Systematic review and meta-analysis for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.

OBJECTIVES: To update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology (JCR) clinical practice guidelines (CPG) for the management of rheumatoid arthritis (RA). METHODS: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, 2 independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses. RESULTS: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to csDMARD. Rituximab with and without concomitant csDMARDs showed similar efficacy to other bDMARDs in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients. CONCLUSION: This systematic review provides latest evidence for the 2024 update of the JCR CPG for RA management.

New-onset of rheumatic diseases following COVID-19 vaccination: the report of three cases and a literature review.

Vaccines against coronavirus disease 2019 (COVID-19) have been distributed in most countries for the prevention of onset and aggravation of COVID-19. Recently, there have been increasing numbers of reports on new-onset autoimmune and autoinflammatory diseases following COVID-19 vaccination, however, only little information is available on the long-term safety of these vaccines. Here, we experienced three cases of new-onset rheumatic diseases following COVID-19 vaccination, one case each of rheumatoid arthritis (RA), anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). The symptom onset ranged from one day to a few days following vaccination. The patients of AAV and SLE were treated successfully with glucocorticoid therapy, and the patient of RA died due to COVID-19. In the literature review of new-onset rheumatic diseases following COVID-19 vaccination, which including seven cases of RA, 37 cases of AAV and 18 cases of SLE, the mean time from vaccination to onset was approximately 11 to 12 days. Most cases improved with glucocorticoid, immunosuppressive drugs and biologic agents. Although such adverse effects are rare, and vaccines are useful in prevent onset and severity of infections, continued accumulation of similar cases is important in terms of examining the long-term safety and understanding pathogenic mechanism of rheumatic diseases.

Successful Treatment of Diffuse Large B-cell Lymphoma Involving Multiple Renal and Bone Infiltrations Presenting with Giant Cell Arteritis-like Manifestations: A Case Report.

We herein report a case of diffuse large B-cell lymphoma (DLBCL) involving multiple renal and bone infiltrations presenting with giant cell arteritis-like (GCA)-like manifestations. One month prior, the present patient had left-sided temporal headache, jaw claudication, and renal failure. The patient was diagnosed with DLBCL based on a renal biopsy. After rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus intrathecal methotrexate/cytarabine/prednisone and rituximab, high-dose methotrexate, and cytarabine (R-MA) chemotherapy, the patient's clinical manifestations improved, and complete remission was achieved. DLBCL rarely but occasionally presents with GCA-like manifestations or multiple renal and bone infiltrations, highlighting the need for prompt and aggressive combination chemotherapy.

New-onset Immune-mediated Necrotizing Myopathy and Trigeminal Neuropathy after SARS-CoV-2 mRNA Vaccination in a Patient with Rheumatoid Arthritis and Sjögren's Syndrome.

We present the case of a 42-year-old woman with rheumatoid arthritis and Sjögren's syndrome treated with adalimumab who developed immune-mediated necrotizing myopathy (IMNM) and trigeminal neuropathy after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination. Trigeminal neuralgia and elevated serum creatine kinase levels emerged 12 days post-vaccination, followed by myalgia in the femoral muscles. IMNM was histologically diagnosed. The pathogenesis may involve molecular mimicry between the SARS-CoV-2 spike glycoprotein and autologous tissues triggered by vaccination. This case emphasizes the association between SARS-CoV-2 vaccination, tumor necrosis factor inhibitor, IMNM, and trigeminal neuropathy, as well as the importance of monitoring immune-mediated adverse events following SARS-CoV-2 vaccination in patients with autoimmune disease.

Prognostic significance of pre-treatment albumin-bilirubin grade in metastatic urothelial carcinoma receiving pembrolizumab.

