K. Hiromura

Revised classification of lupus nephritis is valuable in predicting renal outcome with an indication of the proportion of glomeruli affected by chronic lesions

OBJECTIVES To determine if the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis (LN) is helpful in predicting renal outcome. METHODS A total of 92 patients with LN who underwent renal biopsy in our hospital were re-classified according to the ISN/RPS 2003 criteria. RESULTS The mean patient age was 36.8 yrs and the median observation period was 65 months. The relative frequency for each class was as follows: Class I (minimal mesangial LN) 0%, Class II (mesangial proliferative LN) 13%, Class III (focal LN) 17%, Class IV (diffuse LN) 60% and Class V (membranous LN) 10%. Within Class IV, diffuse segmental (Class IV-S) was 25% and diffuse global (Class IV-G) 75%. During the observation period, renal function was more likely to deteriorate in Class IV-G cases than in Class IV-S cases. Importantly, when Class IV-G was subdivided into cases involving active lesion alone [IV-G (A)] or chronic lesion [IV-G (A/C)], the majority of cases in IV-G (A) was nephrotic, but responded well to therapy. In contrast, renal function declined only in IV-G (A/C) cases. Patients with Class IV-G (A/C) had persistent proteinuria in spite of intensified therapies. Moreover, the higher proportion of chronic lesions was related with the deterioration of renal function. CONCLUSIONS This study showed that in Class IV-G cases, renal outcome differed in the presence of chronicity. Chronicity could be a critical factor in predicting outcome. Thus, the revised classification of LN is clinically valuable in identifying different renal outcomes among patients with diffuse LN.

Expression of IL-19 and its receptors in RA: potential role for synovial hyperplasia formation

OBJECTIVE IL-19 is a novel cytokine of the IL-10 family. In this study, we sought to examine whether IL-19 plays a role in the pathogenesis of RA. METHODS Expression of IL-19, IL-20 receptor 1 (IL-20R1) and IL-20R2 was examined by RT-PCR and immunohistochemical analysis in rheumatoid synovium. The effects of IL-19 on synovial cells established from rheumatoid synovium (RASCs), with regard to IL-6 production and signal transducers and activators of transcription3 (STAT3) activation, were examined by ELISA and western blot analysis, respectively. The effect of IL-19 on RASC apoptosis was examined by Hoechst staining, flow cytometry analysis of annexin V binding and caspase-3 activity. RESULTS IL-19, IL-20R1 and IL-20R2 mRNA were detected by RT-PCR in synovial tissues from RA patients. Immunohistochemical analysis showed IL-19 was predominantly expressed in the hyperplastic lining layers of RA synovial tissues. The majority of IL-19-positive cells were vimentin-positive and CD68-positive synovial cells, serving as markers of fibroblasts and macrophages, respectively. IL-20R1 and IL-20R2 (IL-20Rs) were expressed in both the lining and sublining layers of RA synovium. In RASC, IL-19 was induced by lipopolysaccharide stimulation and constitutive expression of IL-20Rs was observed, suggesting IL-19 has an autocrine action. In terms of this function, IL-19 induced STAT3 activation and increased IL-6 production by RASC above the medium control. Moreover, IL-19 significantly reduced RASC apoptosis induced by serum starvation. CONCLUSIONS These data suggest that IL-19, produced by synovial cells, promotes joint inflammation in RA by inducing IL-6 production and decreasing synovial cell apoptosis.

Increased levels of serum sulfite in patients with acute pneumonia.

Sulfite, a common air pollutant, is toxic for humans, causing hypersensitivity or chronic airway diseases. We previously reported that sulfite is actively produced from neutrophils by stimulation with bacterial endotoxin, lipopolysaccharide (LPS). We also found that the serum sulfite concentration is increased in a rat model of sepsis induced by systemic injection of LPS. However, information on sulfite metabolism in human inflammatory conditions is limited. In the current study, the serum concentration of sulfite was determined in 25 patients with acute pneumonia. Serum sulfite concentration in pneumonia patients was significantly higher than that in control subjects (3.75 ± 0.88 vs. 1.23 ± 0.48 &mgr;M, respectively, P < 0.05). Among 20 patients, serum sulfite was serially determined before and after antibiotic therapy. The levels of serum sulfite were significantly reduced during the recovery phase compared with those during the acute phase (1.34 ± 0.56 vs. 3.65 ± 0.92 &mgr;M, respectively, P < 0.05). Moreover, neutrophils obtained from three patients during the acute phase of pneumonia spontaneously produced higher amounts of sulfite in vitro than those obtained after recovery. There was a close positive correlation (r = 0.71, P < 0.05) between serum sulfite and C-reactive protein (CRP) in patients with pneumonia. Taken together, the current findings suggest that serum sulfite increases during systemic inflammation in humans. Activated neutrophils might be responsible, at least in part, for the up-regulation of sulfite. Given various biological effects reported previously, sulfite may act as a mediator in inflammation.

