Effect of porphyrin ligands on the catalytic CH4 oxidation activity of monocationic µ-nitrido-bridged iron porphyrinoid dimers by using H2O2 as an oxidant.

The µ-nitrido-bridged iron phthalocyanine homodimer is a potent molecule-based CH4 oxidation catalyst that can effectively oxidize chemically stable CH4 under mild reaction conditions in an acidic aqueous solution including an oxidant such as H2O2. The reactive intermediate is a high-valent iron-oxo species generated upon reaction with H2O2. However, a detailed comparison of the CH4 oxidation activity of the µ-nitrido-bridged iron phthalocyanine dimer with those of µ-nitrido-bridged iron porphyrinoid dimers containing one or two porphyrin ring(s) has not been yet reported, although porphyrins are the most important class of porphyrinoids. Herein, we compare the catalytic CH4 and CH3CH3 oxidation activities of a monocationic µ-nitrido-bridged iron porphyrin homodimer and a monocationic µ-nitrido-bridged heterodimer of an iron porphyrin and an iron phthalocyanine with those of a monocationic µ-nitrido-bridged iron phthalocyanine homodimer in an acidic aqueous solution containing H2O2 as an oxidant. It was demonstrated that the CH4 oxidation activities of monocationic µ-nitrido-bridged iron porphyrinoid dimers containing porphyrin ring(s) were much lower than that of a monocationic µ-nitrido-bridged iron phthalocyanine homodimer. These findings suggested that the difference in the electronic structure of the porphyrinoid rings of monocationic µ-nitrido-bridged iron porphyrinoid dimers strongly affected their catalytic light alkane oxidation activities.

MCAM+CD161- Th17 Subset Expressing CD83 Enhances Tc17 Response in Psoriasis.

Recent studies have highlighted the pathogenic roles of IL-17-producing CD8+ T cells (T-cytotoxic 17 [Tc17]) in psoriasis. However, the underlying mechanisms of Tc17 induction remain unclear. In this study, we focused on the pathogenic subsets of Th17 and their mechanism of promotion of Tc17 responses. We determined that the pathogenic Th17-enriched fraction expressed melanoma cell adhesion molecule (MCAM) and CCR6, but not CD161, because this subset produced IL-17A abundantly and the presence of these cells in the peripheral blood of patients has been correlated with the severity of psoriasis. Intriguingly, the serial analysis of gene expression revealed that CCR6+MCAM+CD161-CD4+ T cells displayed the gene profile for adaptive immune responses, including CD83, which is an activator for CD8+ T cells. Coculture assay with or without intercellular contact between CD4+ and CD8+ T cells showed that CCR6+MCAM+CD161-CD4+ T cells induced the proliferation of CD8+ T cells in a CD83-dependent manner. However, the production of IL-17A by CD8+ T cells required exogenous IL-17A, suggesting that intercellular contact via CD83 and the production of IL-17A from activated CD4+ T cells elicit Tc17 responses. Intriguingly, the CD83 expression was enhanced in the presence of IL-15, and CD83+ cells stimulated with IL-1ß, IL-23, IL-15, and IL-15Rα did not express FOXP3. Furthermore, CCR6+MCAM+CD161-CD4+ T cells expressing CD83 were increased in the peripheral blood of patients, and the CD83+ Th17-type cells accumulated in the lesional skin of psoriasis. In conclusion, pathogenic MCAM+CD161- Th17 cells may be involved in the Tc17 responses via IL-17A and CD83 in psoriasis.

Tumor doubling time as preoperative predictor of malignancy and recurrence in newly diagnosed meningioma.

