Gaucher Disease: Clinical Guidelines

List of Abbreviations

aPTT – activated partial thromboplastin time

GD – Gaucher disease

ERT – enzyme replacement therapy

CT – computed tomography

MRI – magnetic resonance imaging

SRT – substrate reduction therapy

US – ultrasound examination

ALT – alanine aminotransferase

AST – aspartate aminotransferase

Terms and Definitions

Β-D-glucocerebrosidase (β-glucosidase) – a lysosomal enzyme involved in the degradation of cellular metabolism products

Gaucher cells – lipid-engorged macrophages, approximately 70–80 µm in diameter, oval or polygonal in shape with pale foamy cytoplasm.

Erlenmeyer flask deformity – flask-like widening of the distal parts of the femurs detected on radiography

Enzyme diagnostics – diagnostic methods for diseases, pathological conditions, and processes based on determining the activity of enzymes in biological fluids.

Enzyme replacement therapy – a treatment method for genetic diseases resulting from biochemical dysfunction due to reduced enzyme activity.

Substrate reduction therapy – a treatment method for lysosomal storage diseases aimed at suppressing the production of the substrate – glucocerebroside (in the case of Gaucher disease), which deposits in the macrophage cytoplasm.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Gaucher disease – the most common form of rare hereditary enzymopathies grouped under lysosomal storage diseases

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The disease is based on a hereditary deficiency in the activity of β-D-glucocerebrosidase (β-glucosidase), a lysosomal enzyme involved in the degradation of cellular metabolism products [1–5]. Gaucher disease is inherited in an autosomal recessive manner. The disease is caused by mutations in the β-D-glucocerebrosidase gene located in the chromosomal region 1q22 [3,4]. The presence of biallelic pathogenic variants of the GBA gene is accompanied by a decrease in the catalytic activity of glucocerebrosidase, which leads to the accumulation of unutilized lipids in macrophage lysosomes and the formation of characteristic storage cells (Gaucher cells) – lipid-engorged macrophages. The consequences of this metabolic defect are:

1. Chronic activation of the macrophage system;

2. Autocrine stimulation of monocytopoiesis and an increase in the absolute number of macrophages in "physiological home" sites: spleen, liver, bone marrow, resulting in splenomegaly, hepatomegaly, and bone marrow infiltration;

Impairment of macrophage regulatory functions, which is presumed to underlie

1.3 Epidemiology of the Disease or Condition

Gaucher disease occurs with an incidence ranging from 1:40,000 to 1:100,000 among individuals of all ethnic groups; in the Ashkenazi Jewish population, the incidence reaches 1:45 [7]. The prevalence of Gaucher disease among the adult population of Russia in 2019 was 1:360,000 [8], and the prevalence among the pediatric population in 2015 was 0.32:100,000 children [9].

1.4 Features of Coding the Disease or Condition

Heading E75.2 – Other sphingolipidoses.

1.5 Classification of the disease or condition

Depending on the presence or absence of CNS involvement and its specific features, three types of Gaucher disease are distinguished:

• type I – without neurological manifestations, the most frequent variant of the disease, observed in 94% of patients with GD [10];

• type II (acute neuronopathic) – occurs in early childhood, characterized by a progressive course and severe CNS involvement leading to a fatal outcome (patients rarely survive to 2 years of age);

• type III (chronic neuronopathic) – unites a more heterogeneous group of patients in whom neurological complications can manifest in early childhood as well as adolescence.

Type I is the most frequent clinical variant of GD and occurs in both children and adults. The average age of patients at the onset of the disease ranges from 30 to 40 years. The spectrum of clinical manifestations is very broad: at one end are "asymptomatic" patients (10–25%), and at the other are severely affected patients with massive hepatosplenomegaly, profound anemia and thrombocytopenia, marked cachexia, and severe, life-threatening complications (hemorrhages, splenic infarctions, bone destruction). Between these polar clinical groups are patients with moderate hepatosplenomegaly and a nearly normal blood count, with or without bone involvement. In children, there is a lag in physical and sexual development; a characteristic hyperpigmentation of the skin in the knee and elbow joint areas is noted [7].

In Gaucher disease type II, the main symptoms appear in the first 6 months of life. In the early stages of the disease, muscular hypotonia, psychomotor development delay, and regression are noted. As the disease progresses, spasticity with characteristic neck retraction and limb flexion, oculomotor disorders with the development of convergent strabismus, laryngospasm, and dysphagia appear. Bulbar disorders with frequent aspirations are characteristic, leading to the patient's death from apnea, aspiration pneumonia, or dysfunction of the brain's respiratory center. In late stages, tonic-clonic seizure attacks develop that are resistant to antiepileptic drug therapy [11–13]. The disease leads to a fatal outcome in the first or second year of the child's life.