Nephrotic Syndrome Associated with Liver Metastasis of Rectal Cancer

Keiju Hiromura MD, Third Department of Internal Medicine, Gunma University School of Medicine, Maebashi 371 (Japan) Dear Sir, The most common renal lesion associated with carcinoma is membranous nephrop-athy [1]. We present an unusual case of non-membranous nephrotic syndrome associated with liver metastasis of a rectal cancer. A 66-year-old Japanese man was admitted to the surgical ward on September 17, 1992, because of edema of the lower extremities. His medical history revealed that a rectal cancer, i.e., a moderately differentiated adenocarcinoma, had been resected on October 7, 1991. Although the serum tumor markers CA19-9 and carcinoembryonic antigen (CEA) were mildly increased, abdominal CT scan and ultrasonography initially revealed no evidence of relapse or of metastasis of the rectal cancer. The nephrotic syndrome was diagnosed, and prednisolone, 30 mg daily for 1 month, was administered without improvement. The patient was referred from the surgical to the medical ward on November 24, 1992. Edema of face and lower extremities was present. Daily urinary protein excretion was 15-25 g without occult blood or sugar. Blood urea nitrogen was 58 mg/dl, creatinine 1.6 mg/dl (142 μmol/l), total cholesterol 279 mg/dl, total protein 4.3 g/dl, albumin 2.3 g/dl, aspartate aminotransferase 36 IU/1, alanine aminotransferase 29IU/1, alkaline phosphatase 147 IU/1 and creatinine clearance 35.4 ml/min. A renal biopsy was performed on November 26, 1992 (yield 22 glo-meruli per specimen). Eleven glomeruli showed minor abnormalities: 3 showed mild to moderate segmental mesangial proliferation: 2 showed segmental mesangiolysis, and 5 were completely sclerosed (fig. 1). Immunofiuorescent study revealed no significant deposition of immunoglobulins or complements. Electron microscopy demonstrated the effacement of foot processes of the epithelial cells. No electron-dense deposits were detected in the glomerular basement membrane (fig. 2). The dose of prednisolone was increased from 30 to 60 mg daily on December 2, 1992. Nevertheless, the intravenous administration of albumin and diuretics was required to maintain sufficient urine output.

Platelet-Activating Factor Antagonist, SM-12502, Attenuates Experimental Glomerular Thrombosis in Rats

Platelet-activating factor (PAF) is involved in many pathologic conditions through its potent proinflammatory and vasoactive effects. Using a specific PAF antagonist, SM-12502, we investigated the role of PAF in rat experimental glomerular thrombosis. In this model, sequential injections of nephrotoxic serum (NTS) and lipopolysaccharide (LPS) selectively induce glomerular fibrin deposition accompanied by neutrophil accumulation. SM-12502, when injected simultaneously with either NTS or LPS, strongly inhibited glomerular fibrin deposition in a dose-dependent manner. In contrast, neutrophil invasion was similar in both SM-12502-injected and uninjected rats, suggesting that the antithrombotic effect was not mediated by inhibition of neutrophil migration. However, serum myeloperoxidase activity, a marker of neutrophil activation, was significantly suppressed by treatment with SM-12502. From a previous finding supporting the indispensable role of neutrophils in this model and the current observations, SM-12502 is suggested to attenuate glomerular thrombosis by inhibiting neutrophil activation. Thus, the present findings suggest an involvement of PAF in this glomerular thrombosis model.

