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Objective: To determine whether tumor necrosis factor (TNF) blockade improves small airway obstruction in rheumatoid arthritis (RA) patients without apparent respiratory symptoms.Methods: Pulmonary function tests were performed before and one year after TNF blockade therapy in 29 RA patients without apparent respiratory symptoms. As a control, pulmonary function was examined at a one-year interval in 27 RA patients with conventional disease-modifying antirheumatic drugs (DMARDs) alone. Small airway obstruction was diagnosed when one of maximal mid-expiratory flow rate (MMEF), forced expiratory flow at 50% (FEF50) or 75% (FEF75) of the vital capacity was decreased to less than 60%, 55%, or 45% of predicted values, respectively.Results: Small airway obstruction was found in 62.5% of RA patients. No differences were found in age, sex, disease duration, or disease activities. TNF inhibitors dramatically reduced disease activities. However, TNF inhibitors failed to improve small airway obstructions but worsened them.Conclusions: TNF blockade fails to improve small airway obstruction, suggesting that TNF-independent pathways play important roles in the development of small airway obstruction in RA.

To clarify the differences and similarities in the cytokine profiles of macrophage activating syndrome (MAS) between systemic lupus erythematosus (SLE) and adult-onset Still's disease (AOSD). The study participants included 9 patients with MAS-SLE, 22 with non-MAS-SLE, 9 with MAS-AOSD, and 13 with non-MAS-AOSD. Serum cytokine levels were measured using a multiplex bead assay. Cytokine levels were compared between patients with SLE and AOSD with/without MAS. Moreover, cytokine patterns were examined using principal component analysis (PCA) and cluster analysis. IL-6, IL-8, IL-18, and TNF-α levels were elevated in patients with SLE and AOSD. IFN-α levels were elevated in SLE, whereas IL-1β and IL-18 levels were elevated in AOSD. In SLE, IFN-α and IL-10 levels were higher in MAS than in non-MAS and controls. PCA revealed distinctive cytokine patterns in SLE and AOSD, SLE with IFN-α and IP-10, AOSD with IL-1β, IL-6, and IL-18, and enhanced cytokine production in MAS. PCA and cluster analysis showed no differences in cytokine patterns between the MAS and non-MAS groups. However, serum ferritin levels were correlated with IFN-α levels in SLE. Cytokine profiles differed between SLE and AOSD but not between MAS and non-MAS. MAS is induced by the enhancement of underlying cytokine abnormalities rather than by MAS-specific cytokine profiles. Type I IFN may be involved in MAS development in patients with SLE.

Background and Aim Wilson's disease (WD) is a rare inherited disease that causes systemic copper accumulation. This study examined the long‐term course of WD patients with liver disease. Methods The 12 patients (9 female patients) enrolled in the study had a median age of 28 years (range: 19–57 years) at their first visit to our hospital. Clinical course and fibrosis markers were assessed in all patients. Results The median age at diagnosis was 24 years (range: 5–42 years). One patient had acute liver failure (ALF) and 11 patients had chronic liver disease (CLD, 5 with cirrhosis). The patients were followed‐up for >20 years. The patient with ALF underwent liver transplantation; the postoperative course during the subsequent 20 years was good. Of the six patients with CLD, liver cirrhosis developed in four patients with interrupted chelating therapy. Two of the patients with cirrhosis died; one of these two patients died at 21 years after liver transplantation. However, the remaining patients with continued treatment exhibited a favorable clinical course for 30 years and none developed hepatocellular carcinoma (HCC). The duration of chelation therapy was significantly negatively correlated (P, The duration of chelation therapy for Wilson's disease complicated by liver disease was significantly negatively correlated with the fibrosis‐4 index and aspartate aminotransferase to platelet ratio index (APRI) score at the last visit.

Enzalutamide is a potent inducer of cytochrome P450 substrates. Hence, it induces major metabolizing enzyme effects in some of the concomitant drugs, raising the possibility of decreased efficacy. We investigated the actual status of drugs for which precautions for co-administration are indicated during concomitant use with enzalutamide.We retrospectively investigated the duration of enzalutamide use, concomitant medications, laboratory values, and events using the medical records of patients prescribed enzalutamide for castration-resistant prostate cancer at the National Cancer Center Hospital from May 2014 to May 2017.The median age of the 107 studied patients was 74 years[range: 53-93], median duration of enzalutamide prescriptions was 120 days[range: 14-1,008], and the median number of concomitant medications(components)was 6[range: 0-16]. Sixty nine patients(64%)were taking drugs that could be affected by enzyme induction. The medications listed in the concomitant use section of the package insert were warfarin(3 patients) and omeprazole(2 patients). In this study, 4 patients(except for 1 on warfarin)were taking other drugs that could be affected by enzyme induction. Events considered to possibly reduce their efficacy during concomitant use with enzalutamide were elevated blood pressure and blood clots.When enzalutamide is used in combination with other drugs, there exists the possibility that the effect of concomitant medications may be weakened by enzyme induction.

