Clinical outcomes in a subpopulation of adults with Morquio A syndrome: results from a long-term extension study of elosulfase alfa.

BACKGROUND: This post hoc subanalysis examined outcomes in adult patients with Morquio A (mucopolysaccharidosis IVA) who received enzyme replacement therapy (ERT) with elosulfase alfa over a 120-weeks period. Patients ≥18 years of age evaluated in an open-label, long-term extension study of elosulfase alfa (modified per protocol [MPP], n = 32; intent-to-treat [ITT], n = 37; MOR-005; NCT01415427) were compared with the ≥18-year-old untreated population with 2-years follow-up from a Morquio A natural history study (n = 10; MorCAP; NCT00787995). The MOR-005 MPP population excluded patients who underwent orthopedic surgical procedures or were noncompliant with study protocol (defined as missing ≥20% of ERT infusions). No MorCAP patients underwent orthopedic surgical procedures during the relevant time period. Endurance was assessed by the 6-min walk test (6MWT) and 3-min stair climb test (3MSCT). Activities of daily living (ADLs) were assessed by the MPS Health Assessment Questionnaire (MPS HAQ). RESULTS: Least squares (LS) mean (SE) 6MWT distances increased by 34.9 (11.7) m (MPP) and 30.5 (10.8) m (ITT) by week 120; LS mean (SE) change in 3MSCT at week 120 was 6.7 (1.8) stairs/min (MPP) and 5.9 (1.7) stairs/min (ITT). MorCAP patients showed no improvement in 6MWT distance or 3MSCT over a similar period of time. Pulmonary function measures remained unchanged in both MOR-005 and MorCAP adults. All MPS HAQ domain scores improved in MOR-005 adults, whereas MorCAP adults had unchanged caregiver assistance and mobility outcomes and worsened self-care outcomes. CONCLUSIONS: Long-term ERT in adult patients with Morquio A was associated with increased endurance and improvement in performance of ADLs. TRIAL REGISTRATION: Trial Registration NCT01415427 . Name of registry: Long-Term Efficacy and Safety Extension Study of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome). Registered 8 August 2011, retrospectively registered.

The effect of galsulfase enzyme replacement therapy on the growth of patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome).

Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnormalities such as dysostosis multiplex and short stature. Reference height-for-age growth charts for treatment-naïve MPS VI patients have been published for both the slowly and rapidly progressing populations. Categorization of disease progression for these charts was based on urinary GAG (uGAG) level; high (>200µg/mg creatinine) levels identified subjects as rapidly progressing. Height data for 141 patients who began galsulfase treatment by the age of 18years were collected and stratified by baseline uGAG level and age at ERT initiation in 3-year increments. The reference MPS VI growth charts were used to calculate change in Z-score from pre-treatment baseline to last follow-up. Among patients with high baseline uGAG levels, galsulfase ERT was associated with an increase in Z-score for those beginning treatment at 0-3, >3-6, >6-9, >9-12, and >12-15years of age (p<0.05). Increases in Z-score were not detected for patients who began treatment between 15 and 18years of age, nor for patients with low (≤200µg/mg creatinine) baseline uGAG levels, regardless of age at treatment initiation. The largest positive deviation from untreated reference populations was seen in the high uGAG excretion groups who began treatment by 6years of age, suggesting an age- and severity-dependent impact of galsulfase ERT on growth.

Current therapy for Lambert-Eaton myasthenic syndrome: development of 3,4-diaminopyridine phosphate salt as first-line symptomatic treatment.