BACKGROUND: Pre-treatment albumin-bilirubin grade is a useful biomarker for predicting prognosis in patients receiving immune checkpoint inhibitors for advanced malignancies. We evaluated the prognostic impact of pre-treatment albumin-bilirubin grade in patients receiving pembrolizumab for metastatic urothelial carcinoma. METHODS: In this multicenter retrospective study, we calculated pre-treatment albumin-bilirubin scores of 96 patients who received pembrolizumab for metastatic urothelial carcinoma between January 2018 and March 2022. Patients were classified according to albumin-bilirubin grade. Progression-free survival and cancer-specific survival were compared between the groups. To evaluate the prognostic impact of pre-treatment albumin-bilirubin grade, we also performed Cox proportional regression analyses for progression-free survival and cancer-specific survival. RESULTS: The median pre-treatment albumin bilirubin score was -2.52 (quartile: -2.76 to -2.10), and albumin-bilirubin grade was grade 1 in 37 patients (39%), grade 2a in 30 patients (31%), 2b in 22 patients (23%) and grade 3 in 7 patients (7%). The median progression-free survival and cancer-specific survival were 2 and 7 months, respectively. Progression-free survival and cancer-specific survival were significantly different between the albumin-bilirubin grade groups (P < 0.01 and P < 0.01, respectively) and prognosis became poorer as albumin-bilirubin grade increased. High albumin-bilirubin grade was shown in multivariable Cox proportional analyses to be independently associated with both poor progression-free survival and poor cancer-specific survival. CONCLUSIONS: High pre-treatment albumin-bilirubin grade could be a significant independent predictor of poor prognosis in patients receiving pembrolizumab for advanced urothelial carcinoma.

Evaluation of anti-severe acute respiratory syndrome coronavirus 2 antibody levels in coronavirus disease breakthrough infection during immunosuppressive therapy in a patient with connective tissue disease-related interstitial lung disease.

Herein, we report the case of a 67-year-old man with severe coronavirus disease (COVID-19) pneumonia and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine breakthrough infection during immunosuppressive therapy for connective tissue disease-related interstitial lung disease (CTD-ILD). The patient received glucocorticoids combined with tacrolimus as maintenance therapy. His serum anti-SARS-CoV-2-immunoglobulin G (IgG) antibody levels were extremely low at the onset of COVID-19 pneumonia, even after the second dose of SARS-CoV-2 mRNA vaccine (BNT162b2). After treatment for COVID-19 pneumonia, the levels of anti-SARS-CoV-2-IgG antibodies increased. These results indicated a lack of the ability to produce neutralising antibodies from immune cells despite the booster vaccination. Therefore, we suggest that advanced-age patients with CTD-ILD receiving immunosuppressive therapy with polypharmacy require consistent personal protection, vaccination of close caregivers, increased awareness, and booster vaccination. Moreover, we recommend that tacrolimus should be withdrawn for a while after vaccination under controlled conditions.

Encapsulating Peritoneal Sclerosis in Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Systemic Sclerosis.

We encountered a 57-year-old Japanese woman with encapsulating peritoneal sclerosis (EPS) in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis. The patient was admitted to our hospital because of ascites retention. Administration of tocilizumab, an anti-interleukin-6 receptor antibody, for her RA reduced the refractory ascites remarkably; however, she developed sudden acute gastrointestinal bleeding and died a year later. On autopsy, sclerotic thickening of the peritoneum showed diffuse infiltration of podoplanin-positive fibroblast-like cells, and a diagnosis of EPS was made. EPS rarely occurs in SLE, and tocilizumab may be a new treatment candidate for EPS.

New-onset Adult-onset Still's Disease Following COVID-19 Vaccination: Three Case Reports and a Literature Review.

Since December 2020, coronavirus disease 2019 (COVID-19) vaccines have been distributed in most countries to prevent the onset and aggravation of COVID-19. There is little information regarding the long-term safety of the vaccines. We report three cases and a literature review of new-onset adult-onset Still's disease (AOSD) that occurred following COVID-19 vaccination. Our cases include moderate to severe AOSD, and two were complicated with macrophage activation syndrome. Seventeen cases of new-onset or relapse of AOSD following COVID-19 vaccination, including 14 identified in the literature review and our 3 patients, were all treated successfully with glucocorticoid therapy, immunosuppressive drugs, or biologic agents.

