Efficacy and safety of 5-aminolevulinic acid in adult-onset Still's disease: A preclinical study in mice and a pilot study in humans.

The study aimed to investigate the therapeutic effects of 5-aminolevulinic acid/sodium ferrous citrate (5-ALA/SFC) on adult-onset Still's disease (AOSD), specifically focusing on arthritis and macrophage activation syndrome (MAS). We used mouse models to assess the impact of 5-ALA/SFC on collagen-induced arthritis (CIA) and MAS induced by synthetic oligonucleotides containing CpG motifs (CpG-S-ODN). Additionally, we conducted a pilot study with AOSD patients receiving prednisolone (PSL) treatment and 5-ALA/SFC administration to evaluate its efficacy and safety. The 5-ALA/SFC group exhibited significantly lower joint scores in CIA mice. In CpG-S-ODN-treated mice, 5-ALA/SFC administration led to reduced hemophagocytosis and splenomegaly. The anti-inflammatory properties of 5-ALA/SFC were attributed to the suppression of CCL4 and CXCL10 production in monocytes and the induction of M2 macrophages. AOSD patients treated with 5-ALA/SFC demonstrated successful PSL tapering without adverse events. Collectively, the administration of 5-ALA/SFC showed promising potential in ameliorating arthritis and MAS in AOSD patients.

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.

Clinical predictors of inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) including methotrexate (MTX) in untreated rheumatoid arthritis patients: A single-center observational study.

Objectives: To investigate predictors of inadequate response to first conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) including methotrexate (MTX) in untreated rheumatoid arthritis (RA) patients in daily clinical practice.Methods: Inadequate response to MTX or other csDMARDs was defined as being not low disease activity at 12 months in more than 3 of 4 composite measures, and discontinuation or start of biologic DMARDs. The association between baseline factors and csDMARDs-IR was assessed by univariate and multivariate logistic regression analyses.Results: Four hundred and eleven and 146 patients were started on MTX and other csDMARDs, respectively; 218 patients were responsive to MTX, with a response rate of 47.0%. Tender joint count (TJC, ≥6 in 28joints, odds ratio [OR] = 1.67, 95% confidence interval [CI] 1.06-2.64) and CRP (≥1.0 mg/dL, OR = 1.72, 95%CI: 1.10-2.70) at baseline were identified as predictors on multivariate logistic regression analysis. TJC (OR = 3.60, 95%CI: 1.29-10.00) was the factor identified as a predictor of the development of other csDMARDs-IR.Conclusion: In this observational study, patients with untreated RA at risk of inadequate response to MTX included those with a higher TJC and higher CRP, while a higher TJC was the only independent predictor of an inadequate response to csDMARDs other than MTX.

Swollen joints and peripheral arthritis are signs of malignancy in polymyalgia rheumatica.

Aim: To analyze the clinical course and prognosis in patients diagnosed with polymyalgia rheumatica (PMR) complicated by the presence of malignancies.Methods: We retrospectively screened the case files of 216 patients hospitalized in our department between 2011 and December 2016 for the results of a thorough physical examination and data on treatment for rheumatic diseases. We identified 53 patients with PMR according to Bird's criteria and 43 patients with 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for PMR, then analyzed the clinical and serologic manifestations of PMR in patients with (n = 6) and without (n = 47 in Bird' criteria, n = 37 in 2012 EULAR/ACR criteria) malignancy.Result: No significant differences in age, gender, smoking, and serum markers were observed between PMR patients with and without malignancy, but there were statistically significant differences in tender joint counts and the presence of swollen joints and peripheral arthritis in both Bird's criteria and 2012 EULAR/ACR criteria.Conclusion: The presence of swollen joints and peripheral arthritis may be useful signs that indicate the coexistence of malignancies in patients with PMR.

Acute exacerbation of rheumatoid interstitial lung disease during the maintenance therapy with certolizumab pegol.

We report a case involving a 68-year-old woman with rheumatoid arthritis (RA) with acute exacerbated interstitial lung disease (ILD) during certolizumab pegol maintenance therapy. She recovered quickly with steroid pulse therapy and was discharged without deterioration of basal pulmonary function. Immunoblot analysis demonstrated the circulating cleaved interleukin-1ß at the phase of acute exacerbation of RA-associated ILD (RA-ILD) in this patient. The findings from this case suggested that the Nod-like receptor pyrin domain-containing protein 3 inflammasome is implicated in acute RA-ILD exacerbation.

Identification of risk factors for elevated serum IgG4 levels in subjects in a large-scale health checkup cohort study.