In Gaucher disease type III, neurological symptoms occur later, usually at the age of 6–15 years. A characteristic symptom is paresis of the muscles innervated by the oculomotor nerve. Myoclonic and generalized tonic-clonic seizures may be observed; extrapyramidal rigidity, intellectual decline, trismus, facial grimacing, dysphagia, and laryngospasm appear and progress. The degree of intellectual impairment varies from minor personality changes to severe dementia. Cerebellar disorders, speech and writing disorders, behavioral changes, and episodes of psychosis may be observed. In most cases, the course of the disease is slowly progressive. A fatal outcome ensues due to severe pulmonary and hepatic damage. The life expectancy of patients with GD type III can reach 12–17 years, and in isolated cases, 30–40 years.

1.6 Clinical presentation of the disease or condition

The main clinical manifestations of GD include splenomegaly, hepatomegaly, cytopenia, and bone involvement.

Splenomegaly – the spleen can be enlarged by 5–80 times compared to normal. As splenomegaly progresses, infarctions may develop in the spleen, which, as a rule, have no clinical manifestations [14–16].

Hepatomegaly – liver dimensions usually increase by 2–4 times. Ultrasound may reveal focal liver lesions, which are presumably the consequence of ischemia and fibrosis. Liver function is generally unaffected, but 30–50% of patients show a mild increase in serum aminotransferase activity, usually no more than 2-fold, and occasionally 7–8-fold [4,14,15].

Cytopenic syndrome – the earliest and most characteristic manifestation is thrombocytopenia with spontaneous hemorrhagic syndrome in the form of subcutaneous hematomas, mucosal bleeding, or prolonged bleeding after minor surgical interventions. Subsequently, anemia and leukopenia develop with relative lymphocytosis and absolute neutropenia, although no apparent increase in the frequency of infectious diseases is observed in patients [4,14,15,17].

Bone involvement ranges from asymptomatic osteopenia and Erlenmeyer flask deformity of the distal femurs to severe osteoporosis and ischemic (avascular) necroses with the development of secondary osteoarthrosis. The musculoskeletal system involvement can manifest as acute or chronic pain, pathological fractures, and the development of irreversible orthopedic defects requiring surgical treatment (joint replacement). Children and young adults are characterized by the development of so-called bone crises – episodes of severe bone pain accompanied by fever and local acute inflammatory symptoms (swelling, redness) simulating the clinical picture of osteomyelitis. A risk factor for bone crises and severe musculoskeletal system involvement is splenectomy, which predisposes to hypercoagulation syndrome and ischemic bone damage (osteonecrosis) underlying bone crises [4,18,19]. Musculoskeletal involvement is usually the main clinical problem in GD type I, determining the severity of the disease course and patients' quality of life [15,20]. In patients with GD type III, bone pathology manifests as chest deformities and marked kyphoscoliosis with or without bone pain and bone crises [21–23].

Symptoms of CNS involvement are observed only in neuronopathic types of GD in children (types II and III) and may include oculomotor apraxia or convergent strabismus, ataxia, sensory disturbances and progressive intellectual loss, myoclonic and generalized tonic-clonic seizures, extrapyramidal rigidity, intellectual decline, trismus, facial grimacing, dysphagia, and laryngospasm. The degree of intellectual impairment varies from minor personality changes to severe dementia, behavioral changes, and episodes of psychosis [4,15].

Pulmonary involvement occurs in 1–2% of patients: in GD type I with prolonged absence of specific treatment, predominantly in those who have undergone splenectomy; in GD type II and III regardless of spleen size at disease onset; and it manifests as interstitial lung disease or pulmonary vascular involvement with the development of pulmonary hypertension symptoms [4,15].

2. Diagnostics, medical indications and contraindications for diagnostic methods

A preliminary diagnosis of Gaucher disease is established based on the characteristic clinical picture (splenomegaly and/or hepatomegaly, 1–3 lineage cytopenia, signs of musculoskeletal involvement, see section 1.6) and the detection of numerous Gaucher cells in bone marrow cytologic and/or histologic specimens. The definitive diagnosis of GD is verified by the results of enzyme diagnostics – testing of blood cell beta-glucocerebrosidase and the results of molecular genetic testing (diagnostic panel for Gaucher disease) revealing a biallelic mutation in the glucocerebrosidase (GBA) gene [4,15].

2.1 Complaints and Anamnesis

- family history (presence of an established diagnosis of Gaucher disease or characteristic symptoms of the disease in relatives), ethnicity (the prevalence of Gaucher disease is higher in the Ashkenazi Jewish population);

- asthenia symptoms: weakness, fatigue, low exercise tolerance;

- symptoms associated with thrombocytopenia and/or coagulopathy: spontaneous mucocutaneous hemorrhagic syndrome, bleeding after surgical or dental interventions;

- symptoms associated with hepatosplenomegaly: complaints of abdominal enlargement, abdominal heaviness;

- symptoms associated with musculoskeletal involvement: history of bone crises, presence of pathological fractures, bone and joint pain, gait disturbance;

- symptoms associated with pulmonary hypertension (in patients who have undergone splenectomy): dyspnea, exertion fatigue, chest discomfort, syncopal episodes;

- history of splenectomy;

- symptoms associated with nervous system involvement (in adult patients with Gaucher disease type III): oculomotor apraxia, convergent strabismus, myoclonic and generalized tonic-clonic seizures, extrapyramidal rigidity.

