Merrilee Needham

Background and aims: IBM is a rare, progressive disease characterized by invasion of muscle by highly differentiated cytotoxic CD8+ T cells. Ulviprubart, a monoclonal antibody, selectively depletes cytotoxic CD8+ KLRG1+ T cells by targeting KLRG1 expressed on most IBM-muscle–infiltrating T cells. Here, we describe PK/PD and safety of ulviprubart in patients with IBM.

Methods: In this phase 1, open-label study (NCT04659031), initial patients received subcutaneous ulviprubart (0.1, 0.5, or 2.0 mg/kg) as a single dose prior to dosing every 8 weeks (Q8W) ~6−12 months later, while later patients received 2.0 mg/kg Q8W; patients received ulviprubart for up to 18 months. PK/PD and safety with ulviprubart were assessed.

Results: Nineteen patients (mean age, 66 years; 79% male) were enrolled (0.1 mg/kg: n = 3; 0.5 mg/kg: n = 3; 2.0 mg/kg: n = 13). Ulviprubart displayed a long absorption phase, slow clearance, and 21-day half-life. Peripheral CD8+ KLRG1+ and CD4+ KLRG1+ T-cell depletion was achieved, with mean CD8+ KLRG1+ T-cell maximum depletions of 69%, 97%, and 98% after single doses of 0.1, 0.5, and 2.0 mg/kg, respectively. Effector CD8+ T-cell populations (T-cell effector memory [TEM] and TEMs expressing CD45RA [TEMRA]) were depleted to the extent of their KLRG1 expression. Regulatory T cells and B cells were preserved. No serious adverse events (AEs) or discontinuations due to AEs were reported.

Conclusion: In patients with IBM, ulviprubart led to sustained selective depletion of peripheral blood CD8+ KLRG1+ T cells and had a favorable safety profile.

Disclosure: M Needham, RD Henderson, and C Liang: Abcuro, Inc. − Consultant D Soler-Ferran and HJ Wilkins: Abcuro, Inc. – Employment S Greenberg: Abcuro, Inc. – Founder; Consultant

Inclusion body myositis (IBM) is a late-onset, treatment-resistant inflammatory myopathy. Approximately half of IBM patients develop autoantibodies against cytosolic 5′-nucleotidase 1A (cN1A), but their role in disease pathogenesis remains unclear. This pilot study examined the effects of anti-cN1A-positive IBM serum on human primary myotubes’ transcriptome profile, using anti-cN1A-negative IBM and healthy sera as controls. Exposure to anti-cN1A-positive serum altered the expression of 1126 genes, with upregulation of adaptive immune response genes, notably CTSH and CTSZ, encoding cathepsins H and Z. These findings were validated using a publicly available independent dataset comprising transcriptomes from fresh muscle tissue samples. NT5C1A mRNA, which encodes cN1A, was not detected in cultured myotubes regardless of the presence of autoantibodies. The findings suggest distinct pathological mechanisms in anti-cN1A-positive IBM, independent of direct antibody-target interactions. The role of cathepsins in IBM pathogenesis warrants further investigation.

Heterogeneous and predominantly sporadic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), remain highly challenging to model. Patient-derived induced pluripotent stem cell (iPSC) technologies offer great promise for these diseases; however, large-scale studies demonstrating accelerated neurodegeneration in patients with sporadic disease are limited. Here we generated an iPSC library from 100 patients with sporadic ALS (SALS) and conducted population-wide phenotypic screening. Motor neurons derived from patients with SALS recapitulated key aspects of the disease, including reduced survival, accelerated neurite degeneration correlating with donor survival, transcriptional dysregulation and pharmacological rescue by riluzole. Screening of drugs previously tested in ALS clinical trials revealed that 97% failed to mitigate neurodegeneration, reflecting trial outcomes and validating the SALS model. Combinatorial testing of effective drugs identified baricitinib, memantine and riluzole as a promising therapeutic combination for SALS. These findings demonstrate that patient-derived iPSC models can recapitulate sporadic disease features, paving the way for a new generation of disease modeling and therapeutic discovery in ALS.

IBM is a rare, progressive disease characterized by invasion of muscle by highly differentiated cytotoxic CD8+ T cells. Ulviprubart, a monoclonal antibody, selectively depletes cytotoxic CD8+ KLRG1+ T cells by targeting KLRG1 expressed on most IBM-muscle–infiltrating T cells. Here, we describe PK/PD and safety of ulviprubart in patients with IBM. In this phase 1, open-label study (NCT04659031), initial patients received subcutaneous ulviprubart (0.1, 0.5, or 2.0 mg/kg) as a single dose prior to dosing every 8 weeks (Q8W) ∼6−12 months later, while later patients received 2.0 mg/kg Q8W; patients received ulviprubart for up to 18 months. PK/PD and safety with ulviprubart were assessed. Nineteen patients (mean age, 66 years; 79% male) were enrolled (0.1 mg/kg: n=3; 0.5 mg/kg: n=3; 2.0 mg/kg: n=13). Ulviprubart displayed a long absorption phase, slow clearance, and 21-day half-life. Peripheral CD8+ KLRG1+ and CD4+ KLRG1+ T cell depletion was achieved, with mean CD8+ KLRG1+ T cell maximum depletions of 69%, 97%, and 98% after single doses of 0.1, 0.5, and 2.0 mg/kg, respectively. Effector CD8+ T cell populations (T-cell effector memory [TEM] and TEMs expressing CD45RA [TEMRA]) were depleted to the extent of their KLRG1 expression. Regulatory T cells and B cells were preserved. No treatment-related serious adverse events (AEs) or discontinuations due to AEs were reported. In patients with IBM, ulviprubart led to sustained selective depletion of peripheral blood CD8+ KLRG1+ T cells and had a favourable safety profile.

