Rapid home therapy infusion of velaglucerase alfa in naïve patients with Gaucher disease.

BACKGROUND: Enzyme replacement therapy (ERT) has revolutionised the management of patients with Gaucher disease (GD). In 2018, we published the safety and efficacy of rapid 10-min infusion of velaglucerase alfa in previously treated patients, mostly on low-dose therapy. AIM: To improve quality of life (QoL) for patients needing lifelong bi-weekly infusions by introducing a 10-min infusion instead of 1 h per label in patients naive to ERT and on high-dose therapy. METHODS: Fifteen naive patients were enrolled; all received bi-weekly infusions of 60 units/kgBW velaglucerase alfa; the infusion rate was gradually reduced in the hospital, followed by home infusions. Each infusion was followed for safety. Efficacy parameters were assessed every 3 months. Patient-reported outcome questionnaires were collected at baseline and follow-up. RESULTS: Ten-minute rapid infusions were well tolerated without related severe adverse events (SAEs). Two patients experienced a non-related SAE and another a possibly related AE. In three patients, the infusion rate was increased to 30 or 60 min (two because of suboptimal response and one because of AE). Two patients dropped out because of an unwillingness to attend follow-up visits during the COVID-19 pandemic. All 13 remaining patients reached the 24-month end-point. The platelet counts increased by a median (range) of 68.38% (12.5-300%) and the lyso-Gb1 levels decreased by 62.6% (32.9-89.9%). CONCLUSION: Home therapy with rapid infusion of high-dose velaglucerase alfa was a safe, effective and preferable alternative for patients with GD naïve to treatment. We believe that shortening the infusion time improves the QoL of patients with GD who have a lifelong commitment to intravenous therapy.

A Comprehensive Assessment of Qualitative and Quantitative Prodromal Parkinsonian Features in Carriers of Gaucher Disease-Identifying Those at the Greatest Risk.

Carriers of GBA1 gene variants have a significant risk of developing Parkinson's disease (PD). A cohort study of GBA carriers between 40−75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40−74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7−33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14−32%), Unified Parkinson's Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2−26.4%), smell assessment (12.4%, 95% CI 6.6−20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7−19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as "abnormal". Then we calculated the percentage of "abnormal" tests for each subject; the median (range) was 4.55 (0−43.5%). Twenty-two subjects had more than 15% "abnormal" tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD.

The Effect of Nutritional Therapy on Bone Mineral Density and Bone Metabolism in Pediatric Crohn Disease.

OBJECTIVES: Both the inflammatory burden of Crohn disease (CD) and corticosteroids have a negative effect on bone density. Exclusive enteral nutrition (EEN) avoids corticosteroids and promotes endoscopic healing. We aimed to explore the effect of nutritional therapy on bone health in pediatric CD. METHODS: This was a planned sub-study of a clinical trial enrolling children with new-onset mild-moderate CD. Children were randomized to either 6 weeks EEN followed by 6 weeks 25% partial enteral nutrition (PEN) or 6 weeks of 50% PEN with a CD exclusion diet followed by 6 weeks of 25% PEN with exclusion diet. Bone formation and resorption were measured at baseline, week 12 and week 24 by serum C-Propeptide of Type I Procollagen (CICP) and type I Collagen N-Telopeptide (NTX), respectively. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) scan at baseline and week 24. RESULTS: Median CICP improved from 130 ng/mL (106-189) at baseline to 223 (143-258) at week 12 and 193 (143-252) at week 24 (P = 0.016 for both, n = 29 children). Median NTX remained unchanged (P = 0.45 and P = 0.45). Thirty-six children had DXA scans performed at diagnosis; 81% and 33% had z scores of <-1 and <-2, respectively. DXA z scores did not improve from baseline (adjusted total body less head [TBLH] BMD -1.62 ±â€Š0.87) to week 24 (-1.76 ±â€Š0.75; P = 0.30, n = 21 with both scans). CONCLUSIONS: Low bone density is common in new-onset mild-moderate pediatric CD. CICP, a sensitive marker of bone formation, improved following dietary intervention but this was not associated with improved BMD.

Comparison of Bone Mineral Density by Dual-Energy X-Ray Absorptiometry and Bone Strength by Speed-of-Sound Ultrasonography in Adults With Gaucher Disease.

