Immunoglobulin and free light chain abnormalities in Gaucher disease type I: data from an adult cohort of 63 patients and review of the literature

Gaucher disease type I, the most common lysosomal storage disorder, is associated with immunoglobulin abnormalities. We studied the prevalence, risk factors, pathogenesis, and effect of enzyme relation therapy (ERT) on gammopathies in an adult Gaucher disease type I cohort (N = 63) and related the results to a review of the currently available literature. Polyclonal gammopathies and monoclonal gammopathy of undetermined significance (MGUS) in our adult GD I cohort were found in 41% and 19% of patients. These results are similar to the data from the literature and correspond to the increased risk of multiple myeloma (MM) that has been described. The prevalence of MGUS in our cohort increased with age but was not associated with disease severity or exposure time. The serum levels of free light chains of immunoglobulins were measured and were not found predictive for the development of MGUS or MM. Levels of pro- as well as anti-inflammatory cytokines, growth factors, and chemokines, especially those involved in inflammation and B-cell function, are disturbed in GD I, with the most impressive and consisting elevations for interleukin-10 and pulmonary and activation-regulated chemokine. A beneficial effect of ERT on the occurrence and progression of gammopathies was suggested from longitudinal data.     

The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: A position statement

N-Butyldeoxynojirimycin (NB-DNJ, miglustat 'Zavesca') is an orallyactive iminosugar which inhibits the biosynthesis of macromolecular substrates that accumulate pathologically in glycosphingolipidoses. Clinical trials of NB-DNJ in patients with Gaucher's disease demonstrate the therapeutic potential of such substrate inhibitors in the glycolipid storage disorders. However, macrophage-targetted enzyme replacement using intravenous mannose-terminated human glucocerebrosidase (imiglucerase, Cerezyme) is highly effective in ameliorating many of the manifestations of Gaucher's disease and is a treatment in widespread use. Given that imiglucerase and miglustat are now both licensed for the treatment of Gaucher's disease, there is a need to review their therapeutic status. Here the treatment of type 1 (non-neuronopathic) Gaucher disease is evaluated with particular reference to the emerging role of oral N-butyldeoxynojirimycin (miglustat) as a substrate-reducing agent. This position statement represents the consensus viewpoint of an independent international advisory council to the European Working Group on Gaucher Disease. This revised version was published online in August 2006 with corrections to the Cover Date.     

Increased incidence of cancer in adult Gaucher disease in Western Europe

The adult form of Gaucher disease (type I GD) is associated with a high prevalence of hypergammaglobulinemia and monoclonal gammopathy of undetermined significance (MGUS). A significantly increased risk of cancer, especially of hematological types, has been found in Ashkenazi-Jewish GD type 1 patients. In this study, incidence and mortality of cancer were assessed in a total of 131 GD patients of mixed ancestry in a population from Western Europe, i.e. 2 Gaucher referral centers in Germany (Düsseldorf) and the Netherlands (Amsterdam). Standardized rate ratios were determined by indirect standardization, using age- and sex-specific incidence and mortality rates of the Dutch population. A total of 14 GD patients of non-Ashkenazi-Jewish descent were identified of whom 5 had a hematologic malignancy. These numbers correspond to an increased risk of cancer of 2.5 (95% CI 1.1-4.7) and an increased risk of hematologic cancer of 12.7 (95% CI 2.6-37.0) among GD patients compared to the general population. In particular, the incidences of multiple myeloma and hepatocellular carcinoma in absence of preexisting cirrhosis were highly elevated, with standardized rate ratios of 51.1 (95% CI 6.2-184) and 141.3 (95% CI 17.1-510.5), respectively. These strongly increased risks on developing cancer suggest that measures for early detection and prevention of hematological and hepatic malignancies in patients with Gaucher type I disease are mandatory.     

Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease

It has been shown that treatment with miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) improves key clinical features of type I Gaucher disease after 1 year of treatment. This study reports longer-term efficacy and safety data. Patients who had completed 12 months of treatment with open-label miglustat (100-300 mg three times daily) were enrolled to continue with therapy in an extension study. Data are presented up to month 36. Liver and spleen volumes measured by CT or MRI were scheduled every 6 months. Biochemical and haematological parameters, including chitotriosidase activity (a sensitive marker of Gaucher disease activity) were monitored every 3 months. Safety data were also collected every 3 months. Eighteen of 22 eligible patients at four centres entered the extension phase and 14 of these completed 36 months of treatment with miglustat. After 36 months, there were statistically significant improvements in all major efficacy endpoints. Liver and spleen organ volumes were reduced by 18% and 30%, respectively. In patients whose haemoglobin value had been below 11.5 g/dl at baseline, mean haemoglobin increased progressively from baseline by 0.55 g/dl at month 12 (NS), 1.28 g/dl at month 24 (p =0.007), and 1.30 g/dl at month 36 (p =0.013). The mean platelet count at month 36 increased from baseline by 22 x 10(9)/L. No new cases of peripheral neuropathy occurred since previously reported. Diarrhoea and weight loss, which were frequently reported during the initial 12-month study, decreased in magnitude and prevalence during the second and third years. Patients treated with miglustat for 3 years show significant improvements in organ volumes and haematological parameters. In conclusion, miglustat was increasingly effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years.     

Epidemiologic background and long-term course of disease in human immunodeficiency virus type 1-infected blood donors identified before routine laboratory screening. Transfusion Safety Study Group

BACKGROUND: The long-term course of human immunodeficiency virus type 1 (HIV-1)-related disease among seropositive blood donors has not been described. The enrollment and epidemiologic background of HIV-1- infected donors in the Transfusion Safety Study and their immunologic and clinical progression are described. STUDY DESIGN AND METHODS: Through the testing of approximately 200,000 sera from donations made in late 1984 and early 1985, 146 anti-HIV-1-positive donors and 151 uninfected matched donors were enrolled. These two cohorts were followed with 6-month interval histories and laboratory testing. RESULTS: Seropositive donors detected before the institution of routine anti-HIV-1 screening disproportionately were first-time donors and men with exclusively male sexual contacts. The actuarial probability of a person's developing AIDS within 7 years after donation was 40 percent; the probability of a person's dying of AIDS was 28 percent. AIDS developed more often when the donor was p24 antigen-positive at donation. Over a 3-year period, significant decreases occurred in CD4+, CD2+CD26+, CD4+CD29+, and CD20+CD21+ counts, but not in CD8+ subsets, CD20+, or CD14+. CONCLUSION: The high proportions of first-time donations and exclusively homosexual men among seropositive donors suggest that test-seeking may have contributed to the high HIV-1 prevalence in the repository. Implementation of alternative test sites when routine donor screening began in 1985 may have averted many high- risk donations. The disease course in HIV-1-infected donors had the same wide spectrum of immunologic and clinical manifestations as were reported for other cohorts.     

Different dose-dependent correction of MIP-1β and chitotriosidase during initial enzyme replacement therapy

Summary  In tissue lesions of type I Gaucher patients, characteristic lipid-laden macrophages, ‘Gaucher cells’, are surrounded by inflammatory phagocytes. Gaucher cells secrete the elevated plasma chitotriosidase. The elevated plasma MIP-1β in Gaucher patients stems from the phagocytes surrounding the Gaucher cells. Plasma chitotriosidase and MIP-1β decrease upon successful enzyme replacement therapy (ERT) with mannose-terminated recombinant glucocerebrosidase (alglucerase). Previous histochemical analysis of Gaucher spleens revealed that Gaucher cells express little mannose receptor, in contrast to surrounding phagocytes. We therefore investigated the corrective effects of ERT on plasma MIP-1β and chitotriosidase in more detail. We also compared effects of one year of treatment with a relatively low dose and a relatively high dose of ERT. A more rapid correction in plasma MIP-1β, compared to chitotriosidase, was observed in most patients on low-dose ERT. Correction of plasma MIP-1β and chitotriosidase levels was more pronounced in the higher-dosed patient group. Upon prolonged treatment, differences in the effects of enzyme dose were no longer significant. Normalization of plasma MIP-1β and chitotriosidase levels was attained in the majority of patients. In conclusion, ERT with mannose-terminated gluocerebrosidase results in prominent corrections of plasma chitotriosidase, a marker of Gaucher cells, and in particular of plasma MIP-1β, a marker of inflammatory phagocytes. The sharper response in plasma MIP-1β to ERT is in line with the observation that especially phagocytes surrounding Gaucher cells express mannose-receptors. Competing interests: None declared References to electronic databases: Non-neuronopathic Gaucher disease, type I: OMIM 230800. Glucocerebrosidase: EC 3.2.1.45.     

