Clinical outcomes and medical management of achondroplasia in Japanese children: A retrospective medical record review of clinical data.

Achondroplasia (ACH) is a rare, autosomal dominant skeletal dysplasia characterized by short stature, characteristic facial configuration, and trident hands. Before vosoritide approval in Japan, patients with ACH could start growth hormone (GH) treatment at age 3 years. However, ACH and its treatment in young Japanese children have not been studied. This retrospective, longitudinal, medical records-based cohort study (before vosoritide approval) summarized symptoms, complications, monitoring, surgery/interventions, and height with/without GH in Japanese patients with ACH <5 years. Complications were observed in 89.2% of all 37 patients; 75.7% required surgery or intervention. All patients were monitored by magnetic resonance imaging; 73.0% had foramen magnum stenosis, while 54.1% had Achondroplasia Foramen Magnum Score 3 or 4. Of 28 GH-treated patients, 22 initiating at age 3 years were generally taller after 12 months versus 9 non-GH-treated patients. Mean annual growth velocity significantly increased from age 2 to 3 versus 3 to 4 years in GH-treated patients (4.37 vs. 7.23 cm/year; p = 0.0014), but not in non-GH-treated patients (4.94 vs. 4.20 cm/year). The mean height at age 4 years with/without GH was 83.6/79.8 cm. These results improve our understanding of young patients with ACH in Japan and confirm that early diagnosis of ACH and monitoring of complications help facilitate appropriate interventions.

[Neonatal Fc receptor (FcRn)-A Novel Therapeutic Approach for Autoimmune Disease].

Neonatal Fc receptor (FcRn) is involved in recycling of IgG. Recycling begins with IgG-uptake into the cell through pinocytosis. Subsequently, IgG binds to FcRn in acidic vesicles, which results in the recycling of the FcRn-IgG complex to cell surface, and the release of IgG in blood with neutral pH. Whereas IgG unbound to FcRn is not recycled and thus degraded in lysosomes. Therefore, FcRn plays a critical role in maintaining IgG levels in the blood. Recently, FcRn has been considered a therapeutic target for autoimmune diseases caused by IgG autoantibodies, and FcRn inhibitors are developed as therapeutic agents for the diseases. As one example, the administration of an FcRn inhibitor, efgartigimod, reduced IgG and anti-acetylcholine receptor antibody levels in patients with generalized myasthenia gravis (gMG), and improved Myasthenia Gravis Activities of Daily Living score in the phase III trial. In 2022, Efgartigimod Alfa was approved for the treatment of gMG (only when treatment with steroids or non-steroidal immunosuppressive drugs do not lead to sufficient response), regardless of antibody status in Japan. Since FcRn inhibitors have just begun to be used in clinical practice, it is important to accumulate real-world data regarding their efficacy and safety. (Received August 21, 2023; Accepted October 6, 2023; Published February 1, 2024).

Multifaced risk factors and clinical impact of a deep Y descent in patients with heart failure irrespective of RV-PA coupling.

Background: A deep Y descent in the jugular venous pulse (JVP) is associated with diseases such as a decrease in right ventricular (RV) preload reserve. The present study investigated the relationship between RV-pulmonary arterial (PA) coupling and a deep Y descent, examined risk factors for a deep Y descent and clarified whether a deep Y descent was an independent risk factor for cardiac events irrespective of RV-PA coupling in patients with heart failure (HF). Methods: We enrolled 350 patients with HF who underwent echocardiography and JVP examination. A deep Y descent was identified by a deeper 'Y' descent than 'X' descent in the JVP waveform. We defined cardiac events of HF as follows: sudden death, death from HF, the emergent infusion of loop diuretics, or hospitalization for decompensated HF. Results and Conclusions: A deep Y descent and cardiac events were observed in 129 and 83 patients, respectively. The prevalence of a deep Y descent increased with decreases in the tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary arterial pressure (SPAP) ratio. Not only the TAPSE/SPAP ratio (odds ratio,0.756 per0.1 mm/mmHg, 95 %confidence interval [CI], 0.660-0.866, p < 0.001), but also age, atrial fibrillation, and the use of beta-blockers were independent factors for a deep Y descent in multivariate logistic model. Multivariate Cox hazard model demonstrated that a deep Y descent was for cardiac events in patients with HF (Hazard ratio,2.682, 95 %CI, 1.599-4.497, p < 0.001) irrespective of the TAPSE/SPAP ratio. The development of therapeutic strategies based on central venous waveform may be needed for patients with HF.

Myasthenia Gravis Disease Burden and Its Impact on Satisfaction with Life: A Qualitative Survey of Patients' Perspectives in Japan.

INTRODUCTION: Myasthenia gravis (MG) has a negative impact on patients' health-related quality of life; however, many clinicians do not fully understand their patients' lived experience of the disease. To understand the actual conditions of patients with MG and clarify the problems they perceive, we conducted a survey to evaluate the effects of the disease on patients' daily life and work. METHODS: A questionnaire-based, qualitative, cross-sectional, non-interventional survey was conducted in Japan between April and May 2022 in patients with MG who were receiving regular outpatient treatment. The questionnaire included items regarding the patients' disease characteristics and experience, satisfaction with life, current treatment status, and treatment satisfaction. RESULTS: In total, 452 patients were included in the survey population (66.6% aged ≥ 60 years; 64.6% with MG disease duration ≥ 10 years; 76.6% acetylcholine receptor [AChR] autoantibody positive). The symptoms of MG had a significant impact on the patients' daily lives, with the most common symptoms being fatigability (74.8%), ptosis (59.7%), diplopia (54.2%), and weakness in the arms and/or legs (50.9%). Patients commonly identified exercise (73.7%), work 68.0%), hobbies (60.4%), travel (60.0%), and socializing with friends (59.7%) as being difficult to perform, with approximately 50% of patients reporting that hospitalization sometimes interfered with their ability to work. In total, 27.2% of patients were dissatisfied with life, with the highest rates of dissatisfaction among patients who were either positive for muscle-specific kinase (MuSK) autoantibodies or seronegative for both AChR and MuSK autoantibodies. CONCLUSION: In Japanese patients with MG, over 25% are dissatisfied with life, indicating several unmet needs in this population.

Efficacy and Safety of Transitioning to Lemborexant from Z-drug, Suvorexant, and Ramelteon in Japanese Insomnia Patients: An Open-label, Multicenter Study.

INTRODUCTION: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety. METHODS: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases). RESULTS: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition. CONCLUSIONS: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04742699.