C.-K. Lee

Acute abdominal pain in systemic lupus erythematosus: focus on lupus enteritis (gastrointestinal vasculitis)

Objective: To determine the causes of acute abdominal pain in systemic lupus erythematosus (SLE) and to compare the clinical and laboratory data, especially antiphospholipid antibodies and the SLE Disease Activity Index (SLEDAI), between lupus enteritis (gastrointestinal vasculitis) and acute abdominal pain without lupus enteritis in patients with SLE. Methods: A retrospective study was carried out for all patients admitted with SLE from 1993 to March 2001. The SLEDAI and laboratory data were collected at the time of diagnosis of SLE and at the time of acute abdominal pain. Lupus enteritis (gastrointestinal vasculitis) was diagnosed by clinical investigation and abdominal computed tomographic findings. Results: Chart review identified 175 patients (20 male, 155 female) who had been admitted with SLE. Of these patients, 38 (22%) presented with acute abdominal pain. Lupus enteritis was the most common cause of acute abdominal pain. Patients were divided into three groups: group 1: lupus enteritis (n=17), group 2: acute abdominal pain without lupus enteritis (n=21), and group 3: SLE without acute abdominal pain (n=137). There was no difference in age and sex among the three groups. Antiphospholipid, anti-RNP, anti-Sm, anti-Ro, and anti-La antibodies did not differ among the three groups. There was no difference in the SLEDAI at the time of diagnosis and at the time of acute abdominal pain between groups 1 and 2. Complement, erythrocyte sedimentation rate, C reactive protein, and anti-dsDNA measured at the time of acute abdominal pain did not differ between groups 1 and 2. A drop in the white blood cell count at the time of abdominal pain was more prominent in group 1 than group 2. In lupus enteritis, the jejunum and ileum were the sites most commonly affected. Rectal involvement was rare. Even though four patients relapsed, all the patients with lupus enteritis, including those who relapsed, responded well to corticosteroid. Conclusion: Lupus enteritis is the most common cause of acute abdominal pain in SLE. All patients with lupus enteritis responded well to a high dose of a corticosteroid without surgical intervention. The SLEDAI and laboratory data, except leucopenia, do not correlate with the occurrence of lupus enteritis.

Effects of advanced glycation end products on the expression of COX-2, PGE2 and NO in human osteoarthritic chondrocytes

OBJECTIVEnAdvanced glycation end products (AGE) accumulate in articular cartilage with age. We investigated the effects of AGE in primary-cultured human OA chondrocytes.nnnMETHODSnChondrocytes were cultured with/or without AGE-bovine serum albumin (AGE-BSA) and the expression levels of inducible nitric oxide (iNOS), cyclooxygenase (COX)-2 microsomal prostaglandin E synthase-1 (mPGES-1) were evaluated using RT-PCR and western blot analysis. Prostaglandin E(2) (PGE(2)) was analysed by ELISA and nitric oxide (NO) was analysed by Griess reaction assay. Pharmacological studies to elucidate the involved pathway were executed using specific inhibitors of MAPK and receptor for AGE (RAGE).nnnRESULTSnWe found that treatment of OA chondrocytes with AGE-BSA increased COX-2, mPGES-1 and iNOS mRNA and protein, as well as elevating production of PGE(2) and NO. Pre-treatment with the MAPK inhibitors SP600125 (JNK inhibitor), SB202190 (p38 inhibitor) or PD98059 (ERK inhibitor) significantly inhibited AGE-BSA induction of COX-2 expression and production of PGE(2). In contrast, SN50, a nuclear factor-kappaB (NF-kappaB) inhibitor, had no effect on levels of COX-2 and PGE(2). SB202190 and SN50, but not SP600125 and PD98059, decreased AGE-BSA-induced production of NO. Pre-treatment with soluble receptor for AGE (sRAGE) also reduced AGE-stimulated COX-2, iNOS and PGE(2), implicating the involvement of RAGE.nnnCONCLUSIONSnThese results show that AGE may augment inflammatory responses in OA chondrocytes by increasing PGE(2) and NO levels, possibly via the MAPK pathway for PGE(2) and the NF-kappaB pathway for NO.