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

2.2 Physical Examination

- nutritional status: body mass index (body weight deficit is characteristic of GD);

- presence of skin pallor, spontaneous mucocutaneous hemorrhagic syndrome;

- presence and degree of enlargement of the spleen and liver, presence of a post-splenectomy scar;

- musculoskeletal system involvement: abnormal bone shape, limb length discrepancy, joint mobility impairment, presence of local signs of inflammation (if bone crisis is suspected);

- clinical and auscultatory signs of pulmonary hypertension: acrocyanosis, digital clubbing and watch-glass nails, jugular venous distension, accentuation and splitting of the second heart sound ($ ext{S}_2$) over the pulmonary artery, murmur of tricuspid regurgitation.

- signs of nervous system involvement: oculomotor apraxia, convergent strabismus, extrapyramidal rigidity (if type 3 Gaucher disease is suspected).

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

2.3 Laboratory Diagnostics

- enzyme diagnostics – assay of blood cell beta-glucosidase [4,19];

- molecular genetic testing for Gaucher disease – mutation screening in the GBA gene (panel of tests for the diagnosis of Gaucher disease) [4,15].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Blood cell beta-glucosidase assay – the diagnosis of GD is confirmed when enzyme activity is reduced below reference values. The degree of reduction in enzyme activity does not correlate with the severity of clinical manifestations and the course of the disease.

Molecular genetic diagnostics for Gaucher disease (panel of tests for the diagnosis of Gaucher disease) allows verification of the GD diagnosis upon detection of biallelic pathogenic variants in the GBA gene.

Cytological examination of a bone marrow smear (myelogram) and/or cytological examination of bone marrow trephine biopsy imprints allows the detection of numerous lipid-engorged macrophages that are pathognomonic for Gaucher disease – Gaucher cells. However, the presence or absence of Gaucher cells in bone marrow preparations is not a criterion to confirm or exclude the diagnosis of Gaucher disease. Occasionally, isolated cells with similar morphology (pseudo-Gaucher cells) are found in other conditions accompanied by increased cell destruction, such as chronic myeloid leukemia and lymphoproliferative disorders, reflecting overload of the macrophage system with degradation products of the leukemic clone cells. At the same time, the absence of Gaucher cells in bone marrow preparations may reflect technical features of smear preparation: Gaucher cells are easily disrupted and/or present at the periphery of the smear – in zones not typically examined.

In adult patients with suspected GD, cytological examination of a bone marrow smear (myelogram) and/or cytological examination of bone marrow trephine biopsy imprints is generally performed prior to enzyme diagnostics (blood cell beta-glucosidase assay) since its purpose is to rule out hemoblastosis or non-neoplastic blood system disorders characterized by similar clinical symptoms (hepatosplenomegaly and cytopenia) that occur in the general population much more frequently than GD. In children, conversely, the painful bone marrow examination should be performed only after receiving enzyme diagnostics results that reveal normal glucocerebrosidase activity and thereby exclude the diagnosis of GD, the frequency of which in the pediatric population is higher than that of hemoblastoses [30].

- complete blood count (CBC) with differential [15,16,31];

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

- routine urinalysis [32–35];

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

- general general-practice blood biochemistry test:

• assay of total bilirubin in blood, assay of conjugated (bound) bilirubin in blood, assay of free (unconjugated) bilirubin, determination of gamma-glutamyltransferase activity in blood, determination of alkaline phosphatase activity in blood to rule out cholestatic syndrome secondary to specific hepatic infiltration in Gaucher disease [36]

• determination of aspartate aminotransferase activity in blood, determination of alanine aminotransferase activity in blood, determination of lactate dehydrogenase activity in blood to rule out cytolytic syndrome secondary to specific hepatic infiltration in Gaucher disease [36,37];

• - assay of total protein in blood, assay of albumin in blood, determination of the albumin/globulin ratio in blood to rule out impaired protein-synthetic function of the liver secondary to specific infiltration in Gaucher disease [36];

• - assay of blood cholesterol, assay of blood triglycerides, assay of low-density lipoprotein cholesterol, assay of high-density lipoprotein cholesterol to rule out lipid metabolism disorders as a reflection of Gaucher disease activity [38–41];

• - assay of blood glucose to rule out insulin resistance and diabetes mellitus [41]

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

- assay of serum iron, total iron-binding capacity, serum ferritin, serum transferrin, and transferrin saturation to detect iron metabolism abnormalities characteristic of Gaucher disease and associated with disease activity [42,43];

