The International Collaborative Gaucher Group GRAF (Gaucher Risk Assessment for Fracture) score: a composite risk score for assessing adult fracture risk in imiglucerase-treated Gaucher disease type 1 patients.

Funder: Sanofi Genzyme; doi: http://dx.doi.org/10.13039/100013995BACKGROUND: Fractures in Gaucher disease type 1 (GD1) patients cause significant morbidity. Fracture risk may be decreased by enzyme replacement therapy (ERT) but not eliminated. When considering initiation of treatment, it is useful to know to what extent fixed patient-specific factors determine risk for future fractures beyond standard risk factors that change with time and treatment, such as decreased bone mineral density. We developed a tool called the GRAF score (Gaucher Risk Assessment for Fracture) that applies 5 widely available characteristics (sex, age at treatment initiation [ATI], time interval between diagnosis and treatment initiation, splenectomy status, history of pre-treatment bone crisis) and provides a practical method to assess future fracture risk when imiglucerase ERT is initiated. METHODS: Inclusion criteria: GD1 patients in the International Collaborative Gaucher Group Gaucher Registry as of September 2019 initially treated with alglucerase/imiglucerase; known splenectomy status; at least one skeletal assessment on treatment (3216 of 6422 patients). Data were analyzed by ATI group (< 18, ≥ 18 to < 50, or ≥ 50 years of age) using Cox proportional hazards regression with all 5 risk factors included in the multivariable model. A composite risk score was calculated by summing the contribution of each parameter weighted by the strength of its association (regression coefficient) with fracture risk. RESULTS: Patients were followed from the date of treatment initiation (or age 18 years for patients if treatment started earlier) to the date of first adult fracture (n = 288 first fracture endpoints), death, or end of follow-up. The GRAF score for each ATI group was associated with a 2.7-fold increased risk of adult fracture for each one-point increase (p < 0.02 for < 18 ATI, p < 0.0001 for ≥ 18 to < 50 ATI and ≥ 50 ATI). CONCLUSIONS: The GRAF score is a tool to be used with bone density and other modifiable, non-GD-specific risk factors (e.g. smoking, alcohol intake, frailty) to inform physicians and previously untreated GD1 patients about risk for a future fracture after starting imiglucerase regardless of whether there is an eventual switch to an alternative ERT or to substrate reduction therapy. GRAF can also help predict the extent that fracture risk increases if initiation of treatment is further delayed

Development and validation of Gaucher disease type 1 (GD1)-specific patient-reported outcome measures (PROMs) for clinical monitoring and for clinical trials.

BACKGROUND: Disease-specific patient-reported outcome measures (PROMs) are fundamental to understanding the impact on, and expectations of, patients with genetic disorders, and can facilitate constructive and educated conversations about treatments and outcomes. However, generic PROMs may fail to capture disease-specific concerns. Here we report the development and validation of a Gaucher disease (GD)-specific PROM for patients with type 1 Gaucher disease (GD1) a lysosomal storage disorder characterized by hepatosplenomegaly, thrombocytopenia, anemia, bruising, bone disease, and fatigue. RESULTS AND DISCUSSION: The questionnaire was initially developed with input from 85 patients or parents of patients with GD1 or GD3 in Israel. Owing to few participating patients with GD3, content validity was assessed for patients with GD1 only. Content validity of the revised questionnaire was assessed in 33 patients in the US, France, and Israel according to US Food and Drug Administration standards, with input from a panel of six GD experts and one patient advocate representative. Concept elicitation interviews explored patient experience of symptoms and treatments, and a cognitive debriefing exercise explored patients' understanding and relevance of instructions, items, response scales, and recall period. Two versions of the questionnaire were subsequently developed: a 24-item version for routine monitoring in clinical practice (rmGD1-PROM), and a 17-item version for use in clinical trials (ctGD1-PROM). Psychometric validation of the ctGD1-PROM was assessed in 46 adult patients with GD1 and re-administered two weeks later to examine test-retest reliability. Findings from the psychometric validation study revealed excellent internal consistency and strong evidence of convergent validity of the ctGD1-PROM based on correlations with the 36-item Short Form Health Survey. Most items were found to show moderate, good, or excellent test-retest reliability. CONCLUSIONS: Development of the ctGD1-PROM represents an important step forward for researchers measuring the impact of GD and its respective treatment

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Purpose Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets

Patient management problem-preferred responses

Following are the preferred responses for the Patient Management Problem in this CONTINUUM issue. The case, questions, and answer options are repeated, and the preferred response appears in bold print, followed by an explanation and a reference with which you may seek more specific information. You are encouraged to review the responses and explanations carefully to evaluate your general understanding of the material. The comment and references included with each question are intended to encourage independent study