Introduction: To allow the identification of IgG4-related disease (IgG4-RD) from a subclinical phase as it is important to understand the risk of elevated serum IgG4 levels. We planned to evaluate serum IgG4 levels in the participants of the Nagasaki Islands Study (NaIS), a large-scale health checkup cohort study. Methods: This study included 3,240 individuals who participated in the NaIS between 2016 and 2018 and consented to participate in the study. Serum IgG4, IgG, and IgE levels and human leukocyte antigen (HLA) genotyping results of the NaIS subjects as well as lifestyle habits and peripheral blood test results were analyzed. The magnetic bead panel assay (MBA) and the standard nephelometry immunoassay (NIA) were used to measure serum IgG4 levels. The data were evaluated using multivariate analysis to identify lifestyle and genetic factors associated with elevated serum IgG4 levels. Results: Serum IgG4 levels measured with the NIA and MBA showed a tight positive correlation between the two groups (correlation coefficient 0.942). The median age of the participants in the NaIS was 69 years [63-77]. The median serum IgG4 level was 30.2 mg/dL [IQR 12.5-59.8]. Overall, 1019 (32.1%) patients had a history of smoking. When the subjects were stratified into three groups based on the smoking intensity (pack-year), the serum IgG4 level was significantly higher among those with a higher smoking intensity. Accordingly, the multivariate analysis identified a significant relationship between smoking status and serum IgG4 elevation. Conclusion: In this study, smoking was identified as a lifestyle factor correlating positively with elevated serum IgG4 levels.

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 lung microbiota between antineutrophil cytoplasmic antibody-associated vasculitis and sarcoidosis.

Microbial involvement in the pathogenesis have been suggested in both antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and sarcoidosis, both of which have lung involvement. However, exhaustive research to assess the bacteria in the lung in AAV and in sarcoidosis have not been performed. We sought to elucidate the distinct dysbiotic lung microbiota between AAV and sarcoidosis. We used 16S rRNA gene high-throughput sequencing to obtain the bacterial community composition of bronchoalveolar lavage fluid (BALF) in patients with AAV (n = 16) compared to patients with sarcoidosis (n = 21). The patients had not undergone therapy with immunosuppressive medication when their BALF was acquired. No difference was observed in α-diversity between patients with AAV and patients with sarcoidosis when using all the detected taxa. We defined the taxa of the oral cavity by using the data of oral microbiota of healthy individuals from the Human Microbiome Project (HMP). The analysis using only oral taxa made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. Besides, the analysis using detected taxa except for oral taxa also made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. A linear negative relationship between the α-diversity and Birmingham vasculitis activity score (BVAS) was detected in the AAV group. The observed p-value for the effect of the disease groups on the ß-diversity was small while the effect of other factors including sex and smoking status did not have small p-values. By excluding oral taxa from all the detected taxa, we found a cluster mainly consisted of sarcoidosis patients which was characterized with microbial community monopolized by Erythrobacteraceae family. Our results suggested the importance of considering the influence of oral microbiota in evaluating lung microbiota.

Protein-losing gastroenteropathy in a patient with concomitant systemic lupus erythematosus and Sjögren's syndrome.

We report a female in her twenties who developed generalized edema. She was diagnosed as systemic lupus erythematous (SLE) and Sjögren's syndrome (SS) based on her physical manifestations and positive findings for antinuclear antibody and anti-SS-A/SS-B-antibody. Although she manifested hypoproteinemia, a possibility of lupus nephritis was denied due to a lack of significant abnormality in kidney function tests and urinalysis. The nature of hypoproteinemia and related symptoms was identified as protein losing gastroenteropathy (PLGE) based on α 1-antitrypsin clearance and histopathology findings. Physicians should be aware that PLGE may develop as an underlying cause of edema in SLE and SS.

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.

TAFRO syndrome with primary Sjogren's syndrome.

A 25-year-old woman diagnosed 1 year earlier with Primary Sjogren's syndrome was admitted to a nearby hospital with fever of unknown origin. Examination revealed anasarca, systemic lymphadenopathy, hepatosplenomegaly and high C-reactive protein level. The patient's symptoms were initially suspected to be caused by severe bacterial infection with Sjogren's syndrome flare. She was given antibiotics and prednisolone (PSL) at 50 mg/day. However, the patient developed anemia and thrombocytopenia and was transferred to our hospital for further care. Histological examination of the right inguinal lymph node showed neutrophilic infiltration. Bone marrow aspiration revealed a normocellular marrow with increased megakaryocytes and mild reticulin fiber hyperplasia. After initiation of minocycline hydrochloride, the patient's symptoms improved. However, as PSL was tapered, her symptoms worsened. The patient's clinical symptoms and laboratory data improved again with initiation of intravenous steroid pulse therapy and cyclosporine. TAFRO syndrome is characterized by a constellation of symptoms: Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis and Organomegaly. Although histological findings of the lymph node in this case differed from previous reports, the patient's other symptoms and clinical course were similar to TAFRO syndrome. TAFRO syndrome can occur with several diseases, including infection, rheumatic disease and malignancies. We report a case in which infection might have triggered TAFRO syndrome.