Inactivation of factor XIa in human plasma assessed by measuring factor XIa-protease inhibitor complexes: major role for C1-inhibitor

From experiments with purified proteins, it has been concluded that factor XIa (FXIa) is inhibited in plasma mainly by alpha 1-antitrypsin (a1AT), followed by antithrombin III (ATIII), C1-inhibitor (C1Inh), and alpha 2-antiplasmin (a2AP). However, the validity of this concept has never been studied in plasma. We established the relative contribution of different inhibitors to the inactivation of FXIa in human plasma, using enzyme-linked immunosorbent assays (ELISAs) for the quantification of complexes of FXIa with a1AT, C1Inh, a2AP, and ATIII. We found that 47% of FXIa added to plasma formed complexes with C1Inh, 24.5% with a2AP, 23.5% with a1AT, and 5% with ATIII. The distribution of FXIa between these inhibitors in plasma was independent of whether FXIa was added to plasma, or was activated endogenously by kaolin, celite, or glass. However, in the presence of heparin (1 or 50 U/mL), C1Inh appeared to be the major inhibitor of FXIa, followed by ATIII. Furthermore, at lower temperatures, less FXIa-C1Inh and FXIa-a1AT complexes but more FXIa-a2AP complexes were formed. These data demonstrate that the contribution of the different inhibitors to inactivation of FXIa in plasma may vary, but C1Inh is the principal inhibitor under most conditions.     

The value of flow cytometric analysis of platelet glycoprotein expression of CD34+ cells measured under conditions that prevent P- selectin-mediated binding of platelets

In the present study, we show by adhesion assays and ultrastructural studies that platelets can bind to CD34+ cells from human blood and bone marrow and that this interaction interferes with the accurate detection of endogenously expressed platelet glycoproteins (GPs). The interaction between these cells was found to be reversible, dependent on divalent cations, and mediated by P-selectin. Enzymatic characterization showed the involvement of sialic acid residues, protein(s). The demonstration of mRNA for the P-selectin glycoprotein ligand 1 (PSGL-1) in the CD34+ cells by polymerase chain reaction (PCR) analysis suggests that this molecule is present in these cells. Under conditions that prevent platelet adhesion, a small but distinct subpopulation of CD34+ cells diffusely expressed the platelet GPIIb/IIIa complex. These cells were visualized by immunochemical studies. Furthermore, synthesis of mRNA for GPIIb and GPIIIa by CD34+ cells was shown using PCR analysis. The semiquantitative PCR results show relatively higher amounts of GPIIb mRNA than of PF4 mRNA in CD34+CD41+ cells in comparison with this ratio in platelets. This finding is a strong indication that the PCR results are not caused by contaminating adhering platelets. MoAbs against GPIa GPIb alpha, GPV, P- selectin, and the alpha-chain of the vitronectin receptor did not react with CD34+ cells. The number of CD34+ cells expressing GPIIb/IIIa present in peripheral blood stem cell (PBSC) transplants was determined and was correlated with platelet recovery after intensive chemotherapy in 27 patients. The number of CD34+CD41+ cells correlated significantly better with the time of platelet recovery after PBSC transplantation (r = .83, P = .04) than did the total number of CD34+ cells (r = .55). Statistical analysis produced a threshold value for rapid platelet recovery of 0.34 x 10(6) CD34+CD41+ cells/kg. This study suggests that if performed in the presence of EDTA the flow cytometric measurement of GPIIb/IIIa on CD34+ cells provides the most accurate indication of the platelet reconstitutive capacity of the PBSC transplant.