Background IgA nephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages' function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI. A spontaneous IgAN model, grouped ddY (gddY) mouse, revealed the requirement of AIM for the overall inflammatory glomerular injury following IgA deposition. Methods We established an AIM-deficient IgAN model (AIM -/- gddY) using CRISPR/Cas9 and compared its phenotype with that of wild-type gddY with or without recombinant AIM administration. An IgA-deficient IgAN model (IgA -/- gddY) was also generated to further determine the role of AIM. Results In both human and murine IgAN, AIM colocalized with IgA/IgM/IgG in glomeruli, whereas control kidneys did not exhibit AIM deposition. Although AIM -/- gddY showed IgA deposition at levels comparable with those of wild-type gddY, they did not exhibit glomerular accumulation of IgM/IgG complements, CD45+ leukocyte infiltration, and upregulation of inflammatory/fibrogenic genes, indicating protection from glomerular lesions and proteinuria/hematuria. Recombinant AIM administration reconstituted the IgAN phenotype, resulting in IgM/IgG/complement IgA codeposition. Neither spontaneous IgM/IgG codeposition nor disease was observed in IgA -/- gddY mice. Conclusions AIM may contribute to stable immune complex formation in glomeruli, thereby facilitating IgAN progression. Therefore, AIM deposition blockage or disassociation from IgM/IgG may present a new therapeutic target on the basis of its role in IgAN inflammation initiation.

We aimed to assess the prognostic impact of hyperhomocysteinemia (HHcy) on the recurrent vascular event risk in stroke patients with or without chronic kidney disease (CKD).In this prospective observational study, 621 patients (mean age, 69.5 years; male, 62.2%) with ischemic stroke or transient ischemic attack were consecutively enrolled within 1 week of onset and followed-up for 1 year. HHcy was defined as elevated levels of fasting total homocysteine ＞15 µmol/L. CKD was defined as an estimated glomerular filtration rate of ＜60 mL/min/1.73 mThe prevalence of HHcy was 18.5%. Patients with HHcy were more likely to have intracranial (37.4% versus 24.8%; p=0.008) and extracranial (20.9% versus 13.0%; p=0.037) artery stenosis than were those without HHcy. At 1 year, patients with HHcy were at a greater risk of MACE than were those without HHcy (annual rate, 17.8% versus 10.4%; log-rank p=0.033). In the Cox proportional hazard regression models, HHcy was independently associated with an increased risk of MACE in patients with CKD (adjusted hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.02-4.20), whereas HHcy was not predictive of MACE in those without CKD (adjusted HR, 1.00; 95% CI, 0.30-3.32).Elevated levels of serum homocysteine can be an important modifiable risk factor in stroke patients with CKD, but not in those without CKD.

A 47-year-old Japanese woman presented with epigastric discomfort and anorexia. Upper endoscopy showed type 4 advanced gastric cancer in the gastric antrum with stenosis of the pyloric portion. Abdominopelvic CT revealed peritoneal dissemination, and stage IV advanced gastric cancer was diagnosed. Laparoscopic gastrojejunostomy and enterostomy were performed. Trousseau syndrome occurred 7 days post-surgery. Despite appropriate treatment, the patient developed a pulmonary embolism 13 days later and died 18 days post-surgery. Even in young cancer patients without lifestyle disease complications, it is important to pay attention to Trousseau syndrome as part of cancer management.

Summary: The sterile inflammation caused by damage-associated molecular patterns (DAMPs) worsens the prognosis following primary injury such as ischemic stroke. However, there are no effective treatments to regulate DAMPs. Here, we report that AIM (or CD5L) protein reduces sterile inflammation by attenuating DAMPs and that AIM administration ameliorates the deleterious effects of ischemic stroke. AIM binds to DAMPs via charge-based interactions and disulfide bond formation. This AIM association promotes the phagocytic removal of DAMPs and neutralizes DAMPs by impeding their binding to inflammatory receptors. In experimental stroke, AIM-deficient mice exhibit severe neurological damage and higher mortality with greater levels of DAMPs and associated inflammation in the brain than wild-type mice, in which brain AIM levels increase following stroke onset. Recombinant AIM administration reduces sterile inflammation in the infarcted region, leading to a profound reduction of animal mortality. Our findings provide a basis for the therapies targeting DAMPs to improve ischemic stroke.