Immune-mediated necrotising myopathy (IMNM) with autoantibodies targeting 3-hydroxy-3-methylglutaryl-CoA reductase (anti-HMGCR) is considered a rare complication of statin therapy. We calculate the incidence of anti-HMGCR IMNM and describe clinical characteristics in four independent cohorts: Manchester (UK), Bristol (UK), Western Australia (WA, Australia) and South Australia (SA, Australia).
Adults (≥18 years) with anti-HMGCR IMNM (ENMC criteria; 2018-2023) were identified from myositis clinic and laboratory records. Nationwide UK anti-HMGCR testing was performed at Oxford University Hospital Laboratories and state-based WA/SA testing at PathWest Laboratories.
109 anti-HMGCR IMNM cases were identified (51% female, median 66 years [IQR 58-72.2]) with median follow-up 2.3 years [IQR 1.5-4.2]. Mean annual incidence was 2.9 cases/million person-years. In statin-users, incidence was 20.4 (UK) and 24.1 (WA/SA) cases/million statin-users/year. 101 patients were statin-exposed, mostly atorvastatin (77/101, 76.2%). Median statin duration before diagnosis was 3 years (range: 1 month-23 years). Eight (7.5%) were statin-naïve and compared with statin-exposed patients, younger (median 46.1 vs 67 years, p= 0.02), frequently of non-white ethnicity (5/8 vs 20/77, p= 0.04) and more commonly had dysphagia (4/8 vs 14/94, p= 0.03). The median peak creatine kinase (CK) was 7,020 IU/l (range: 964-39 076). 48/105 (45.7%) received intravenous immunoglobulin. At follow-up, less than half had normal CK (50/105 [47.6%]) or muscle power (48/104 [46.2%]).
For the first time, we have calculated an incidence of anti-HMGCR IMNM using a large, multinational cohort. We highlight the refractory nature of anti-HMGCR IMNM. We also describe the unique phenotype of statin-naïve anti-HMGCR IMNM, and the rare occurrence of self-limiting myopathy.

Objective
A revision of the 2017 EULAR-ACR myositis classification criteria, namely EULAR-ACR funded Myositis Revision of Classification (MyoROC) project, is currently underway involving a large international group of experts. In the first phase of this project, we identified additional items to be tested in the criteria.

Methods
We distributed an electronic survey to International Myositis Assessment and Clinical Studies (IMACS) members to identify new items. The identified items were discussed within the Steering Committee and a multi-step Delphi consensus process consisting of an open discussion and three rounds of e-voting were conducted to reach the final item list.

Results
The IMACS survey results revealed 24 new items. After an open discussion with Steering Committee members, 14 items were dropped and five new items were added, resulting in a total of 15 items. After three rounds of e-voting, the following variables were agreed to be tested in addition to the original items: finger flexion, knee extension ≥ hip flexion weakness, myonecrosis pattern on biopsy, magnetic resonance imaging and electromyography findings of myositis, additional rashes, skin biopsy, capillaroscopy, interstitial lung disease, arthritis, Raynaud’s phenomenon, myositis-specific (MSA) and -associated autoantibodies, enzyme elevation at ≥2 time points, and aldolase.

Conclusion
The new items that will be tested in the revised criteria were generated with input from a wide range of stakeholders and included, most importantly, MSA, pattern of weakness, skin changes, and additional diagnostic modalities. The next steps of the project are data collection followed by statistical analysis for development and validation of the revised criteria.

Autoantibodies targeting cytosolic 5′-nucleotidase 1A (cN1A) are found in several autoimmune diseases, including inclusion body myositis (IBM), Sjögren’s syndrome, and systemic lupus erythematosus. While they have diagnostic relevance for IBM, little is known about the autoreactive B cells that produce these antibodies. To address this, we developed a robust protocol for the expression and site-specific biotinylation of recombinant human cN1A in
Escherichia coli
. The resulting antigen is suitable for generating double-labelled fluorescent baits for the isolation and characterisation of cN1A-specific B cells by flow cytometry. Site-specific biotinylation was achieved using the AviTag and BirA ligase, preserving the protein’s structure and immunoreactivity. Western blot analysis confirmed that the biotinylated cN1A was recognised by both human and rabbit anti-cN1A antibodies. Compared to conventional chemical biotinylation, this strategy minimises structural alterations that may affect antigen recognition. This approach provides a reliable method for producing biotinylated antigens for use in immunological assays. While demonstrated here for cN1A, the protocol can be adapted for other autoantigens to support studies of antigen-specific B cells in autoimmune diseases.