QUANTITATION OF PROTEINURIA IN PATIENTS WITH IGA NEPHROPATHY AND MEMBRANOUS NEPHROPATHY IN EARLY MORNING AND SPOT URINE SPECIMENS

S. Yano, MD, Third Department of Internal Medicine, Gunma University School of Medicine, 3-39-22 Showa-cho, Maebashi, Gunma 371 (Japan) 600 ^ > Dear Sir, IgA nephropathy (IgA-N) and membranous nephropathy (MN-N) are common forms of chronic glomerulonephritis whose management relies on evaluation of urinary protein. Such measurements are usually done in the outpatient clinic on spot urine specimens, as the protein/creatinine ratio is reportedly well correlated with that in 24-hour urine specimens [1, 2]. We previously investigated the effects of posture on urinary protein excretion in patients with various renal diseases [3]. Urine was collected after 60 min spent in the supine position, following the collection of urine after standing for 60 min. We found that the increase in urinary protein excretion in patients with MN-N after standing significantly exceeded that in patients with IgA-N. We questioned whether there may also be a difference in urinary protein excretion between routine ‘spot’ urine and ‘early morning’ urine as collected from patients with IgA-N and MN-N at outpatient clinics. Our objective was to evaluate the urinary excretion of protein, albumin, IgG, and transferrin in early morning and spot urine specimens in patients with IgA-N and MN-N. A total of 22 Japanese patients, 13 patients with IgA-N (10 males and 3 females, mean age 42.5 ± 13.5 years) and 9 patients with MN-N (4 males and 5 females, mean age 55.8 ± 7.8 years) were included in this study, in which the diagnosis was determined by renal biopsy. Any patient with a serum creatinine level of > 2.0 mg/dl was excluded from the study. Serum creatinine lev-

SAT0337 Hypertrophic Pachymeningitis Associated with ANCA Vasculitis; A Case Series of 16 Patients

Background Recent reports indicate that hypertrophic pachymeningitis (HPM) develops in association with myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis1,2). However, little is known about clinical features and outcomes of the disease. Objectives We aimed to describe clinical, laboratory and radiological features and treatment course of HPM occurred in patients with ANCA-associated vasculitis (AAV). Methods We retrospectively analyzed 16 Japanese adult patients (11 males and 5 females), who had been treated at our hospital in a study period from January 2006 through December 2015. Diagnosis of HPM was made with MRI T1 sequence with gadolinium by detecting thickening and enhancing of brain and/or spinal dura mater in patients manifesting neurological symptoms. Diagnosis and classification of AAV was performed according to a report by Watts, et.al.3). Results The mean age at HPM onset was 60.1 years (range, 35–78 years). Out of 16 patients, HPM was detected at the onset of AAV in 9 (56.3%), at the relapsing AAV under treatment in 6 (37.5%), and before the diagnosis of AAV as idiopathic HPM in 1 (6.3%). Headache and cranial nerve palsy due to HPM were observed in 13 (81.3%) and 11 (68.8%) patients, respectively. Otitis media and sinusitis were found as complications of AAV in 7 (43.8%) and 6 (37.5%) patients. Twelve patients (75%) were classified as granulomatosis with polyangiitis (GPA). Microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis and unclassifiable vasculitis were applied to 2 (12.5%), 1 (6.3%) and 1 (6.3%) patients, respectively. Serum myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA were positive in 9 (56.3%) and 5 (31.3%), respectively, and 2 (12.5%) patients had neither of them. The mean serum C-reactive protein levels were 4.87 mg/dL (range, 0.26–17.11 mg/dL). Spinal fluids were analyzed in 6 patients, and a mild increase in spinal cell counts and protein levels were identified in 3 patients each. With MRI, thickening of dura mater in cranial fossa and tentorium cerebelli were found in 11 (68.8%) and 9 (56.3%) patients, respectively. All patients were treated with corticosteroids and 10 (62.5%) patients were concomitantly administered with other agents including cyclophosphamide, methotrexate, azathioprine and mizoribine for remission induction. All patients achieved remission of the neurological symptoms and improvement of dura mater thickening. In a mean follow-up period of 41.8 months (range, 5–89 months) after diagnosis, 4 (25%) patients experienced a relapse of HPM and received re-induction therapy. Conclusions Our results indicate that occurrence of HPM is mostly associated with GPA having either type of ANCA serology. Dura mater in cranial fossa and tentorium cerebelli was commonly involved, which could lead to cranial nerve impairment. Immunosuppressive therapy is effective, but a relapse of HPM occasionally occurs. References Yokoseki A, et al. Brain. 2014 Feb;137(Pt2):520–36. Nagashima T, et al. Neuropathology. 2000 Mar;20(1):23–30. Watts R, et al. Ann Rheum Dis. 2007 Feb;66(2):222–7. Disclosure of Interest None declared

