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Lupus (2015) 0,

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Lupus cystitis in Korean patients with systemic lupus erythematosus: risk factors and clinical outcomes JH Koh1, J Lee1, SM Jung1, JH Ju1, S-H Park1, H-Y Kim2 and S-K Kwok1 1

Division of Rheumatology, Department of Internal Medicine, School of Medicine, Seoul St. Mary’ Hospital, The Catholic University of Korea, Seoul, South Korea; and 2Divison of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine, Seoul St. Mary’ Hospital, Seoul, South Korea

This study was performed to investigate the clinical characteristics of lupus cystitis and determine the risk factors and clinical outcomes of lupus cystitis in patients with systemic lupus erythematosus (SLE). We retrospectively reviewed 1064 patients at Seoul St. Mary’s Hospital in Seoul, Korea, from 1998 to 2013. Twenty-four patients had lupus cystitis. Lupus cystitis was defined as unexplained ureteritis and/or cystitis as detected by imaging studies, cystoscopy, or bladder histopathology without urinary microorganisms or stones. Three-fourths of patients with lupus cystitis had concurrent lupus mesenteric vasculitis (LMV). The initial symptoms were gastrointestinal in nature for most patients (79.2%). High-dose methylprednisolone was initially administered to most patients (91.7%) with lupus cystitis. Two patients (8.3%) died of urinary tract infections. Sixty-five age- and sex-matched patients with SLE who were admitted with other manifestations were included as the control group. Patients with lupus cystitis showed a lower C3 level (p ¼ 0.031), higher SLE Disease Activity Index score (p ¼ 0.006), and higher ESR (p ¼ 0.05) upon admission; more frequently had a history of LMV prior to admission (p < 0.001); and less frequently had a history of neuropsychiatric lupus (p ¼ 0.031) than did patients with SLE but without lupus cystitis. The occurrence of lupus cystitis was associated with a history of LMV (OR, 21.794; 95% CI, 4.061–116.963). The median follow-up period was 3.4 years, and the cumulative one-year mortality rate was 20%. Complications developed in 33.3% of patients with lupus cystitis and were related to survival (log-rank p ¼ 0.021). Our results suggest that the possibility of lupus cystitis should be considered when a patient with SLE and history of LMV presents with gastrointestinal symptoms or lower urinary tract symptoms. Development of complications in patients with lupus cystitis can be fatal. Thus, intensive treatment and follow-up are needed, especially in the presence of complications. Lupus (2015) 0, 1–8. Key words: Interstitial cystitis; hydronephrosis; systemic lupus erythematosus; enterocolitis

Introduction Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease. The genitourinary system is also affected; glomerulonephritis occurs in 40% to 60% of patients during the course of the disease and is one of the most serious complications of SLE.1 However, interstitial cystitis is a rare manifestation of SLE.2–4 Boye et al.5 first described a patient with immune complex-mediated interstitial cystitis. In Correspondence to: Seung-Ki Kwok, Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul 137-701, South Korea. Email: [email protected] Received 4 August 2014; accepted 5 May 2015

1983, Orth et al.6 described six such patients and proposed the term ‘‘lupus cystitis,’’ indicating involvement of SLE in the bladder. Approximately 40 patients with lupus cystitis have since been described in 21 case reports during the last three decades.3,4,6–25 In those reports, lupus cystitis occurred in patients with gastrointestinal manifestations of SLE. Lupus mesenteric vasculitis (LMV) is the main cause of gastrointestinal manifestations of SLE. LMV can result in life-threatening complications and has a high mortality of up to 50%.26 Additionally, since lower urinary tract symptoms are uncommon in patients with lupus cystitis and LMV, coexisting lupus cystitis might be underestimated. However, not every patient with lupus cystitis sufficiently responds to high-dose prednisolone

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10.1177/0961203315588575

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Lupus cystitis in Korean patients with SLE: risk factors and clinical outcomes JH Koh et al.

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therapy. Delayed diagnosis and treatment of lupus cystitis might lead to irreversible obstructive uropathy or renal failure.2,3,6,9,24 Although an understanding of the factors that suggest the presence of lupus cystitis may allow for timely diagnosis and management, there is a lack of overall information about lupus cystitis in patients with SLE. We herein investigated the demographic data, laboratory and clinical features, treatment, and clinical outcomes of patients with concurrent SLE and lupus cystitis. We also analyzed the risk factors that might distinguish patients with concurrent SLE and lupus cystitis from patients with SLE but without lupus cystitis.

Materials and methods Cases and controls We retrospectively reviewed the medical records of 1064 patients with SLE who were treated at the Rheumatology Department of Seoul St. Mary’s Hospital from January 1998 to December 2013. All patients satisfied the 1997 revised criteria for the classification of SLE.27 Of all 1064 patients, 758 had undergone abdominal computed tomography (CT) at least once during the 16-year period. We screened patients for ureteritis and/or cystitis during performance of the abdominal CT scan. We excluded patients with urinary tract infection, mechanical obstruction, transverse myelopathy, and cyclophosphamide (CYP)-induced hemorrhagic cystitis according to clinical data. In this study, lupus cystitis was defined as unexplained ureteritis and/or cystitis as detected by image studies, cystoscopy, or bladder histopathology without the presence of urinary microorganisms or stones. Complications of lupus cystitis included acute complications, relapse of lupus cystitis, development of lower urinary tract sequelae, and lupus cystitis-related death. Diagnosis of LMV was based on abdominal CT, if at least three of the following signs were noted: focal or diffuse bowel wall thickening, dilated bowel, abnormal bowel wall enhancement (target sign), engorgement of mesenteric vessels (comb sign) and increased attenuation of mesenteric fat.26 We identified 24 patients with lupus cystitis; 65 age- and sex-matched patients with SLE were included as disease controls. They were randomly chosen among patients with SLE who were admitted with other manifestations at the same time that the patients with concurrent SLE and

lupus cystitis were admitted. The study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital. Methods The medical records of all patients were reviewed, and the following conditions were evaluated: history of major organ involvement, demographic data such as age and sex, disease duration, initial presentation of lupus cystitis, various clinical features and laboratory findings, treatment modalities for lupus cystitis management, and outcomes. Of the laboratory tests, anti-doublestranded DNA (anti-dsDNA) antibody was measured using enzyme-linked immunosorbent assay (ELISA) (anti-dsDNA ELISA kit; GENESIS, Leicester, UK), and anti-DNA antibody was determined by the Farr assay. Anti-Sm, anti-Ro, anti-La, and anti-RNP were measured by Western blot (ImmunoblotTM antinuclear antibodies (ANA) Western blot; IMMCO, USA). Medications that had been prescribed by the last outpatient clinic before admission and administered to the patients for flare control were reviewed. The glucocorticoid dosage was given in prednisolone equivalents.28 Our institute has measured the SLE Disease Activity Index (SLEDAI)29 upon admission to evaluate the disease activity of all patients with SLE since 1993. Thus, lupus activity was evaluated with the SLEDAI score in the present study. Statistical analysis Continuous variables are expressed as medians and interquartile ranges, while categorical data are expressed as absolute values and percentages. To compare categorical variables, two-sided Fisher’s exact test was used. Comparisons of descriptive data between groups were performed by the Mann-Whitney U test. The cumulative incidence of complications and mortality of lupus cystitis over time were determined using a Kaplan-Meier plot, and the events were compared using the log-rank test. To identify independent risk factors, a multiple logistic regression model was used to control the effects of confounding variables. Variables with a p value of 0.10 by univariate analysis were included in the multivariate analysis. All data were analyzed using SAS software, version 9.0 (SAS Inc, Cary, NC, USA). A p value of