Transition from epoprostenol to selexipag in a patient with systemic sclerosis and pulmonary hypertension during the postoperative period of colon cancer surgery: A case report.

Introduction: Most pulmonary vasodilators are administered orally; however, in patients with pulmonary hypertension undergoing gastrointestinal surgery, a switch to parenteral drugs is needed. Parenteral pulmonary vasodilators carry a risk of infection and reduced quality of life owing to long-term central venous catheterization; therefore, it is preferable to switch them to oral vasodilators after surgery. Here, we present the case of a patient with systemic sclerosis complicated by pulmonary hypertension and colon cancer, for which treatment was successfully switched from epoprostenol to selexipag postoperatively. Case Description: A 59-year-old woman, who was diagnosed with mixed group I and III pulmonary hypertension and systemic sclerosis, was on oral triple pulmonary vasodilators for pulmonary hypertension and Raynaud's phenomenon. She was diagnosed as having colon cancer 3 months before admission. Despite the severe pulmonary condition and treatment with oral triple pulmonary vasodilators, colon cancer resection surgery was performed with the management for pulmonary hypertension through multidisciplinary treatments in collaboration with cardiology specialists. Medications for patients with pulmonary hypertension undergoing gastrointestinal surgery need to be switched from oral vasodilators to epoprostenol perioperatively. On postoperative day 19, 0.4 mg/day of selexipag was administered with epoprostenol. Subsequently, the epoprostenol dosage was gradually decreased, and selexipag was increased. On postoperative day 30, the dose of selexipag was increased to 1.2 mg/day and epoprostenol was discontinued. The patient was discharged on postoperative day 40. Conclusion: In our case, transition from epoprostenol to selexipag contributed to a more useful management strategy for systemic sclerosis and pulmonary hypertension in the postoperative period.

Gut dysbiosis is associated with acceleration of lupus nephritis.

The gut microbiota (GM) exerts a strong influence over the host immune system and dysbiosis of this microbial community can affect the clinical phenotype in chronic inflammatory conditions. To explore the role of the GM in lupus nephritis, we colonized NZM2410 mice with Segmented Filamentous Bacteria (SFB). Gut colonization with SFB was associated with worsening glomerulonephritis, glomerular and tubular immune complex deposition and interstitial inflammation compared to NZM2410 mice free of SFB. With SFB colonization mice experienced an increase in small intestinal lamina propria Th17 cells and group 3 innate lymphoid cells (ILC3s). However, although serum IL-17A expression was elevated in these mice, Th17 cells and ILC3s were not detected in the inflammatory infiltrate in the kidney. In contrast, serum and kidney tissue expression of the macrophage chemoattractants MCP-1 and CXCL1 were significantly elevated in SFB colonized mice. Furthermore, kidney infiltrating F4/80+CD206+M2-like macrophages were significantly increased in these mice. Evidence of increased gut permeability or "leakiness" was also detected in SFB colonized mice. Finally, the intestinal microbiome of SFB colonized mice at 15 and 30 weeks of age exhibited dysbiosis when compared to uncolonized mice at the same time points. Both microbial relative abundance as well as biodiversity of colonized mice was found to be altered. Collectively, SFB gut colonization in the NZM2410 mouse exacerbates kidney disease, promotes kidney M2-like macrophage infiltration and overall intestinal microbiota dysbiosis.

Revisiting Alkane Hydroxylation with m-CPBA (m-Chloroperbenzoic Acid) Catalyzed by Nickel(II) Complexes.