International audience; The influence of excess salt intake on acute kidney injury (AKI) has not been examined precisely except for some clinical data, unlike in chronic kidney disease. Here, we addressed the influence of high salt (HS) on AKI and its underlying mechanisms in terms of the activity of circulating apoptosis inhibitor of macrophage (AIM, also called CD5L) protein, a facilitator of AKI repair. HS loading in mice subjected to ischemia/reperfusion (IR) resulted in high mortality with advanced renal tubular obstruction and marked exacerbation in biomarkers of proximal renal tubular damage. This AKI exacerbation appeared to be caused mainly by the reduced AIM dissociation from IgM pentamer in serum, as IgM-free AIM is indispensable for the removal of intratubular debris to facilitate AKI repair. Injection of recombinant AIM (rAIM) ameliorated the AKI induced by IR/HS, dramatically improving the tubular damage and mouse survival. The repair of lethal AKI by AIM was dependent on AIM/ kidney injury molecule-1 (KIM-1) axis, as rAIM injection was not effective in KIM-1 deficient mice. Our results demonstrate that the inhibition of AIM dissociation from IgM is an important reason for the exacerbation of AKI by HS, that AIM is a strong therapeutic tool for severe AKI.

An internal system designed to ward off and remove unnecessary or hazardous materials is intrinsic to animals. In addition to exogenous pathogens, a number of self-molecules, such as apoptotic or necrotic dead cells, their debris, and the oxides or peroxides of their cellular components, are recognized as extraneous substances. It is essential to eliminate these internal pathogens as quickly as possible because their accumulation can cause chronic inflammation as well as autoimmune responses, possibly leading to onset or progression of certain diseases. Apoptosis inhibitor of macrophage (AIM, also called CD5L) is a circulating protein that is a member of the scavenger receptor cysteine-rich superfamily, and we recently found that during acute kidney injury, AIM associates with intraluminal dead cell debris accumulated in renal proximal tubules and enhances clearance of luminal obstructions, thereby facilitating repair. Thus, AIM acts as a marker for phagocytes so that they can efficiently recognize and engulf the debris as their targets. In this chapter, we give an overview of the professional and non-professional phagocytes, and how soluble scavenging molecules such as AIM contribute to improvement of diseases by stimulating phagocytic activity.

Objective We aimed to determine the outcome of combination therapy with tofacitinib (TOF) in a case series of refractory rapidly progressive interstitial lung disease (ILD) associated with anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive (Ab+) DM. Patients who had poor prognostic factors and failed to respond to immunosuppressive therapy were selected for TOF treatment. Methods Five patients with anti-MDA5 Ab+ DM-ILD who failed to respond to triple therapy with high dose glucocorticoids, CSA and CYC were given additional TOF (10 mg/day). To identify the poor prognostic factors, data from 15 consecutive patients (seven survived and eight died) with anti-MDA5 Ab+ DM-ILD before induction of TOF were analysed. Results Three poor prognostic factors were identified: serum ferritin level >1000 ng/ml before therapy; ground-glass opacities in all six lung fields before therapy; and worsening of pulmonary infiltrates during therapy. All six patients who had all of the three factors and received triple therapy died before TOF therapy. There were five patients who had all of the three prognostic factors and failed to respond to triple therapy, but were able to receive the combination therapy with TOF; among them, three survived and two died. The survival rate of patients who received TOF was significantly better than that of the historical controls with immunosuppressive therapy before TOF. The patients who received TOF experienced complicated adverse events, particularly viral infection. Conclusion Combination therapy with TOF might have the potential to control refractory anti-MDA5 Ab+ DM-ILD.

Circulating immunoglobulin M (IgM) exists in a pentameric form, possessing a polyreactive nature that responds not only to foreign antigens but also to autoantigens; thus, it is involved in both beneficial and detrimental immune responses, including protection from infection and the progression of autoimmunity. On the other hand, IgM also behaves as a carrier of the apoptosis inhibitor of macrophage (AIM) protein, storing a large amount of the inactivated form of AIM in the blood through this association. Under different disease conditions, AIM can dissociate from IgM locally or systemically to exert its function, inducing the removal of various biological debris such as excess fat, bacteria, cancer cells or dead cell debris. Most typically, upon induction of acute kidney injury (AKI), IgM-free AIM is filtered by the glomerulus in the kidney, which stimulates the clearance of intraluminal dead cells debris at the obstructed proximal tubules, thereby facilitating the repair of kidney injury. Interestingly, cats exhibit a deficiency in AIM release from IgM, which may increase their susceptibility to renal failure. Conversely, association with AIM inhibits IgM binding to the Fcα/μ receptor on follicular dendritic cells at the splenic germinal center, thereby protecting the IgM immune complex from Fcα/μ receptor-mediated internalization, which supports IgM-dependent antigen presentation to B cells and stimulates high-affinity IgG antibody production. The regulation of AIM-IgM binding, resulting from the discovery of reciprocal actions between AIM and IgM, could lead to the development of novel therapies against different diseases.

