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.

Glucocorticoid-free remission in patients with SLE in the era of biologics: Immune complex disease is likely to benefit from current medications.

OBJECTIVES: In addition to various immunosuppressive agents, belimumab and anifrolumab became available in Japan. We aimed to investigate glucocorticoid-free clinical remission in a single-centre retrospective cohort in October 2023. METHODS: Our cohort included patients with SLE who needed to start or increase glucocorticoids for disease activity and were followed up for more than 1 year. We investigated the rate of achievement of clinical remission off corticosteroids (CR off C), defined as no clinical score on the SLEDAI-2K without glucocorticoids, baseline predictors of CR off C, medications used when CR off C was achieved, and flare rates following CR off C. RESULTS: Out of the 60 patients followed for an average of 5.4 (±2.6) years, 17 (28.3%) achieved CR off C in 3.6 (±1.2) years after enrolment. Use of belimumab and anifrolumab accounted for eight (47.1%) of the achievers. Among the baseline data, male sex, recent enrolment, high glucocorticoid dose, and detection of immune complex (IC) significantly predicted CR off C, while lupus nephritis (LN) and a low C3 level tended to predict it. In the multivariate analysis, IC detection was the only predictor of CR off C. Clinical flares were observed in 5.9% of the achievers during a median 1.2 years after achievement of CR off C. CONCLUSION: In the era of biologics, CR off C was achieved in 28.3% of the patient cohort requiring the start or increase of glucocorticoids for disease activity, with a relatively low rate of flares, suggesting that glucocorticoid-free clinical remission is an achievable target in SLE. IC disease, represented by male sex or nephritis, is likely to benefit from currently available medications.

Duodenal tuberculosis with gastric outlet obstruction: a case report of successful diagnosis and treatment, with review of literature.

BACKGROUND: Duodenal tuberculosis (TB) is extremely rare, and its diagnosis is challenging owing to the lack of specific symptoms and radiological or endoscopic findings. When it leads to gastric outlet obstruction (GOO), diagnosing it accurately and providing appropriate treatment is crucial. However, this is often overlooked. CASE PRESENTATION: A 35-year-old man presented with abdominal pain, fullness, vomiting, and weight loss. Upper gastrointestinal endoscopy and radiography revealed nearly pinpoint stenosis with edematous and reddish mucosa in the D1/D2 portion of the duodenum. Computed tomography (CT) showed the duodenal wall thickening, luminal narrowing, multiple enlarged abdominal lymph nodes, and portal vein stenosis. Conventional mucosal biopsy during endoscopy revealed ulcer scars. We initially suspected stenosis due to peptic ulcers; however, chest CT revealed cavitary lesions in both lung apices, suggesting tuberculosis. Due to the suspicion of duodenal TB and the need to obtain deeper tissue samples, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was performed. The tissue sample showed caseating granulomas with multinucleated giant cells, and acid-fast bacilli were positive by Ziehl-Neelsen staining. The patient was diagnosed with duodenal TB and subsequent GOO. Because the patient had difficulty eating, surgical intervention was prioritized over antitubercular drugs, and laparoscopic gastrojejunostomy was performed. The patient started an oral diet on the 3rd postoperative day and began antitubercular treatment immediately after discharge on the 11th day. During the 6th month of treatment, endoscopic examination revealed residual duodenal stenosis; however, the bypass route functioned well, and the patient remained asymptomatic. CONCLUSIONS: An aggressive biopsy should be performed to diagnose duodenal TB. EUS-FNA has proven to be a useful tool in this regard. Both nutritional improvement and antitubercular treatment were achieved early and reliably by performing laparoscopic gastrojejunostomy for duodenal TB with GOO.

Seasonal Influence on Development of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Retrospective Cohort Study Conducted at Multiple Institutions in Japan (J-CANVAS).

OBJECTIVE: To clarify seasonal and other environmental effects on the onset of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: We enrolled patients with new-onset eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA) registered in the database of a Japanese multicenter cohort study. We investigated the relationship between environmental factors and clinical characteristics. Seasons were divided into 4 (spring, summer, autumn, and winter), and the seasonal differences in AAV onset were analyzed using Pearson chi-square test, with an expected probability of 25% for each season. RESULTS: A total of 454 patients were enrolled, with a mean age of 70.9 years and a female proportion of 55.5%. Overall, 74, 291, and 89 patients were classified as having EGPA, MPA, and GPA, respectively. Positivity for myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA was observed in 355 and 46 patients, respectively. Overall, the seasonality of AAV onset significantly deviated from the expected 25% for each season (P = 0.001), and its onset was less frequently observed in autumn. In ANCA serotypes, seasonality was significant in patients with MPO-ANCA (P < 0.001), but not in those with PR3-ANCA (P = 0.97). Additionally, rural residency of patients with AAV was associated with PR3-ANCA positivity and biopsy-proven pulmonary vasculitis. CONCLUSION: The onset of AAV was influenced by seasonal variations and was less frequently observed in autumn. In contrast, the occurrence of PR3-ANCA was triggered, not by season, but by rural residency.