AB0521 Repeat Biopsy in Lupus Nephritis: A Single Center Analysis in Japan

Background Repeat renal biopsy is occasionally performed in lupus nephritis (LN) patients in case of flare or worsening renal function. However, limited data are available regarding the histological changes of LN at repeat biopsy, especially by ISN/RPS 2003 classification. Objectives In the present study, we sought to determine characteristics of patients who received repeat renal biopsy and to elucidate histological changes. Methods We retrospectively analyzed LN patients with repeat renal biopsy among 150 biopsy-proven Japanese LN patients (19 males and 131 females with mean age of 36.8±13.8 years) at our department between 1976 and 2012. Renal histology was categorized by ISN/RPS 2003 classification. The chi-square test was used to compare the percentages between groups. Results Nineteen patients (6 males and 13 females with mean age of 31.5±10.2 years) received repeat renal biopsy. The mean intervals between initial and repeat biopsy was 6.4±2.6 years. The reasons for the repeat biopsy were flare of LN in 18 patients and persistent proteinuria despite treatment in 1 patient. Among 79 patients who had class IV or III/IV+V (mixed type) at initial biopsy, 16 patients (20.3%) received repeat biopsy, whereas only 3 patients (4.2%) underwent it among patients with class II, III, or V at initial biopsy (p=0.003). A repeat biopsy was more frequently performed in male (31.6%) than in female (10.3%, p=0.008). The histological changes who underwent repeat biopsy was shown in Table. The class switches were observed in 7 patients (37%). Six patients changed to mixed type, and 1 patent with mixed type transformed to class III. In addition, chronic lesions (A/C or C by ISN/RPS) were increased from 4 patients at initial biopsy to 12 patients in repeat biopsy (p=0.020). Repeat biopsy Initial biopsy II III IV V Mixed Total II 0 0 0 0 0 0 III 0 0 0 0 1 1 (5%) IV 0 0 7 0 0 7 (37%) V 0 0 0 1 0 1 (5%) Mixed 1 1 4 0 4 10 (53%) Total 1 (5%) 1 (5%) 11 (58%) 1 (5%) 5 (26%) 19 (100%) Conclusions Repeat biopsy was more frequently performed in male and in patients who had class IV or mixed type at initial biopsy. Approximately 40% patients showed class switches on repeat biopsy during a flare and most of them were a transition to mixed type. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4586

THU0406 Histological Findings of Spleen Affected by Adult Onset Still's Disease: an Analysis of 3 Cases

Background Diagnosis of adult onset Stills disease (AOSD) is based on sets of several clinical and laboratory criteria, because no specific test is available. The differential diagnosis includes malignant lymphoma and infection. A recent case-series study using positron emission tomography/computed tomography (PET/CT) have shown that injected 18F-fluoro-deoxyglucose (FDG) accumulates in spleens of AOSD patients with high frequency up to 90.9%, along with bone marrow (100%) [1]. It is currently unknown which cell types contribute to the FDG retention in spleens of AOSD patients, while granulocytic hyperplasia in bone marrow reported as a common feature of AOSD may be responsible for the FDG uptake by bone marrow [2]. Objectives We aimed to present AOSD cases that underwent spleen biopsies to rule out malignant lymphoma. Methods Three AOSD patients (aged 31, 40 and 48 years) with high FDG accumulation in spleens and bone marrow (mean max SUV, 5.46 and 4.70, respectively) were subjected to percutaneous spleen and bone marrow biopsies, and specimens were histologically analyzed. The diagnosis of AOSD was made according to Yamaguchi criteria. Results Severe infiltration of neutrophils into red pulps was observed in all spleen biopsies (shown in image), which resembled acute splenitis caused by sepsis [3]. Plasmacytic hyperplasia was found in 1 among the 3 biopsies. In addition, we identified mild eosinophilic infiltration in each biopsy. Bone marrow examination revealed hypercellular bone marrow with granulocytic hyperplasia and histiocytic hemophagocytosis in 1, and normocellular bone marrow with normal myeloid/erythroid ratio in 2 among the 3 biopsies, which is inconsistent to the previous report [2]. Conclusions Our results indicate that neutrophils infiltrating in red pulps are relevant to the FDG-uptake by spleens among AOSD patients. Spleen biopsies are useful to differentiate AOSD from malignant lymphoma, but unable to exclude sepsis. References Yamashita, H., et al., Clinical value of F-fluoro-dexoxyglucose positron emission tomography/computed tomography in patients with adult-onset Stills disease: A seven-case series and review of the literature. Mod Rheumatol, 2013. [Epub ahead of print] Min, J.K., et al., Bone marrow findings in patients with adult Stills disease. Scand J Rheumatol, 2003. 32(2): p. 119-21. Feig, J.A. and S.J. Cina, Evaluation of characteristics associated with acute splenitis (septic spleen) as markers of systemic infection. Arch Pathol Lab Med, 2001. 125(7): p. 888-91. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.1443