Fungal peritonitis in a patient on peritoneal dialysis (PD) is a refractory injury accompanied by severe inflammation, predisposing patients to a poor prognosis. Defective clearance of necrotic tissue interferes with amelioration of tissue injury and induces abnormal tissue remodeling. In the recent reports, apoptosis inhibitor of macrophage (AIM, also called CD5L) prevents obesity, hepatocellular carcinoma and acute kidney injury. Here, we investigated potential roles of AIM in prevention of progression of fungal peritonitis models. AIM−/− mice subjected to zymosan-induced peritonitis exhibited progressive inflammation and sustained peritoneal necrosis tissue on day 28 after the disease induction, whereas there was an improvement in AIM+/+ mice. This appeared to be caused by deposition of AIM at the necrotic peritoneum in AIM+/+ mice. In vitro, AIM enhanced the engulfment of necrotic debris by macrophages derived from zymosan-induced peritonitis, M1- and M2a-like bone marrow derived macrophages, as well as by mesothelial cells. In addition, administration of recombinant AIM dramatically ameliorated severe inflammation associated with necrosis in zymosan-induced peritonitis of AIM−/− mice. Our observations suggest that AIM appears to be involved in the repair process of zymosan-induced peritonitis, and thus, could be the basis of development of new therapeutic strategies for PD-related fungal peritonitis.

Background: By autoantibodies, myositis is recently classified into subgroups with distinctive clinical features. Cytokines play critical roles in the development of the clinical features. However, it is not fully unknown whether myositis subgroups defined by autoantibodies have unique cytokine profiles. Objectives: To clarify the relationship between cytokine profiles and autoantibodies in myositis. Methods: Subjects were myositis patients who admitted Dokkyo Medical University and whose serum before starting therapy were available. Serum cytokine levels (IL-1a, 1b, 2, 4,5, 6, 10,12, 13,15,17, 23,IFN-g, TNF-a, IFN-a, b,IP-10 and MCP-1) in sera from the patients and controls were measured using Q-Plex™ Multiplex Arrays. Demographic and clinical data were obtained by reviewing medical record retrospectively. Results: Subjects were 45 myositis patients with male/female; 22/23 and 59.4 years of mean age. Amyopathic dermatomyositis (ADM), classical DM and polymyositis (PM) were 21, 11 and12 cases, respectively. Autoantibodies were anti-MDA5+ in 21, anti-ARS+ in18 and anti-TIF1g+ in 5 cases. ILD and malignancy was complicated in 39 and 5 cases, respectively. Serum cytokine levels were measured. As shown in Fig.1, IP-10 levels were increased in all types of myositis patients, but not in controls. In ant-MDA5 Ab + myositis, IL-6, IL-10, IL-15, TNF-a, IFN-a and MCP-1 levels were increased. In anti-ARS Ab+ cases, IFN-b levels were elevated as well as TNF-a and MCP-1. Through the correlation analysis between cytokine levels, cytokine groups were identified (Fig.2). In anti-MDA5 Ab+ cases, 2 cytokine groups were identified; one includes IFN-a, IL-15, TNF-a and IL-10, and the other involved IL-6, MCP-1. Both groups connected with IP-10. In In anti-ARS Ab+ cases, 2 groups were found; one included TNF-a, MCP-1and IP-10, and the other had IFN-b as a sole component. Conclusion: Cytokine profiles differ among subgroups in myositis. In anti-DDA5+ myositis, IL-15 and IFN-a with strong correlation and IL-6 were characteristic cytokines, while IFN-b was a unique one in anti-ARS+ myositis Disclosure of Interests: None declared

A skewed TCR repertoire does not directly trigger inflammation in adipose tissue, Obesity is accompanied by chronic, low-grade inflammation in adipose tissue, which is associated with insulin resistance and consequent multiple metabolic diseases. In addition to M1 macrophage infiltration, multiple involvements of adipose tissue T lymphocytes in the progression of inflammation have been highlighted recently. Here, we isolated a specific Vα5/Vβ8.2 TCR-bearing T cell that accumulated in obese adipose tissue of mice, and generated transgenic mice expressing this TCR. Under lean conditions with a normal chow diet, CD4+FoxP3+ Treg cells and M2 macrophages increased in adipose tissue with ageing in wild-type mice, but not in transgenic mice. However, both mice exhibited no obvious adipose tissue inflammation such as the formation of crown-like structures (CLSs) of infiltrating macrophages. When fed a high-fat diet, the proportion of adipose tissue Treg cells was markedly small at a similar level in transgenic and wild-type mice. Both types of mice exhibited comparable inflammatory states in adipose tissue, including vast formation of macrophage CLSs, accompanied by insulin resistance. Together, our findings suggest that the absence of an increase in Treg cells and M2 macrophages is not sufficient to initiate inflammatory macrophage infiltration in lean adipose tissue and also provide a new view about the involvement of T cells in promoting obesity-associated inflammation.

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.

Endogenous lipoid pneumonia is an uncommon inflammatory pulmonary disease that is caused by lipids from an endogenous source, the treatment for which has not been established. We report the first case of endogenous lipoid pneumonia presenting as lung consolidation and which was associated with rheumatoid arthritis. Treatment was successful with intensive immunosuppressive therapy. When a physician finds lung consolidation in a patient with active rheumatic disease, lipoid pneumonia should be considered.