Hemodialysis Patient with Streptococcal Toxic Shock Syndrome and Penile Necrosis.

A 72-year-old man on hemodialysis due to diabetic nephropathy presented with a fever and penile pain. Although his physical examination was unremarkable, his general condition deteriorated. Penile necrosis was observed by evening on the same day of presentation, and the patient died the next morning. Blood cultures revealed the presence of Group G Streptococcus, leading to a diagnosis of streptococcal toxic shock syndrome (STSS). Autopsy suggested penile necrosis due to septic shock. STSS in hemodialysis patients with vascular calcification, even in the absence of calciphylaxis, can lead to severe organ damage due to ischemia.

C-reactive protein and ground-glass opacity as predictors for intractable interstitial lung disease in patients with systemic sclerosis under cyclophosphamide treatment regardless of concomitant glucocorticoids.

OBJECTIVES: Cyclophosphamide (CYC) has been proposed as a standard induction regimen for interstitial lung disease (ILD) associated with systemic sclerosis (SSc). However, there remain patients with SSc-ILD who are intractable to the therapy. This study aimed to identify factors associated with inadequate response to CYC and investigate how to treat SSc-ILD, especially in the need for glucocorticoids (GCs) combined with CYC. METHODS: This retrospective study included consecutive patients diagnosed with SSc-ILD and treated with CYC between 2009 and 2020. Logistic regression models were used to determine the prognostic factors indicating significant progression of ILD (SP-ILD). The clinical findings of patients treated with vs. without GCs were compared. RESULTS: Nineteen patients were registered, with a median age of 61.0 years. Fifteen were females, and five were classified into SP-ILD. Baseline high C-reactive protein (CRP) levels and non-widespread or localized ground-glass opacities (GGOs) predicted SP-ILD in multivariable analyses, and the cut-off level of CRP was 0.41 mg/dL. In clinical courses, SSc-ILD with high inflammation temporarily responded to CYC, regardless of the combined use of GCs; however, the therapeutic effects deteriorated soon after stopping CYC. CONCLUSION: High CRP levels with non-widespread GGO predicted progressive ILD in patients with SSc treated with CYC.

The Efficacy of Amenamevir for the Treatment of Disseminated Herpes Zoster Complicated with Probable Varicella-zoster Pneumonia in an Immunocompromised Patient.

We herein report the case of a 78-year-old woman who was diagnosed as having disseminated herpes zoster (DHZ) complicated with probable varicella-zoster pneumonia during maintenance therapy for microscopic polyangiitis. Because the patient had severe renal dysfunction, amenamevir administration was started to avoid any neurotoxicity of acyclovir, which is suggested to be optimal for treatment. It ameliorated her symptoms without any adverse events. This is the first report suggesting the efficacy of amenamevir in the treatment of severe herpes zoster infection with coexisting DHZ and probable varicella-zoster pneumonia. Amenamevir could thus be a treatment option for severe varicella zoster virus infections.

The clinical characteristics and predictors of severe digital ischemia in patients with anti-aminoacyl transfer RNA synthetase antibodies.

Severe digital ischemia (SDI), which presents with digital ulcers, necrosis, or gangrene, has been reported to be a rare manifestation of anti-aminoacyl transfer RNA synthetase (ARS) antibody-positive polymyositis/dermatomyositis or anti-synthetase syndrome. A retrospective study was conducted between 2009 and 2020 at our department to investigate the clinical features of anti-ARS antibody-positive patients with SDI and identify their predictors. A total of 46 patients who were positive for anti-ARS antibody were included, four of whom (8.7%) presented with SDI. The characteristics of the patients with SDI were as follows: the median age was 74 years, with 75% being female; anti-Jo-1 antibody, Raynaud's phenomenon, interstitial lung disease, and myositis were observed in two (50%), four (100%), four (100%), and three patients (75%), respectively. Next, we reviewed the literature of anti-ARS antibody-positive patients with SDI and investigated the predictors of SDI by analyzing a total of 51 patients, including the previously reported five patients with SDI. Multivariable analyses revealed that Raynaud's phenomenon and myositis independently predicted the development of SDI in patients with anti-ARS antibody. In conclusion, digital ulcers, necrosis, or gangrene seem to be more common presentations in our study, and Raynaud's phenomenon and myositis can predict the complications of SDI in anti-ARS antibody-positive patients.

Mixed neuroendocrine-non-neuroendocrine neoplasms of the gallbladder: a case report.

