Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry

PURPOSE: Gaucher disease is the first lysosomal storage disorder to be treated with macrophage-targeted enzyme replacement therapy. Previous studies in relatively small numbers of patients demonstrated short-term efficacy of this treatment. This study describes the effects of 2 to 5 years of treatment on specific manifestations of type 1 Gaucher disease. SUBJECTS AND METHODS: Physicians reported data from 1028 patients to the Gaucher Registry. Assessment of response included serial measurements of hemoglobin concentration, platelet count, liver and spleen volumes, and the occurrence of bone pain and bone crises. RESULTS: Among anemic patients, hemoglobin concentration increased to normal or near normal within 6 to 12 months, with a sustained response through 5 years. In thrombocytopenic patients with intact spleens, the most rapid response occurred during the first 2 years, with slower improvement thereafter. The likelihood of achieving a normal platelet count decreased with increasing severity of baseline thrombocytopenia. In patients who had undergone splenectomy, platelet counts returned to normal within 6 to 12 months. Hepatomegaly decreased by 30% to 40% during follow-up; splenomegaly decreased 50% to 60%, but rarely to volumes below five times normal size. In patients with pretreatment bone pain or bone crises, 52% (67/128) were pain free after 2 years and 94% (48/51) reported no additional crises. CONCLUSION: Enzyme replacement therapy prevents progressive manifestations of Gaucher disease, and ameliorates Gaucher disease-associated anemia, thrombocytopenia, organomegaly, bone pain, and bone crises.     

Rebound hepatosplenomegaly in type 1 Gaucher disease

A 19-year-old male patient with type 1 Gaucher disease was put on regular biweekly infusions of alglucerase. After 1 yr of treatment, hepatic and splenic volumes decreased from 38 and 45 mL/kg to 31 and 34 mL/kg, respectively. In addition, hemoglobin concentration, platelet count and white cell count increased, acid phosphatase level decreased, and the patient gained weight and energy. Despite improvement, the patient refused enzyme replacement therapy (ERT) because of muscle rigidity, chest pain, trembling and anxiety, which he attributed to enzyme substitution. Two and 4.5 year after cessation of therapy, hepatic and splenic volumes increased to 36 and 53 mL/kg and to 53 and 110 mL/kg, respectively. The patient developed non-tractable hematuria because of compression and dislocation of the left kidney by the enlarged spleen, which necessitated splenectomy. This report suggests that cessation of ERT in Gaucher disease may result in severe and complicated rebound visceromegaly.     

Dixon quantitative chemical shift imaging is a sensitive tool for the evaluation of bone marrow responses to individualized doses of enzyme supplementation therapy in type 1 Gaucher disease

Type 1 Gaucher disease can be effectively treated with enzyme supplementation therapy. Bone disease is a debilitating feature of the disorder and results from infiltration of the bone marrow by Gaucher cells. The effect of treatment on bone marrow infiltration is difficult to measure, necessitating the development of sensitive techniques to allow adequate dosing. Dixon quantitative chemical shift imaging (Dixon-QCSI) is a MRI technique to measure displacement of fatty marrow by Gaucher cells. Low bone marrow fat fractions have been found in Gaucher disease. We studied the effect of individualized low doses of enzyme therapy on the fat fractions of the lumbar spine in 12 adult Gaucher disease patients before and during treatment and in 9 untreated Gaucher controls. Fat fractions were decreased in 9/12 patients (median 0.20, range 0.08-0.40) and equally low in the untreated Gaucher controls compared to age-matched healthy volunteers (normal values 0.27-0.43, P < 0.01). During treatment, fat fractions increased significantly already after 1 year in 11/12 patients (P = 0.007). After 4 to 5 years, fat fractions normalized in 11/12 patients. Fat fractions remained low in the untreated Gaucher controls (P = 0.5 and 0.6 at 1 and 2 years, respectively). Six of 11 patients had a dose increase, which did not clearly affect fat fractions. Dixon-QCSI is a sensitive tool for the measurement of the response of bone marrow to enzyme therapy.     

Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis

Data from the International Collaborative Gaucher Group Gaucher Registry were analysed to assess the relationship between enzyme replacement therapy with imiglucerase (ERT) and incidence of avascular necrosis (AVN) in type 1 Gaucher disease (GD1), and to determine whether the time interval between diagnosis and initiation of ERT influences the incidence rate of AVN. All patients with GD1 enrolled in the Gaucher Registry who received ERT and did not report AVN prior to starting therapy ( n  = 2700) were included. The incidence rate of AVN following initiation of ERT was determined. An incidence rate of AVN of 13·8 per 1000 person-years was observed in patients receiving ERT. Patients who initiated ERT within 2 years of diagnosis had an incidence rate of 8·1 per 1000 person-years; patients who started ERT ≥2 years after diagnosis had an incidence rate of 16·6 per 1000 person-years. The adjusted incidence rate ratio was 0·59 [95% confidence interval (CI) 0·36–0·96, P  = 0·0343]. Splenectomy was an independent risk factor for AVN (adjusted incidence rate ratio 2·23, 95% CI 1·61–3·08, P  < 0·0001). In conclusion, the risk of AVN was reduced among patients who initiated ERT within 2 years of diagnosis, compared to initiating treatment ≥2 years after diagnosis. A higher risk of AVN was observed among patients who had previously undergone splenectomy.     

Guidance on the use of miglustat for treating patients with type 1 Gaucher disease

Type 1 Gaucher disease (GD) is a progressive lysosomal storage disorder due to an autosomal recessive deficiency of glucocerebrosidase. Clinical manifestations include anemia, thrombocytopenia, hepatosplenomegaly, and bone and pulmonary disease. Intravenous enzyme replacement (ERT) with imiglucerase is the accepted standard for treatment of symptomatic patients. More than 3,500 patients worldwide have received ERT with well-documented beneficial effects on the hematological, visceral, skeletal, and pulmonary manifestations, and with resultant improvement in health-related quality of life. Miglustat, an imino sugar that reversibly inhibits glucosylceramide synthase and reduces intracellular substrate burden, is an oral treatment for patients with type 1 GD that was recently approved in the United States for symptomatic patients with mild to moderate clinical manifestations for whom ERT is not an option. Because responses to miglustat are slower and less robust than those observed with ERT, and because miglustat is associated with significant side effects, clinicians who care for patients with GD should become familiar with the limited indications for miglustat use and the circumstances when it may be prescribed appropriately. This review article and position statement represents the current opinion of American physicians with extensive expertise in GD regarding patient management in the context of the availability of standard imiglucerase treatment and the recent introduction of miglustat.     

Overweight, insulin resistance and type II diabetes in type I Gaucher disease patients in relation to enzyme replacement therapy

Type I Gaucher disease, a lysosomal storage disorder is associated with metabolic abnormalities such as high resting energy expenditure, low circulating adiponectin and peripheral insulin resistance. Treatment with enzyme replacement therapy (enzyme therapy) leads to a decrease in resting energy expenditure, but its influence on weight and risk of development of type II diabetes is unknown.We studied the BMI, prevalence of overweight, insulin resistance and type II diabetes in untreated and enzyme therapy treated Gaucher patients before and after several years of follow-up and compared this to data on healthy subjects from literature.We established that in untreated Gaucher patients the prevalence of overweight is lower than in the general population. Long-term treatment with enzyme therapy induces a larger than average weight gain leading to a similar prevalence of overweight in enzyme therapy treated patients and the general population. The prevalence of type II diabetes increases significantly during treatment with enzyme therapy, resulting in a comparable prevalence of type II diabetes in enzyme therapy treated patients and the general population.     

Thrombocytopenia and GBA gene mutation in a patient with adult type 1 Gaucher disease

A 38-year-old female patient was diagnosed with anemia for 3 years. Medical examination showed slight splenomegaly (250 × 62 mm), thrombocytopenia (platelets 51 × 10⁹/L), anemia (Hb levels 107 g/L), and β-glucocerebrosidase activity (GBA) in leukocytes was lower than normal. Microscopic findings of bone marrow smear demonstrated that Gaucher cells in bone marrow and periodic acid–Schiff staining of them were positive. Sequencing of GBA genomic and cDNA identified one novel homozygous mutation, c.484A> G (p.Met162Val). This case suggests that we should pay attention to adult Gaucher disease as a differential diagnosis for cryptogenic thrombocytopenia and one novel homozygous mutation in GBA gene was reported for the first time. The novel mutation in homozygosity is apparently associated with mild, non-neuronopathic type 1 disease which is relatively uncommon in Asian populations.     