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

- determination of vitamin B12 (cyanocobalamin) level in blood, serum folic acid assay to rule out the impact of deficiency states on the degree of cytopenia in patients with Gaucher disease [44,45];

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

- coagulogram (exploratory hemostasis screening): activated partial thromboplastin time (APTT), prothrombin time in blood or plasma, blood fibrinogen assay, platelet aggregation assay to rule out concomitant coagulopathy and thrombocytopathy [46–49];

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

- determination of antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-1 in blood for differential diagnosis – to rule out cytopenia and/or splenomegaly caused by HIV infection [50];

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

- determination of antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-2 in blood for differential diagnosis – to rule out cytopenia and/or splenomegaly caused by HIV infection [51,52];

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

- determination of hepatitis B virus surface antigen (HBsAg) in blood, determination of antibodies to hepatitis C virus in blood for differential diagnosis – to rule out cytopenia caused by viral hepatitis [53,54];

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

- determination of antibodies to Treponema pallidum using non-treponemal tests (RPR, VDRL) (qualitative and semi-quantitative assay) in blood serum for differential diagnosis – to rule out cytopenia, splenomegaly, and skeletal bone lesions caused by syphilis [55];

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

- Blood immunoglobulin assay. Assay of blood immunoglobulin A. Assay of blood immunoglobulin M. Assay of blood immunoglobulin G. Assay of blood paraproteins [56].

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

2.4 Instrumental Diagnostics

- comprehensive ultrasound examination of the abdominal cavity with determination of baseline dimensions and structure of the liver and spleen, kidney ultrasound [57,58];

- radiography or computed tomography of the femurs including the knee and hip joints (according to the nomenclature of medical services: radiography of the femur (bilateral), radiography of the knee joint (bilateral), radiography of the hip joint (bilateral) – to reduce radiation exposure, should be performed as a single procedure; computed tomography of the bones (femurs bilaterally), computed tomography of the joint (femur and knee joints bilaterally) – to reduce radiation exposure, should be performed as a single procedure) [59–61];

- magnetic resonance imaging of the femur with inclusion of the knee and hip joints (according to the medical services nomenclature: magnetic resonance imaging of bone tissue (one region) – femurs, magnetic resonance imaging of joints (one joint) – knee and hip joints) [58,60–62];

- magnetic resonance imaging of the abdominal organs or computed tomography of the abdominal organs with determination of organ volumes [58,62]

- electrocardiogram recording [63,64] .

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

2.5 Other Procedures

- Echocardiography – in patients who have undergone splenectomy, and when type III GD is suspected [65].

- Esophagogastroduodenoscopy – in the presence of dyspepsia, abdominal pain, or signs of portal hypertension [66,67].

- Radiography of the affected part of the skeletal system and/or computed tomography of the bones (affected skeletal region) in the presence of pain or musculoskeletal disorders in these segments [68].

- X-ray densitometry of the lumbar spine and proximal femur – mandatory examinations in the presence of a history of pathological bone fractures [69].

- Computed tomography of the chest organs – to rule out focal infiltrative changes in the bronchopulmonary system [70].

For echocardiography, radiography, and computed tomography – Level of Recommendations C (Level of Evidence – 5)

For esophagogastroduodenoscopy – Level of Recommendations C (Level of Evidence – 4

Comments: glycosylsphingosine (lyso-Gb1) is used as an additional marker of GD activity – a biomarker representing the deacylated form of glucosylceramide. The concentration of lyso-Gb1 in the plasma of patients with Gaucher disease correlates with clinical indicators of disease severity, spleen and liver volume, history of splenectomy (higher in splenectomized patients), and the presence of neurological manifestations (significantly higher in patients with neuronopathic forms). The concentration of lyso-Gb1 generally decreases in response to enzyme replacement therapy and typically reaches a plateau 3–4 years after treatment initiation. Unlike chitotriosidase and chemokine CCL18, glycosylsphingosine is characterized by 100% sensitivity and specificity for Gaucher disease; an increase in its concentration above the cutoff point has not been described in other diseases, including lysosomal storage disorders. The concentration value of glycosylsphingosine can be used as an additional indicator in an individual comprehensive program for assessing Gaucher disease activity, especially in splenectomized patients [71–74].

Specialist consultations

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Gaucher disease is the first hereditary enzymopathy for which highly effective ERT was developed [4,20,48]. To date, global experience in treating Gaucher disease with enzyme preparations is approximately 30 years, and ERT is the "gold standard" of treatment for this condition. Long-term international and domestic experience with ERT in GD demonstrates its exceptional efficacy and high safety profile. In 2013, an efficacy analysis of ERT was published that included over 750 patients treated with imiglucerase** for 10 years. It was shown that the overwhelming majority of patients achieve GD treatment goals: 90% of patients normalize their hemoglobin concentration; over 90% of patients with baseline profound thrombocytopenia show a significant increase in platelet count (a platelet count <60×10⁹/L after 10 years of therapy was registered in only 1% of patients); 97% of patients show a reduction in spleen size (on average by 4 times) [85].

