Evaluation of Spanish Gaucher disease patients after a 6-month imiglucerase shortage.

Recently, an acute restriction of imiglucerase has occurred as a result of viral contamination and manufacturing problems. A position statement from the European Working Group for Gaucher Disease and European Gaucher Alliance established a set of key recommendations for identifying and monitoring at-risk patients. In Spain, a profile of the shortage situation was obtained through follow-up of patients with Gaucher disease (GD) and compliance with the therapy recommendations. Here we describe a group of patients, with modified doses of imiglucerase, during the shortage. Fifty adult GD1 patients (25 males/25 females), previously on ERT, were analysed before and after the 6-month shortage. The mean age was 45.3 ± 15.3 years (range: 18-84). The mean Severity Score Index at diagnosis was 8.7 ± 3.8 (range: 3-19); 20% of patients were splenectomized; and 78% had bone disease. During the shortage, 23 patients (46%) discontinued therapy; as complications in this group only one patient suffered a bone crisis and another anaemia (Hb <10.0 g/dL). The mean reduction of haemoglobin level (-2.7%) and platelet counts (-5.4%) were non-significant. Chitotriosidase (CT) activity was increased 135% (p<0.03) and CCL18/PARC 8.2% (p<0.08) in this group. Imiglucerase was reduced by 50% in 17 patients (34%) in this group, seven patients (41.0%) suffered bone pain, three of them true bone crisis and four (23.5%) required support therapy. The mean reduction of haemoglobin (-2.8%) and platelet counts (-10.7%), CT activity was increased 48.2% (p<0.03) and no changes were observed in CCL18/PARC concentration. In both groups no significant changes in visceral size were observed. In 3 patients (6%), imiglucerase was reduced 75% and 7 patients (14%) needed to switch to another ERT (4 patients) or miglustat (3 patients) due to a restart of symptomatic disease. In Spain the 6 first months shortage of imiglucerase have produced a 20% incidence of bone pain, one case of anaemia, and a significant increase in CT activity. Fourteen percent of patients had to switch to another therapy. No significant changes in blood counts, visceral volumes and CCL18/PARC concentration were observed.

Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study.

BACKGROUND: Between 30% and 60% of patients with thrombotic thrombocytopenic purpura (TTP) relapse and mortality remains at 15-20%. Limited clinical data suggest that the administration of anti-CD20 antibody (rituximab) may be useful in preventing acute refractory and chronic relapsing TTP. DESIGN AND METHODS: We studied the clinical response to rituximab in 24 adult patients (median age 42 years, range 24-72 years) from 15 Spanish centers with an acute refractory (14 patients) or acute relapsing (10 patients) episode of idiopathic TTP. On admission, every patient received daily plasma exchange (PE). Rituximab was administered at a dose of 375 mg/m(2) weekly for a median of 13 days (range 0-57 days) after starting PE for a median of 4 doses (range 1-8 doses). RESULTS: No severe acute or delayed toxicity was observed in the patients treated with rituximab. Three (12.5%) patients died because of TTP-related causes. The remaining 21 (87.5%) patients achieved complete remission in a median of 21 days (range 2-35 days) after initiating rituximab. After a median follow-up of 30 months (range 7.5-74 months), 18 patients are in remission and 3 patients have relapsed at 7, 29, and 29 months. CONCLUSIONS: Rituximab appears to be a safe, effective therapy and has a high response rate for the treatment of acute refractory or relapsing idiopathic TTP in adult patients.

Common variable immunodeficiency: association between memory B cells and lung diseases.

BACKGROUND: Malabsorption syndrome often develops in patients with common variable immunodeficiency (CVID). Why structural damages appear in some CVID patients and not in others is not fully understood. Memory B cells (MBs) are responsible for the production of specific antibodies, and their defects have previously been related to autoimmune, granulomatous, and lymphoproliferative complications of CVID. The objective of this study was to ascertain whether a relationship exists between MB defects and the clinical outcome of respiratory and intestinal involvement in these patients. METHODS: Forty-one CVID patients were grouped as follows, according to the quantification of peripheral MBs: the MB2 group (n = 7) included patients with normal MBs; the MB1 group (n = 16) included patients with low switched MBs; and the MB0 group (n = 18) included patients with absent/low MBs. The clinical outcome of respiratory and intestinal involvement of patients was then compared among the three groups. RESULTS: In the MB0 group, chronic lung disease (ie, bronchiectasis and diminished FVC and/or FEV1) developed in 50% of patients vs 13% in the MB1 group and 0% in the MB2 group (p < 0.05). In the MB0 group, malabsorption syndrome or chronic noninfectious diarrhea developed in 50% of patients vs 19% in the MB1 group and 0% in the MB2 group (p < 0.05). No differences were found among the three groups for age at onset of symptoms, delay in diagnosis/treatment, months of follow-up/treatment, and prediagnostic serum IgG concentration. CONCLUSIONS: Alterations in MB count appear to be associated with a severe clinical outcome of respiratory and intestinal involvement in CVID. The MB count could be a useful laboratory parameter for orienting the prognosis and management of CVID patients.

