Association of denosumab with serum cytokines, chemokines, and bone-related factors in patients with rheumatoid arthritis: A post hoc analysis of a multicentre, open-label, randomised, parallel-group study.

OBJECTIVES: To clarify changes in serum cytokines, chemokines, and bone-related factors during denosumab treatment in rheumatoid arthritis (RA) patients. METHODS: This was a post hoc analysis of a multicentre, open-label, randomised, parallel-group study. Patients were randomly assigned to continue treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) plus receive treatment with denosumab (csDMARDs plus denosumab group) or to continue treatment with csDMARD therapy alone for 12 months. Serum biomarker levels were measured at baseline and 6 and 12 months. RESULTS: Baseline and 6-month data from the csDMARDs plus denosumab (n = 22) and csDMARD therapy alone (n = 22) groups were analysed. Statistically significant changes from baseline were seen: dickkopf-related protein 1 decreased at 6 and 12 months (both groups); osteopontin decreased at 6 months in the csDMARDs plus denosumab group; osteopontin and soluble CD40 ligand increased at 6 and 12 months in the csDMARD therapy alone group; osteocalcin decreased at 6 and 12 months, epidermal growth factor decreased at 12 months, and macrophage-derived chemokine decreased at 6 months in the csDMARDs plus denosumab group; and interferon gamma-induced protein-10 increased at 12 months in the csDMARD therapy alone group. CONCLUSIONS: Denosumab may inhibit bone destruction by suppressing bone-related factors/chemokines.

Increase in the number of new cases of ANCA-associated vasculitis in the COVID-19 vaccine era.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune vasculitis characterized by the production of antibodies against ANCA, with unclear pathogenesis. With the ongoing COVID-19 pandemic, COVID-19 mRNA vaccination has been available in Japan since February 2021. Although autoimmune symptoms have been reported after COVID-19 vaccinations, there have been no clinical investigations regarding the relationship between COVID-19 mRNA vaccines and the pathogenesis of AAV. Thus, the present study aimed to investigate whether the administration of COVID-19 mRNA vaccines affects the development of AAV. The study identified patients with new-onset AAV who were MPO-ANCA or PR3-ANCA positive and met the entry criteria of the AAV EMA classification algorithm. The study compared the number of new AAV cases per year before and after the start of the COVID-19 mRNA vaccine program in Japan. The study found that the annual number of new cases of AAV in Japan's Nagasaki Prefecture increased by approximately 1.5-fold since the COVID-19 vaccine program was initiated, suggesting a possible link between the COVID-19 mRNA vaccines and the development of AAV. Although the study provides insight into the clinical evaluation and management of autoimmune symptoms following COVID-19 vaccination, further investigation of the possible association between COVID-19 mRNA vaccines and the pathogenesis of AAV is required.

Immunoglobulin G4-related Disease with Marked Eosinophilia: A Case Report and Literature Review.

We encountered a 78-year-old Japanese man with IgG4-related sialoadenitis complicated with marked eosinophilia. We diagnosed him with IgG4-RD (related disease) with a submandibular gland tumor, serum IgG4 elevation, IgG4-positive plasma cell infiltration, and storiform fibrosis. During follow-up after total incision of the submandibular gland, the peripheral eosinophil count was markedly elevated to 29,480/µL. The differential diagnosis of severe eosinophilia without IgG4-RD was excluded. The patient exhibited a prompt response to corticosteroid therapy. His peripheral blood eosinophil count was the highest ever reported among similar cases. We also review previous cases of IgG4-RD with severe eosinophilia.

Subjective achievement from psychiatry rotation in the Japanese postgraduate residency system: a longitudinal questionnaire study.

BACKGROUND: Psychiatry rotation has been mandatory in the Japanese postgraduate residency system since 2020. Some psychiatry-related competency items are stipulated as mandatory for residents. The current study aimed to clarify whether psychiatry rotation affected residents' subjective achievement of these competency items. METHODS: This longitudinal study was conducted among postgraduate residents who completed a rotation in the psychiatry department at Nagasaki University Hospital across two academic years (2020-2021). The survey was administered at the start and at the end of the psychiatry rotation. Residents evaluated their subjective understanding and confidence regarding initiating treatment for these competency items using a six-point Likert scale. The average scores for each item were compared between pre-rotation and post-rotation. RESULTS: In total, 99 residents (91.7%) responded to this survey. Residents had significantly higher scores at post-rotation compared with pre-rotation in all psychiatry-related competency items in both subjective understanding and confidence in initiating treatment. Additionally, strong effect sizes were found for many items. CONCLUSION: Residents improved learning about psychiatry-related competency items through psychiatry rotation. This finding suggests that it is reasonable for psychiatry rotation to be mandatory in the current Japanese postgraduate residency system. The importance of psychiatry is likely to increase in both undergraduate and postgraduate medical education in the future. It is necessary to continuously update educational strategies to meet changing social needs over time. As this study was conducted at a single institution, a multi-center study is needed to expand the current findings.

Efficacy and safety of canakinumab for colchicine-resistant or colchicine-intolerant familial Mediterranean fever: A single-centre observational study.