In the Russian Federation, ERT has been provided to patients with Gaucher disease under the state program "7-14 High-Cost Nosologies" since 2007.

Evaluation of the effectiveness of pathogenetic therapy is guided by the treatment goals of GD, which include [86]:

• stable increase in hemoglobin concentration (>120 g/L in men, >110 g/L in women);

• increase in platelet count (to normal values in splenectomized patients and to a level sufficient to prevent hemorrhagic syndrome in non-splenectomized patients);

• reduction of spleen size to a volume not exceeding 8 times normal; reduction of liver size by 30–40% from baseline;

• cessation of bone pain, prevention of osteonecrosis development, and increase in bone mineral density;

According to the International Collaborative Gaucher Group (ICGG) Registry, after 4 years of ERT, 41% of patients achieve all Gaucher disease treatment goals and 77% achieve all goals except one (most commonly, spleen size) [87].

Indications for initiating enzyme replacement therapy in adult patients are:

• clinically significant, persistent cytopenia; cytopenias caused by other conditions must be ruled out, for example, thrombocytopenia associated with chronic viral infections and/or liver cirrhosis, and anemia caused by vitamin B12 and folic acid deficiency;

• clinical and radiological signs of bone involvement; complaints of ossalgia and/or arthralgia must be confirmed by radiological and/or MRI findings typical of GD (bone marrow infiltration, necrosis, pathological fractures); Erlenmeyer flask deformities are not a basis for prescribing enzyme replacement therapy;

• clinically significant splenomegaly and/or hepatomegaly (in splenectomized patients);

• symptoms of pulmonary and other vital organ involvement in the absence of other obvious causes for their damage [10,14].

Four enzyme preparations for the treatment of Gaucher disease are registered in the Russian Federation:

• 2 imiglucerase** enzyme preparations – synthesized by a cell line derived from Chinese hamster ovaries;

• velaglucerase alfa** – produced by a human fibroblast cell line HT-1080.

• taliglucerase alfa** – synthesized by genetically modified plant cells.

3.1 Conservative Treatment

Comments: imiglucerase**, velaglucerase alfa**, and taliglucerase alfa** are provided to patients under the state program "14 High-Cost Nosologies". The dosage form of imiglucerase** and velaglucerase alfa** is 400 U vials; taliglucerase alfa is supplied in 200 U vials. The route and frequency of administration: intravenous administration of the drugs every 2 weeks (twice a month). The contents of each vial are reconstituted with water for injections and mixed gently to avoid bubble formation. The entire prepared solution is pooled into a single infusion bag/bottle and diluted with 0.9% sodium chloride solution** for intravenous injection to a total volume of 100–200 ml. Intravenous administration of the drugs is carried out over 1–2 hours. The drug should not be co-administered simultaneously with other medicinal products. Treatment is characterized by excellent tolerability and high clinical efficacy in patients with type 1 and type 3 Gaucher disease.

The starting dose of enzyme replacement therapy is a subject of discussion and varies in different countries from 10 to 60 U/kg of body weight with an administration frequency of every 2 weeks (twice a month). When determining the dose, the patient's age, the nature and severity of clinical manifestations, the prognosis of the disease course, the presence of complications, and comorbid conditions are taken into account. In countries providing ERT free of charge as part of a state program, there are expert panels on Gaucher disease whose functions include prescribing and monitoring the effectiveness of ERT.

Comments: in individual cases (severe osteoporosis with recurrent pathological fractures of long bones; pulmonary involvement with the development of pulmonary hypertension or hepatopulmonary syndrome), the starting dose of enzyme preparations in adult patients may be increased to 60 U/kg per single administration, but the decision on this is made by the Expert Panel established on April 1, 2009, with the support of the Russian Ministry of Health.

The decision to modify the dose (increase or decrease) or to change the drug (inefficacy or intolerance) for patients of any age receiving ERT is made by the Expert Panel established on April 1, 2009, with the support of the Russian Ministry of Health.

Comments: the regimen and dose of maintenance therapy are determined individually based on an analysis of a combination of clinical (baseline severity of GD, achievement of treatment goals, presence and nature of comorbidities) and social factors (age, employment, adherence to treatment, etc.). The efficacy and safety of the maintenance regimen of enzyme replacement therapy were demonstrated within the clinical approbation protocol (No. 18-1, 2015): increasing the intervals between enzyme infusions up to 4 weeks in patients who achieved treatment goals did not lead to a clinically significant deterioration of laboratory and instrumental parameters associated with GD activity over the subsequent 12–36 months of follow-up [92].

