Abstract
BackgroundGD1-DS3 is an integrated assessment of type 1 Gaucher disease (GD1) burden based on bone, hematologic and visceral domains. We investigated this disease severity scoring system (DS3) methodology for initial assessment, long-term follow-up and evaluation of treatment responses.MethodsWe enrolled 133 treated adult GD1 patients. Baseline DS3 scores were calculated near the initial treatment date and patients stratified by severity as marked (DS3 6.00-19.00), moderate (DS3 3.00-5.99), mild (DS3 < 3.00). Follow-up scores were calculated annually. Minimal clinically important improvement (MCII), is defined as ΔDS3 of -3.1.ResultsPatient characteristics: N370S was the most common allele (118 patients had at least one), 52 were N370S/N370S (48/52 were Ashkenazi Jews), N370S/L444P was the most common genotype among non-Jews. Median age of treatment: 45 years; median follow-up: 14 years. Baseline DS3 scores: Patients with marked disease (N = 58; median 7.84) were least likely to be N370S homozygous (19 %) and most likely to have had splenectomy (53 %), early age at diagnosis (median 18 years) and major pre-treatment bone pathology (76 %). Among patients with moderate disease (N = 53; median 4.33), 49 % were N370S/N370S, 15.1 % had splenectomy and 17 % had major bone disease. Median age at diagnosis: 32 years. No patient with mild disease (N = 22; median 2.4) had splenectomy or major skeletal disease. Median age at diagnosis: 40 years. 68 % were N370S homozygous. Response to treatment: Health-state transitions occurred primarily during the early treatment years. At Year 5, among 48 evaluable patients with marked baseline disease, eight were unchanged in severity status whereas 40 had MCII of varying degrees with 11 scored as mild. Among 42 evaluable moderate patients, none worsened, 16 remained moderate and 26 improved to mild. Among 16 evaluable mild patients, 14 remained so and 2 had DS3 scores in the low moderate range.ConclusionsDS3 is effective for assessing disease burden in GD1 and for monitoring response. ERT was associated with MCII in DS3 scores in patients with high severity. Nevertheless, despite better DS3 scores with treatment, GD1 patients especially those with splenectomy and pre-treatment bone pathology, continued to have bone complications.
Highlights
GD1-DS3 is an integrated assessment of type 1 Gaucher disease (GD1) burden based on bone, hematologic and visceral domains
All participating patients who were alive prior to the inception of the DS3 study signed separate informed consents to participate in the DS3 Severity Score Study and the International Collaborative Gaucher Group (ICGG) Registry using forms approved by the respective institutional review boards
DS3 is an effective tool for assessing pre-treatment disease burden in GD1 and for monitoring response to therapy
Summary
GD1-DS3 is an integrated assessment of type 1 Gaucher disease (GD1) burden based on bone, hematologic and visceral domains We investigated this disease severity scoring system (DS3) methodology for initial assessment, long-term follow-up and evaluation of treatment responses. There are few well-designed studies that have comprehensively annotated phenotypic variation over time or measured treatment efficacy and dose response [7, 8] Design of such studies was partly hindered by lack of a validated disease severity scoring system for GD1 to standardize the monitoring of progression and treatment response and to define patient cohorts in clinical studies [9]. Disease severity scoring indices such as Zimran score [10] and Hermann score for bone disease [11] primarily emphasized advanced and irreversible disease manifestations These scores had limited sensitivity for annotating changes observed over time in untreated patients with slow progression or in treated patients with irreversible manifestations. Other models for monitoring treatment response focused on composite achievement of therapeutic goals that are assigned equal weight without attention to relative clinical import [5]
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