality ratios (PMR), standardised for age and sex, for the CoDs. RESULTS: The underlying CoD in 20% of the patients was AGel amyloidosis (PMR = 114.2; 95% CI: 85.6-149.4). The frequency of fatal cancers (10%) was significantly diminished (PMR = 0.47; 95% CI: 0.31-0.69). Renal complications were overrepresented as the immediate CoD in female patients (PMR = 2.82 95% CI: 1.13-5.81). The mean life span for male patients was 73.9 years (95% CI: 72.0-75.6) and 78.0 years for female patients (95% CI: 76.4-79.5) compared to 72.1 and 80.1 years for the general population. CONCLUSIONS: Our results suggest that the disease increases the risk of fatal renal complications but does not substantially shorten the life span, possibly due to the significantly lower frequency of fatal cancers. Key Messages AGel amyloidosis may increase the risk of renal complications, especially among female patients. The frequency of fatal cancers is significantly lower. The patients' life span is comparable to that of the general population.
Assuntos
Amiloidose Familiar/epidemiologia , Gelsolina/genética , Nefropatias/epidemiologia , Neoplasias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose Familiar/complicações , Causas de Morte , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
PURPOSE: To investigate gender differences in Finnish gelsolin amyloidosis (AGel amyloidosis). PATIENTS AND METHODS: AGel amyloidosis patients, who were members of Finnish Amyloidosis Association (SAMY), filled in a questionnaire compiling known and suspected aspects of their disease. Telephone interviews and hospital medical records, when available, complemented the questionnaire. The data were entered to the database in order to create a national AGel amyloidosis patient registry (FIN-GAR). RESULTS: A total of 227 patients, 156 women and 71 men, participated in the study. The women in our registry noticed their first symptoms at the median age of 39 years versus 43 years for men (p = 0.01). At the age in which the diagnosis was made there was a trend to be observed between men and women (women: 39 years versus men: 43 years, p = 0.053). Corneal lattice dystrophy was diagnosed in significantly younger women than men (median ages 41 versus 49 years, respectively, p = 0.01). Of other ophthalmological manifestations, corneal ulcer, impaired vision and glaucoma were all diagnosed at least 5 years earlier in women, although differences were not statistically significant. Ophthalmological manifestations, such as dry eyes and corneal ulcer; dermatological signs, such as blepharochalasis, and also neurological symptoms, such as myokymia and carpal tunnel syndrome, were more prevalent among women. CONCLUSIONS: In the largest so far available study on AGel amyloidosis we show that women developed symptoms and signs of AGel amyloidosis at younger age. Especially eye-related problems occurred earlier and together with nerve and skin manifestations, the characteristic clinical triad in AGel amyloidosis, were more common in women. However, a clear limitation of our study was a selection bias caused by a significant underrepresentation of men in the study population.
Assuntos
Amiloidose Familiar/epidemiologia , Amiloidose Familiar/patologia , Gelsolina/genética , Adulto , Idade de Início , Amiloidose Familiar/genética , Progressão da Doença , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição por SexoRESUMO
BACKGROUND: Finnish type of hereditary gelsolin amyloidosis (FGA) is one of the most common diseases of Finnish disease heritage. Existing FGA knowledge is based only on smaller patient series, so our aim was to elucidate the natural course of the disease in a comprehensive sample of patients and to build up a national FGA patient registry. METHODS: An inquiry about the known and suspected signs of FGA, sent to the members of Finnish Amyloidosis Association, telephone contacts, and hospital records were utilized to create the registry. RESULTS: A total of 227 patients were entered to the database. The first symptom was ophthalmological for 167 patients (73.6%) at the mean age of 39 years. Corneal lattice dystrophy (CLD) was reported at the mean age of 43 years. Impaired vision, polyneuropathy, facial nerve paresis, and cutis laxa appeared on average between 52 and 57 years. Carpal tunnel syndrome (CTS) was reported by 86 patients (37.9%). Nine patients (4.0%) had a pacemaker, and 12 (6.1%) had cardiomyopathy. CONCLUSIONS: The first symptom was ophthalmological in most cases. Except for CLD no prominent difference in the age of appearance was found between the major symptoms. CTS, cardiac pacemakers, and cardiomyopathy were remarkably more common compared to the general population.
