Takuji Itakura

Multidisciplinary genomic evaluation is increasingly recognized for its diagnostic and therapeutic implications in adults with suspected inborn errors of immunity (IEI) presenting with rheumatic and musculoskeletal disease (RMD) phenotypes. We retrospectively analyzed 50 adults with suspected IEI who underwent genetic testing and were pre-classified into immunodeficiency (ID), autoinflammatory disorders (AID), and non-ID/AID groups. Genetic findings, clinical classification, treatment modifications, and exploratory machine learning analyses were evaluated. A final genetic diagnosis consistent with IEI was identified in 15 patients (30.0%), with the highest yield in the non-ID/AID group (44.4%). Variants were most frequently associated with autoinflammatory diseases (40.0%). Four patients, all initially classified as non-ID/AID, were reclassified based on genetic findings and IUIS classification. Treatment was modified in 12 patients, including eight genetically diagnosed patients and three genotype-driven interventions. Two patients died from disease-related complications. Machine learning analyses provided heterogeneous feature contributions across groups. These findings highlight the utility of multidisciplinary genomic evaluation for refining diagnoses in challenging adult patients.

Percutaneous conchotome muscle biopsy, a semi-open technique, provides significant diagnostic yields especially for inflammatory myopathies. In patients with small vessel vasculitis, muscle involvement could sometimes be sole or most prominent organ involvement. While open muscle biopsy has been reported to be useful for diagnosis of vasculitis, diagnostic utility with conchotome muscle biopsy for vasculitis remains unclear. Here we report four cases in which conchotome muscle biopsy made a significant contribution to their diagnosis of small vessel vasculitis. All cases presented with myalgia and weakness at the onset of their diseases and with elevation of myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA). Pathological examination of muscle tissues revealed the significant inflammatory infiltration with fibrinoid necrosis in perimysial arterioles measuring 50-100 mm in diameter in all of four cases. Disruption of elastic plates of arterioles was found with Elastica van Gieson staining in three cases. Low levels of patients’ pain evaluated with visual analogue scale (0-100) ranging 0-30 and no occurrence of adverse events in our cases indicated the safety of this technique. All patients were treated successfully with glucocorticoid with or without immunosuppressants. Conchotome muscle biopsy could yield the pathological features of small vessel vasculitis with minimal invasiveness.

T cell receptor rearrangement excision circles (TRECs) and immunoglobulin κ-deleting recombination excision circles (KRECs) represent the lymphopoiesis capacity, widely used for newborn screening of inborn errors of immunity. To clarify the significance of TRECs and KRECs as immune indicators in patients with systemic autoimmune diseases, we prospectively evaluated TREC and KREC levels with qPCR, lymphocyte phenotypes with flow cytometry, along with lymphocyte counts and serum immunoglobulin levels in peripheral blood samples from newly diagnosed patients. Each variable was assessed before immunosuppressive treatments (baseline), 3-, 6-, and 12-months after the treatment. Severe infections were recorded until 6 months after treatment. Among 35 patients, TREC and KREC levels were associated positively with the proportion of recent thymic emigrants, naïve T and B cells at all the timepoints. TREC and KREC levels decreased after treatment. The ratios of TREC and KREC levels under treatment to baseline were significantly lower in patients with severe infection than those without. In conclusion, TREC and KREC levels reflect peripheral blood immunophenotypes, specifically recent-emigrated T and B cells, in patients under treatment-naïve and immunosuppressive conditions. The longitudinal changes in TREC and KREC levels were beneficial markers for predicting the risk of severe infection during immunosuppressive treatments.

Takuji Itakura, Hirokazu Sasaki, Tadashi Hosoya, Taiki Yamaguchi, Erika Mimori, Yukino Saimon, Hideyuki Iwai, Natsuka Umezawa, Daisuke Kawata, Naoki Kimura, Mor