BACKGROUND:  Primary neuroendocrine tumors of the gallbladder (GB-NETs) are rare, accounting for 0.5% of all NETs and 2.1% of all gallbladder cancers. Among GB-NETs, mixed neuroendocrine-non-neuroendocrine neoplasms of the gallbladder (GB-MiNENs) are extremely rare. CASE PRESENTATION: We present the case of a 66-year-old woman who was referred to us for the management of a gallbladder tumor (incidentally found during abdominal ultrasonography indicated for gallbladder stones). The patient had no history of abdominal pain or fever, and the findings on a physical examination were unremarkable. Blood tests showed normal levels of tumor markers. Imaging studies revealed a mass of approximately 10 mm in diameter (with no invasion of the gallbladder bed) located at the fundus of the gallbladder. A gallbladder cancer was suspected. Therefore, an open whole-layer cholecystectomy with regional lymph nodes dissection was performed. The postoperative course was uneventful, and she was discharged on postoperative day 6. Pathological findings showed GB-MiNENs with invasion of the subserosal layer and no lymph node invasion (classified T2aN0M0 pStage IIA according to the Union for International Cancer Control, 8th edition staging system). Analysis of the neuroendocrine markers revealed positive chromogranin A and synaptophysin, and a Ki-67 index above 95%. Fourteen months after the operation, a local recurrence was detected, and she was referred to another hospital for chemotherapy. CONCLUSIONS:  GB-MiNENs are extremely aggressive tumors despite their tumor size. Optimal therapy should be chosen for each patient.

A case of systemic lupus erythematosus associated with cerebral arteritis: a case report and case-based literature review.

A 62-year-old female patient with systemic lupus erythematosus (SLE) was admitted for cerebral infarction. The magnetic resonance angiography showed focal narrowing of the cerebral arteries that was initially considered as atherosclerosis due to her cardiovascular risk factors. Ten weeks later, she was again admitted for multiple cerebral infarctions. Vessel wall magnetic resonance imaging revealed gadolinium enhancement of the arterial walls of the narrowing lesions, leading to a diagnosis of cerebral arteritis. Based on a literature review, cerebral medium-sized arteritis in SLE likely progresses insidiously during the active phase of SLE, which may later result in occlusion irrespective of disease activity.

Continuation Rate, Safety and Efficacy of Hydroxychloroquine Treatment in a Retrospective Cohort of Systemic Lupus Erythematosus in a Japanese Municipal Hospital.

Objective We investigated the continuation rate, safety and efficacy of treatment with hydroxychloroquine (HCQ) in a retrospective cohort of systemic lupus erythematosus (SLE) in a Japanese municipal hospital. Methods All of the patients with SLE who started treatment with HCQ were included in this study. A retrospective chart review was performed. Our primary outcomes were the continuation rate of HCQ treatment for 1 year and adverse events (AEs) during the treatment. We also investigated the efficacy of HCQ treatment in cases in which treatment with immunosuppressive therapies remained unchanged for the preceding six months. Results Forty-seven patients with SLE were included in this study. Twenty-five patients (53.2%) had AEs. Eleven (64.7%) of the 17 patients who tried the readministration of HCQ could continue HCQ treatment. The continuation rate of HCQ for a period of 1 year was 78.3% (36 of 46 patients). The development of cutaneous lesions was the most frequent adverse event (25.5%) followed by gastrointestinal symptoms (8.5%). In the 16 cases in which the immunosuppressive therapies remained unchanged for at least six months prior to starting HCQ treatment, the SLE disease activity index, anti-DNA antibody, immune complex, and serum complement activity significantly decreased over a period of 1 year, while the prednisolone dose significantly decreased. Conclusion The continuation rate of HCQ treatment was high in an SLE cohort of a Japanese municipal hospital. Although more than half of the patients experienced AEs, the readministration of HCQ was often successful. HCQ treatment provided benefits regarding the clinical and immunological findings in Japanese patients with SLE, which would likely lead to glucocorticoid tapering.

[A Case of Primary Testicular Mucinous Carcinoma].

A 68-year-old man presented withleft testicular painless swelling. His carbohydrate antigen 19-9 and carcinoembryonic antigen levels were elevated but his germ cell tumor markers were not high. Magnetic resonance imaging showed multiloculated cystic lesions with solid components in his left testis. Abdominal and chest computed tomography revealed multiple lung metastases, peritoneal dissemination and multiple lymph node metastases. Left high orchiectomy was performed. Histopathological examination demonstrated testicular mucinous carcinoma withsimilarity to gastric cancer. Since no tumor was found by the endoscopy of the upper gastrointestinal and the lower digestive tract, we diagnosed the patient with primary testicular mucinous carcinoma. Standard chemotherapy for gastric cancer, which consisted of tegafur, gimeracil and oteracil (TS-1) and cisplatin was administered for 16 months, and there was no progression of the disease. He died from testicular mucinous cancer 30 months after the diagnosis. In the literature, only 4 cases of testicular mucinous carcinoma have been reported. TS-1 and cisplatin are useful chemotherapeutic options for testicular mucinous carcinoma withmetastasis.