Mechanistic studies are performed on the alkane hydroxylation with m-CPBA (m-chloroperbenzoic acid) catalyzed by nickel(II) complexes, NiII (L). In the oxidation of cycloalkanes, NiII (TPA) acts as an efficient catalyst with a high yield and a high alcohol selectivity. In the oxidation of adamantane, the tertiary carbon is predominantly oxidized. The reaction rate shows first-order dependence on [substrate] and [NiII (L)] but is independent on [m-CPBA]; vobs =k2 [substrate][NiII (L)]. The reaction exhibited a relatively large kinetic deuterium isotope effect (KIE) of 6.7, demonstrating that the hydrogen atom abstraction is involved in the rate-limiting step of the catalytic cycle. Furthermore, NiII (L) supported by related tetradentate ligands exhibit apparently different catalytic activity, suggesting contribution of the NiII (L) in the catalytic cycle. Based on the kinetic analysis and the significant effects of O2 and CCl4 on the product distribution pattern, possible contributions of (L)NiII -O. and the aroyloxyl radical as the reactive oxidants are discussed.

Successful rechallenge with cetuximab after progression with nivolumab for recurrent cervical lymph node metastasis from carcinoma of the tongue.

We can infer that the immunostimulatory effect of nivolumab and reactivation of cetuximab enhance the antitumor effect of the therapy.

Effects of Menstrual Cycle Phase on Fluid Regulation during Walking Exercise.

To elucidate the fluid regulation in different menstrual cycle phases during exercise. Sex hormones affect fluid regulation in different ways. Moreover, the renin angiotensin-aldosterone system is activated in the luteal phase in rest. However, there are limited studies on fluid regulation affected by such hormone excretion in the menstrual cycle during exercise, especially during a light walking exercise. A non-invasive method using urine samples to determine menstrual cycle phases was used, and the follicular and luteal phases were successfully confirmed in 10 participants (age, 21 ± 1 years; body mass index, 20.5 ± 2.1 kg/m2). The experimental exercise sessions consisted of 5-min standing and 15-min walking at 2 km/h on 15% slope (approximately 8.3°) on a treadmill. Each participant carried a backpack weighing 5% of her own weight, and performed three sessions of walking exercise. Urine aldosterone excretion was significantly higher in the luteal than in the follicular phase before and after walking (p < 0.05). Urinary excretion of aldosterone was five times higher in the luteal than in the follicular phase before and after walking exercise. Heart rates during walking, after rest, and after recovery were all significantly higher in the luteal than in the follicular phase (p < 0.05). The participants' ratings of perceived exertion during the first and third session of walking in the luteal phase was not higher than that at the follicular phase. The results of our study suggested that increased activity of the renin-angiotensin-aldosterone system in the luteal phase of the menstrual cycle might be further activated during exercise. This may increase the circulatory load, which is reflected as increased heart rate. These results suggested that premenopausal women may better take into account a possibility of an increased circulatory load in the luteal phase even when they perform light exercise.

Age-related differences in prognosis and prognostic factors among patients with epithelial ovarian cancer.

Approximately 40% of all patients with ovarian cancer in Japan are aged ≥65 years. The aim of the present study was to evaluate the differences in prognosis and prognostic factors between elderly and younger patients with epithelial ovarian cancer. A total of 114 patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-IV ovarian cancer who were initiated on primary treatment at the Osaka City University Hospital (Osaka, Japan) were included in this study. Patient characteristics, treatment outcome and prognosis were compared between elderly (aged ≥65 years) and younger patients, and the prognostic factors associated with overall survival were evaluated by univariate and multivariate analyses. The most common histological type in younger patients was clear cell carcinoma (33.8%) vs. serous carcinoma in elderly patients (44.1%), with a significant difference in the distribution of histological type (P=0.006). Complete resection was achieved in 56.2% of younger patients compared with 32.4% of elderly patients (P=0.03). The rates of standard primary treatment were comparable (56.7% of younger vs. 50.0% of elderly patients). Overall and disease-free survival did not differ significantly between the two groups. Multivariate analyses identified FIGO stage and standard primary therapy as prognostic factors in younger patients and performance status in elderly patients. Age was not an independent significant prognostic factor among patients with ovarian cancer. Therefore, performance status, rather than age, should be considered when selecting the optimal treatment for elderly patients based on objective assessment.

Expression of UCP2 is associated with sensitivity to platinum-based chemotherapy for ovarian serous carcinoma.