To clarify the clinical features of organizing pneumonia (OP) associated with rheumatoid arthritis (RA) and to determine whether development of OP is related to RA activity.A cross-sectional study was conducted, in which medical records of 499 consecutive RA patients who visited our hospital during one month were reviewed. OP was diagnosed by pathological findings by trans-bronchial biopsy or by clinical features (typical computed tomography findings, no causative agents, good response to glucocorticoids, and lack of response to antibiotics).Among 499 patients, OP was found in 19 patients and the estimated prevalence was 1.9-4.8%. No differences in clinical features were noted between the OP and non-OP groups. The mean age of OP development was 57.2 years and the period from the onset of RA to OP ranged from -4 to +34 years. Although 14 patients presented OP after the onset of RA, two developed OP before RA and three developed OP simultaneously with RA. Patients receiving tumor necrosis factor inhibitors also developed OP. RA disease activity just before onset of OP was low in 8 of 14 RA cases. At the onset of OP, only two patients showed exacerbations of arthritis, whereas most patients presented with fever and serum C-reactive protein (CRP) elevations. Glucocorticoids were effective for OP in all patients who received them. Relapse occurred in 4 of 19 cases.OP develops in approximately 4% of RA patients, which occurs independently from arthritis activity and at any time in RA patients.

Apoptosis inhibitor of macrophage (AIM) expressed on macrophages prolongs inflammation by protecting macrophages from apoptosis. Most circulating AIM co-exists with immunoglobulin M (IgM). AIM’s pathophysiological role in relation to IgM remains unclear. Here we evaluated the glomerular expression/deposition of AIM and IgM in the kidney using immunohistochemistry and its associations with clinical manifestations in 43 patients with biopsy-confirmed kidney diseases. Kidney biopsy tissue from all patients was immunostained for AIM and IgM. Staining patterns and percent stained areas within the glomeruli were determined. Cells expressing AIM were identified by co-staining with macrophage and endothelial cell surface markers. Correlations between staining results and clinical parameters were evaluated using univariate and multivariate analyses. AIM was deposited in various areas, such as mesangial and capillary area. A part of AIM expression was localized to CD68-positive macrophages in the glomerulus. Amount of glomerular expression was positively correlated with urinary protein in patients with severe proteinuria (urinary protein ≥0.5 g/day) and kidney dysfunction [estimated glomerular filtration ratio (eGFR)

Background:Interstitial lung disease (ILD), frequent lung involvement, determine the prognosis of patients with RA. The presence of ILD also influences the selection of RA therapy. However, it is not fully elucidated what groups of RA-ILD patients worsen ILD.Objectives:To identify the risk factors for worsening of ILD in RA patients under biological DMARD (bDAMARDs) therapy; particularly to determine whether types of bDMARDs are associated with exacerbation of ILD.Methods:A retrospective cohort study was conducted. Subjects were consecutive 91 RA-ILD patients who received HR-CT examination at starting and during bDMARDs therapy. Clinical data were collected by reviewing.ILD was diagnosed, when patients showed ground-glass opacity (GGO), consolidation, reticular pattern or honeycomb; the former two were acute and the latter two were chronic ILD lesions. The extent of each lesion was scored and recorded. When the score was increased, the lesion was judged as worsened. The incidence of exacerbation of ILD under an indicated agent was calculated as follows; the sum of (exposure period of the agent/exposure period of any agent) in patients with the exacerbation was divided by total exposure period of the agent.Results:Subjects were 36 males and 55 females with a mean age of 66.8 years. At the entry, GGO, consolidation, reticular and honeycomb were found in16, 20, 63 and 17, respectively. Acute and chronic ILD were observed in 34 and 68, respectively. ILD worsened in 35 (38.5%). Between patients with and without ILD exacerbation, no differences were found in demographics (sex, age, disease duration, the positivity for anti-CCP ab and RF) and radiographic findings of pulmonary abnormalities. Disease activities at as 1st and sequential CT examinations were similar in both groups.The incidences of the worsening of ILD varied according to bDMARDs (Fig 1). The incidence of total ILD worsening was high in TCZ compared to TNF and ABT. The incidence of acute ILD worsening was similar among the three groups. However, the worsening of chronic ILD was more frequently found in TCZ than other bDMARDs. The incidence of death by respiratory failure was similar in TNF, ABT, and TCZ (Fig. 2).Fig. 1Conclusion:TCZ might be a risk factor for exacerbation of ILD, particularly of chronic ILD.Fig. 2Disclosure of Interests:None declared