Diagnostic Performance of a Temporal Artery Biopsy for the Diagnosis of Giant Cell Arteritis in Japan-A Single-center Retrospective Cohort Study.

Objectives To investigate the sensitivity and specificity of a temporal artery biopsy (TAB) in the diagnosis of giant cell arteritis (GCA) in a single-center retrospective cohort in Japan. Methods A retrospective chart review was performed on consecutive patients who visited our hospital between April 2009 and October 2018 and underwent a TAB. The sensitivity and specificity were calculated for the three pathological standards for a TAB, predetermined according to the pathological criterion of the 1990 American College of Rheumatology (ACR) criteria: A) vasculitis characterized by predominant mononuclear cell infiltration; B) vasculitis with granulomatous inflammation; and C) vasculitis with multinucleated giant cells. We also analyzed the clinical parameters predicting the diagnosis of GCA and the impact of a diagnostic delay of ≥3 months on cardiovascular complications of GCA. Results Our study population was 16 cases in the GCA group and 13 in the non-GCA group. The sensitivity and specificity for Standard A of a TAB were 81% and 85%, respectively, while those for stricter Standards B or C were identical, at 75% and 100%, respectively. These pathological standards, but not any other parameters, significantly predicted the diagnosis. A diagnostic delay tended to cause cardiovascular complications (p=0.057). Conclusion The sensitivity and specificity of the pathological standards of a TAB were favorable in our cohort and were the only predictors for the diagnosis of GCA. Considering the possible impact of a diagnostic delay on cardiovascular complications, the early recognition and prompt initiation of glucocorticoid therapy is needed, even in Japan, where GCA is uncommon.

Syringomatous adenoma of the nipple: a case report.

INTRODUCTION: Syringomatous adenoma of the nipple is a very rare benign tumor. To the best of our knowledge, there are no reports of a syringomatous adenoma of the nipple metastasizing, although these tumors are known to infiltrate locally and to recur if not totally resected. CASE PRESENTATION: Our patient was a 41-year-old Japanese woman who complained of stiffness of her right nipple with abnormal discharge. Local resection of the tumor was performed. The pathological diagnosis was syringomatous adenoma of the nipple, and the resection margin was found to be positive. Accordingly, additional resection was recommended, but our patient did not allow another operation. After 1.5 years of careful follow-up, no local recurrence or distant metastasis has been observed. CONCLUSION: The optimal initial management of syringomatous adenoma of the nipple demands complete resection with histologically negative margins. However, from a cosmetic viewpoint, nipple-sparing resection could represent an alternative option for the treatment of syringomatous adenoma of the nipple.

Uncommon lymphoepithelial cyst with sebaceous glands of the pancreas.

CONTEXT: Lymphoepithelial cysts with sebaceous glands of the pancreas are extremely rare, with only 7 cases, including this case, published in English literature. CASE REPORT: We herein present the case of a 67-year-old Asian man who underwent a resection of a lymphoepithelial cyst of the pancreas during the follow up care for lung cancer. Fourteen years previously he underwent a right lower lobectomy at the right segment nine for lung cancer. A 20 mm mass in the body of the pancreas was identified by CT scan 4 years ago, and the diagnosis was intraductal papillary mucinous neoplasm (IPMN) at that time. Over a 5-year period, this mass grew to 42 mm without dilatation of the main pancreatic duct. The preoperative evaluation, including endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), indicated a cystic neoplasm with suspicion of malignancy. Intraoperative frozen section revealed a squamous-lined cyst accompanied by sebaceous glands without any malignant findings. Following this pathological finding, resection of the cyst was performed. Consequently, microscopic examination revealed that it was a lymphoepithelial cyst with sebaceous glands of the pancreas. CONCLUSIONS: Pancreatic lymphoepithelial cysts can be cured by conservative resection, but if they are asymptomatic and are diagnosed before surgery, no treatment is necessary. To our knowledge, this is the first ever published case of a lymphoepithelial cyst with sebaceous glands of the pancreas, which was found during the follow up care for lung cancer.

[A case of hypervascular hyperplastic nodule in chronic alcoholic liver disease with corona-like enhancement in the late phase image of CT during hepatic arteriography].

A 46-year-old woman was admitted to our hospital with hepatic encephalopathy due to alcoholic liver disease. A hepatic nodule (20 mm in diameter) in S7 was enhanced in the early phase of contrast CT. No significant findings were observed in the late phase of contrast CT and SPIO MRI. The late phase of CT during hepatic arteriography showed corona-like enhancement of the nodule. The nodule was diagnosed as a hypervascular hyperplastic nodule, based on histological examinations and immunohistochemical results with antibodies against CD68 and CD34.