The standard treatment for ovarian serous carcinoma is maximum debulking surgery and platinum-based chemotherapy. Despite the high response rate for chemotherapy, the majority of patients will be resistant to first-line agents and the prognosis for these patients is particularly poor. Currently there are no reliable methods to determine or predict platinum resistance. Uncoupling protein 2 (UCP2) is widely expressed in cancer cells and regulates the production of mitochondrial reactive oxygen species (ROS). A reduction in ROS is associated with carcinogenesis and chemoresistance. Downregulation of UCP2 significantly causes increased cell death following chemotherapy. The present study investigated the association between UCP2 expression and platinum sensitivity. The study included 54 patients with ovarian serous carcinoma (FIGO stages III and IV) who were treated at Osaka City University Hospital between January 2005 and December 2012. Patients were divided into a platinum-sensitive group (n=27) and platinum-resistant group (n=27) based on the platinum-free interval, which was calculated from the time of last platinum administration to the time of recurrence. UCP2 expression in human ovarian serous carcinoma cells was inhibited by genipin, and changes in carboplatin sensitivity were examined. The UCP2 weighted score was lower in the platinum-sensitive group than in the platinum resistant-group (P=0.005). In addition, patients in the low UCP2 expression group were more sensitive to platinum-based chemotherapy than those in the high UCP2 expression group (P=0.001). Sensitivity to carboplatin was significantly increased when UCP2 was inhibited in human ovarian serous carcinoma cells in vitro. UCP2 expression may be a predictive marker of the efficacy of platinum-based chemotherapy for patients with ovarian serous carcinoma.

The proinflammatory protein HMGB1 is a substrate of transglutaminase-2 and forms high-molecular weight complexes with autoantigens.

High-mobility group box 1 (HMGB1) is a chromatin-associated protein that, in response to stress or injury, translocates from the nucleus to the extracellular milieu, where it functions as an alarmin. HMGB1's function is in part determined by the complexes (HMGB1c) it forms with other molecules. However, structural modifications in the HMGB1 polypeptide that may regulate HMGB1c formation have not been previously described. In this report, we observed high-molecular weight, denaturing-resistant HMGB1c in the plasma and peripheral blood mononuclear cells of individuals with systemic lupus erythematosus (SLE) and, to a much lesser extent, in healthy subjects. Differential HMGB1c levels were also detected in mouse tissues and cultured cells, in which these complexes were induced by endotoxin or the immunological adjuvant alum. Of note, we found that HMGB1c formation is catalyzed by the protein-cross-linking enzyme transglutaminase-2 (TG2). Cross-link site mapping and MS analysis revealed that HMGB1 can be cross-linked to TG2 as well as a number of additional proteins, including human autoantigens. These findings have significant functional implications for studies of cellular stress responses and innate immunity in SLE and other autoimmune disease.

XPA expression is a predictive marker of the effectiveness of neoadjuvant chemotherapy for locally advanced uterine cervical cancer.

The standard treatment for locally advanced uterine cervical cancer is concurrent chemoradiotherapy. Successful neoadjuvant chemotherapy (NAC) may reduce tumor size and facilitate a hysterectomy, thereby improving the prognosis for patients with locally advanced cervical cancer. In contrast, unsuccessful NAC may worsen the prognosis because if a hysterectomy is not possible, the change in treatment plan may delay the initiation of core treatment. Therefore, there is a need to identify biomarkers that predict the efficacy of NAC in patients with uterine cervical cancer. The xeroderma pigmentosum complementation group A (XPA) protein serves a major role in nucleotide excision repair, which is a key DNA damage response pathway involved in cisplatin resistance. In the present study, the association between XPA expression in tumor tissue and the efficacy of NAC for locally advanced uterine cervical cancer was investigated. Data from 56 patients aged <70 years with locally advanced uterine cervical cancer (FIGO stages IIIA or IIIB) who were classified into two groups based on effective (n=31) and ineffective (n=25) responses to NAC treatment was evaluated. Tumor tissue samples were obtained by punch biopsy prior to NAC and XPA expression was examined immunohistochemically and scored using a weighted scoring system. In addition, the effects of RNA interference-mediated downregulation of XPA on the cisplatin sensitivity of uterine cervical cancer cells was investigated in vitro. It was revealed that the NAC effective group had significantly lower weighted XPA scores than the NAC ineffective group (P=0.001). Similarly, low tumor expression of XPA was significantly associated with higher sensitivity to NAC (P=0.001). Additionally, the downregulation of XPA expression in cervical cancer cells significantly increased their sensitivity to cisplatin in vitro. The results of the present study suggest that low XPA expression may be a predictive biomarker of NAC efficacy for patients with locally advanced uterine cervical cancer, which may be helpful for improving their prognosis.