Most meningiomas are benign, and the indications for surgery are determined by size and symptoms, but some are malignant and have a high recurrence rate. Currently, no preoperative prognostic factors have been established. The purpose of this study was to investigate whether tumor doubling time (Td) is useful in predicting tumor prognosis. Patients who underwent surgery for newly diagnosed meningioma at our hospital between 2007 and 2021 with preoperative magnetic resonance (MR) imaging evaluation over a period of 6 months were included in this study. We calculated the Td from the preoperative MR images and examined the correlation between Td and WHO grade, MIB-1 SI, and other conditions. A total of 269 newly diagnosed meningiomas were operated on during the study period, of which 62 met inclusion criteria. The median Td was 1082 days (54-8579 days), and MIB-1 SI was 2.45% (0.7-14.6%). Td and MIB-1 SI had a negative correlation (r = - 0.319, p = 0.0122). MIB-1 SI was higher in patients with Td < 3 years than in those with Td ≥ 3 (p = 0.005), and the incidence of high WHO grade (grade2) was higher in patients with Td < 1 year than in patients with Td ≥ 1 (p = 0.014). Meningiomas with Td < 3 years had significantly higher MIB-1 SI, and tumors with Td < 1 year had a higher likelihood of malignancy. Therefore, early treatment should be considered in patients with short Td meningioma even if asymptomatic, and further consideration could be given to radical resection at the time of surgery.

Synthesis of a monocationic µ-nitrido-bridged iron porphycene dimer and its methane oxidation activity.

Herein, we report the synthesis of a monocationic µ-nitrido-bridged iron porphycene dimer, a structural analogue of a monocationic µ-nitrido-bridged iron phthalocyanine dimer, which is known to be one of the most potent molecule-based catalysts for methane oxidation. 1H-NMR and single-crystal X-ray structural analyses showed that the porphycene complex includes two Fe(IV) ions, and the structure around the Fe-NFe core is quite similar to that of the monocationic µ-nitrido-bridged iron phthalocyanine dimer. Although methane was oxidized into MeOH, HCHO, and HCOOH in the presence of a silica-supported catalyst of this monocationic µ-nitrido-bridged iron porphycene dimer in an acidic aqueous solution containing excess H2O2, its reactive intermediate was not a high-valence iron-oxo species, as in the case of a monocationic µ-nitrido-bridged iron phthalocyanine dimer, but ˙OH. It is suggested that the high-valent iron-oxo species of the µ-nitrido-bridged iron porphycene dimer was gradually decomposed under these reaction conditions, and the decomposed compound catalyzed a Fenton-type reaction. This result indicates that the stability of the oxo-species is indispensable for achieving high catalytic methane oxidation activity using a µ-nitrido-bridged iron porphyrinoid dimer with an Fe-NFe core as a catalyst.

Anti-MDA-5 antibody-positive clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease treated with therapeutic plasma exchange: A case series.

We present six cases of antimelanoma differentiation-associated gene 5 antibody (anti-MDA5-Ab)-positive clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD), which is known to have a poor prognosis. The outcomes of these cases are described after treatment with therapeutic plasma exchange (TPE). Clinical and therapeutic data for patients with CADM with RP-ILD were collected retrospectively from medical records. All six patients received early intensive care including high-dose corticosteroids, intravenous cyclophosphamide, and a calcineurin inhibitor, but lung disease and hypoxia became more severe. TPE was performed over a median of 9.5 sessions (range 3-14) per patient, and the median duration from admission to TPE was 23 days. Three patients received combined direct hemoperfusion using a polymyxin B-immobilized fiber column (PMX-DHP) therapy on successive days to manage acute respiratory failure. Four patients survived and two died due to respiratory failure. In the survival cases, ferritin decreased, and ferritin and KL-6 were lower at diagnosis. The patients who died had a higher alveolar-arterial oxygen difference and more severe lung lesions at the time of initiation of TPE. These findings indicate that a combination of conventional therapy and TPE may be useful for improvement of the prognosis of CADM with RP-ILD at the early stage of onset.

Serum anti-Müllerian hormone levels in women with rheumatoid arthritis during tumor necrosis factor-α inhibitor treatment: Exploratory research.