Serum ferritin as a serologic marker of activity in systemic lupus erythematosus

Abstract. To investigate the relationship between serum ferritin and disease activity in systemic lupus erythematosus (SLE), we enrolled 128 patients with SLE (18 males and 110 females). Twenty-eight patients (2 males and 26 females) with rheumatoid arthritis (RA) served as controls. The SLE patients were subdivided into three groups according to Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores: groups A (0–5), B (6–9), and C (≥10). We prospectively evaluated 48 SLE patients before and after treatment. Serum ferritin and anti-dsDNA antibody were measured by radioimmunometric assay. C-reactive protein (CRP) was measured quantitatively by immunonephelometry. Complements 3 and 4 (C3 and C4) were measured by nephelometry. Serum levels of ferritin during the more active stage of SLE (group C) exceeded those of RA patients and patients at less active stages of SLE (groups A and B). There were no significant differences between RA patients and groups A and B. Serum ferritin was elevated especially in serositis and hematologic manifestation. In this prospective study, changes in SLEDAI scores before and after treatment correlated significantly with serum ferritin levels and inversely to C3 and C4 levels. We confirm that serum ferritin levels can be a useful marker of disease activity in SLE patients.

Behcet's disease associated with bone marrow failure in Korean patients: clinical characteristics and the association of intestinal ulceration and trisomy 8

OBJECTIVESnThe aim of this study was to determine the clinical characteristics of Behcets disease (BD) associated with bone marrow failure (BMF), classified as conditions such as myelodysplastic syndrome (MDS) or aplastic anaemia (AA), in Korea.nnnMETHODSnA retrospective analysis was made of 13 patients with BD associated with BMF (MDS 8 cases, AA 5 cases) and 66 patients with BD not associated with BMF. These patients all fulfilled the diagnostic criteria of the international BD study group.nnnRESULTSnBD patients with BMF showed significantly lower leucocyte count, haemoglobin level and platelet count when compared with patients without BMF (P < 0.001). BD patients with BMF had significantly higher serum CRP level at the time of BD diagnosis compared with patients without BMF (P = 0.03). Intestinal lesions were more frequent in BD patients with BMF than those without BMF (61.5% vs 13.6%, P = 0.001). Cytogenetic abnormality was observed in 90.9% of BD patients with BMF. Of the cytogenetic abnormalities, trisomy 8 was most common, occurring in 70% of the patients. In four patients with refractory BD associated with BMF, successful treatment of BMF by haematopoietic stem cell transplantation resulted in clinical remission of BD.nnnCONCLUSIONSnOur study indicates that intestinal ulceration is a characteristic finding in BD associated with BMF. It also suggests that cytogenetic aberration, especially trisomy 8, may play an important role in the pathogenesis of BD associated with BMF.

The difference between lupus nephritis class IV-G and IV-S in Koreans: focus on the response to cyclophosphamide induction treatment

OBJECTIVESnTo evaluate the response to induction therapy with intravenous (i.v.) cyclophosphamide (CYC) in Korean patients with class IV-G (diffuse global proliferative glomerulonephritis) and class IV-S (diffuse segmental proliferative glomerulonephritis) lupus nephritis (LN) according to the classification system of the International Society of Nephrology/Renal Pathology Society (ISN/RPS).nnnMETHODSnOf the 52 patients with biopsy-proven diffuse proliferative LN, who had been treated with i.v. CYC over a 10-yr period, 42 had been treated with i.v. CYC (equal to or more than 500 mg) for 6 consecutive months and had biopsy specimens containing more than nine glomeruli. The renal pathology of these 42 patients was reclassified according to the International Society of Nephrology and the Renal Pathology Society 2003 classification, and their renal response rates and laboratory indices after induction therapy were analysed.nnnRESULTSnOf the 42 patients assessed, 30 (71%) had IV-G and 12 (29%) had IV-S. Pre-treatment 24 h urinary protein was significantly higher and pre-treatment concentration of anti-dsDNA antibody was significantly lower in IV-G than in IV-S patients. Following induction therapy, complete remission rates were significantly higher in patients with IV-S (67%, 8/12) than in patients with IV-G (33%, 10/30) LN.nnnCONCLUSIONSnClass IV-G LN responded more poorly to induction therapy with i.v. CYC pulse than class IV-S LN.

Serum cholesterol in idiopathic and lupus-related protein-losing enteropathy.