Comments: the advantage of SRT is the intake of oral pills instead of i.v. infusions of enzyme preparations as in ERT. From 2006 to 2015, clinical trials (phases 2–3) of a new SRT drug, eliglustat, were conducted, which demonstrated its high efficacy, good tolerability, and long-term (8 years) safety profile comparable to those of ERT.

In 2014–2015, eliglustat was approved in the USA and the EU as a first-line therapy for adult patients with type 1 Gaucher disease. In 2016, eliglustat was approved in the Russian Federation. The National Research Center for Hematology has 15 years of experience with eliglustat in patients with moderate to severe Gaucher disease without clinically significant comorbidities, including cardiac pathology. According to our observations, eliglustat is an effective, well-tolerated, and safe treatment for type 1 Gaucher disease in adults.

3.2 Surgical Treatment

Comments: Indications for surgical orthopedic treatment are determined by orthopedic trauma surgeons with experience in monitoring and treating GD patients, with the participation of hematologists, radiologists, and, if necessary, other specialists involved in the management of the given patient. Planned orthopedic surgeries should preferably be performed in medical institutions specializing in the diagnosis and treatment of orphan diseases, possessing experience in the surgical treatment of patients with Gaucher disease and the capabilities for blood component replacement therapy in the event of hemorrhagic complications.

Comments: once a diagnosis of GD is established, splenectomy is permissible only for absolute indications (e.g., traumatic splenic rupture). If diagnostic and therapeutic splenectomy is required in young patients with unexplained splenomegaly and cytopenia, it is advisable to perform preliminary enzyme diagnostics to rule out GD.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

There is no prevention for GD as a hereditary metabolic disease.

1. Medical and genetic counseling for families with children suffering from Gaucher disease and adult GD patients during family planning and childbearing [107]

2. Comprehensive screening for prenatal diagnosis of fetal developmental disorders (in utero) for timely decision-making regarding pregnancy termination in women who previously had children with type II-III GD [108].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Monitoring of Gaucher disease course and evaluation of ERT efficacy

Comments: to evaluate treatment efficacy and adjust the dose of enzyme preparations, follow-up examinations of patients are performed once every 1–3 years with evaluation of the results by multidisciplinary specialists: a general practitioner, hematologist, radiologist, orthopedic trauma surgeon, neurologist, and cardiologist with experience in the diagnosis and treatment of Gaucher disease.

Table 1. Monitoring schedule for adult patients with Gaucher disease

6. Organization of Medical Care

Patients with Gaucher disease receive enzyme replacement therapy on an outpatient basis. Enzyme preparations are provided in accordance with Decree of the Government of the Russian Federation No. 1416 dated November 26, 2018, "On the procedure for organizing the provision of medicinal products to persons suffering from hemophilia, cystic fibrosis, pituitary nanism, Gaucher disease, malignant neoplasms of lymphoid, hematopoietic and related tissues, multiple sclerosis, hemolytic-uremic syndrome, systemic-onset juvenile arthritis, mucopolysaccharidosis types I, II and IV, unspecified aplastic anemia, hereditary deficiency of factors II (fibrinogen), VII (labile), X (Stuart-Prower), and persons after organ and/or tissue transplantation."

Indications for planned hospitalization:

• Upon establishing the diagnosis of Gaucher disease – hospitalization to assess disease severity and determine indications for enzyme replacement therapy

• Evaluation of treatment efficacy and dose adjustment of enzyme preparations every 1 to 3 years;

• Need for orthopedic treatment;

• Need for surgical interventions;

• Presence of comorbidities aggravating the patient's condition.

Indications for emergency hospitalization:

• Need for emergency care in acute surgical pathology and trauma;

• Immediate initiation of enzyme replacement therapy

Indications for patient discharge from the hospital:

• Improvement of the patient's condition

• Completion of follow-up examination

To achieve the maximum effect regarding all clinical manifestations of the disease, it is necessary to develop an individualized treatment plan based on an expert assessment of the severity of Gaucher disease and involving the patient's examination in a specialized medical facility with multidisciplinary specialists having significant experience in the diagnosis and treatment of this disease.

7. Additional Information

7.1 Prognosis

In type I Gaucher disease, the prognosis is favorable if enzyme replacement therapy is prescribed in a timely manner. When irreversible musculoskeletal lesions develop, orthopedic surgery is indicated to correct orthopedic defects. In case of vital internal organ involvement, the prognosis is determined by the degree of dysfunction of the affected organs and the development of complications (e.g., bleeding from esophageal and gastric varices in patients with liver cirrhosis and portal hypertension; respiratory failure in patients with pulmonary involvement) [1–3,16,19,31].

In type II and III Gaucher disease, the prognosis is unfavorable [17].

7.2 Errors and Unjustified Prescriptions

1. Repeated acquisition of a bone marrow cytologic preparation via puncture and other invasive diagnostic procedures (liver and/or spleen biopsy via laparoscopy) are not necessary once the diagnosis of Gaucher disease is confirmed [15,19,31].