Assuntos
Amiloidose Familiar/genética , Amiloidose Familiar/patologia , Gelsolina/genética , Gelsolina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/epidemiologia , Amiloidose/genética , Amiloidose/metabolismo , Amiloidose/patologia , Amiloidose Familiar/epidemiologia , Amiloidose Familiar/metabolismo , Distrofias Hereditárias da Córnea/epidemiologia , Distrofias Hereditárias da Córnea/genética , Distrofias Hereditárias da Córnea/metabolismo , Distrofias Hereditárias da Córnea/patologia , Progressão da Doença , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Sistema de RegistrosRESUMO
Treatment is initiated when the McDonald criteria for relapsing-remitting multiple sclerosis (RRMS) are fulfilled. High-risk patients with clinically isolated syndrome are followed using magnetic resonance imaging for one year after the first imaging. Interferon-beta or glatiramer acetate are the first-line immunomodulating drugs (IMD) for RRMS. MxA protein is measured 12 and 24 months after initiation of Interferon-beta to evaluate possible development of neutralizing antibodies. If MxA protein may not be detected repeatedly interferon-beta treatment is discontinued. If the disease is active in spite of treatment with first-line IMD, natalizumab may be considered as a second-line therapy. IMD is stopped when the transition to secondary progressive phase has occurred (or upon transition to secondary progressive phase).
Assuntos
Imunossupressores/uso terapêutico , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Progressão da Doença , Proteínas de Ligação ao GTP/análise , Acetato de Glatiramer , Humanos , Interferon Tipo I/uso terapêutico , Imageamento por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Proteínas de Resistência a Myxovirus , Peptídeos/uso terapêutico , Proteínas Recombinantes , Resultado do TratamentoRESUMO
The efficacy and safety of a single intravenous (I.V.) infusion of clodronate 1500 mg or 900 mg was compared with a single I.V. infusion of pamidronate 90 mg in the treatment of malignant hypercalcemia. Primary efficacy data from two separate, but parallel, randomized double-blind controlled multi-center studies (N = 63), involving patients with malignant hypercalcemia (S-Ca(cor) > 2.68 mmol/l), were pooled along with results from a study (N = 4), in which an open I.V. phase was followed by a randomized oral phase. The primary efficacy variable, the proportion of normocalcemic patients at day 5 could be evaluated from 51 subjects. Of them, 21 were in the clodronate 1500 mg group, 10 in the clodronate 900 mg group and 20 in the pamidronate 90 mg group. After the rehydration, the patients were given a single I.V. infusion of clodronate 1500 mg, clodronate 900 mg or pamidronate 90 mg. The patients were followed up for five days and S-Ca(cor) was measured daily. At day 5, a total of 16 patients (76%) in the clodronate 1500 mg group, six patients (60%) in the clodronate 900 mg group and 17 patients (85%) in the pamidronate 90 mg group were normocalcemic, the differences between the treatment groups being statistically non-significant. The differences in the mean S-Ca(cor) between the treatment groups were statistically non-significant. I.V. clodronate given either as 900 mg or 1500 mg single-dose was safe and well tolerated.