Abstract The characteristics of protein-losing enteropathy were evaluated in patients with systemic lupus erythematosus. Among the patients with systemic lupus erythematosus (n = 380) in a tertiary hospital, we reviewed the records of seven patients with generalized edema, hypoalbuminemia without proteinuria and positive results on 99mTc-labelled human serum albumin scintigrams. Patient characteristics and laboratory findings were compared between these seven patients and patients with lupus enteritis (n = 15) or idiopathic protein-losing enteropathy (n = 11). Compared with the lupus enteritis patients, the erythrocyte sedimentation rate and serum total cholesterol levels were significantly increased in patients with systemic lupus erythematosus–related protein-losing enteropathy. Compared with idiopathic protein-losing enteropathy patients, the level of serum total cholesterol was significantly increased, but the level of serum albumin was decreased in patients with systemic lupus erythematosus–related protein-losing enteropathy. Among patients with systemic lupus erythematosus–related protein-losing enteropathy, four patients had high serum total cholesterol levels (≥248 mg/dL) and achieved complete remission after receiving high doses of steroid treatment. However, three patients who had low serum total cholesterol levels (≤219 mg/dL) responded poorly to the steroid-only treatment, and could achieve complete remission only after 3 months of cyclophosphamide pulse treatment with concurrent corticosteroid therapy. The levels of serum total cholesterol are intriguing feature in systemic lupus erythematosus–associated protein-losing enteropathy patients.

Successful treatment of recurrent lupus enteritis with rituximab

Sir, A 23-year-old Korean woman was admitted to our hospital in August 2007 with a 4-day history of abdominal pain associated with nausea and vomiting. Three years prior to admission she had been diagnosed with systemic lupus erythematosus (SLE) based on malar rash, lymphocytopenia, positive anti-nuclear antibody, anti-Ro antibody, and anti-double-stranded (ds)DNA antibody. Antiphospholipid antibodies including lupus anticoagulant, anti-cardiolipin antibodies (immunoglobulin [Ig]M and IgG), beta2-glycoprotein I antibodies (IgM and IgG) were all negative on two repeated tests. Prior to this admission, the patient had experienced six episodes of recurrent lupus enteritis from May 2005 to July 2007. With each episode of lupus enteritis, she complained of abdominal pain with or without vomiting and diarrhea, and enhanced computed tomography (CT) scans of the abdomen showed diffuse mucosal edema and bowel wall thickening involving the small and large intestine (target-like appearance) with variable amounts of ascites (Figure 1). Laboratory findings at each admission were unremarkable except for hypocomplementemia. On each occasion, she completely recovered after intravenous (IV) treatment with high-dose steroids (methylprednisolone 1mg/kg/day) and conservative treatments including bowel rest and IV fluids. After the third episode of recurrent lupus enteritis, she received mycophenolate mofetil (MMF) until the fourth episode, and was treated with oral cyclophosphamide (CYC) for 3 months, followed by azathioprine (AZA) for 4 months. However, she experienced two more episodes of recurrent lupus enteritis until July 2007. At the seventh admission for lupus enteritis in August 2007, we decided to administer rituximab 500mg per week IV for 2 consecutive weeks in addition to high-dose steroids. The patient’s absolute CD19 count was 36.7/mm at the time of the first infusion, which decreased to 17.4/mm at 2 weeks after the first rituximab infusion. In September 2007, 3 weeks after the first infusion, the lupus enteritis recurred and high-dose methylprednisolone (2mg/kg/day IV) was administered. At four weeks after the first rituximab infusion, the patient’s CD19 count decreased to 3.1/mm. Thereafter, with gradual tapering of oral corticosteroids, no further lupus enteritis relapse occurred. At 6 months after the first infusion, the patient’s CD19 count was increased to 47.3/mm. For fear of possible relapse of lupus enteritis, she wanted repeated infusion of rituximab rather than observation without rituximab therapy. She received a second cycle of rituximab with concomitant methylprednisolone 100mg/day IV. At 7 months after this second infusion, with a CD19 count of 52.3/mm, the patient received a third cycle of rituximab with concomitant methylprednisolone. In December 2008, 15 months after discharge, the oral methylprednisolone was tapered off and no subsequent symptoms and signs of lupus flare have been reported (Figure 2). Lupus enteritis is one of the most serious complications of SLE. High doses of steroids are required and surgical intervention is indicated if extensive bowel infarction or perforation occurs. Antiphospholipid antibody syndrome can induce intestinal ischemia or infarction and cause symptoms similar to those of mesenteric vasculitis. In our patient, there was no evidence of anti-phospholipid antibodies or thrombosis, and diffuse mucosal edema with bowel wall thickening (target-like appearance) and complete reversibility after immunosuppressive treatments were strongly indicative of intestinal ischemia secondary to mesenteric vasculitis. The recommended initial treatment for lupus enteritis is high-dose parenteral steroids together with complete bowel rest. However, relapse is not uncommon, even in patients who show a good initial response to this treatment. Recently, a case of severe relapsing lupus enteritis treated successfully with a combination of CYC and rituximab was reported. This patient remained free of relapse for 2 years after treatment with two cycles of intra-venous (IV) methylprednisolone 100mg rituximab 500mg IV and CYC 500mg IV. However, the use of single-agent rituximab in lupus enteritis has not been reported. Rituximab is a chimeric monoclonal antibody directed against the CD20 molecule present on B lymphocytes. Several reports have described the use of rituximab to successfully treat refractory lupus Correspondence to: Yong-Gil Kim, Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388–1 Pungnap-dong, Songpa-gu, Seoul 138–736, Korea. E-mail: bestmd2000@amc.seoul.kr Received 9 April 2009; accepted 4 June 2009