AB0934 Clinical Features and Prognosis of Adult-Onset Still's Disease: S Single Center Study in Japan

Background Adult-onset Stills disease (AOSD) is an inflammatory diseases characterized by spiking fever, arthritis and evanescent rash. Although AOSD is considered as a benign disease, relapses are common and life-threatening severe complications occur in some patients. Objectives In this study, we reviewed the clinical features and outcomes of AOSD patients to seek out risk factors for unfavorable outcomes. Methods We retrospectively reviewed medical charts of AOSD patients who were admitted to our department between 1997 and 2013. For the statistical analyses, Mann Whitney U test and Fishers exact test were carried out. Multivariate logistic analysis was used to identify factors independently associated with death. It was considered statistically significant if p value was less than 0.05. Results A total of 27 patients (8 male and 19 female) were available to analysis. The median age was 33 years (range, 15-64) and the median follow-up period was 2.2 years (range, 0.1-9.1). Corticosteroids and immunosuppressants were used in 92.6% and 33.3% of the patients, respectively. Methylprednisolone pulse therapy was applied in 18.5% of the patients and the median initial dose of steroids was 50 mg/day (range, 30-70; equivalent dose of prednisolone, excluding the dose of pulse therapy). All patients responded to the initial therapy, including 2 patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) alone. Twelve patients (44.4%) continued remission, whereas 15 patients (55.6%) had at least one relapse (median 2 times; range, 1-6). Five patients (18.5%) died from multiple organ failure in 3, sepsis in 1 and respiratory failure in 1 patient. The comparison of baseline characteristics between dead and alive patients was shown in Table. The complications of hemophagocytic syndrome (HPS) and disseminated intravascular coagulation (DIC) were significantly more frequent, and the hemoglobin level was significantly lower in dead patients than patients who survived. Multivariate logistic analysis showed a presence of DIC was an independent risk factor for death (OR 20.0, 95%CI 1.613-247.981, p=0.020). Table 1. Comparison of baseline characteristics between dead and alive patients Dead patients (n=5) Alive patients (n=22) P value Age (year) 46.0 (31.0–64.0) 29.0 (15.0–63.0) 0.1112 Time to diagnosis (days) 77.0 (0–498.0) 29.0 (0–120.0) 0.0802 HPS (patients) 3 (60.0%) 1 (4.5%) 0.0008 DIC (patients) 4 (80.0%) 4 (18.2%) 0.0048 Serum ferritin (ng/ml) 3889 (1039.9–89242.5) 3984.6 (158.0–100000.0) 0.6621 CRP (mg/dl) 7.0 (0.8–24.1) 7.6 (0.1–44.5) 0.8452 White blood cells (/μl) 10900 (8200–26700) 9300 (4600–32500) 0.5365 Lymphocytes (/μl) 620 (380–984) 860 (280–5525) 0.0699 Hemoglobin (g/dl) 8.5 (8.0–11.3) 11.4 (8.2–14.7) 0.0076 Platelets (/103) 27.4 (9.4–34.8) 24.4 (9.9–71.6) 0.5365 LDH (U/ml) 555.0 (330.0–1908.0) 564.0 (170.0–2530.0) 0.4945 Data expressed as the median with range or number with percentage. Conclusions Relapse rate was relatively high and death occurred not rarely in our cohort. The complication of DIC at the initial presentation was associated with death. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4939