Real-world clinical experience with long-term miglustat maintenance therapy in type 1 Gaucher disease: the ZAGAL project

There are few published data from real-world clinical experience with miglustat (Zavesca®), an oral inhibitor of glucosylceramide synthase, in type 1 Gaucher disease. We report data from a prospective, open-label investigational study that evaluated substrate reduction therapy with miglustat 100 mg t.i.d. as a maintenance therapy in patients with Type 1 Gaucher disease who had been switched from previous enzyme replacement therapy. Long-term data on changes in organ size, blood counts, disease severity bio-markers, bone marrow infiltration, overall clinical status and safety/tolerability were analyzed from 28 patients with Type 1 Gaucher disease who were attending routine clinic visits. Assessments were performed at six, 12, 24, 36 and 48 months of therapy. Disease severity biomarkers improved up to 48 months after initiation of miglustat, while other disease parameters remained stable. Miglustat showed an acceptable profile of safety and tolerability throughout treatment. In conclusion, miglustat is an effective therapy for the long-term maintenance of patients with Type 1 Gaucher disease previously stabilized with enzyme replacement therapy.     

Enzyme replacement therapy reduces Gaucher cell burden but may accelerate osteopenia in patients with type I disease - a histological study

Enzyme replacement treatment (ERT) is effective in controlling the clinical and biochemical manifestation of type I Gaucher disease. Little is known on the evolution of bone marrow histology caused by ERT. We compared the pretreatment trephine bone marrow biopsies in five patients (F32, F41, F50, M55, and M46) with the control biopsies performed after 26-32 months of imiglucerase treatment. The planimetric estimates revealed significant decrease in Gaucher cell burden in all the patients. The post-ERT values ranged from 24% to 65% of the initial total volumes occupied by the Gaucher cells. This resulted mainly from disappearance of Gaucher cells, and to a lesser extent from their shrinkage. Normal hemopoiesis was markedly increased in four of five patients, fat tissue in all the five patients. Surprisingly, the estimated volumes of trabecular bone in the control biopsies were significantly smaller than in the pre-ERT trephines (0.61%, 0.64%, 0.64%, 0.97%, and 0.22% of the initial volumes, P = 0.043). The bone loss correlated rather with the degree of reconstitution of normal hemopoiesis than with the decrease in the Gaucher cell burden. The histological response did not correlate strictly with initial clinical parameters and the genotype, with different reactions to ERT in two sibs (cases 3 and 4). Particularly, ERT alleviated bone manifestations in all four patients with previous bone pains or fractures. ERT may accelerate progress of osteopenia in men and premenopausal women. The clinical significance of this phenomenon remains to be established. Its mechanism may be linked to increased osteolytic activity exerted directly or indirectly by regenerating hemopoietic cells.     

Serum levels of osteoprotegerin and osteoprotegerin polymorphisms in Gaucher disease

Bone involvement in Gaucher disease causes disability and reduced quality of life; loss of function and pain are important indications for enzyme replacement therapy. The purpose of this study was to ascertain whether osteoprotegerin (OPG), which decreases osteoclast activity, is indicative of incipient bone involvement by comparing OPG serum levels to Gaucher disease severity (SSI) and bone mineral density (BMD), and to correlate bone and disease markers to OPG polymorphisms: OPG1-2(A163G), OPG3-4(T129C) and OPG5-6(C1217T). Of 554 patients, 173 Ashkenazi Jewish patients with non-neuronopathic Gaucher disease were enrolled and 32 healthy Ashkenazi Jews served as controls. Serum OPG levels were detected by enzyme-linked immunosorbent assay and BMD was obtained by dual X-ray absorptiometry. OPG polymorphisms were determined in 63 randomly chosen patients. Serum OPG values for patients were not greater than in controls, but showed a statistically significant trend to increase with age (P = 0.057). No correlation existed between OPG levels and BMD or with genotype or other disease markers. A significant correlation was noted between OPG5-6 genotype and SSI. A significant difference was found between the allele distributions of each OPG polymorphism when compared with Caucasians and Ashkenazi Jews. OPG levels probably do not predict BMD in Gaucher disease and hence are not indicative of osteoporosis in Gaucher disease.     

Molecular aspects of osteopathy in type 1 Gaucher disease: correlation between genetics and bone density

Bone-related complications in Gaucher disease are considered to be poorly responsive to specific enzyme replacement therapy. Polymorphisms of candidate genes associated with low bone density were investigated to see whether they are correlated with bone mineral density (BMD) and bone involvement in Gaucher disease. Genotyping for polymorphisms in candidate genes (interleukins 1alpha and 1beta, interleukin-1 receptor antagonist; cytochrome P450; collagen 1A1; low-density Lipoprotein Receptor; bone morphogenic protein 4; vitamin D receptor; and estrogen receptor 2beta) were performed using standard methodologies. BMD was measured by dual energy X-ray absorptiometry (DXA). One hundred and ninety-four patients and 100 controls were genotyped for the above polymorphisms. Thirteen haplotypes were obtained, with several correlations with BMD in patients; also, a haplotype (T889-T3954-C511-240VNTR of IL1) was significantly correlated with T-scores and Z-score for femur neck and lumbar spine (p = 0.01) in patients. Haplotypes of bone-specific candidate genes associated with BMD may predict severity of these features in Gaucher disease.     