Cholesterol embolism: still an unrecognized entity with a high mortality rate.

BACKGROUND: Cholesterol embolism (CE) is an increasingly common but often underdiagnosed medical problem. The recognition of clinical manifestations of CE is the first step toward a correct diagnosis. OBJECTIVE: Our aim was to characterize the features of CE and the risk factors for fatal outcome. METHODS: Clinical records of patients with clinical and histopathologic diagnoses of CE seen from January 1993 through March 2003 were reviewed. RESULTS: Twenty-six male patients were identified. Mean age was 64 years (range, 48-88 years). All patients had two or more risk factors for atherosclerosis. All but one patient had preexisting symptomatic atherosclerotic disease. At least one precipitating factor was identified in 23 patients (88%). Diagnosis of CE at admission was made in 9 patients only (35%). Cutaneous lesions (88%) and renal failure (73%) were the most common clinical findings. Complications (dialysis, acute pulmonary edema, amputation, or gastrointestinal surgery) were present in 21 patients (81%), and 15 patients died (58%). Previous chronic renal failure was the only variable associated with mortality (relative risk: 4.54, 95% confidence interval 1.26-16.6; P = .02). LIMITATIONS: The results were obtained from patients admitted to a university hospital. This fact may have selected a higher proportion of severe cases. CONCLUSIONS: CE was frequently misdiagnosed. Skin lesions were the most common clinical findings and skin biopsy provided histologic confirmation in most of the patients. Chronic renal failure was the only factor related to death.

Procoagulant microparticles are increased in patients with Behçet's disease but do not define a specific subset of clinical manifestations.

Microparticles (MP) are considered a key component in the haemostatic response. Beyond their in vitro procoagulant properties, a number of pieces of evidence points to procoagulant MP as efficient effectors in the haemostatic response and as pathogenic markers of thrombotic disorders and vascular damage. The aim of the present study was to analyze the procoagulant activity of MP and its correlation with clinical manifestations focusing on vascular involvement in patients with Behçet's disease (BD). We analyzed 55 BD patients in inactive phase of the disease (26 men; mean age, 35 ± 15 years) of which 19 had previously suffered from thrombosis (deep venous thrombosis in 17 and ischemic stroke in 2), and 73 healthy controls matched for age and sex. Procoagulant MP were assessed by a functional assay. BD patients showed higher procoagulant MP values than controls (22.89 ± 15.74 nM versus 14.47 ± 7.34 nM; p < 0.0001). Conversely, we did not find differences in the levels of procoagulant MP according to the gender of patients (22.22 ± 16.23 nM for men versus 21.46 ± 16.47 for women; p = 0.846) or to previous and current treatments. Moreover, the plasmatic concentration of MP does not define any clinical phenotype and it was not related to the time of evolution of the disease. Although inactive BD patients had high values of procoagulant MP, they did not differentiate between BD patients with or without thrombosis.

Changes in biochemical, hematological and immunological profiles after low-dose intravenous immunoglobulin administration in patients with hypogammaglobulinemia.

We assessed the immediate effect of intravenous immunoglobulins (IVIG) on the biochemical, immunological and hematological profiles in patients with hypogammaglobulinemia. Over a period of three months, patients with antibody deficiencies, who had been established on stable IVIG treatment as replacement therapy in our hospital, were enrolled in the study. Participants underwent pre-therapy determinations of their biochemical, immunological and hematological profiles. Laboratory determinations were repeated after completion of IVIG infusions. Over the study period, fourteen patients were enrolled and a total of 34 pre- and post-IVIG infusion determinations were performed and results compared. We found that low-dose IVIG treatment in patients with hypogammaglobulinemia results in post-infusion biochemical and hematological changes, as follows: an increase in total protein concentration and a reduction in albumin, total cholesterol, sodium and alkaline phosphatase concentrations as well as lymphocyte and platelet counts. All these biochemical and cellular changes seems to be transient, since they were not observed in the subsequent pre-infusion determination. However, in other patient populations, some of these changes might differ, depending on the dose of IVIG administered and the baseline condition and immunological status of the patient.