Splenomegaly, hypersplenism, and hereditary disorders with splenomegaly

Deshoulières François. L'architecte de la façade de l'ancien Hôtel de Ville d'Orléans. In: Bulletin Monumental, tome 85, année 1926. p. 402

Causes of Death in 184 Patients with Type 1 Gaucher Disease From the United States Who Were Never Treated with Enzyme Replacement Therapy

Abstract Abstract 3128 Type 1 Gaucher disease (GD1) is caused by deficient lysosomal glucocerebrosidase activity with resultant accumulation of glucosylceramide predominantly within hepatic, splenic, pulmonary and bone marrow macrophages. Intravenous recombinant glucocerebrosidase (ERT) is generally safe and effective in decreasing morbidity due to the heterogeneous manifestations of GD1: hematological cytopenias, hepatosplenomegaly, bone pain, osteonecrosis, osteopenia and fractures. There are other complications whose responsiveness to conventional treatment is yet undetermined: atypical Parkinsonism and an increased risk for cancer (CA), particularly plasma cell and other hematological and lymphoid malignancies and hepatocellular carcinoma. Because of the widespread use of ERT during the past 20 years and attrition of older medical records, a phenotypically representative control group of untreated symptomatic patients for study of these late outcome events is hard to find. From 1961–97, one of us (REL) collected information on 395 US patients with GD1. We determined through public records that 217 died from 1950–2010 of whom 184 never received ERT. Here, we report confirmed causes of death (COD) for the untreated GD1 patients compared to COD reported for this time period in an age comparable overall US population. Methods: After IRB approval, COD recorded in death certificates were accessed via the National Death Index for available years 1979–2008. COD prior to 1979 were determined based on autopsy or physician communication with REL and, where possible, by death certificates obtained from State Bureaus of Vital Records. Information on COD (1950–2008) for the general US population is from US National Vital Statistics Reports. The analysis included descriptive statistics, calculation of proportional mortality ratios (PMR), and 2-tailed Fisher exact test calculations based on absolute death numbers in the GD1 and general populations. Results: COD is unknown for 9 patients who died before 1979. 111 pts were male (60.3%); 124 (67.4%) were Ashkenazi Jewish. Median age at death was 66y (2–97y). Median age at GD1 diagnosis (N=102): 39y (1–83y). Spleen status: Splenectomy 94 (51.1%); Intact 56 (30.4%); Unknown 34 (18.5%). Median age at splenectomy: 36y (1.3–78y). Symptomatic bone disease was present in 74 (40.2%), absent in 7 (3.8%) and undocumented for 103 (60.0%). COD for which the PMR was significantly increased (P<0.01): malignant neoplasms (PMR 1.57), suicide/drug overdose (PMR 3.86), chronic liver disease (PMR 4.76) and septicemia (PMR 9.22). Other COD that were disproportionately high included CNS and gastrointestinal bleeding, post-splenectomy complications, pulmonary hypertension (PHT), and Parkinsonism. Heart disease/atherosclerosis was the only COD for which PMR was very significantly decreased (0.33). PMR for cerebrovascular disease was 0.48 (P=0.027). For 57 pts with a CA COD, PMRs for myeloma (9.66), kidney CA (4.63), liver CA (4.36), NHL (4.13), and all leukemia (3.19) were significantly elevated (P<0.01). Conversely, the PMR for lung CA was 0.32 (P=0.002). There was 1 death from breast CA and none from gynecological CA. PMR for colorectal, pancreatic and prostate CA were not divergent from expected. Compared to the control population, the age distribution of deaths was identical for heart disease, septicemia, and suicide. Age at death was not younger than expected in pts with myeloma but there was a tendency for death at a younger age for GD pts with NHL, chronic liver disease and Parkinsonism. COD significantly more prevalent in surgically asplenic pts included chronic liver disease, septicemia, GI bleeding, PHT and post-splenectomy complications. Spleen status was statistically irrelevant to CA deaths including myeloma except for hepatocellular CA (splenectomy) and CLL (intact spleen). Conclusions: With earlier diagnosis, improved risk assessment and phase-out of splenectomy, COD that we encountered (chronic liver disease, GI bleeding, septicemia, PHT, suicide and drug dependency) should be increasingly rare with timely institution of appropriate treatment. Our study population of untreated pts (estimated at 5% of all US GD1 deaths from 1950–2008 but a substantially greater percentage of GD1 deaths over age 60y), should serve as a valuable control for future studies of the effect of GD1 treatment on mortality due to malignancy or other later course events. Disclosures: Weinreb: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire HGT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Actelion Corporation: Speakers Bureau