Assuntos
Ácido Clodrônico/uso terapêutico , Hipercalcemia/tratamento farmacológico , Neoplasias/complicações , Cálcio/sangue , Difosfonatos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Hipercalcemia/etiologia , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , PamidronatoRESUMO
INTRODUCTION: Long-term safety and tolerance is paramount when treating women who are otherwise healthy after the primary adjuvant therapy of breast cancer. Efficacy and limited safety results of a large-scale clinical trial, using adjuvant oral clodronate to prevent bone metastases in primary breast cancer patients, have been reported previously, demonstrating a reduction in the rate of bone metastases during treatment. Here we present expanded safety and tolerability results for clodronate treatment from this trial (cut-off date extended from June 1997 to June 2000). STUDY DESIGN AND METHODS: For this randomised, double-blind, placebocontrolled, multicentre study, patients were enrolled and randomised to receive oral clodronate (Bonefos) 1600 mg/day or placebo for 2 years. The total median treatment period plus follow-up was 5.5 years. Adverse events (AEs) and laboratory parameters were followed up regularly for the total study period. The 95% CIs were estimated for the difference in the rate of AEs between the treatment groups. PATIENTS: A total of 1079 women with primary operable breast cancer were enrolled to the study; 538 received clodronate and 541 received placebo. RESULTS: Overall incidence of AEs (96.5% of the patients) was the same in both treatment groups, although gastrointestinal disorders were significantly more frequent in the clodronate group during the total study period (66% vs 56.2%; 95% CI 4.0-15.6; p < 0.05). This was mainly due to an increase in non-severe diarrhoea beginning 3-4 months after treatment start. Serious AEs (SAEs) were reported for 39.4% of the patients receiving clodronate and 44.5% of those receiving placebo; no drug-related (clodronate or placebo) SAEs were identified. Clodronate significantly lowered mortality (98 deaths vs 129 deaths; hazard ratio 0.77; 95% CI 0.59-1.00; p = 0.047) reducing the risk of death over the total study period by 23%. AEs caused 58 early discontinuations (five drug-related events) in the clodronate group and 43 discontinuations (three drug-related events) in the placebo group. CONCLUSION: These results indicate that in women with early breast cancer receiving adjuvant systemic therapy, oral clodronate for 2 years is generally well tolerated with no serious long-term sequelae, providing a safe, long-term therapy in the adjuvant setting.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Ácido Clodrônico/efeitos adversos , Administração Oral , Análise de Variância , Neoplasias da Mama/mortalidade , Ácido Clodrônico/administração & dosagem , Ácido Clodrônico/uso terapêutico , Intervalos de Confiança , Método Duplo-Cego , Feminino , Seguimentos , Gastroenteropatias/induzido quimicamente , Humanos , Modelos de Riscos Proporcionais , TempoRESUMO
PURPOSE: The development of bone metastases depends on tumor-induced osteoclastic resorption of bone, which may be inhibited by the antiosteolytic bisphosphonate clodronate. Given to patients with primary breast cancer, clodronate might reduce the subsequent incidence of bone metastases. PATIENTS AND METHODS: This double-blind, multicenter trial accrued 1,069 assessable patients with operable breast cancer between 1989 and 1995. All patients received surgery, radiotherapy, chemotherapy, and tamoxifen as required. Patients were randomized to receive oral clodronate 1,600 mg/d or a placebo for 2 years starting within 6 months of primary treatment. The primary end point was relapse in bone, analyzed on an intent-to-treat basis, during the medication period and during the total follow-up period (median follow-up, 2,007 days). Secondary end points were relapse in other sites, mortality, and toxicity. RESULTS: During the total follow-up period, there was a nonsignificant reduction in occurrence of bone metastases (clodronate, n = 63; placebo, n = 80; hazards ratio [HR], 0.77; 95% confidence interval [CI], 0.56 to 1.08; P =.127). During the medication period there was a significant reduction in the occurrence of bone metastases (clodronate, n = 12; placebo, n = 28; HR, 0.44; 95% CI, 0.22 to 0.86; P =.016). The occurrence of nonosseous metastases was similar (clodronate, n = 112; placebo, n = 128; P =.257), but there was a significant reduction in mortality (clodronate, n = 98; placebo, n = 129; P =.047) during the total follow-up period. CONCLUSION: Clodronate, given to patients with primary operable breast cancer, may reduce the occurrence of bone metastases, although this reduction was only significant during this medication period. There was a significant reduction in mortality.