Vascular involvement in Behçet's disease: relation with thrombophilic factors, coagulation activation, and thrombomodulin.

PURPOSE: Thrombosis, usually venous, occurs in 10% to 25% of patients with Behçet's disease, but its pathogenesis is poorly understood. We evaluated parameters of hemostasis and their relation with thrombosis in a series of patients with Behçet's disease. SUBJECTS AND METHODS: We studied 38 patients with Behçet's disease (13 with venous thrombosis), 38 patients with venous thrombosis without thrombophilia, and 100 control subjects. Levels or presence of protein C, protein S, antithrombin, methylenetetrahydrofolate reductase C677T, factor V Leiden, prothrombin gene G20210A, antiphospholipid antibodies, plasminogen, tissue-type plasminogen activator (tPA), type-1 tPA inhibitor (PAI-1), PAI-1 4G/5G polymorphism, prothrombin fragment 1+2, plasmin/alpha(2)-antiplasmin complexes, thrombomodulin, and activated factors VII and XII were determined. RESULTS: There were no deficiencies in protein C, protein S, antithrombin, or factor V Leiden in the patients with Behçet's disease, nor was there evidence of most other thrombotic abnormalities. Compared with control subjects, however, the Behçet's disease group had elevated mean (+/- SD) levels of prothrombin fragment 1+2 (2091 +/- 1323 pmol/L vs. 804 +/- 398 pmol/L, P <0.001), plasmin/alpha2-antiplasmin complexes (410 +/- 220 microg/L vs. 214 +/- 92 microg/L, P <0.001), and thrombomodulin (37 +/- 24 ng/mL vs. 27 +/- 10 ng/mL, P <0.001). These levels did not differ between patients with or without thrombosis. CONCLUSIONS: Thrombophilic factors do not seem to explain most thromboses in Behçet's disease. There is increased thrombin generation, fibrinolysis, and thrombomodulin in Behçet's disease, but these abnormalities are not related to thrombosis.

Multidrug resistance-1 (MDR-1) in autoimmune disorders IV. P-glycoprotein overfunction in lymphocytes from myasthenia gravis patients.

Multidrug resistance (MDR) mechanisms have been widely studied in cancer. Among them, P-glycoprotein (P-gp) overfunction has been associated with resistance to several antineoplastic agents. The physiological role of P-gp involves hormone and metabolite secretion, bacterial product detoxification, and transport of several drugs to the extracellular space, thus inhibiting their toxic or therapeutic effects. The study of MDR-1 in diseases of autoimmune origin has just recently emerged. Corticosteroids remain the mainstay therapy for autoimmune diseases. As prednisone (PDN) is transported by P-gp, the aim of this study was to evaluate the P-gp function in lymphocytes from myasthenia gravis (MG) patients. Thirty MG patients and 25 healthy controls were studied. Peripheral blood mononuclear cells were isolated by gradient centrifugation and incubated with daunorubicin (DNR) (a fluorescent drug extruded by P-gp). Functional activity of P-gp was analyzed by flow cytometry. Results were expressed as percentage of gated lymphocytes able to efflux DNR. Overall, MG patients showed increased numbers of lymphocytes with functional P-gp activity when compared with controls (x = 4.92 +/- 5.26% vs. x = 0.7 +/- 0.48%, respectively) (P < 0.0001). When patients were classified as responders (n = 21) or refractory (n = 9) to treatment, the latter group exhibited higher values of functional P-gp (x = 10.18 +/- 6.39%) when compared to the responder group (x = 2.66 +/- 2.45%) (P = 0.0076). These data suggest, on the one hand, that drug resistance may be induced by long-term treatment or by high PDN doses and, on the other, emphasize the need for the study of P-gp antagonists in order to improve the current therapeutical schemes for the treatment of MG.