Concurrent occurrence of chylothorax and chylous ascites in a patient with Henoch-Schönlein purpura.

Chylothorax or chylous ascites, characterized by the presence of chyles in the pleural or peritoneal cavity, is an uncommon condition rarely seen other than in trauma or malignant lymphoma (1, 2). Other rare causes include tuberculosis, constrictive pericarditis, radiation, systemic lupus erythematosus (3), and the nephrotic syndrome (1, 2). Here we report on a patient with Henoch-Schönlein purpura (HSP) who developed chylothorax and chylous ascites during treatment with a high-dose steroid regimen. A 68-year-old man was admitted to our hospital with a 20-day history of general oedema, diffuse abdominal pain, and purpuric skin rashes involving both legs. The results of initial laboratory studies were: serum albumin 22 g/L, total cholesterol 133 mg/dL, and 24 h urine protein 1.104 g/day. Antineutrophil cytoplasmic autoantibody, antinuclear antibody, and cryoglobulin test were negative. A skin biopsy specimen of the purpuric rash showed leukocytoclastic vasculitis. A percutaneous kidney biopsy specimen showed mesangial proliferative glomerulonephritis with focal global glomerular sclerosis. An immunofluorescence study revealed diffuse staining of IgA and C3 on mesangial cells. A diagnosis of HSP was made and the patient was started on a high dose of prednisolone (1mg/kg/day). After 5 days of treatment, his abdominal pain, skin rash, and general oedema were improved, and he was discharged from hospital. However, he was readmitted 7 days later for relapsed general oedema, abdominal distension and dyspnea, despite continuous high-dose steroid treatment. Laboratory studies showed serum albumin 22 g/L, total cholesterol 230 mg/dL, and 24 h urine protein 11.616 g/day. A chest radiograph showed bilateral pleural effusions without active lung lesions. Using paracentesis, we obtained milky fluid that had the following biochemical values: white blood cells 260|10/L, protein 10 g/L, lactic dehydrogenase (LDH) 81 IU/L, adenosine deaminase (ADA) v2.8 U/L, cholesterol 15 mg/dL, triglyceride 54 mg/dL. Using thoracentesis, we obtained the same type of milky fluid that had the following biochemical values: white blood cells 480|10/L, protein 10 g/L, LDH 141 IU/L, ADAv2.8 U/L, cholesterol 15 mg/dL, triglyceride 65 mg/dL. Gram staining and staining for acid-fast bacilli of the pleural and peritoneal fluid did not reveal any microorganisms. Cytologic examination of the pleural and peritoneal fluid was negative for malignant cells. Lipoprotein electrophoresis of the pleural and peritoneal fluids showed an increase in the chylomicron fractions. A lymphangiography scan revealed no evidence of lymphatic leak or obstruction in the thoracic or peritoneal cavity. A computer tomographic (CT) scan was performed because of the suspicion of malignancy, such as lymphoma, but did not show any evidence of malignancy. The patient was fed a medium chain triglyceride diet and started on a 500 mg/m bolus of monthly intravenous cyclophosphamide in addition to the high-dose steroid treatment. After two cycles of monthly intravenous cyclophosphamide, the chylothorax, chyloascites, and general oedema resolved. After six monthly cycles, 24 h urine protein had decreased to 0.73 g/day. Most cases of chylous effusions respond well to a low-fat diet with medium chain triglyceride or total parenteral alimentation (4). When managing patients for whom the causes of the chyous effusion are known, treating these underlying causes is of pivotal importance. HSP is a small vessel vasculitis that often involves the kidneys and can cause severe nephrotic syndrome. Although some authors (5) maintain that combination therapy with prednisolone and cyclophosphamide is more effective in managing severe HSP nephropathy, the optimal treatment regimen remains controversial. Our patient was diagnosed with HSP nephropathy initially, and received high-dose steroid treatment. But during the course of treatment, chylothorax and chylous ascites developed, with worsening proteinuria. On examination, there was no evidence of malignancies, infections, lymphatic leak, or obstruction. The patient was successfully treated with cyclophosphamide in addition to a high dose of steroid, and a low-fat diet with medium-chain triglycerides. In conclusion, this case shows that HSP is one of the rare causes of chylous effusions, and that cytotoxic therapy, such as cyclophosphamide, has an effect on HSP nephropathy refractory to highdose steroid treatment. Chang-Keun Lee, Division of Allergy and Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Korea. E-mail: cklee@amc.seoul.kr