OBJECTIVES: To evaluate the efficacy and safety of canakinumab in Japanese patients with colchicine-resistant or colchicine-intolerant familial Mediterranean fever (FMF) in a real-world clinical setting. METHODS: We reviewed 13 Japanese FMF patients to whom canakinumab was introduced during the period of October 2017 to December 2020. All patients were diagnosed as FMF according to Tel-Hashomer criteria. We performed genetic analyses for Mediterranean fever or MEFV by targeted next-generation sequencing. Efficacy was assessed by attack frequency and the percentage of patients who achieved attack improvement at 24 weeks. Safety was assessed by adverse events observed during canakinumab treatment. RESULTS: The median duration and follow-up of canakinumab treatment were 13 and 16 months, respectively. The median attack frequency was 0.50 [0.30-1.00] at 24 weeks, which was a significant decrease from 2.00 [0.85-2.88] at the time of induction (p = .019). There were three patients (23%) with complete resolution of attacks at 24 weeks. No serious adverse events were observed. However, one patient had small intestinal ulceration which led to the discontinuation of canakinumab. CONCLUSIONS: Although the number of cases is small, this study suggests that canakinumab is efficacious and safe for use in Japanese patients with colchicine-resistant or colchicine-intolerant FMF in a real-world clinical setting in Japan.

Real-world comparative effectiveness and safety of tofacitinib and baricitinib in patients with rheumatoid arthritis.

OBJECTIVE: To compare the efficacy and safety of tofacitinib and baricitinib in patients with RA in a real-world setting. METHODS: A total of 242 patients with RA who were treated with tofacitinib (n = 161) or baricitinib (n = 81) were enrolled. We evaluated efficacy and safety between tofacitinib and baricitinib using multivariable analyses to avoid confounding. Their clinical disease activity and AEs were evaluated for 24 weeks. RESULTS: The mean (SD) DAS28-ESR change from baseline to 24 weeks was 1.57 (1.55) (tofacitinib) and 1.46 (1.36) (baricitinib). There was no significant difference in the clinical response between the two groups (adjusted mean difference, 0.04; 95% CI, -0.35 to 0.28). The efficacy was not significantly changed in the patients without concomitant MTX use in both groups, but the concomitant MTX use showed better clinical efficacy in the cases of baricitinib treatment. In both groups, the most common AE was herpes zoster infection, and the AE rates were similar between the two groups. However, the predictive factors contributing to clinical response as revealed by a multivariable logistic analysis differed. The concomitant oral steroid use was independently associated with the achievement of DAS-low disease activity in the tofacitinib group, whereas in the baricitinib group, the number of biological and/or targeted synthetic DMARDs previously used was associated. CONCLUSIONS: Our findings indicate that tofacitinib and baricitinib had comparable continuing efficacies and safety profiles. However, there is a possibility that the influence of clinical characteristics on the treatment response differs. The comparison provides useful information to the optimal use of JAK inhibitors in real-world settings.

Comparison of the quantitative measurement of 18F-FDG PET/CT and histopathological findings in IgG4-related disease.

OBJECTIVES: To investigate the utility of 18F-FDG PET/CT in the diagnostic procedure of IgG4-related disease (IgG4-RD), we analysed the association between quantitative method of 18F-FDG PET/CT and histological findings. METHODS: Twenty-one patients with IgG4-RD in whom 18F-FDG PET/CT was performed at the time of diagnosis were enrolled. Tissue biopsy was performed at 24 sites in 21 patients. To perform quantitative analysis of 18F-FDG PET/CT imaging, the highest standardised uptake value (SUV) of the pixels (SUVmax) and the average SUV (SUVmean) within the biopsied lesion were measured. The SUVmean of the liver was also measured as a reference. RESULTS: The mean age at diagnosis was 64.6±11.9 years, and the median serum IgG4 level was 650 mg/dl. Histological findings were consistent with IgG4-RD (histopathology-positive) at 19 out of 24 sites. Although there was no significant difference in the values of SUVmax between histopathology-positive and histopathology-negative tissues, the values of SUVmean were significantly higher in the histopathology-positive tissue (4.98 and 3.54, respectively p<0.05). The values of SUVmean/liver were also higher in the histopathology-positive tissue (2.17 and 1.52, respectively p<0.05). To establish a cut-off value of SUVmean to determine which of multiple lesions should be biopsied, a ROC curve was constructed. ROC curve analysis indicated SUVmean=4.07 or SUVmean/liver=1.66 as a cut-off value. CONCLUSIONS: Our present study suggested that quantitative analysis of 18F-FDG-PET/CT imaging might be useful for selecting the biopsy site in IgG4-RD. The calculation of SUVmean, not of SUVmax, is important for evaluating IgG4-RD-related lesions in 18F-FDG PET/CT imaging.

Reactive Arthritis Caused by Yersinia enterocolitica Enteritis.