TBX2 expression is associated with platinum-sensitivity of ovarian serous carcinoma.

The standard treatment for ovarian serous carcinoma comprises maximum debulking surgery and platinum-based chemotherapy. Despite the high response rate to chemotherapy, the majority of patients will be resistant to first-line agents and the prognosis for these patients is particularly poor. At present there are no reliable methods to determine or predict platinum resistance. T-box 2 (TBX2) is widely expressed in cancer cells and is involved in embryonic development and cell cycle regulation. TBX2 enables cells to bypass senescence through its ability to repress the cell cycle regulators p21 and p14ARF; silencing TBX2 induces senescence. Ectopic expression of TBX2 is associated with conferred resistance to the DNA-damaging chemotherapeutic drugs cisplatin and doxorubicin. In the present study the association between TBX2 expression and platinum sensitivity was investigated. A total of 54 patients with ovarian serous carcinoma (FIGO stages III and IV) were treated at Osaka City University Hospital (Osaka, Japan) from January 2005 to December 2012. Patients were divided into platinum-sensitive (n=27) and resistant (n=27) groups, according to the platinum-free interval calculated from the last platinum administration to the time of recurrence. TBX2 expression in human ovarian serous carcinoma cells was inhibited by a TBX2-specific siRNA and changes in cisplatin and carboplatin sensitivity were determined. The TBX2-weighted score was significantly lower in the platinum-sensitive group than the platinum-resistant group (P=0.005) and the low TBX2 expression group was significantly more sensitive to platinum-based chemotherapy (P=0.004). Sensitivity to cisplatin and carboplatin significantly increased when TBX2 expression was inhibited in human ovarian serous carcinoma cells in vitro (P<0.05). TBX2 expression may serve as a predictive marker of the efficacy of platinum-based chemotherapy for patients with ovarian serous carcinoma.

Detection of synovial inflammation in rheumatic diseases using superb microvascular imaging: Comparison with conventional power Doppler imaging.

AIM: Superb microvascular imaging (SMI), a novel ultrasonography, is based on the sensitivity of Doppler technology. This study evaluated power Doppler (PD) ultrasound signals in patients with rheumatic disease using SMI and conventional PD imaging (cPDI) and compared the correlations of these signals to clinical assessments. METHODS: Thirty-nine patients with rheumatic disease (27 rheumatoid arthritis [RA] and 12 non-RA) were enrolled. We investigated SMI and cPDI signals in 26 joints using an Aplio 300. Individual scores were summed to calculate total SMI and cPDI scores. RESULTS: Total SMI scores were significantly higher than total cPDI scores in patients with RA, but not in those with the non-RA disease. Total SMI score was associated with serum levels of C-reactive protein (CRP) and matrix metalloproteinase-3; disease activity score 28-CRP and health assessment questionnaire disability index scores, and SMI were more sensitive to detect active synovitis than cPDI in RA patients. Among the joint regions, the wrists and metacarpophalangeal joints were more sensitive to the detection of synovial inflammation using SMI in patients with RA. CONCLUSION: SMI was more sensitive in detecting synovial inflammation than cPDI in patients with RA. SMI could be a potentially useful imaging modality for accurately diagnosing and monitoring the disease activity of RA.