BACKGROUND: We evaluated serum anti-Müllerian hormone in women with rheumatoid arthritis newly introduced to tumor necrosis factor-α inhibitor treatment for 54 weeks to investigate the treatment's effect on ovarian reserve. METHODS: A total of 12 premenopausal women with rheumatoid arthritis aged 20-50 years were recruited at our division, who had been newly treated with tumor necrosis factor-α inhibitor (infliximab or etanercept) from 1 April 2008 to 31 March 2014. Serial serum anti-Müllerian hormone levels and disease activity scores (DAS28-CRP) were examined at defined periods: start of treatment and 14, 30, and 54 weeks after start of treatment. RESULTS: DAS28-CRP scores in 12 women were significantly decreased from a mean of 4.6 (±SD: 0.4) to 2.3 (±0.4) after 54 weeks of treatment (p < 0.001). Serum anti-Müllerian hormone levels and its z scores did not change significantly. CONCLUSION: Treatment with a tumor necrosis factor-α inhibitor did not affect serum anti-Müllerian hormone levels in 12 women with rheumatoid arthritis during 54-week treatment.

Is the serum oxytocin level altered by treatment in rheumatoid arthritis patients complicated with depression?

OBJECTIVE: The objective of this study was to investigate the factors associated with depression, including serum oxytocin (OXT) levels, disease activity, activities of daily living (ADL), and quality of life (QOL), and their effects on rheumatoid arthritis (RA). METHODS: This study included 42 RA patients who received treatment with a biological agent. We measured the following variables before and after 6 months of treatment: baseline characteristics, including age, sex, disease duration, smoking, and body mass index (BMI); prednisolone and methotrexate dose; serum level of matrix metalloproteinase-3 (MMP-3); erythrocyte sedimentation rate (ESR); and C-reactive protein (CRP) level. The disease activity of RA was assessed using the Simplified Disease Activity Index (SDAI); depression was assessed using the Hamilton Depression Rating Scale (HAM-D); ADL was assessed using the Health Assessment Questionnaire; and QOL was assessed using the Short Form (SF)-36. Serum OXT levels were determined using enzyme-linked immunosorbent assay. RESULTS: The HAM-D score significantly correlated with the SDAI, and the mental component summary (MCS) score of SF-36. However, the serum OXT levels did not correlate with the HAM-D score. Regression analysis using the HAM-D score as the objective variable identified female sex, smoking, BMI, and all the three component scores of SF-36, but not serum OXT levels, as significant factors. Comparisons between before and after treatment showed that the HAM-D score improved from 5 to 1.5; however, the serum OXT levels did not change. CONCLUSION: The variables of female sex, smoking, BMI, and QOL correlated with depression complicated with RA. However, serum OXT levels did not correlate directly.

The Relationship between the Serum Oxytocin Levels, Disease Activity, the ADLs and the QOL in Patients with Rheumatoid Arthritis.

Objective To investigate the factors associated with depression, including the serum oxytocin (OXT) levels, disease activity, activities of daily living (ADLs) and quality of life (QOL), and their effects on rheumatoid arthritis (RA). Methods This study included 42-RA-patients. We measured the following variables before and after 6 months of treatment with biological disease-modifying antirheumatic drugs (bDMARDs): the baseline characteristics (including age, sex, disease duration, smoking, and body mass index), the doses of prednisolone and methotrexate, the serum level of matrix metalloprotease-3, the erythrocyte sedimentation rate and the C-reactive protein level. The disease activity of RA was assessed using the Simplified Disease Activity Index (SDAI), depression was assessed using the Hamilton Depression Rating Scale (HAM-D), the ADLs were assessed using the Health Assessment Questionnaire disability index and the QOL was assessed using the Short Form (SF)-36. The serum OXT levels were determined using an enzyme-linked immunosorbent assay. Results The HAM-D score was significantly correlated with the SDAI, and the mental component summary score of the SF-36. However, the serum OXT levels were not correlated with the HAM-D score. The serum OXT levels before and after bDMARDs treatment did not differ to a statistically significant extent, regardless of the presence of depression. Although the differences in the serum levels of OXT were observed prior to the initiation of treatment, there was no gender difference after treatment. Conclusion Although RA complicated by depression may be related to the following high disease activity, a poor QOL and poor ADLs, the serum OXT levels were not directly correlated.

Clinical Characteristics of Rheumatoid Arthritis Patients Achieving Functional Remission after Six Months of Non-tumor Necrosis Factor Biological Disease-Modifying Antirheumatic Drugs (DMARDs) Treatment.