We report a case of reactive arthritis (ReA) triggered by Yersinia enterocolitica enteritis. A 24-year-old Japanese man developed polyarthritis in the lower limbs. Two weeks prior to these symptoms, he noted diarrhea, right lower abdominal pain and a fever. Y. enterocolitica was not isolated from a stool culture; however, he was diagnosed with ReA based on the colonoscopic findings of a high anti-Y. enterocolitica antibody titer and HLA-B27 antigen positivity. Following treatment with methotrexate and steroids, his arthritis improved. This is the first reported Japanese case of ReA in the English literature after a gastrointestinal infection caused by Y. enterocolitica.

Synovitis of sternoclavicular and peripheral joints can be detected by ultrasound in patients with SAPHO syndrome.

OBJECTIVES: To determine the prevalence of ultrasonographic abnormalities of sternoclavicular joints (SCJ) and peripheral joints (PJ) in patients with synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. METHODS: Thirteen patients with SAPHO syndrome who fulfilled diagnostic criteria proposed by Kahn for SAPHO syndrome 2003 and 13 healthy individuals age- and sex-matched were enrolled. Synovitis, defined by synovial hypertrophy with power Doppler (PD) signals, of the SCJ and the PJ including wrist, MCP, PIP, and the other symptomatic joints were evaluated by ultrasound (US). RESULTS: Synovitis with PD signals was detected in 16 (61.5%) of the 26 SCJ and 11 (84.6%) of the SAPHO syndrome patients, and none of the controls. Synovitis with PD signals in any PJ was detected in 4 (30.7%) of the SAPHO syndrome patients. CONCLUSIONS: Synovitis of the SCJ and PJ in SAPHO syndrome was detectable by US with a PD method. US can be useful for the diagnosis of SAPHO syndrome.

Giant Cell Arteritis which Developed after the Administration of Granulocyte-colony Stimulating Factor for Cyclic Neutropenia.

A 78-year-old woman diagnosed with cyclic neutropenia 5 years previously had been treated with recombinant granulocyte-colony stimulating factor (G-CSF). She developed fever, tenderness and distension of temporal arteries after the treatment with G-CSF. Magnetic resonance imaging and ultrasonography revealed wall thickening of the temporal arteries. She was therefore diagnosed with giant cell arteritis (GCA). Small vessel vasculitis has been reported as a complication of G-CSF. However, the development of large vessel vasculitis after G-CSF treatment is quite rare. To our knowledge, the present case is the first report of GCA suspected to be associated with coexisting cyclic neutropenia and G-CSF treatment.

Magnetic Resonance Imaging Bone Edema at Enrollment Predicts Rapid Radiographic Progression in Patients with Early RA: Results from the Nagasaki University Early Arthritis Cohort.

OBJECTIVE: To clarify whether magnetic resonance imaging (MRI) bone edema predicts the development of rapid radiographic progression (RRP) in the Nagasaki University Early Arthritis Cohort of patients with early-stage rheumatoid arthritis (RA). METHODS: Patients with early-stage RA (n = 76) were enrolled and underwent 1.5-T MRI of both wrists and finger joints. Synovitis, bone edema, and bone erosion were evaluated using the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS). RRP was defined as an annual increment > 3 at 1 year by the Genant-modified Sharp score of plain radiographs. A multivariate logistic regression analysis was performed to establish the risk factors for RRP. RESULTS: Median disease duration at enrollment was 3 months. RRP was found in 12 of the 76 patients at 1 year. A univariate analysis revealed that matrix metalloprotease-3, RAMRIS bone edema score, and RAMRIS bone erosion score were associated with RRP. Multivariate logistic regression analyses demonstrated that the RAMRIS bone edema score at enrollment (5-point increase, OR 2.18, 95% CI 1.32-3.59, p = 0.002) was the only independent predictor of the development of RRP at 1 year. A receiver-operating characteristic analysis identified the best cutoff value for RAMRIS bone edema score as 5. RRP was significantly rare among the patients with a RAMRIS bone edema score < 5 at enrollment (2 from 50 patients). CONCLUSION: Our findings suggest that MRI bone edema is closely associated with the development of RRP in patients with early-stage RA. Physicians should carefully control the disease activity when MRI bone edema is observed in patients with early RA.

Soluble α-klotho is a potential biomarker associated with neuropsychiatric systemic lupus erythematosus.

A reduced level of the single-pass transmembrane protein α-Klotho is known to be associated with neuronal damage. We investigated whether α-Klotho in cerebrospinal fluid (CSF) could be a candidate marker for the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE). We analyzed the laboratory data, symptoms and radiological image findings of 34 NPSLE patients. Patients with SLE without neuropsychiatric manifestations (SLE) (n=25), and patients with viral meningitis (VM) (n=19), multiple sclerosis (MS) (n=20) or neuromyelitis optica (NMO) (n=20) were included as controls. The multivariable analyses revealed that lower CSF α-Klotho level, lower serum anti-Smith antibodies (U/mL) and higher serum C3 (mg/dL) were significant factors for predicting NPSLE. The CSF α-Klotho levels of the NPSLE patients were inversely correlated with the level of granulocyte/macrophage-colony stimulating factor. Our data suggested that the determination of CSF α-Klotho levels will contribute to the diagnosis of NPSLE and help elucidate the mechanisms underlying this disease.