Iron storage in liver,bone marrow and splenic Gaucheroma reflects residual disease in type 1 Gaucher disease patients on treatment

Gaucher disease (GD) is a lysosomal storage disorder characterized by the storage of glycosphingolipids in macrophages. Despite effective therapy, residual disease is present in varying degrees and may be associated with late complications, such as persistent bone or liver disease and increased cancer risk. Gaucher macrophages are capable of storing iron and locations of residual disease may thus be detectable with iron imaging. Forty type 1 GD (GD1) patients and 40 matched healthy controls were examined using a whole‐body magnetic resonance imaging protocol consisting of standard sequences, allowing analysis of iron content per organ, expressed as R2* (Hz). Median R2* values were significantly elevated in GD1 patients as compared to healthy controls in liver [41 Hz (range 29–165) vs. 38 Hz (range 28–53), P < 0·01], femoral bone marrow [54 Hz (range 37–129) vs. 49 Hz (range 39–69), P = 0·036] and vertebral bone marrow (118 Hz (range 82–210) vs. 105 Hz (range 76–149), P < 0·01). In the spleen, primarily focal Gaucher lesions known as Gaucheroma were found to have increased R2* values. R2* values of liver, spleen and vertebral bone marrow strongly correlated with serum ferritin levels. GD1 patients with persistent hyperferritinaemia demonstrate increased iron levels in liver and bone marrow, which may carry a risk for liver fibrosis and cancer.     

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.     

Focal splenic lesions in type I Gaucher disease are associated with poor platelet and splenic response to macrophage-targeted enzyme replacement therapy

Focal splenic lesions (FSL) occur in Gaucher disease type I (GD1), but their clinical significance is not known. Previous studies estimated the prevalence of FSL at 4% (pediatric) to 33% (adult) of GD1 patients and reported an association with splenomegaly. We tested the hypothesis that the presence of FSL is associated with suboptimal response to macrophage-directed enzyme replacement therapy (ERT). Additionally we investigated whether FSL were associated with other phenotypic features of GD1. The splenic parenchyma was assessed by MRI performed for routine evaluation of GD1 in 239 consecutive GD1 patients with intact spleens. The prevalence of FSL was 18.4% (44/239). Following a mean of 3.5 years of ERT, platelet response was inferior among patients with FSL (80,700 ± 9,600 to 90,100 ± 7,200/mm³ , P = 0.2) compared to patients without FSL in whom there was a robust platelet response: 108,600 ± 5,670 to 150,200 ± 6,710/mm³, P < 0.001. Compared to patients without FSL, patients harboring FSL had worse thrombocytopenia (platelet count: 83,700 ± 8,800 vs. 112,100 ± 4,200/mm³, P = 0.004), greater frequency of pre-ERT splenomegaly, and greater post-ERT splenomegaly (8.5 ± 0.77 vs. 4.8 ± 0.25× normal, P < 0.001). Additionally, the prevalence of osteonecrosis was higher among patients with FSL compared to patients without FSL (38 vs. 20.7%, P = 0.026). FSL appear to be a determinant of response to ERT, suggesting studies comparing relative efficacy of newly emerging therapies for GD1 should adjust for this factor. Moreover, occurrences of FSL coincide with more severe manifestations of GD1 such as avascular osteonecrosis.     