Insuficiencia cardiaca aguda en el anciano: características clínicas y mortalidad según la fracción de eyección ventricular izquierda / Acute heart failure in the elderly: clinical features and mortality according to the left ventricular ejection fraction

Resumen Objetivos: Describir y analizar las características clínicas de la insuficiencia cardiaca en el anciano, así mismo, la influencia en la mortalidad según su fracción de eyección ventricular izquierda. Método: Estudio ecológico multigrupo descriptivo en 115 pacientes hospitalizados por la insuficiencia cardiaca aguda con un período de seguimiento de un año. Según la fracción de eyección ventricular izquierda los pacientes se dividieron en dos grupos (fracción de eyección ventricular izquierda preservada y no preservada, si presentaban ≥ 50% o < 50%, respectivamente). Se recogió la tasa de mortalidad al año del alta hospitalaria y se realizó un análisis de Cox de mortalidad. Resultados: La edad media fue de 83,9 años y el 40% fueron hombres. En 76 (66%) pacientes la fracción de eyección ventricular izquierda era preservada. Al año, 35 pacientes (30,4%) fallecieron. En el grupo de la fracción de eyección ventricular izquierda preservada predominaron más las mujeres y presentaron más comorbilidades como: la hipertensión arterial, la diabetes mellitus, la fibrilación auricular y la enfermedad pulmonar obstructiva crónica y por otro lado presentaron menos cardiopatía isquémica. Aunque la mortalidad era mayor en el grupo de la fracción de eyección ventricular izquierda no preservada, no se alcanzaba significación estadística (38,5% vs. 26,3%; p = 0,180). Conclusiones: La mortalidad al año de los pacientes ancianos con insuficiencia cardiaca es alta, así mismo tienen una mayor proporción de la fracción de eyección ventricular izquierda preservada, que a la vez asocia un mayor número de comorbilidades y una tendencia a mayor supervivencia al año con respecto a la fracción de eyección ventricular izquierda no preservada.

Abstract Motivation: To describe and analise the clinical features of heart failure in the elderly, as well as the influence in mortality according to their left ventricular ejection fraction. Method: Ecological multigroup descriptive study in 115 patients who had been hospitalised due to acute heart failure with a one year follow-up period. Depending on their left ventricular ejection fraction, patients were divided into two groups: preserved or non preserved left ventricular ejection fraction, if they showed ≥ 50% or <50%, respectively. Mortality rate one year after discharge was registered and Cox regression model was used for survival analysis. Results: Average age was 83.9 years and 40% were men. The left ventricular ejection fraction was preserved in 76 (66%) of patients. 35 (30.4%) died after one year. The preserved left ventricular ejection fraction group consisted of women predominantly, and they had more comorbidities, such as high blood pressure, diabetes mellitus, atrial fibrillation and chronic obstructive pulmonary disease, whereas their incidence of myocardial ischemia was lower. Despite mortality being higher in the non preserved left ventricular ejection fraction group, statistical significance was not reached (38.5% vs. 26.3%; p = 0.180). Conclusions: Mortality rate after one year of old patients with heart failure is high, and they also have a higher proportion of preserved left ventricular ejection fraction, which in turn is associated to a higher number of comorbidities and a higher tendency to survival after one year in comparison to non preserved left ventricular ejection fraction.

Churg-Strauss syndrome involving the breast: a rare cause of eosinophilic mastitis.

Churg-Strauss syndrome is a rare immunoallergic disorder that usually affects lungs, skin and nervous system. The clinical and radiological findings of Churg-Strauss disease involving the breast are reported and attention is drawn to the fact that, although uncommonly, the breast can be involved by immunological diseases.

Meningeal carcinomatosis as the first manifestation of a transitional cell carcinoma of the bladder.

Meningeal carcinomatosis (MC) as first manifestation of a transitional cell carcinoma (TCC) of the bladder is rare. We report a 66-year-old man, smoker, who presented with two episodes of secondarily generalized partial motor seizures. The routine blood test, brain computed tomography (CT) scan, brain magnetic resonance imaging and electroencephalogram were normal. Cerebral spinal fluid (CSF) revealed a significant pleocytosis and a morphology compatible with non-differentiated non-small cell carcinoma. Broncofiberscopy, gastrofiberscopy, thoracicoabdominopelvic CT-scan and bone scintigraphy were normal but the urine cytology revealed malignant cells similar to those found in the CSF. TCC was diagnosed by cystoscopy and later necropsy confirmed the MC of this tumor. In this report we review the literature and analyze patient survival.