Owing to changes in lifestyle, nonalcoholic fatty liver disease (NAFLD) is becoming a common form of chronic liver injury. NAFLD comprises a wide variety of disease stages, from simple steatosis to nonalcoholic steatohepatitis, which is a risk factor for the development of hepatocellular carcinoma (HCC). Because animal models for NAFLD are needed to investigate the precise pathogenesis, we aimed to establish a new mouse model employing mice deficient for apoptosis inhibitor of macrophage (AIM-/-), which exhibit accelerated lipid storage in the liver and high susceptibility to developing HCC in response to a high-fat diet (HFD). AIM-/- mice were fed the D09100301 diet, which contains 40 kcal% fat (trans fat 30 kcal%), high cholesterol (2%), and 40 kcal% carbohydrates (20 kcal% fructose), and then features of obesity and NAFLD including steatosis, inflammation, fibrosis, and HCC development were analyzed. Although a comparable grade of liver steatosis was promoted in AIM-/- mice by the D09100301 diet and the standard HFD (60 kcal% largely lard fat), significantly less lipid storage in visceral fat was observed when the mice were fed the D09100301 diet. Accelerated liver inflammation was promoted by the D09100301 diet compared with the HFD, but interestingly, HCC development was decreased in mice fed the D09100301 diet. Our findings suggest that AIM-/- mice fed the D09100301 diet exhibited a phenotype that resembled nonobese NAFLD patients and thus could be an appropriate tool to study the pathophysiology by which obesity increases the risk of HCC.

We demonstrate the bona fide 2D structure of the IgM pentamer and its association with AIM protein., Soluble immunoglobulin M (IgM) forms a pentamer containing a joining (J) chain polypeptide. While IgM pentamer has various immune functions, it also behaves as a carrier of circulating apoptosis inhibitor of macrophage (AIM; also called CD5L) protein that facilitates repair during different diseases. AIM binds to the IgM pentamer solely in the presence of the J chain. Here, using a single-particle negative-stain electron microscopy, we found that the IgM pentamer exhibits an asymmetric pentagon containing one large gap, which is markedly different from the textbook symmetric pentagon model. A single AIM molecule specifically fits into the gap, cross-bridging two IgM-Fc that form the edges of the gap through a disulfide bond at one side and a charge-based interaction at the other side. The discovery of the bona fide shape of the IgM pentamer advances our structural understanding of the pentameric IgM and its binding mode with AIM.

Background Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects joints and various organs. The lung is one of the most common site of extra-articular involvement. Interstitial lung disease (ILD) is one form of the lung involvement and influences prognosis of the patients. RA-ILD frequently developed acute exacerbation. Once acute exacerbation occurs, the prognosis of patients is poor. However, it is not fully elucidated what the risk factors for severe exacerbation of ILD are. Objectives The purpose of thisstudy was to identify the risk factors for severe exacerbation of ILD in RApatients during bDMARDs therapy.The purpose of this study was to identify therisk factors for exacerbation of ILD in RA patients under the bDMARDs therapy. Methods A retrospective cohort study. Subjects were consecutive 208 RA patients who were treated with bDMARDs from 2004 to 2015 in our department and received HRCT scan before and during the therapy. Based on HR-CT imaging, pulmonary abnormalities were classified into 4 categories (ILD, nodular lesions, airway disease (AD) and others) and 20 lesions such as ground-glass opacity (GGO), reticular pattern, bronchiolitis and bronchiectasis. We recorded their existence and distribution before andduring the therapy and examined their changes. Severe exacerbation of ILD was judged when patients revealed newly emerging/worsening of ILD lesions regardless of pre-existing pulmonary lesions and deceased or had to stop bDMARDs due to exacerbation of ILD. To identify risk factors, logistic regression analysis was conducted. Results Subjects were 208 RApatients, M/F; 64/144, mean age; 59.2 years old, disease duration; 7.9 years positive for RF in 84.1%. bDMARDs used for the longest period were TNFinhibitors in 79.8% of the subjects, abatacept in 15.4% and tocilizmab in 4.8%. Pulmonary abnormalities were found in 146 (70.2%) of RA patients before bDMARDs (ILD 81,(38.9%); nodular lesions 45, (21.6%); and ADs, 115, (55.3%)). GGO, consolidation, reticular pattern and honey combing was found in 14.8%, 19.8%, 51.9%, and 17.3% of ILD patients. Most of ILD lesions coexisted with ADs. During the observation period (3.26±2.61 years), newly emerging/worsening pulmonary lesions were found in 42.3% of patients and the incidence of which was 13.7/100person year. The incidence of newly development and worsening of ILD were 7.0/100 person years and 1.5/100 person years, respectively. Severe exacerbation of ILD was developed in 13 patients (6.3%) and the incidence of which was 2.0/100 person year. Of 13 patients, 9 died of respiratory failure. All patients with severe exacerbation revealed GGO/consolidation.Interestingly, all these active ILD lesions were newly emerging lesions, however, most of the patients had pre-existing pulmonary lesions. We identified risk factors for severe exacerbation of ILD (Table1). The risk factors for severe exacerbation of ILD were older age and pre-existing pulmonary lesions of ILD and of ADs, particularly reticular pattern, honeycomb and bronchiectasis. Sero-positivity and choice of biologics were not identified as risk factors. Conclusions The incidence of severe exacerbation of ILD was 2.0/100 person years. The risk factors forsevere exacerbation of ILD were older age and pre-existing reticular pattern,honeycomb and bronchiectasis. Disclosure of Interest: None declared