Objectives We aimed to identify the factors that predict the likelihood of remission based on a health assessment questionnaire (HAQ) in rheumatoid arthritis (RA) patients who received non-tumor necrosis factor (TNF) biologics for six months before they commenced definitive treatment. Methods The subjects consisted of 97 RA patients treated with tocilizumab or abatacept for 6 months. The following characteristics were investigated: age, gender, body mass index, steroid and methotrexate dosage, serum matrix metalloproteinase-3 levels, simplified disease activity index (SDAI) score, HAQ score (for assessing the activities of daily living [ADL]) and the short form (SF)-36 score (for assessing the quality of life [QOL]). Remission based on the HAQ score is defined as HAQ ≤0.5 after 6 months of treatment. The subjects were divided into two groups: patients with HAQ score ≤0.5 and HAQ score >0.5, and a retrospective study was conducted. Results The group of RA patients who entered remission based on the HAQ (53 patients) had a lower SDAI than the patients who did not enter remission (44 patients), and the RA patients had a lower tender joint count (TJC) and HAQ scores and a lower physician's global assessment (PGA) than those who did not enter remission. The physical component summary score (PCS) and role/social component summary score (RCS) of the SF-36 summary score were higher in the remission patients than in those without. Before the start of the treatment, the HAQ score, patients' global assessment (PtGA) and PCS and mental component summary score (MCS) of the SF-36 were determined based on a logistic regression analysis. Conclusion Our findings suggest that RA patients with lower HAQ scores and PtGA and higher PCS and MCS of the SF-36 at baseline are more likely to achieve HAQ remission with non-TNF biologic treatment than others.

Clinical Characteristics of Rheumatoid Arthritis Patients Achieving Functional Remission with Six Months of Biological DMARDs Treatment.

Objective Although previous studies have reported the prognostic factors for functional remission, no reports have cited the predictive factors. Our aim was to study the predictive factors for functional remission, which is a treatment goal in rheumatoid arthritis (RA), after receiving biological disease-modifying antirheumatic drugs (bDMARDs) treatment for six months. Methods The study consisted of 333 RA patients treated with bDMARDs for six months. The following patient characteristics were investigated: age, gender, disease duration, type of bDMARDs, baseline steroid and methotrexate dosage, and levels of serum rheumatoid factor, matrix metalloprotease, anti-cyclic citrullinated peptides antibody, tumor necrosis factor-α, and interleukin-6. In our evaluation, we used the Simplified Disease Activity Index (SDAI) for RA disease activity, health assessment questionnaire disability index (HAQ-DI) for activity of daily living, Short Form (SF)-36 for quality of life, and Hamilton Depression Rating Scale (HAM-D) or Self-rating Depression Scale (SDS) to determine the patients' depression status. The subjects were divided into two groups: patients with HAQ-DI≤0.5 and HAQ-DI>0.5 at 6 months. Results A univariate analysis comparing a group of RA patients without functional remission (n=68) showed that the patients with functional remission (n=164) had the following in common compared with those without remission: younger age, shorter disease duration, lower baseline steroid dosage, lower SDAI, lower HAQ-DI, higher SF-36, and lower HAM-D. Only lower HAQ-DI scores and "mental health" score on the SF-36 were detected using a logistic regression analysis. Conclusion These findings suggested that RA patients with lower HAQ-DI and lower depression scores at baseline were more likely to achieve functional remission using bDMARDs treatment than those without these variables.

Predictor of the Simplified Disease Activity Index 50 (SDAI 50) at Month 3 of bDMARD Treatment in Patients with Long-Established Rheumatoid Arthritis.