Successful Treatment with Intravenous Cyclophosphamide for Refractory Adult-Onset Still's Disease.

We report a 64-year-old female case of intractable adult-onset Still's disease (AOSD). Initial high-dose steroid therapy combined with cyclosporin A was ineffective against macrophage-activation syndrome (MAS), which was accompanied by the systemic type of AOSD. Treatment for MAS with intravenous cyclophosphamide resulted in remission of AOSD and a reduction in the high doses of steroids. Efficacy of biologics against MAS in AOSD is unclear. Cyclophosphamide, a conventional cytotoxic agent, should be considered as one of the therapeutic options for refractory types of AOSD with MAS.

Granulomatosis with polyangiitis presenting as a choroidal tumor.

Granulomatosis with polyangiitis (GPA) sometimes involves the eye orbit; however, choroidal involvements in GPA had been rarely reported. We report a rare case presenting with a choroidal mass in an 83-year-old Japanese woman who presented with left eye pain. Diagnostic biopsy revealed necrotizing vasculitis with infiltrates of inflammatory cells. Diagnosis was localized granulomatosis with polyangiitis. Combined treatments with corticosteroid plus azathioprine resolved the choroidal mass region. Although treatment with corticosteroid and immunosuppressive agents improves the prognosis of the disease, ocular morbidity is still well recognized. Clinicians should consider a differential diagnosis of GPA in patients with inflammatory choroidal tumors.

Incidence of Symptomatic Vertebral Fractures Among Newly Diagnosed Autoimmune Diseases Initiating Glucocorticoid Therapy.

Few data are available regarding vertebral fracture risk in patients treated with corticosteroids including patients with interstitial lung disease (ILD). The aim of the present study was to identify risk factors for symptomatic vertebral fracture analyzed in patients with newly diagnosed autoimmune diseases.This was an observational cohort study conducted in the National Hospital Organization-EBM study group from 2006 to 2008. The study subjects were autoimmune disease patients who were newly treated with glucocorticoids (GCs). The primary endpoint was the first occurrence of vertebral fracture diagnosed by x-rays. Cox proportional-hazards regression was used to determine independent risk factors for vertebral fracture with covariates including sex, age, comorbidity, laboratory data, use of immunosuppressants, and dose of GCs. Survival was analyzed according to the Kaplan-Meier method and assessed by the log-rank test.Among 604 patients of mean age 59.5 years and mean GC dose 50.4 mg/d (first 1 months), 19 patient (3.1%) had at least 1 symptomatic vertebral fracture during 1.9 years of follow-up period. Cox regression model demonstrated that the relative risk for symptomatic vertebral fracture was independently higher in patient with ILD (hazard ratio [HR] = 2.86, 95% confidence interval [CI] = 1.10-7.42, P = 0.031) and in every 10-year increment of the age of disease onset (HR = 1.57, 95% CI = 1.09-2.26, P = 0.015). Kaplan-Meier analyses demonstrated that the incidence of vertebral fractures in patients with ILD was significantly higher in comparison with those without ILD.Our results indicate a higher risk of vertebral facture in patients with ILD and elderly patients during the initial GC treatment against autoimmune diseases. There is a need for further, even longer-term, prospective studies subjected patients with autoimmune disease, including ILD, under GC treatment.

Successful Management of Lupus Nephritis with High Titers of Myeloperoxidase Anti-Neutrophil Cytoplasmic Antibodies Using Tacrolimus.

A 63-year-old Japanese woman with a 30-year history of systemic lupus erythematosus developed macrohematuria and massive proteinuria after seroconversion of myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA). A renal biopsy indicated focal proliferative lupus nephritis (class III A/C) with a fibrous crescent formation. Methylprednisolone pulse therapy (500 mg, 3 successive days) was administered because of progressive proteinuria. Steroid therapy did not suppress the progressive proteinuria; therefore, tacrolimus was added as an alternative immunosuppressive therapy, resulting in the improvement of proteinuria and renal impairment. This case report suggests that MPO-ANCA might play a pathogenic role in the exacerbation of immune-complex-type lupus nephritis.