Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the GBA1 gene should be identified as they may be of prognostic value in some cases. Patients with type-1 GD—but also carriers of GBA1 mutation—have been found to be predisposed to developing Parkinson’s disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat).

Objective To determine predictors of in-hospital mortality related to COVID-19 in older patients. Design Retrospective cohort study. Setting and Participants Patients aged 65 years and older hospitalized for a diagnosis of COVID-19. Methods Data from hospital admission was collected from the electronic medical records. Logistic regression and Cox proportional-hazard models were used to predict mortality, our primary outcome. Variables at hospital admission were categorized according to the following domains: demographics, clinical history, comorbidities, previous treatment, clinical status, vital signs, clinical scales and scores, routine laboratory analysis and imaging results. Results Of a total of 235 Caucasian patients, 43% were male, with a mean age of 86 ± 6.5 years. Seventy-six patients (32%) died. Non-survivors had a shorter number of days from initial symptoms to hospitalization (p=0.007) and the length of stay in acute wards than survivors (p<0.001). Similarly, they had a higher prevalence of heart failure (p=0.044), peripheral artery disease (p=0.009), crackles at clinical status (p<0.001), respiratory rate (p=0.005), oxygen support needs (p<0.001), C-reactive protein (p<0.001), bilateral and peripheral infiltrates on chest radiographs (p=0.001) and a lower prevalence of headache (p=0.009). Furthermore, non-survivors were more often frail (p<0.001), with worse functional status (p<0.001), higher comorbidity burden (p<0.001) and delirium at admission (p=0.007). A multivariable Cox model showed that male sex (HR 4.00, 95% CI 2.08-7.71, p=0.0001), increased fraction of inspired oxygen (HR 1.06, 95% CI 1.03-1.09, p<0.0001) and crackles (HR 2.42, 95% CI 1.15-6.06, p=0.0190) were the best predictors of mortality, while better functional status was protective (HR 0.98, 95% CI 0.97-0.99, p=0.0013). Conclusions and implications In older patients hospitalized for COVID-19 male sex, crackles, a higher fraction of inspired oxygen and functionality were independent risk factors of mortality. These routine parameters, and not differences in age, should be used to evaluate prognosis in older patients.

BackgroundClinical features, complications and treatments of Gaucher’s disease (GD), a rare autosomal–recessive disorder due to a confirmed lysosomal enzyme (glucocerebrosidase) deficiency, are described.MethodsAll patients with known GD, living in France, with ≥1 consultations (1980–2010), were included in the French GD registry, yielding the following 4 groups: the entire cohort, with clinical description; and its subgroups: patients with ≥1 follow-up visits, to investigate complications; recently followed (2009–2010) patients; and patients treated during 2009–2010, to examine complications before and during treatment. Data are expressed as medians (range) for continuous variables and numbers (%) for categorical variables.ResultsAmong the 562 registry patients, 265 (49.6%) were females; 454 (85.0%) had type 1, 22 (4.1%) type 2, 37 (6.9%) perinatal–lethal type and 21 (3.9%) type 3. Median ages at first GD symptoms and diagnosis, respectively, were 15 (0–77) and 22 (0–84) years for all types. The first symptom diagnosing GD was splenomegaly and/or thrombocytopenia (37.6% and 26.3%, respectively). Bone-marrow aspiration and/or biopsy yielded the diagnosis for 54.7% of the patients, with enzyme deficiency confirming GD for all patients. Birth incidence rate was estimated at 1/50,000 and prevalence at 1/136,000. For the 378 followed patients, median follow-up was 16.2 (0.1–67.6) years. Major clinical complications were bone events (BE; avascular necrosis, bone infarct or pathological fracture) for 109 patients, splenectomy for 104, and Parkinson’s disease for 14; 38 patients died (neurological complications for 15 type-2 and 3 type-3 patients, GD complications for 11 type-1 and another disease for 9 type-1 patients). Forty-six had monoclonal gammopathy. Among 283 recently followed patients, 36 were untreated and 247 had been treated during 2009–2010; 216 patients received treatment in December 2010 (126 with imiglucerase, 45 velaglucerase, 24 taliglucerase, 21 miglustat). BE occurred before (130 in 67 patients) and under treatment (60 in 41 patients) with respective estimated frequencies (95% CI) of first BE at 10 years of 20.3% (14.1%–26.5%) and 19.8% (13.5%–26.1%).ConclusionThis registry enabled the epidemiological description of GD in France and showed that BE occur even during treatment.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

ObjectivesThe rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.MethodsThis was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or ‘no immunosuppressant’. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival.ResultsOf 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: −4.0 (−5.2 to −2.7) units for methotrexate, −4.1 (−5.3 to −2.9) for MMF, −3.3 (−4.9 to −1.7) for cyclophosphamide and −2.2 (−4.0 to −0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months.ConclusionsThese findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed.Trial registration numberNCT02339441.