Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome.

OBJECTIVES: To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. METHODS: Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median onset age (IQR) 69.3 years (62.1-77.6)]. Peptide nucleic acid-clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants, and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR (pdPCR) or targeted amplicon deep sequencing (TAS) was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and ­negative patients and assessed the diagnostic value of our system using receiver operating characteristic (ROC) curve analysis. RESULTS: Forty patients with reported pathogenic UBA1 variants (40/89, 44.9%) were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering >50 years of age, cutaneous lesions, lung involvement, chondritis, and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908). CONCLUSIONS: Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants.

Combined B-cell immunomodulation with rituximab and belimumab in severe, refractory TAFRO syndrome associated with Sjögren's syndrome: A case report.

TAFRO syndrome is a systemic inflammatory disease of unknown aetiology. It is characterised by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly. Herein, we report the case of a 60-year-old male with TAFRO syndrome. A few weeks after the patient developed an intermittent fever, he presented to our hospital with diarrhoea, abdominal distension, and whole-body oedema (face, extremities, and abdomen). Autoantibody and lip biopsy findings supported the diagnosis of primary Sjögren's syndrome. High-dose steroids and tocilizumab were used to treat his refractory thrombocytopenia and ascites. However, systemic inflammation and renal dysfunction did not improve, resulting in temporary haemodialysis. Eventually, combined B-cell immunomodulation therapy with rituximab and belimumab ameliorated the patient's symptoms. About 16 weeks after discharge, the overall condition of the patient had improved. The TAFRO syndrome may be a severe manifestation of primary Sjögren's syndrome. Considering the immunological context, combined B-cell immunomodulation therapy provides new insights into improving this life-threatening disease and enables rapid steroid tapering.

Efficacy and tolerability of subcutaneously administered methotrexate including dose escalation in long-term treatment of rheumatoid arthritis in a Japanese population.

OBJECTIVES: The aim of this article is to evaluate the efficacy and safety of subcutaneously administered methotrexate (MTX) for Japanese patients with active rheumatoid arthritis. METHODS: MTX-naïve patients were randomized in a 1:1 ratio to receive a 12-week administration of either 7.5 mg MTX subcutaneously (MJK101, a prefilled syringe for subcutaneous injection) or 8 mg MTX orally in Part 1 of the trial. The primary end point was a 20% improvement in the American College of Rheumatology criteria (ACR20) at Week 12. In the second part, all enrolled patients received MJK101 weekly for 52 weeks with doses starting from 7.5 to 15 mg with 2.5 mg increments with the option of self-administration of MJK101. RESULTS: The efficacy of MJK101 was comparable to oral MTX following 12 weeks of treatment at the starting doses. A numerically higher ACR20 response rate and fewer adverse events in particular gastrointestinal adverse events were observed. During long-term subcutaneous treatment, MJK101 was well tolerated across all tested doses. Patients clinically improved upon dose escalation. CONCLUSIONS: Subcutaneously applied MTX (MJK101) was efficient and well tolerated over a long-term treatment period in the Japanese population with doses up to 15 mg/week. Subcutaneous administration of MTX is a beneficial option for Japanese patients with rheumatoid arthritis.

Clinical characteristics of patients with spondyloarthritis and inflammatory bowel disease versus inflammatory bowel disease-related arthritis.

The purpose of this study was to clarify the clinical characteristics of spondyloarthritis (SpA) patients with inflammatory bowel disease (IBD) compared to those without IBD. Furthermore, among patients with SpA and IBD, we aimed to clarify what clinical characteristics lead rheumatologists to diagnose "IBD-related arthritis." Utilizing SpA and psoriatic arthritis (PsA) patients' data from an international, cross-sectional, observational study, we analyzed information on demographics and disease characteristics, dichotomizing patients by IBD status. The presence or absence of IBD was determined based on data collection of treating rheumatologists. Patients with SpA (including PsA) and IBD were also categorized based on treating rheumatologists' definitive diagnosis in regard to SpA type, and compared by whether the patients had IBD-related arthritis or not. Among 4465 SpA patients, 287 (6.4%, 95%CI 5.7-7.2%) were identified with IBD. Compared to SpA patients without IBD, patients with SpA and IBD had a longer diagnostic delay (5.1 vs. 2.9 years, p < 0.001). In patients with SpA and IBD, 111 (38.7%, 95%CI 33.0-44.6%) were diagnosed with IBD-related arthritis. Multivariable analyses showed that HLA-B27 positivity [OR = 0.35, (95%CI 0.15-0.80)], psoriasis [OR = 0.14, (95%CI 0.04-0.50)], IBD as first symptom of SpA [OR = 3.32, (95%CI 1.84-6.01)], and need for IBD-specific treatment [OR = 5.41, (95%CI 2.02-14.50)] were independently associated with the definitive diagnosis of IBD-related arthritis. Collaboration with gastroenterologists is needed to shorten the diagnostic delay in patients with SpA and IBD. The recognition of the factors for the diagnosis of "IBD-related arthritis" may lead to the elucidation of the pathogenesis.

Clinical Characteristics of Patients with Spondyloarthritis in Japan in Comparison with Other Regions of the World.

OBJECTIVE: To delineate clinical characteristics of patients with spondyloarthritis (SpA) in Japan in comparison to other areas of the world. METHODS: Using the ASAS-COMOSPA (Assessment of Spondyloarthritis international Society-COMOrbidities in SPondyloArthritis) data, an international cross-sectional observational study of patients with SpA, we analyzed information on demographics, disease characteristics, comorbidities, and risk factors. Patients were classified by region: Japan, other Asian countries (China, Singapore, South Korea, Taiwan), and non-Asian countries (Europe, the Americas, Africa). Patient characteristics, including diagnosis and treatment, were compared. RESULTS: Among 3984 patients included in the study, 161 were from centers in Japan, 933 from other Asian countries, and 2890 from other regions. Of patients with SpA in Japan, 42 (26.1%) had peripheral SpA, substantially more than in other countries. This trend was explained by the predominance of psoriatic arthritis (PsA) among Japanese patients with SpA. In contrast to the relatively low number in Japan, 54% of patients from other Asian countries had pure axial SpA (axSpA) without peripheral features. HLA-B27 testing, considered an integral part of the classification of axSpA, was performed in only 63.6% of Japanese patients with axSpA. More than half of Japanese patients with axSpA were classified using imaging criteria. CONCLUSION: In our study, there was a more substantial number of peripheral SpA cases observed in Japan compared to other parts of Asia and other regions of the world. Aside from ethnic differences, increasing recognition of PsA in Japan, as well as a potential underdiagnosis of axSpA due to the insufficient use of HLA-B27 testing, may partly explain regional discrepancies.