Purpose
This study aimed to investigate bilateral motor control and connectivity between supplementary motor area (SMA) and primary motor cortex (M1) in younger, middle-aged, and older healthy adults.

Methods
32 younger (mean age 22.8 ± 5.3 years), 18 middle-aged (47.6 ± 6.5 years), and 23 older (75.8 ± 6.7 years) adults were tested. Bilateral motor control was assessed using the Purdue pegboard. Dual-site transcranial magnetic stimulation (TMS) was used to measure SMA–M1 connectivity at different conditioning stimulation intensities.

Results
Older adults had significantly poorer motor performance than younger and middle-aged in all pegboard subtests. Notably, there were no conclusive differences in motor performance between younger and middle-aged adults. There was no conclusive evidence supporting age-related and intensity-related differences in SMA–M1 connectivity between younger, middle-aged, and older adults. There was also no conclusive evidence to support clear associations between SMA–M1 connectivity and bilateral motor control.

Conclusion
Age-related declines in bilateral motor functioning was found in older, but not middle-aged adults. The bilateral motor functioning of middle-aged adults is more young-like than old-like. The lack of conclusive age- and intensity-related differences in SMA–M1 connectivity, and lack of conclusive association with bilateral motor performance, might be due to high inter-individual variability in SMA–M1 connectivity. Potential factors contributing to this variability include SMA and M1 morphometry, the structural connectivity between these regions, and the localisation of SMA.

Background:
IBM is a rare, progressive disease characterized by invasion of muscle by highly differentiated cytotoxic CD8+ T cells. Ulviprubart, a monoclonal antibody, selectively depletes cytotoxic CD8+ KLRG1+ T cells by targeting KLRG1 expressed on most IBM-muscle–infiltrating T cells.

Objectives:
Here, we describe PK/PD and safety of ulviprubart in patients with IBM.

Methods:
In this phase 1, open-label study (NCT04659031), initial patients received subcutaneous ulviprubart (0.1, 0.5, or 2.0 mg/kg) as a single dose prior to dosing every 8 weeks (Q8W) ~6−12 months later, while later patients received 2.0 mg/kg Q8W; patients received ulviprubart for up to 18 months. PK/PD and safety with ulviprubart were assessed.

Results:
Nineteen patients (mean age, 66 years; 79% male) were enrolled (0.1 mg/kg: n=3; 0.5 mg/kg: n=3; 2.0 mg/kg: n=13). Ulviprubart displayed a long absorption phase, slow clearance, and 21-day half-life. Peripheral CD8+ KLRG1+ and CD4+ KLRG1+ T cell depletion was achieved, with mean CD8+ KLRG1+ T cell maximum depletions of 69%, 97%, and 98% after single doses of 0.1, 0.5, and 2.0 mg/kg, respectively. Effector CD8+ T cell populations (T-cell effector memory [TEM] and TEMs expressing CD45RA [TEMRA]) were depleted to the extent of their KLRG1 expression. Regulatory T cells and B cells were preserved. No serious adverse events (AEs) or discontinuations due to AEs were reported.

Conclusion:
In patients with IBM, ulviprubart led to sustained selective depletion of peripheral blood CD8+ KLRG1+ T cells and had a favorable safety profile.

Cofilin-2, encoded by CFL2, is an actin-binding protein essential for regulating actin filament dynamics in skeletal muscle. Biallelic variants in CFL2 are associated with an ultra-rare, early-onset myopathy typically presenting as nemaline myopathy. Only 10 patients have been described to date from five unrelated families. Here, we describe two new cases from two unrelated families. The first proband presented clinically with rigid spine syndrome and a biopsy keeping with nemaline myopathy. The second proband presented with a relatively mild congenital myopathy which became rapidly progressive in the fourth decade, the muscle biopsy showed cytoplasmic bodies, internal nuclei and ringbinden. Exome and genome sequencing revealed three novel biallelic missense variants in CFL2, a homozygous c.115 T > G; p.(Cys39Gly) in the proband of Family 1, and bi-allelic heterozygous c.256G > A:(p.Asp86Asn), and c.283A > G (p.Lys95Glu) variants in the proband of Family 2. We characterised the effects of these substitutions using an in vitro F-actin depolymerisation assay and showed all three were associated with significantly reduced filamentous actin depolymerisation rates compared to the wildtype. Taken together, our findings are highly suggestive of a CFL2-related disease in these patients. Since CFL2-related myopathies are ultrarare, the application of ACMG/AMP guidelines and the diagnostic reportability of CFL2 variants identified in patients remains a challenge. The actin depolymerisation assay may be useful to elucidate the impact and pathogenicity of additional CFL2 variants and has the potential to guide variant classification in future.