Classification of Infiltrative Heart Diseases MORAL-STAGE System.

Infiltrative heart disease (InHD) is a group of diseases characterized by the deposition of abnormal substances in the heart tissue, causing diastolic, less often systolic, dysfunction of the ventricle(s). Their classification still does not exist. In 2013, the MOGE(S) classification of cardiomyopathies was published, taking into account, along with the morphological and functional characteristics of the heart, damage to other organs, the presence of genetic mutations, acquired causes (e.g., myocardial inflammation, autoimmune diseases, storage diseases, amyloidosis), etc. By analogy with it we offer the MORAL-STAGE classification for InHD. It includes ten features: morphofunctional characteristics (M), organ damage (O), risk of cardiac death (R), age of clinical presentation, age of disease-specific therapy initiation (A), localization of the infiltrative process (inside or outside the cell, L), information about the functional class heart failure and stage of infiltrative heart disease (S), treatment (T), abnormal rhythm or conduction (A), genetic or familial nature of inheritance (G), etiology of the process (E). This article summarizes the cornerstones of the MORAL-STAGE classification and its clinical relevance. In addition, new issues are discussed that can be considered in future versions of the MORAL-STAGE classification.

Immune tolerance induction for laronidase treatment in mucopolysaccharidosis I.

Enzyme replacement therapy (ERT) can produce anti-drug antibody (ADA) responses that reduce efficacy or lead to hypersensitivity reactions. Six patients with severe mucopolysaccharidosis type I (MPS I/Hurler syndrome) who did not receive hematopoietic stem cell transplantation underwent an immunosuppression regimen prior to initiating ERT with laronidase. The primary endpoint for immune tolerance induction was the number of patients with an ADA titer ≤ 3200 after 24 weeks of laronidase at the labeled dose. Cyclosporine levels were measured weekly and doses adjusted to maintain trough levels above 400 mg/mL. A 6-week (Cohort 1) or 12-week (Cohort 2) immune tolerance induction period with cyclosporine (initial dose: 15 or 20 mg/kg/day), azathioprine (initial dose: 2.5 or 5 mg/kg/day) and low-dose laronidase infusions (0.058-0.29 mg/kg/week) was followed by an immune-challenge period with laronidase infusions at the labeled dose (0.58 mg/kg/week) for 24 weeks. Anti-laronidase IgG titers were determined following treatment. There were 147 treatment-emergent adverse events reported, most of which were mild and not related to the study treatment. While there was no evidence of immune tolerance in 3 of 3 patients in Cohort 1, there were some indications of immune tolerance induction in 2 of 3 patients in Cohort 2. Patients with lower ADA titers showed greater reductions in urinary glycosaminoglycan excretion. Routine monitoring of plasma cyclosporine parent-compound levels by high pressure liquid chromatography proved difficult for clinical practice. The evolving clinical management of MPS I and a better understanding of the clinical impact of laronidase-related immunogenicity require reassessment of immune modulation strategies in patients with MPS I receiving laronidase treatment. CLINICAL TRIAL REGISTRATION: NCT00741338.