2. Surgical treatment of bone crises erroneously considered as manifestations of osteomyelitis [15,19,31].

3. Prescription of glucocorticoids to manage cytopenic syndrome [15,19,31].

4. Prescription of iron supplements to untreated patients with Gaucher disease, since anemia in these cases is of the " anemia of chronic disease" type [15,19,31].

5. Performance of splenectomy [15,19,31].

7.3 Gaucher Disease and Pregnancy

Gaucher disease is not a contraindication for pregnancy. It is advisable to plan pregnancy after achieving the treatment goals of Gaucher disease. The question of continuing enzyme replacement therapy during pregnancy and breastfeeding is decided on an individual basis, taking into account the patient's condition and treatment adherence. Pregnancy management is carried out by experienced obstetrician-gynecologists in collaboration with a hematologist. The mode of delivery is determined by obstetric indications, taking into account the presence of cytopenia and the state of the hemostatic system [111].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Parovichnikova E.N.¹, MD, General Director

2. Lukina E.A.¹, MD, Professor, Head of the Department of Hematology and Chemotherapy of Orphan Diseases

3. Ponomarev R.V.¹, PhD, Head of the Sector for the Study of Non-Neoplastic Blood Diseases, Hematologist at the Department of Hematology and Chemotherapy of Orphan Diseases

4. Sysoyeva E.P.¹, PhD, Leading Researcher at the Sector for the Study of Non-Neoplastic Blood Diseases, Hematologist at the Department of Hematology and Chemotherapy of Orphan Diseases

5. Chavynchak R.B.¹, Hematologist at the Department of Hematology and Chemotherapy of Orphan Diseases

6. Mamonov V.E.¹, PhD, Head of the Department of Hematological Orthopedics, National Medical Research Center for Hematology of the Russian Ministry of Health

7. Solovyova A.A.¹, PhD, Radiologist

8. Yatsyk G.A.¹, PhD, Head of the MRI and Ultrasound Department, National Medical Research Center for Hematology of the Russian Ministry of Health

9. Kostina I.E.¹, PhD, Head of the Radiology and Computed Tomography Department, National Medical Research Center for Hematology of the Russian Ministry of Health

10. Fisenko Andrey Petrovich ², MD, Professor, Director

11. Movsisyan G.B.², PhD, Pediatrician, Gastroenterologist at the Gastroenterology Department with Hepatology Group

12. Savostyanov K.V.², DSc, Head of the Medical Genetic Center

13. Pushkov Alexander Alekseevich ², PhD, Leading Researcher

14. Smetanina N.S.³, MD, Hematologist, Professor, Deputy Director

15. Suponeva N.A.⁴, MD, Professor, Corresponding Member of the RAS, Director of the Institute of Neurorehabilitation and Restorative Technologies

16. Illarioshkin S.N.⁴, Academician of the RAS, Deputy Director for Research

17. Ershova M.V.⁴, PhD in Medicine, Senior Research Fellow, 5th Neurological Department with Molecular Genetics Laboratory

18. Nuzhnykh Evgeny Petrovich, PhD in Medicine, Neurologist, Senior Research Fellow, 5th Neurological Department⁴

19. Sinitsyn V.E.^5,6, MD, Professor, Head of the Department of Radiology and Radiation Therapy, Faculty of Fundamental Medicine, Head of the Department of Radiology

20. Mershina E.A.^5,6, PhD in Medicine, Associate Professor of the Department of Radiology and Radiation Therapy, Head of the X-ray Diagnostics Department with MRI and CT Rooms

21. Mironov S.P.⁷, MD, Professor, Academician of the Russian Academy of Sciences, President

22. Ochurenko A.A.⁷, MD, Professor of the Department of Traumatology and Orthopedics, National Medical Research Center of Traumatology and Orthopedics named after N.N. Priorov of the Russian Ministry of Health

¹ National Medical Research Center for Hematology of the Ministry of Health of the Russian Federation, Moscow.

² National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation, Moscow.

³ National Medical Research Center of Children's Hematology, Oncology and Immunology named after Dmitry Rogachev of the Ministry of Health of the Russian Federation, Moscow.

⁴ Research Center of Neurology, Moscow

⁵ Medical Research and Educational Center of Lomonosov Moscow State University

⁶ Lomonosov Moscow State University

⁷ National Medical Research Center of Traumatology and Orthopedics named after N.N. Priorov of the Ministry of Health of the Russian Federation, Moscow.

Conflict of interest: the authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologists;

2. General practitioners;

3. Gastroenterologists;

4. Infectious diseases physicians;

5. Trauma and orthopedic surgeons;

6. Medical geneticists;

7. Psychiatrists.

Methodology for evidence collection

Methods used for the collection/selection of evidence:

• Search for publications in specialized periodical print media

• Search in electronic databases.