OBJECTIVES: The Simplified Disease Activity Index (SDAI) 50 has good agreement with European League Against Rheumatism (EULAR) response measures for early Rheumatoid Arthritis (RA). There have been reports on early RA, but not on long-established RA. In this study, we analysed the relationships between various baseline factors and SDAI 50 after three months of treatment with biological disease-modifying antirheumatic drugs (bDMARDs) to determine the prognostic factors for long-established RA. METHODS: Subjects were 260 RA patients who had been treated with bDMARDs for 3 months. The following characteristics were investigated: Patient backgrounds, the erythrocyte sedimentation rate (ESR), C-reactive protein and serum matrix metalloproteinase-3 levels, SDAI scores, and health assessment questionnaire disability index and short form-36 scores. As a primary outcome index, the SDAI response was defined as a 50% reduction in the SDAI score between baseline and 3 months (SDAI 50). RESULTS: Baseline values of disease duration (odds ratio: 0.942, 95% CI: 0.902-0.984), smoking history (odds ratio: 2.272, 1.064-4.850), 28-tender joint count (odds ratio: 0.899, 0.827-0.977), evaluator's global assessment (odds ratio: 1.029, 1.012-1.047) and ESR (odds ratio: 1.015, 1.001-1.030) were determined to be significant factors based on logistic regression analysis. CONCLUSION: Our study demonstrated that RA patients with shorter disease duration, no smoking, and higher RA disease activity are more likely to achieve SDAI 50 through bDMARD treatment.

Cancer association as a risk factor for anti-HMGCR antibody-positive myopathy.

OBJECTIVE: To show cancer association is a risk factor other than statin exposure for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibody-positive (anti-HMGCR Ab+) myopathy. METHODS: We analyzed the clinical features and courses of 33 patients (23 female and 10 male) with anti-HMGCR Ab+ myopathy among 621 consecutive patients with idiopathic inflammatory myopathies. RESULTS: Among the 33 patients, 7 (21%) were statin-exposed and 26 were statin-naive. In relation with cancer, there were 12 patients (statin-exposed, n = 4) with cancers detected within 3 years of myopathy diagnosis (cancer association), 3 patients (all statin-naive) with cancers detected more than 3 years before myopathy diagnosis (cancer history), 10 cancer-free patients followed up for more than 3 years (all statin-naive), and 8 patients without cancer detection but followed up for less than 3 years (statin-exposed, n = 3). Therefore, 12 patients with cancer association (36%) formed a larger group than that of 7 statin-exposed patients (21%). Among 12 patients with cancer association, 92% had cancer detection within 1 year of myopathy diagnosis (after 1.3 years in the remaining patient), 83% had advanced cancers, and 75% died of cancers within 2.7 years. Of interest, 1 patient with cancer history had sustained increase in creatine kinase level over 12 years from cancer removal to the development of weakness. CONCLUSIONS: Patients with cancer association formed a large group with poor prognosis in our series of patients with anti-HMGCR Ab+ myopathy. The close synchronous occurrence of cancers and myopathies suggested that cancer association is one of the risk factors for developing anti-HMGCR Ab+ myopathy.

Anti-TIF1-γ antibody and cancer-associated myositis: A clinicohistopathologic study.

OBJECTIVE: We aimed to analyze the clinical and histopathologic features of cancer-associated myositis (CAM) in relation to anti-transcriptional intermediary factor 1 γ antibody (anti-TIF1-γ-Ab), a marker of cancer association. METHODS: We retrospectively studied 349 patients with idiopathic inflammatory myopathies (IIMs), including 284 patients with pretreatment biopsy samples available. For the classification of IIMs, the European Neuromuscular Center criteria were applied. Patients with CAM with (anti-TIF1-γ-Ab[+] CAM) and without anti-TIF1-γ-Ab (anti-TIF1-γ-Ab[-] CAM) were compared with patients with IIM without cancers within and beyond 3 years of myositis diagnosis. RESULTS: Cancer was detected in 75 patients, of whom 36 (48%) were positive for anti-TIF1-γ-Ab. In anti-TIF1-γ-Ab(+) patients with CAM, cancers were detected within 1 year of myositis diagnosis in 35 (97%) and before 1 year of myositis diagnosis in 1. All the anti-TIF1-γ-Ab(+) patients with CAM satisfied the dermatomyositis (DM) criteria, including 2 possible DM sine dermatitis cases, and were characterized histologically by the presence of perifascicular atrophy, vacuolated fibers (VFs), and dense C5b-9 deposits on capillaries (dC5b-9). In contrast, 39 anti-TIF1-γ-Ab(-) patients with CAM were classified into various subgroups, and characterized by a higher frequency of necrotizing autoimmune myopathy (NAM). Notably, all 7 patients with CAM classified into the NAM subgroup were anti-TIF1-γ-Ab(-) and exhibited no dC5b-9 or VFs. CONCLUSIONS: CAM includes clinicohistopathologically heterogeneous disease entities. Among CAM entities, anti-TIF1-γ-Ab(+) CAM has characteristically shown a close temporal association with cancer detection and the histopathologic findings of dC5b-9 and VFs, and CAM with NAM is a subset of anti-TIF1-γ-Ab(-) CAM.