Systemic lupus erythematosus complicated by acquired von Willebrand’s syndrome

Haematological abnormalities are common in systemic lupus erythematosus (SLE). In some cases of acquired von Willebrand syndrome (AvWS), von Willebrand disease (vWD) is associated with autoimmune or lymphoproliferative disorders. In this study, we describe a 36-year-old woman with SLE and AvWS. The patient was referred to our hospital because of easy bruisability and recurrent vaginal bleeding. She had no history of bleeding tendency and no family history of bleeding diathesis, but she had a history of recurrent arthralgia, photosensitivity and sicca symptoms. Tests for antinuclear, anti–double stranded DNA, anticardiolipin and anti–β2-glycoprotein I antibodies were all positive. Analysis of haemostatic parameters showed complete absence of von Willebrand factor ristocetin cofactor (vWF:Rco), von Willebrand antigen (vWF:Ag) and ristocetin-induced platelet aggregation (RIPA). Electrophoretic analysis of plasma showed a complete absence of high–molecular weight vWF multimer. The presence of antibody to vWF was detected by enzyme linked immunosorbent assay (ELISA). Treatment with corticosteroids improved SLE symptoms and corrected bleeding diasthesis. Also, the multimeric patterns of vWF became normalised and anti–vWF antibody disappeared. These findings indicated that this patient had SLE associated with AvWS, which was ameliorated by corticosteroid treatment.

Lupus enteritis: clinical characteristics and predictive factors for recurrence.

Objectives To compare the clinical characteristics of lupus enteritis (LE) and non-enteric lupus (non-LE) patients and identify predictors of LE recurrence. Methods We retrospectively reviewed the medical records of 62 systemic lupus erythematosus (SLE) patients in a tertiary hospital who experienced enteric symptoms and underwent abdominal computed tomography scanning between January 1997 and December 2013. We compared the clinical characteristics between LE and non-LE patients and between recurrent LE and non-recurrent LE cases. Results Out of 62 SLE patients with enteric symptoms, 46 cases (74%) were compatible with LE based on computed tomography findings. The C4 level was decreased in the LE group compared with the non-LE group (9.0u2009±u20095.6 vs. 12.3u2009±u20096.2, pu2009=u20090.032). Recurrence of LE was observed in 14 patients (28%). Initial involvement at the colon (79% vs. 41%, pu2009=u20090.026) and bladder with/without the ureter was more common in the recurrent group (57% vs. 25%, pu2009=u20090.048). By multivariate analysis, the hazard ratios of variables associated with recurrence were 4.689 for colon involvement (95% confidence interval: 1.245–17.659, pu2009=u20090.0220] and 5.468 for cystitis with/without ureteritis (95% confidence interval: 1.629–18.360, pu2009=u20090.006). Conclusion Colon and urinary tract involvement in LE patients may be associated with the recurrence of LE.