Immune activation in the course of HIV‐1 infection: Causes,phenotypes and persistence under therapy

Systemic immune activation is a striking consequence of HIV‐1 infection. Even in virologically suppressed patients, some hyperactivity of the immune system and even of the endothelium and of the coagulation pathway may persist. Apart from immune deficiency, this chronic activation may contribute to various morbidities including atherothrombosis, neurocognitive disorders, liver steatosis and osteoporosis, which are currently main challenges. It is therefore of major importance to better understand the causes and the phenotypes of immune activation in the course of HIV‐1 infection. In this review we will discuss the various causes of immune activation in HIV‐1 infected organisms: the presence of the virus together with other microbes, eventually coming from the gut, CD4+ T cell lymphopenia, senescence and dysregulation of the immune system, and/or genetic factors. We will also describe the activation of the immune system: CD4+ and CD8+ T cells, B cells, NKT and NK cells, dendritic cells, monocytes and macrophages, and neutrophils of the inflammation cascade, as well as of the endothelium and the coagulation system. Finally, we will see that antiretroviral therapy reduces the hyperactivity of the immune and coagulation systems and the endothelial dysfunction, but often does not abolish it. A better knowledge of this phenomenon might help us to identify biomarkers predictive of non AIDS‐linked comorbidities, and to define new strategies aiming at preventing their emergence.     

HbA1c level may be a risk factor for oxygen therapy requirement in patients with coronavirus disease 2019

IntroductionMany clinical studies have identified significant predictors or risk factors for the severity or mortality of coronavirus disease 2019 (COVID‐19) cases. However, there are very limited reports on the risk factors for requiring oxygen therapy during hospitalization. In particular, we sought to investigate whether plasma glucose and HbA1c levels could be risk factors for oxygen therapy requirement.Materials and MethodsA single‐center, retrospective study was conducted of 131 COVID‐19 patients hospitalized at Saitama Medical University Hospital between March 2020 and November 2020. To identify the risk factors for oxygen therapy requirement during hospitalization, a stepwise multivariate binary logistic regression analysis was performed using several clinical parameters commonly obtained on admission, including plasma glucose and HbA1c levels.ResultsOf the 131 patients with COVID‐19, 33.6% (44/131) received oxygen therapy during hospitalization. According to the logistic regression analysis, male sex (odds ratio [OR]: 8.76, 95% confidence interval [CI]: 1.65–46.5, P < 0.05), age (OR: 1.07, 95% CI: 1.02–1.12, P < 0.01), HbA1c levels (OR: 1.94, 95% CI: 1.09–3.44, P < 0.05), and serum C‐reactive protein (CRP) levels (OR: 2.22, 95% CI: 1.54–3.20, P < 0.01) emerged as independent variables associated with oxygen therapy requirement during hospitalization.ConclusionsIn addition to male sex, age, and serum CRP levels, HbA1c levels on admission may serve as a risk factor for oxygen therapy requirement during the clinical course of COVID‐19, irrespective of diabetes history and status. This may contribute to the efficient delegation of limited numbers of hospital beds to patients at risk for oxygen therapy requirement.     

Human factor VIII can be packaged and functionally expressed in an adeno-associated virus background: applicability to haemophilia A gene therapy

Adeno-associated virus (AAV) is a single-stranded DNA parvovirus displaying several attractive features applicable to haemophilia A gene therapy, including nonpathogenicity and potential for long-term transgene expression from either integrated or episomal forms. We have generated and characterized two B-domain-deleted (BDD) fVIII mutants, deleted in residues Phe756 to Ile1679 (fVIIIdelta756-1679) or Thr761 to Asn1639 (fVIIIdelta761-1639). [35S]metabolic labelling experiments and immunoprecipitation demonstrated intact BDD-fVIII of the predicted size in both lysates and supernatants (Mr approximately 155 kD for fVIIIdelta756-1679 and Mr approximately 160 kD for fVIIIdelta761-1639) after transient transfection into COS-1 cells. Functional fVIII quantification appeared maximal using fVIIIdelta761-1639, as evaluated by Coatest and clotting assay (98+/-20mU/ml/1x10(6) cells and 118+/-29 mU/ml/1x10(6) respectively, collection period 48 h). To bypass potential size limitations of rAAV/fVIII vectors, we expressed fVIIIdelta761-1639 using a minimal human 243 bp cellular small nuclear RNA (pHU1-1) promoter, and demonstrated VIII activity approximately 30% of that seen using CMV promoter. This BDD-fVIII (rAAV(pHU1-1) fVIIIdelta761-1639) can be efficiently encapsidated into rAAV (107% of wild type), as demonstrated by replication centre and DNAase sensitivity assays. A concentrated recombinant viral stock resulted in readily detectable factor VIII expression in COS-1 cells using a maximally-achievable MOI approximately 35 (Coatest 15 mU/ml; clotting assay 25+/-20 mU/ml/1x10(6) cells). These data provide the first evidence that rAAV is an adaptable virus for fVIII delivery, and given the recent progress using this virus for factor IX delivery in vivo, provide a new approach towards definitive treatment of haemophilia A.