Clinical effects of tocilizumab on cytokines and immunological factors in patients with rheumatoid arthritis.

Interleukin (IL)-6 is one of the crucial proinflammatory cytokines. The dysregulation of IL-6 plays a pivotal role in rheumatoid arthritis (RA) and is involved in several of the common clinical manifestations associated with active RA. Recent therapies targeting IL-6 and tumor necrosis factor (TNF) have resulted in clinical improvements in signs and symptoms, disability and quality of life in patients with early and long-standing RA. Because it has been demonstrated that cytokines and inflammatory/immunological factors appear to be important and sensitive mediators in RA patients treated with tocilizumab and with anti-TNF biologics, it is important to investigate whether tocilizumab administration has any effect(s) on the profiles of cytokines and inflammatory/immunological factors and whether these changes correlate with the clinical improvement in RA disease activity. In this review, we discuss the effects on cytokine regulation and the differentiation of immune cells, especially T cells, after tocilizumab therapy in patients with RA.

Influence of renal complications on the efficacy and adverse events of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase: a single-centre, prospective study.

OBJECTIVES: The study investigated whether renal complications affected the efficacy and safety of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase. METHODS: Fifty-seven patients with SLE (A: 30 cases with renal complication, B: 27 cases without renal complications) were included. The presence of renal complications was defined as proteinuria ≥0.5 g/day and lupus nephritis on renal biopsy. Major outcome measures included SLE disease activity index (SLEDAI), steroid dose, serum anti-dsDNA Ab, C3 and creatinine (Cr) levels and estimated glomerular filtration rate (eGFR). The patient's background factors included age, gender, disease duration and ACE-I/angiotensin II receptor blocker and statin therapies. We compared these outcome measures pre treatment and after 1 year of treatment. RESULTS: The SLEDAI and serum C3 levels improved in both groups from pretreatment period to post-treatment period: from 7.2±5.0 to 2.8±2.3 in A and 6.4±3.8 to 2.4±2.2 in B, p<0.001, and from 65.9±24.6 to 77.7±18.2 mg/dL in A and 81.8±23.0 to 90.6±19.4 mg/dL in B, p=0.002, respectively. The anti-dsDNA antibody level was reduced, and the serum Cr and eGFR levels were slightly elevated. No patients developed end-stage renal failure that required artificial dialysis. CONCLUSIONS: Tacrolimus combination therapy had additive beneficial effects on reduced proteinuria and increased serum C3 levels in patients with SLE with renal complications during a maintenance phase.

A disintegrin and metalloprotease-10 is correlated with disease activity and mediates monocyte migration and adhesion in rheumatoid arthritis.

A disintegrin and metalloproteases (ADAMs) are a family of proteins that have been reported to be involved in several inflammatory conditions. We examined the secretion of ADAM-10 in biological fluids from patients with rheumatoid arthritis (RA) and the role it plays in monocyte migration. ADAM-10 levels were measured using enzyme-linked immunosorbent assays and immunofluorescence. To examine the role of ADAM-10 in RA synovial fluids (SFs), we studied THP-1 (human acute monocyte leukemia cell line) and monocyte chemotaxis. To determine whether ADAM-10 plays a role in cell proliferation in the RA synovium, we assayed the proliferation of ADAM-10 small interfering RNA (siRNA)-transfected RA fibroblast-like synoviocytes (FLSs). The ADAM-10 level in RA serum was significantly higher than that in normal serum and was correlated with a disease activity score of 28. ADAM-10-depleted RA SFs showed a decrease in THP-1 and monocyte migratory activity compared with that of sham-depleted controls. ADAM-10 siRNA inhibited monocyte adhesion to RA FLSs. Finally, blocking ADAM-10 secretion in RA FLSs resulted in decreased production of fractalkine/CX3CL1 and vascular endothelial cell growth factor. These data indicate that ADAM-10 plays a role in monocyte migration in RA and suggest that targeting ADAM-10 may provide a method of decreasing inflammation and potentially treating other inflammatory diseases.