BACKGROUND: Lambert-Eaton myasthenic syndrome (LEMS) is a rare pre-synaptic auto-immune disorder of neuromuscular transmission that is characterised by proximal muscle weakness, depressed tendon reflexes and autonomic dysfunction. This review summarises the clinical symptoms, aetiology, diagnosis and treatment options for LEMS. Focus is placed on symptomatic treatment with the potassium channel blocker 3,4-diaminopyridine (3,4-DAP). RESEARCH METHODS: English-language publications were searched in MEDLINE and EMBASE to retrieve relevant literature on LEMS. The data submitted to obtain regulatory approval of 3,4-DAP phosphate by the European Medicines Agency (EMA) were also used. FINDINGS: LEMS is a rare disease with few treatment options which are generally categorised as anti-tumour, immunomodulating or immunosuppressing, and symptomatic treatments. Anti-tumour treatment is recommended for patients with the paraneoplastic form of LEMS. While several immunomodulating or immunosuppressing treatments have been identified, these treatments should be initiated when symptomatic treatments are inadequate. As expected, due to the rarity of the disease, few reports of randomised controlled trials (RCTs) exist. Seven RCTs have been conducted to evaluate treatment of patients with LEMS. One RCT evaluated immunomodulating treatment with intravenous immunoglobulin (ivIg), while six evaluated symptomatic treatment with the potassium channel blocker 3,4-DAP. Improvements in LEMS symptoms after ivIg treatment were observed, leading to the recommendation for treatment in patients when symptomatic treatment does not provide satisfactory improvement. Potassium channel blockers evaluated for the treatment of LEMS include guanidine, 4-aminopyridine (4-AP) and 3,4-DAP. However, only 3,4-DAP has been evaluated in RCTs. Results of these RCTs demonstrated that treatment with 3,4-DAP is efficacious in treatment of LEMS and has an acceptable tolerability profile. Hence, 3,4-DAP has been recommended as first-line symptomatic treatment for LEMS by the European Federation of Neurological Societies. While 3,4-DAP base has only been available via named-patient programmes, requiring ad hoc preparations in compounding pharmacies, tablets containing 3,4-DAP phosphate salt, equivalent to 10 mg base, have become available. This formulation has obtained the orphan medicinal product status both in the European Union and in the United States of America, and has received marketing authorisation in Europe as Firdapse*. These tablets have been shown to be essentially bioequivalent with the base preparation. CONCLUSIONS: The results of this review show that anti-tumour treatment is recommended for patients with the paraneoplastic form of LEMS and that one RCT has shown that immunomodulating treatments should be initiated when symptomatic treatments do not provide satisfactory results. A number of RCTs have shown that 3,4-DAP is effective in symptomatic treatment of patients with LEMS and has been recommended as first-line symptomatic treatment of patients with LEMS. The 3,4-DAP phosphate salt formulation was shown to be safe and effective in the treatment of LEMS with a positive benefit:risk ratio.

Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action.

BACKGROUND: Intravenous gammaglobulin (i.v.IG) contains anti-idiotypic antibodies that are potent inhibitors of HLA-specific alloantibodies in vitro and in vivo. In addition, highly HLA-allosensitized patients awaiting transplantation can have HLA alloantibody levels reduced dramatically by i.v.IG infusions, and subsequent transplantation can be accomplished successfully with a crossmatch-negative, histoincompatible organ. METHODS: In this study, we investigated the possible use of i.v.IG to reduce donor-specific anti-HLA alloantibodies arising after transplantation and its efficacy in treating antibody-mediated allograft rejection (AR) episodes. We present data on 10 patients with severe allograft rejection, four of whom developed AR episodes associated with high levels of donor-specific anti-HLA alloantibodies. RESULTS: Most patients showed rapid improvements in AR episodes, with resolution noted within 2-5 days after i.v.IG infusions in all patients. i.v.IG treatment also rapidly reduced donor-specific anti-HLA alloantibody levels after i.v.IG infusion. All AR episodes were reversed. Freedom from recurrent rejection episodes was seen in 9 of 10 patients, some with up to 5 years of follow-up. Results of protein G column fractionation studies from two patients suggest that the potential mechanism by which i.v.IG induces in vivo suppression is a sequence of events leading from initial inhibition due to passive transfer of IgG to eventual active induction of an IgM or IgG blocking antibody in the recipient. CONCLUSION: I.v.IG appears to be an effective therapy to control posttransplant AR episodes in heart and kidney transplant recipients, including patients who have had no success with conventional therapies. Vascular rejection episodes associated with development of donor-specific cytotoxic antibodies appears to be particularly responsive to i.v.IG therapy.

Heart transplantation with bicaval and pulmonary venous anastomoses. A hemodynamic analysis of the first 117 patients.

BACKGROUND: A new surgical technique for orthotopic heart transplantation has been introduced into clinical practice. It accomplishes total atrioventricular transplantation as the recipient's atria are completely excised and the allograft is implanted using bicaval and pulmonary venous anastomoses. MATERIALS AND METHODS: We retrospectively analyzed post-transplant hemodynamic and patient survival in our first 117 patients transplanted with this new operative approach and compared them with 64 patients transplanted with the standard biatrial technique. RESULTS: Patients transplanted with the bicaval technique had a significantly lower right atrial mean, pulmonary arterial systolic, pulmonary arterial mean, and pulmonary capillary wedge pressures. In addition, a significant reduction in post-transplant tricuspid regurgitation and a trend towards less severe mitral regurgitation was observed. The need for permanent pacemaker implantation due to sinus node dysfunction after transplantation was completely eliminated with this new technique. Thirty-day operative survival and actuarial survival at 1, 2, 3, and 4 years was significantly greater in patients transplanted with the bicaval technique. CONCLUSIONS: Orthotopic heart transplantation performed with bicaval and pulmonary venous anastomoses offers improved post-transplant hemodynamics, eliminates the need for permanent pacemaker, and has improved patient survival when compared with the standard biatrial technique. These differences can be related in part to improved hemodynamic function of the cardiac allograft due to preservation of the anatomic configuration and physiologic function of the atria.