Reported outcomes of 453 pregnancies in patients with Gaucher disease: An analysis from the Gaucher outcome survey.

Gaucher disease (GD) may worsen during pregnancy, leading to the discussion of continuing treatment during pregnancy. We examined fetal outcomes of pregnancies reported in the Gaucher Outcome Survey, an international GD-specific registry established in 2010. A total of 453 pregnancies were reported. Most pregnancies (336/453, 74.2%) were in women who did not receive GD-specific treatment during pregnancy, while enzyme replacement therapy (ERT) was received during 117/453 (25.8%) pregnancies. No pregnancies exposed to substrate reduction therapy were reported. The percentage of normal outcomes (live birth delivered at term with no congenital abnormalities) was similar in untreated and treated pregnancies (92.9% vs. 91.4%). The percentage of spontaneous abortions in untreated pregnancies was 3.6% (95% CI, 1.9%- 6.2%) compared with 6.9% (95% CI, 3.0%-13.1%) in treated pregnancies (p=0.1866). In women who received velaglucerase alfa <1month prior to conception and/or during pregnancy, 34/36 (94.4%) pregnancies had normal outcomes and 2 (5.6%) ended in spontaneous abortion. Normal outcomes were observed in the 20 pregnancies with velaglucerase alfa exposure starting <1month prior to conception and continuing through all trimesters. These observations, in addition to information in the literature, suggest that continuation of ERT during pregnancy may be appropriate for GD patients.

Demographics and patient characteristics of 1209 patients with Gaucher disease: Descriptive analysis from the Gaucher Outcome Survey (GOS).

The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD) registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status, designed to evaluate the safety and long-term effectiveness of velaglucerase alfa and other GD-related treatments. As of February 25, 2017, 1209 patients had enrolled, the majority from Israel (44.3%) and the US (31.4%). Median age at GOS entry was 40.4 years, 44.1% were male, and 13.3% had undergone a total splenectomy. Most patients had type 1 GD (91.5%) and were of Ashkenazi Jewish ethnicity (55.8%). N370S/N370S was the most prevalent genotype, accounting for 44.2% of genotype-confirmed individuals (n = 847); however, there was considerable variation between countries. A total of 887 (73.4%) patients had received ≥1 GD-specific treatment at any time, most commonly imiglucerase (n = 587), velaglucerase alfa (n = 507), and alglucerase (n = 102). Hematological and visceral findings at the time of GOS entry were close to normal for most patients, probably a result of previous treatment; however, spleen volume of patients in Israel was almost double that of patients elsewhere (7.2 multiples of normal [MN] vs. 2.7, 2.9 and 4.9 MN in the US, UK and rest of world), which may be explained by a greater disease severity in this cohort. This analysis aimed to provide an overview of GOS and present baseline demographic and disease characteristics of participating patients to help improve the understanding of the natural history of GD and inform the overall management of patients with the disease.

Exploring the patient journey to diagnosis of Gaucher disease from the perspective of 212 patients with Gaucher disease and 16 Gaucher expert physicians.

Gaucher disease (GD) is a rare hereditary disorder caused by a deficiency of the lysosomal enzyme ß-glucocerebrosidase. Diagnosis is challenging owing to a wide variability in clinical manifestations and severity of symptoms. Many patients may experience marked delays in obtaining a definitive diagnosis. The two surveys reported herein aimed to explore the patient journey to diagnosis of GD from the perspectives of Gaucher expert physicians and patients. Findings from the surveys revealed that many patients experienced diagnostic delays and misdiagnoses, with nearly 1 in 6 patients stating that they were not diagnosed with GD for 7years or more after first consulting a doctor. Physicians and patients both reported multiple referrals to different specialties before a diagnosis of GD was obtained, with primary care, haematology/haematology-oncology and paediatrics the main specialties to which patients first presented. Splenomegaly, thrombocytopenia, anaemia and bone pain were reported as the most common medical problems at first presentation in both surveys. These findings support a clear need for straightforward and easy-to-follow guidance designed to assist non-specialists to identify earlier patients who are at risk of GD.