Tissue macrophage-derived apoptosis inhibitor of macrophage (AIM, encoded by cd5l gene) is a circulating protein that has suppressive functions in a broad range of diseases including obesity, liver steatosis, hepatocellular carcinoma (HCC), and acute kidney injury (AKI). In healthy states, high levels of AIM circulate in the inactivated state by associating with the immunoglobulin M (IgM) pentamer in the blood, whereas during AKI, AIM dissociates from IgM and gains disease repair activity. Here, we assessed whether AIM activation via its release from IgM is required to ameliorate other diseases. To this end, we employed a mouse line in which mouse AIM was replaced with feline AIM (AIM-felinized mice). Because feline AIM rarely dissociates from IgM due to its extremely high binding affinity for IgM, these mice exhibited deficient AKI repair as in cats. When fed a high-fat diet (HFD), similar to AIM-deficient (AIM−/−) mice, AIM-felinized mice exhibited enhanced triacylglycerol deposition in visceral adipocytes and hepatocytes, resulting in more prominent obesity and fatty liver than in wild-type mice. In contrast, the incidence of HCC after a 1-year HFD was remarkably lower in AIM-felinized mice than in AIM−/− mice, suggesting that AIM produced by liver Kupffer macrophages might directly facilitate the elimination of HCC cells. Accordingly, the marked deposition of AIM accompanied by accumulation of Kupffer cells was obvious during HCC tumour development in AIM-felinized mice. Δsµ mice, which harbour almost no circulating AIM due to the lack of secreted IgM, showed a phenotype comparable with that of AIM-felinized mice in prevention of those diseases. Thus, blood AIM released from IgM contributes to suppression of obesity and fatty liver as in AKI, whereas macrophage-derived noncirculating AIM mainly prevents HCC development. Our study depicted two different modes of disease prevention/repair facilitated by AIM, which could be the basis for HCC therapy that works by increasing AIM expression in macrophages.

Acute kidney injury (AKI) is associated with prolonged hospitalization and high mortality, and it predisposes individuals to chronic kidney disease. To date, no effective AKI treatments have been established. Here we show that the apoptosis inhibitor of macrophage (AIM) protein on intraluminal debris interacts with kidney injury molecule (KIM)-1 and promotes recovery from AKI. During AKI, the concentration of AIM increases in the urine, and AIM accumulates on necrotic cell debris within the kidney proximal tubules. The AIM present in this cellular debris binds to KIM-1, which is expressed on injured tubular epithelial cells, and enhances the phagocytic removal of the debris by the epithelial cells, thus contributing to kidney tissue repair. When subjected to ischemia-reperfusion (IR)-induced AKI, AIM-deficient mice exhibited abrogated debris clearance and persistent renal inflammation, resulting in higher mortality than wild-type (WT) mice due to progressive renal dysfunction. Treatment of mice with IR-induced AKI using recombinant AIM resulted in the removal of the debris, thereby ameliorating renal pathology. We observed this effect in both AIM-deficient and WT mice, but not in KIM-1-deficient mice. Our findings provide a basis for the development of potentially novel therapies for AKI.

A diagnostic marker is needed enabling early and specific diagnosis of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH). Our recent findings have indicated that circulating apoptosis inhibitor of macrophage (AIM), which usually associates with IgM pentamer in the blood, is activated by its dissociation from IgM. We investigated the serum levels of IgM-free AIM for AIM activation and its possible relationship with development of HCC in NASH. Serum levels of IgM-associated and IgM-free AIM were evaluated in patients with non-alcoholic fatty liver, NASH, and NASH-HCC using enzyme-linked immunosorbent assays and immunoblots. Liver biopsy specimens were graded and staged using Brunt’s classification. Forty-two patients with fatty liver, 141 with NASH, and 26 with NASH-HCC were evaluated. Patients with stage 4 or grade 3 NASH (with or without HCC) exhibited significantly higher levels of both IgM-free and total AIM than those with fatty liver, whereas the ratio of IgM-free-to-total AIM was equivalent in these groups. Among patients with the same fibrosis stage of NASH, those with HCC had significantly higher IgM-free but not total AIM levels, resulting in a proportional increase in the IgM-free/total AIM ratio. Analysis of the areas under the receiver operating characteristic curves indicated the high sensitivity of the IgM-free AIM for NASH-HCC. Our observations suggest the activation of AIM in blood in the presence of NASH-HCC, with a significant increase in IgM-free AIM levels. IgM-free AIM serum levels appear to be a sensitive diagnostic marker for NASH-HCC.