A case of Degos disease: demonstration of C5b-9-mediated vascular injury.

A 68-year-old Japanese male presented with atrophic erythematous white lesions with peripheral dark reddish rims on his back. Multiple ulcers were detected from his stomach to his large intestine using endoscopy. Although the patient was given high doses of a steroid, aspirin, dipyridamole, and intravenous immunoglobulin therapy, he died of gastrointestinal hemorrhage, perforation and septic shock. An autopsy examination revealed pauci-inflammatory thrombotic microangiopathy with endothelial cell injury, fibrous occlusive arteriopathy, and vascular C5b-9 deposition in the wall of the gastrointestinal tract from the esophagus to the large intestine as well as in the dermis of the skin.

Reduction of Serum ADAM17 Level Accompanied with Decreased Cytokines after Abatacept Therapy in Patients with Rheumatoid Arthritis.

A disintegrin and metalloprotease 17 (ADAM17) appears to be recognized as an important player in tissue destruction and also exacerbation of inflammation related with increased activities of angiogenesis in several pathological conditions. To examine the modulation of serum levels of ADAM17 and inflammatory cytokines in patients with rheumatoid arthritis (RA) in response to therapy of abatacept (ABT). Twenty four patients with RA were enrolled in our study. Serum was collected immediately prior to (baseline) and 24 weeks after starting ABT therapy. Serum levels of ADAM17 and cytokines/chemokine were quantified using enzyme-linked immunosorbent assay. ADAM17 level was markedly higher in RA patients than in healthy individuals. Positive correlation was observed between the baseline ADAM17 and CX3CL1 at baseline. There was a significant overall reduction of RA disease activity (Disease Activity Score 28) from 4.73 to 2.79 after 24 weeks after the ABT therapy. Furthermore, there was a significant reduction in serum level of ADAM17 in RA patients, and the patients achieved clinical responses, and also clinical remission had a significant decrease in ADAM17 level and also levels of tumor necrosis factor α, IL-6 and CX3CL1 after 24 weeks of ABT therapy. Our results suggest that the suppression of ADAM17 secretion and function seems to be a crucial therapeutic target in the treatment of ABT in patients with RA.

Correlation of serum CX3CL1 level with disease activity in adult-onset Still's disease and significant involvement in hemophagocytic syndrome.

To investigate the characteristics of patients with adult-onset Still's disease (AOSD), serum cytokines and chemokines were measured to examine their associations with systemic manifestations of AOSD, especially hemophagocytic syndrome (HPS). Nineteen patients diagnosed with AOSD were enrolled. Serial serum samples were obtained from patients with AOSD in both active and inactive stages and controls. The concentrations of cytokines and chemokines, including IL-18, soluble IL-2 receptor (sIL-2R), CX3CL1, CXCL8, CXCL10, CCL2, and CCL3, were determined using enzyme-linked immunosorbent assay. Multivariate analysis was used to evaluate the correlations among serum chemokine levels, disease activity, and the clinical features of AOSD. Significantly higher serum levels of all cytokines and chemokines were observed in patients with active, untreated AOSD than in controls. The level of CX3CL1, but not other chemokines, was elevated in AOSD patients and was positively correlated with clinical activity and the levels of CRP, ferritin, IL-18, and sIL-2R. Among the 19 patients with AOSD, four patients also had HPS. Serum CX3CL1 and ferritin were significantly higher in AOSD patients with HPS than in those without HPS. The serum CX3CL1 level may be used as a clinical marker to assess the disease activity of AOSD, and high serum CX3CL1 and ferritin in patients with AOSD reflected the presence of HPS. The association between the chemokine profile and distinct clinical manifestations or various patterns of disease progression indicates that the pathogenesis of AOSD is heterogeneous.