Clinical picture and treatment of 2212 patients with common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders. OBJECTIVE: This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe. METHODS: Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. RESULTS: Early disease onset (<10 years) was very frequent in our cohort (33.7%), especially in male subjects (39.8%). Male subjects with early-onset CVID were more prone to pneumonia and less prone to other complications suggesting a distinct disease entity. The diagnostic delay of CVID ranges between 4 and 5 years in many countries and is particularly high in subjects with early-onset CVID. Enteropathy, autoimmunity, granulomas, and splenomegaly formed a set of interrelated features, whereas bronchiectasis was not associated with any other clinical feature. Patient survival in this cohort was associated with age at onset and age at diagnosis only. There were different treatment strategies in Europe, with considerable differences in immunoglobulin dosing, ranging from 130 up to 750 mg/kg/mo. Patients with very low trough levels of less than 4 g/L had poor clinical outcomes, whereas higher trough levels were associated with a reduced frequency of serious bacterial infections. CONCLUSION: Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome.

A systematic literature review to examine the considerations around pregnancy in women of child-bearing age with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) or aquaporin 4 neuromyelitis optica spectrum disorder (AQP4+ NMOSD).

BACKGROUND: Aquaporin-4 antibody positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are rare autoimmune diseases with overlapping phenotypes. Understanding their clinical manifestation prior to, during and after pregnancy may influence the management of women of child-bearing age (WOCBA) with these diseases. METHODS: This systematic review identified relevant MEDLINE-indexed publications dated between 01 January 2011 and 01 November 2021, and congress materials from key conferences between 01 January 2019 and 01 November 2021. These were manually assessed for relevance to AQP4+ NMOSD and/or MOGAD in WOCBA, with selected data extracted and considered. RESULTS: In total, 107 articles were retrieved and reviewed for relevancy, including 65 clinical studies. Limited evidence was found regarding a conclusive impact of either disease on female fertility, sexual function or menarche, and impact on maternal outcomes requires further investigation in both conditions to establish risk for pre-eclampsia, gestational diabetes and other complications relative to the general population. Collated data for pregnancy outcomes show clear risks in AQP4+ NMOSD to healthy delivery and a rise in annualised relapse rate postpartum that may require adaptation of treatment regimens. Disease activity appears to be attenuated during pregnancy in MOGAD patients with an increased risk of relapse during the postpartum months, but strong conclusions cannot be made due to a paucity of available data. CONCLUSIONS: This review brings together the literature on AQP4+ NMOSD and MOGAD in WOCBA. The potential impact of pregnancy and the postpartum period on disease activity suggest a proactive management strategy early on may improve maternal and infant outcomes, but more clinical data are needed, particularly for MOGAD.

Patient Pathway to Diagnosis of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): Findings from a Multinational Survey of 204 Patients.

INTRODUCTION: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare demyelinating disorder of the central nervous system. Despite increased recognition of MOGAD as a distinct disease and the availability of sensitive methods of MOG antibody testing, diagnostic challenges remain. We conducted a survey to explore the patient experience from the start of symptoms to final MOGAD diagnosis. METHODS: A 23-question online survey (including multiple-choice and free-text responses) covering symptom history, healthcare interactions and impact of diagnosis was emailed to people living with MOGAD by The MOG Project patient advocacy group. People living with MOGAD could share the survey with their caregivers. Anonymised responses were analysed. RESULTS: In total, 204 people living with MOGAD or their caregivers from 21 countries completed the survey; most respondents were from North America. Age of symptom onset ranged from 1 to 66 (median 28) years. Symptoms that prompted patients to seek medical care included blurred vision/loss of vision (58.2%), eye pain (35.8%) and difficulty walking (25.4%). Patients most frequently presented to emergency care physicians (38.7%) and primary care doctors (26.0%), with the MOGAD diagnosis most often made by general neurologists (40.4%) or neuro-immunologists (30.0%). Patients saw a median of four doctors before diagnosis, with 26.5% of patients seeing at least six doctors. Although 60.6% of patients received a MOGAD diagnosis within 6 months of experiencing initial health problems, 17.7% experienced a ≥ 5-year delay. More than half of patients (55.4%) received an alternative primary diagnosis before final MOGAD diagnosis. Most respondents (60.6%) reported receiving insufficient information/resources at the time of MOGAD diagnosis. Diagnostic delay was associated with long-term negative consequences for physical health. CONCLUSION: This survey provides unique insights from people living with MOGAD and their caregivers that could help address the challenges faced in the pathway to final MOGAD diagnosis.

A charitable access program for patients with lysosomal storage disorders in underserved communities worldwide.