Patients with the lysosomal disorder Gaucher disease (GD) are at risk of osteoporosis and/or avascular necrosis, but to date, no adequate biomarkers are available to ascertain individual predilections. Bone mineral density by dual-energy X-ray absorptiometry (DXA) has traditionally been used to monitor trends. With the availability of a speed-of-sound (SOS) ultrasonography to assess bone strength/elasticity, we aimed to ascertain whether these modalities are complimentary or comparable so SOS, with no radiation risk, might be used more routinely as a potential biomarker. A prospective comparative study in adult GD patients undergoing routine follow-up of bone mineral density T- and Z-scores at forearm (FA), femoral neck, and lumbar spine, and SOS Z-scores at FA was initiated. Interpretation was by qualitative categorization of Z-scores. The kappa measure of agreement beyond chance was calculated between pairs of measurements and the McNemar test was then applied. This noninterventional trial (ClinicalTrials.gov Identifier: NCT02067247) was approved by the institutional ethics committee. There were 89 patients (ages 21-78 years, 61% female, 62% common Ashkenazi genotype, 18% splenectomized, and 18% with avascular necrosis/fractures). When comparing Z-scores at FA by DXA and SOS, only 39.3% correlated, while the remaining results were in disagreement; no trend was noted. Similarly, when comparing Z-scores at the femoral neck by DXA with those at FA by SOS, 44.9% of the results were in agreement; no trend was noted; and Z-scores at the lumbar spine by DXA with FA by SOS, 46% were in agreement and no trend was noted. DXA at the 3 sites did not track in the same direction or the same magnitude of difference with SOS at FA in adult patients with GD. Due to the fundamental differences between the 2 measurements and their clinical correlates, plus the lack of long-term follow-up to assess outcome, the potential added value of the measurements at the FA by SOS in patients with GD awaits further studies.

Booster-effect with velaglucerase alfa in patients with Gaucher disease switched from long-term imiglucerase therapy: early Access Program results from Jerusalem.

BACKGROUND: Decreased spleen and liver volumes and increased hemoglobin levels and platelet counts usually occur with enzyme replacement therapy (ERT) in symptomatic patients with Gaucher disease. Because of decreased supply of imiglucerase, an FDA-approved Early Access Program (EAP) allowed use of a new, pre-licensed ERT, velaglucerase alfa. This report provides safety and efficacy findings in patients on EAP velaglucerase alfa who completed 6, 9, or 12 months as intravenous every-other-week ERT. METHOD: EAP was approved by the Israeli Ministry of Health. All patients enrolled in the EAP were included for safety measures; only those with >6 month evaluations of hemoglobin, platelet counts, and liver and spleen volumes were included for efficacy. Descriptive statistics were employed. RESULTS: Among 71 EAP patients, there were no drug-related serious adverse events or withdrawals; one patient (1.4%) with previous hypersensitivity to a different ERT had a drug-related allergic reaction. Of 44 patients with appropriate time-period evaluations, 8 patients were treatment-naïve and responded well to velaglucerase alfa. The 36 switch-over patients remained at imiglucerase low-doses; a majority of patients showed improvements in each efficacy parameter. CONCLUSION: Switch-over from imiglucerase (10-224 months) was safe and in several patients velaglucerase alfa induced a booster-effect.

Organ volume by computed tomography correlates with longitudinal axis on ultrasound in patients with Gaucher disease.

OBJECTIVES: Although ultrasonography (US) may be recommended for repeat assessments of spleen and liver volumes, it is less readily used than magnetic resonance imaging and computed tomography (CT) because of concerns of accuracy and reproducibility. In monitoring spleen and liver volumes for Gaucher disease where volume changes underlie management decisions, in experienced hands, US has a place because some patients are evaluated for decades and sometimes several times annually. The purpose of this survey was to ascertain whether one can maximize the efficiency of US imaging by use of one US axis if it correlates with CT-generated volumes. METHODS: A patient cohort from a large tertiary clinic dedicated to Gaucher disease was used. Thirty-seven patients with simultaneous abdominal CT and US evaluations (1992-2009), 27 (73%) at the advent of Gaucher-specific therapy, and followed both by CT and US up to 3 additional times (interval, ≥12 months) were included. Ultrasound evaluation of 3 axes, longitudinal, width, and depth, was performed by one radiologist; all organs including idiosyncratically shaped and massively enlarged organs were included. RESULTS: There was a significant correlation between CT volume and US length axis for both spleen (0.619) and for liver (0.557) volumes (P = 0.01; 2-tailed for each). CONCLUSION: With some training, the use of the longitudinal axis by US assessment may suffice to approximate estimation of changes in organ volumes.