Yasushi Suzuki

Efgartigimod, which has been well tolerated and efficacious in individuals with generalized myasthenia gravis (MG), is available in Japan not only for the treatment of anti–acetylcholine receptor–positive (AChR+) but also anti–muscle-specific receptor tyrosine kinase (MuSK+) and seronegative generalized MG. We report details of the use of efgartigimod for generalized MG in clinical practice in Japan. We included patients with generalized MG in the 2021 survey of Japan Myasthenia Gravis Registry (JAMG-R) study group who received an initial cycle of efgartigimod between May and September 2022. We defined “responders” as patients who achieved a score ≥2 points for MG activities of daily living (MG-ADL) in the first treatment cycle. The MG composite and the Revised scale of the 15-item Myasthenia Gravis–Quality of Life scale (MG-QOL15-r) were also evaluated. Of 1,343 JAMG-R patients, 36 (2.7%) started efgartigimod (female 68%, age 53 years). Their serologic profiles were as follows: AChR+, n = 19 (53%); MuSK+, n = 6 (17%); and seronegative, n = 11 (31%). Twenty-six patients (72%) had refractory MG. There were 81 cycles of efgartigimod during the 26-week observation in 34 patients (average, 2.4 cycles). The mean interval between cycles was 5.9 weeks. A continuous 4-weekly infusion of efgartigimod was performed in 65 (80%) of 81 cycles. In the first cycle, the MG-ADL score of the 34 patients decreased significantly from 10.5 ± 4.3 to 6.9 ± 5.1 (p = 0.003). Similarly, the mean MG composite and MG-QOL15-r decreased from 18.4 ± 13.6 to 11.8 ± 9.6 (p = 0.004) and from 19.2 ± 6.3 to 14.2 ± 8.3 (p = 0.007), respectively. Twenty-one (62%) patients were responders. Therapeutic responses were observed in the subsequent cycles. The duration of effectiveness of efgartigimod was varied among the responders; 4 responders had only a single effective cycle. Significant improvement was observed in the MuSK+ patients. Prednisolone dose of 7 patients was reduced. Our examination of the patients' postintervention status revealed that 6 patients achieved minimal manifestations. COVID-19 occurred in 5 patients. We failed to detect clinical or laboratory findings associated with responders. Efgartigimod can be considered for the treatment of patients with generalized MG who do not achieve minimal manifestations, with a broad flexibility of patient selection and treatment schedules.

A 70‐year‐old man presented with dysphagia and difficulty in moving the tongue. Macroscopic findings showed features resembling mild tongue atrophy. We suspected a neurodegenerative disease which causes tongue atrophy such as amyotrophic lateral sclerosis. A needle electromyogram showed a strong resistance from the tongue owing to its hardness. Detection of Bence Jones protein κ type M protein in the serum led to a diagnosis of multiple myeloma‐associated light‐chain (κ) type amyloidosis. Thus, in patients with a rugose‐textured and uneven tongue mimicking atrophy, macroglossia caused by amyloidosis should be considered by examining the tongue hardness.

Dermal fibroblasts generate the extracellular matrix component elastin, which is synthesized as tropoelastin (TE) and play a critical role in maintaining skin elasticity. Lactoferrin (Lf), an 80‐kDa iron‐binding glycoprotein, has biological functions such as anti‐bacterial, ‐inflammatory, and ‐cancer activities. We previously reported that bovine Lf increases TE mRNA expression in human dermal fibroblasts. However, it remains unclear how Lf up‐regulates TE expression. Here, we investigated molecular mechanisms underlying this effect. Lf promoted the phosphorylation of Akt1 and extracellular signal‐regulated protein kinase (ERK)1/2. As expected, the phosphatidylinositol 3‐kinase (PI3K) inhibitor LY294002 and the MAPK inhibitor U0126 inhibited Lf‐induced phosphorylation of Akt1 and ERK1/2, respectively. In contrast, LY294002, but not U0126, inhibited Lf‐induced TE expression. Human dermal fibroblasts expressed lipoprotein receptor‐related protein 1 (LRP‐1) mRNA, and the LRP1 inhibitor receptor‐associated protein attenuated Lf‐induced increases in TE expression. Furthermore, siRNA‐mediated knockdown of LRP‐1 significantly suppressed Lf‐increased TE expression and Lf‐induced Akt1 phosphorylation. Iron‐saturated Lf (holo‐Lf) increased TE expression and promoted Akt1 phosphorylation, when compared to those parameters in cells treated with iron‐free Lf (apo‐Lf). Transforming growth factor (TGF)‐β1 also increased TE expression. LY294002 inhibited TGF‐β1‐mediated TE upregulation, whereas TGF‐β1 activated Akt2, but not Akt1, phosphorylation. These results indicate that holo‐Lf, but not apo‐Lf, increases TE expression through LRP‐1 in human dermal fibroblasts and suggest that holo‐Lf and TGF‐β1 enhance TE expression by activating the PI3K/Akt1 and PI3K/Akt2 pathways, respectively.