Not All Patients with Mild Phenotype of Gaucher Disease (GD) Need Disease Specific Treatment As Reflected By Patients Reported Outcomes Measures
Authors: Revel-Vilk Shoshana , Dinur Tama , Istaiti Majdolen , Frydman Dafna , Becker-Cohen Michal , Zimran Ari 
Published: November 2019

The introduction of disease specific therapy for patients with type 1 Gaucher disease (GD) was a revolution in the management of patients, but not without significant cost to the patient and to society. The management of mildly effected patients is still debated, and reviews about GD as well as chapters in textbooks fail to emphasize the fact that some patients may remain untreated for many years without any GD-related complications. Patient reported outcome measures (PROMs) were developed as a way to ascertain patients' views of their symptoms, their functional status, and their health-related quality-of-life (HRQoL). In this study, we evaluated the responses to a GD -specific PROM of untreated patients with GD1 and compared them to patients on GD-specific therapy.
Methods: A PROM survey was developed for GD including 15 questions; six Point Verbal Response Scale regarding the last month and nine Visual Analogue Scales (VAS) from 0-10 regarding the last week (Elstein D, et al. Molecular Genetics and Metabolism 2019;126:S52). The PROM survey was proven to be accurate in encompassing disease-specific patient concerns. A Hebrew translated version of the GD-PROM was sent via mobile phone survey to 400 adult patients with type 1 GD followed in our Gaucher Unit. Clinical data and treatment status were extracted from the clinical charts. T-test and Mann-Whitney U test were used to compare normally and non-normally distributed data in independent samples, respectively. IBM SPSS version 25 was used for analysis. Results were considered to be statistically significant when two-tailed P-values were ≤0.01.
Results: A total of 181 patients responded (45% response rate) of whom 65 (36%) were followed for at least 5 years in our unit without receiving GD specific therapy, i.e. enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT). The median (range) age of patients, 49 (20-91) years, was not significantly different between treated and untreated patients. The percentage of patients with the N370S/N370S genotype was significantly higher in untreated patients [55/65 (85%)] compared to treated patients [67/116 (57%)]. Significantly more treated patients reported that GD had restricted their education/job (38, 34%) and fun activities (29,25%) compared to untreated patients, (4, 6.5%) and (2, 3%), respectively. Compared to untreated patients, treated patients were more worried to be an emotional burden on others [27 (23%) vs. 3 (5%)], of being financial burden on others [57 (50%) vs. 16 (25%)] and more concerned regarding the risk of bone disease [82 (74%) vs. 26 (40%)], and the risk of Parkinson disease [72 (64%) vs. 27 (42%)]. Treated patients had a significantly higher score on VAS for questions on swollen abdomen, fatigue, physical weakness, severity of bone pain and worry regarding the future over the past week compared to untreated patients (Table 1). Patients concern regarding the risk for cancer (32%) and VAS score for a question on depression were similar between groups.
Conclusion:The GD-specific PROM survey shows that asymptomatic or mildly affected untreated patients with GD1 have good functional status and HRQoL, supporting our practice that not all patients with GD1 require disease-specific therapy. Still, we advise a periodic (annual or bi-annual) follow-up, preferably at a referral center. Inclusion of GD-specific PROMs in the periodic assessments is important for better understanding patients' perspectives.
It is important to note that mildly affected and asymptomatic patients are mainly found among Ashkenazi Jews and from this aspect our cohort reflects patients' populations in Israel, USA, UK, etc. but less relevant to non-Jewish and particularly to Asian cohorts. With the expected increase in early diagnosis via parental and/or newborn screening the understanding that not all subjects diagnosed with GD needs disease-specific therapy is all the more important.
Despite the expected differences between the more severely affected treated patients and the by definition milder untreated ones, still a high percentage of the treated patients show good HRQoL parameters, reflecting the overall success of ERT/SRT. Larger cohorts and further analysis will evaluate potential predictors for differences in PROMs within the treatment group.

Disclosures
Revel-Vilk: Sanofi: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Prevail therapeutics: Honoraria, Other: Travel, Research Funding. Zimran:Prevail Therapeutics: Consultancy; TAKEDA: Honoraria; Centogene: Other: research grant; Targeted Cell Therapies: Consultancy; Pfize: Honoraria, Research Funding; Shire: Consultancy, Honoraria, Research Funding; Bio-events: Honoraria.