Background Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects joints and various organs including the lung. The pulmonary involvement is critical for prognosis of the patients and decision of the treatment. Moreover, the pulmonary involvement showed various abnormalities such as interstitial pneumonia (ILD) and airway disease (AD). Importantly, a pulmonary abnormality coexists with other ones in RA patients. There have been large numbers of studies on the prevalence of pulmonary abnormalities and clinical features of patients with these lesions. However, it remains to be elucidated what existence pattern of pulmonary abnormalities RA patients have. Objectives To reveal the existence pattern of the pulmonary abnormalities in RA patients using cluster analysis, and to clarify the clinical features of patients with multiple pulmonary abnormalities. Methods Subjects were consecutive 208 RA patients who were treated with bDMARDs as the first one from Feb. 2004 to Sep. 2015 in our department and received HRCT scan before and after the therapy. Pulmonary abnormalities were classified into 4 categories (ILD, nodular lesions, AD and other) and 20 lesions such as ground-glass opacity, reticular pattern, bronchiolitis and bronchiectasis and were examined their existence and distribution. Cluster analysis was conducted according to the existence of the lesions by Ward method. Clinical features were analyzed through reviewing medical records. Results Subjects were 208 RA cases (M/F; 64/144, mean age 59.2 year-old, disease duration 13.1 years). Pulmonary lesions were found in 146 (70.2%) of RA patients before treatment Imaging findings were 81of ILD (39%),45 of nodular lesion (21.6%) and 115 of AD (55%). Cluster analysis showed 6 clustered (Fig.), 1; no pulmonary lesions, 2; AD without bronchoectasia, 3; AD with bronchoectasia, 4; AD with curved linear opacities, 5; AD with nodular lesions, and 6; reticular pattern with AD. AD was common abnormalities and coexisted with other pulmonary lesions in RA. AD was found in 79%, 78% and 71% of patients with pulmonary abnormalities, ILD and nodular lesions, respectively. AD alone, AD with ILD, and AD with nodular pattern were found in 16.3%, 8.6% and 28.9%, respectively, while patients without pulmonary lesions were 29.8% in RA. AD was frequently associated with ILD and nodule compare to non-AD. No differences were found in gender, smoking history, disease duration and disease activity between patients with and without AD. New emergence or exacerbation of pulmonary abnormalities developed in AD patients compared to those without pulmonary abnormalities or AD. No significant differences were found in clinical features, among AD alone, AD with ILD and AD with nodules. Conclusions Pulmonary abnormalities were found in 70% in RA. AD was found in 55% of RA patients and coexisted with other pulmonary lesions such as ILD and nodular lesions. Patients with AD frequently showed newly emerging or worsening pulmonary lesions, regardless of the coexistence of other pulmonary lesions. Thus, AD is shared and critical pulmonary abnormality in RA. Disclosure of Interest None declared

Soluble IgM forms a predominantly pentameric complex that also contains a small polypeptide J chain. While the IgM pentamer has various immune functions to defend against foreign pathogens, it also behaves as a carrier of the circulating apoptosis inhibitor of macrophage (AIM, also called CD5L). The binding to IgM pentamer protects AIM from renal excretion, leading to high serum AIM levels. When AIM dissociates from IgM, it becomes functionally active and facilitates the repair of a variety of diseases including acute kidney injury and hepatocellular carcinoma. Since the precise manner of AIM-IgM pentamer binding remains unknown, we examined the structure using a latest single-particle negative-stain electron microscopy. Surprisingly, the IgM pentamer shapes “one-piece missing” hexagon containing one large gap, which is markedly different from the textbook prediction of a symmetric pentagon model. A single AIM molecule stably fits into the gap, cross-bridging two IgM-Fc through a disulfide bond and a charge-based interaction. We also found that the association of AIM with IgM pentamer not only inactivates AIM but also progresses inflammatory immune-complex formation in certain autoimmune diseases such as IgA nephropathy. Thus, our current findings of the bona fide structure of the AIM/IgM pentamer complex provides an important insight into the releasing mechanism of AIM from IgM, which could be the basis for the development of new therapeutic strategies against multiple diseases, via the increase of active AIM as well as the disruption of immune-complex formation.

Apoptosis inhibitor of macrophage (AIM) plays roles in survival of macrophages. In this study, we cloned canine AIM cDNA and observed its transcriptional expression levels in various tissues. The coding sequence of canine AIM was 1,023 bp encoding 340 amino acid residues, which had around 65% homology with those of the human, mouse and rat. Transcriptional expression of AIM was observed in the spleen, lung, liver and lymph node, which confirmed the expression of canine AIM in tissue macrophages. Moreover, AIM was highly expressed in one of the canine histiocytic sarcoma cell lines. CD36, the receptor of AIM, was also expressed in various tissues and these cell lines. These findings are useful to reveal the actual functions of canine AIM.