Databases used for the collection/selection of evidence:

The evidence base for the guidelines includes publications indexed in the Cochrane Library, PUBMED, and MEDLINE databases. The search depth was 30 years.

Methods used for evidence analysis:

• Reviews of published meta-analyses;

• Systematic reviews with evidence tables.

Methods used for assessing the quality and strength of evidence:

• Expert consensus;

• The significance of the evidence was assessed in accordance with the levels of evidence certainty (LEC) scale for diagnostic methods (Table 2) and for prevention, treatment, and rehabilitation methods (Table 3).

Table 2. Scale of levels of evidence certainty (LEC) for diagnostic methods (diagnostic interventions)

Table 3. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Description of the methodology for evidence analysis and recommendation development:

When selecting publications as potential sources of evidence, the methodology used in each study was examined to ensure its compliance with evidence-based medicine principles. The result of this examination influenced the level of evidence assigned to the publication, which in turn affects the strength of the resulting recommendations.

Methodological analysis focused on the study design features that had a significant impact on the quality of results and conclusions.

To eliminate the influence of subjective factors, each study was evaluated independently by at least two independent members of the authoring team. Discrepancies in evaluation were discussed at meetings of the working group of the authoring team for these guidelines.

Based on the evidence analysis, the sections of the clinical guidelines were consistently developed with strength assessment in accordance with the recommendation grading scheme (Table 3).

Methods used to formulate the recommendations:

• Expert consensus;

• Assessment of the significance of recommendations in accordance with the grading scheme (Table 4).

Table 4. Scale of recommendation persuasiveness levels (RPL) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Final version

For the final version and quality control, the guidelines were re-analyzed by the members of the authoring team, who concluded that all significant comments and feedback from experts had been taken into account, and the risk of bias during development was minimized.

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

No.

Appendix B. Physician Action Algorithms

Patient management algorithm for Gaucher disease

Appendix C. Patient Information

Gaucher disease is based on a hereditary deficiency in the activity of the enzyme $\beta$-glucocerebrosidase, which is involved in processing cellular metabolism products. As a result of insufficient activity of this enzyme, unprocessed metabolic "waste" accumulates in scavenger cells (macrophages), and the cells take on the characteristic appearance of Gaucher cells or "storage cells". Cells overflowing with "production waste" accumulate like a warehouse in internal organs, first in the spleen, then in the liver, skeletal bones, bone marrow, and lungs (hence the term "storage disease"). Gaucher disease occurs with a frequency of 1:40,000 to 1:60,000 among representatives of all ethnic groups; in the Ashkenazi Jewish population, the frequency of this disease reaches 1:450.

The main manifestations of Gaucher disease are caused by the accumulation of cells overloaded with "waste products" and the impairment of these cells' function. The accumulation of cells in various organs leads to an increase in their size (spleen, liver) and/or impairment of structure and function (bones, bone marrow, lungs). Impaired function of cells (macrophages) overloaded with waste products results in the development of anemia, bleeding tendency, exhaustion, bone fragility, and bone pain crises. This is because the scope of "professional duties" of macrophages in the human body is very wide and includes the regulation of many vital processes: hematopoiesis, blood coagulation, bone tissue metabolism, etc. The most typical manifestations of Gaucher disease are enlargement of the spleen and liver, development of anemia, thrombocytopenia, chronic bone pain, or sudden attacks of severe bone pain (bone crises). The latter are accompanied by fever and local acute inflammatory phenomena (swelling, redness), resembling the picture of osteomyelitis. Less commonly, the disease may first manifest as a bone fracture due to minor trauma. Bone involvement often presents the main clinical problem and can lead to severe disability (immobility due to multiple pathological fractures, bone and joint deformations, the need to replace destroyed hip or shoulder joints).

The diagnosis of Gaucher disease is established on the basis of biochemical analysis of the activity of the marker enzyme $\beta$-D-glucocerebrosidase in blood leukocytes. A decrease in enzyme activity to less than 30% of the normal level confirms the diagnosis.

The diagnosis of Gaucher disease can also be established using molecular analysis of the glucocerebrosidase gene.

Treatment of Gaucher disease consists of prescribing enzyme replacement therapy using drugs obtained through genetic engineering technologies.

The goals of treatment are the prevention of irreversible damage to the osteoarticular system and other vital organs (liver, lungs, kidneys); regression or alleviation of the cytopenic syndrome; and reduction in the size of the spleen and liver. Upon achieving these goals, maintenance treatment is prescribed at a dose of 7.5–15 U/kg/infusion (for life). Enzyme replacement therapy for Gaucher disease is an exclusively expensive treatment that in all developed countries of the world is provided by special state programs. Patients receive treatment free of charge. In the Russian Federation, free enzyme replacement therapy for Gaucher disease became available in 2007 as part of the "7 Nosologies" program.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

No.