BACKGROUND: Lysosomal storage disorders (LSDs) are rare genetic disorders, with heterogeneous clinical manifestations and severity. Treatment options, such as enzyme replacement therapy (ERT), substrate replacement therapy, and pharmacological chaperone therapy, are available for several LSDs, including Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (mucopolysaccharidosis type II [MPS II]). However, patients in some countries face challenges accessing treatments owing to limited availability of locally licensed, approved drugs. METHODS: The Takeda LSD Charitable access program aims to meet the needs of individuals with GD, FD or MPS II with the greatest overall likelihood of benefit, in selected countries, through donation of ERT to nonprofit organizations, and support for medical capacity-building as well as family support via independent grants. Long-term aims of the program are to establish sustainable healthcare services delivered by local healthcare providers for patients with rare metabolic diseases. Patients receiving treatment through the program are monitored regularly, and their clinical data and progress are reviewed annually by an independent medical expert committee (MEC). The MEC also selects patients for enrollment completely independent from the sponsoring company. RESULTS: As of 31 August, 2019, 199 patients from 13 countries were enrolled in the program; 142 with GD, 41 with MPS II, and 16 with FD. Physicians reported improvements in clinical condition for 147 (95%) of 155 patients with follow-up data at 1 year. CONCLUSIONS: The response rate for follow-up data at 1 year was high, with data collected for > 90% of patients who received ERT through the program showing clinical improvements in the majority of patients. These findings suggest that the program can benefit selected patients previously unable to access disease-specific treatments. Further innovative solutions and efforts are needed to address the challenges and unmet needs of patients with LSDs and other rare diseases around the world.

Characteristics of 26 patients with type 3 Gaucher disease: A descriptive analysis from the Gaucher Outcome Survey.

The Gaucher Outcome Survey (GOS) is an international disease-specific registry established in 2010 for patients with a confirmed diagnosis of Gaucher disease (GD), regardless of GD type or treatment status. Historically, there has been a limited understanding of type 3 GD (GD3) and its natural history in patients irrespective of their treatment status. Here, we describe the disease characteristics of patients with GD3 enrolled in GOS. As of October 2015, 1002 patients had been enrolled, 26 of whom were reported as GD3. The majority of patients with GD3 were from the US (13; 50.0%), seven (26.9%) were from the UK, three (11.5%) from Israel, and three (11.5%) from Brazil. No patients were of Ashkenazi Jewish origin. Median age of symptom onset was 1.4 (interquartile range: 0.5-2.0) years. The most common GBA1 mutation genotype was L444P/L444P, occurring in 16 (69.6%) of 23 patients who had genotyping information available. Nine patients reported a family history of GD (any type). Of 21 patients with treatment status information, 20 (95.2%) had received GD-specific treatment at any time, primarily imiglucerase (14 patients) and/or velaglucerase alfa (13 patients). Hemoglobin concentrations and platelet counts at GOS entry were within normal ranges for most patients, and there were no reports of severe hepatomegaly or of splenomegaly in non-splenectomized patients, most likely indicative of the effects of treatment received prior to GOS entry. This analysis provides information on the characteristics of patients with GD3 that could be used as the baseline for longitudinal follow-up of these patients.

The use of omalizumab in the treatment of severe allergic asthma: A clinical experience update.

Severe persistent asthma causes a substantial morbidity and mortality burden and is frequently inadequately controlled despite intensive guideline-based therapy. Targeting allergic inflammatory processes that underlie the pathogenesis of severe persistent asthma improves asthma control in a significant proportion of patients. Omalizumab, a humanized monoclonal anti-immunoglobulin E (IgE) antibody, has been developed to target IgE, which is central to triggering and maintaining allergic airway inflammation. In a comprehensive program of clinical trials, omalizumab has been shown to reduce asthma exacerbation and emergency visit rates, and to improve quality of life in patients with severe persistent allergic asthma. It is difficult to predict which patients would most benefit from omalizumab treatment; accurate selection and dosing of patients are essential to achieve benefit. Patients need to have convincing IgE-mediated asthma and be dosed according to pre-treatment serum total IgE level and body weight, using a specified dosing table. Based on clinical trial data analysis, it is recommended that treatment response is evaluated by the physician after 16 weeks of therapy. Treatment should only be continued in responders, i.e. those judged by the physician to have achieved a marked improvement or complete asthma control. Omalizumab is generally well tolerated. Anaphylactic-like reactions are rare (0.1% of patients) and less common than encountered with other biologics.