Comparison between Japanese and Non-Japanese Features of Lupus Cystitis Based on Case Reports Including Novel Therapy and a Literature Review

Yuji Nishizaki 1, Hiromichi Tamaki 1, Sonosuke Yukawa 2, Yukio Matsui 1 and Masato Okada 1

Abstract Objective This study was carried out to determine the characteristics of lupus cystitis and to compare those of Japanese cases with those of non-Japanese cases. We also report a novel therapy for lupus cystitis refractory to corticosteroid. Methods For the literature search, published reports on lupus cystitis were searched by MEDLINE and ICHUSHI WEB. The inclusion criterion was interstitial cystitis, fulfilling the SLE classification criteria of American College of Rheumatology in 1997 and with either hydronephrosis detected by image studies (either computed tomography or ultrasonography) or bladder histopathology consistent with lupus cystitis. Interstitial cystitis without the fulfillment of the classification criteria was excluded. Patient demographic data and clinical data were retrieved from the literature and analyzed. Results Including the present 2 cases, a total of 78 cases were identified as definitive cases of lupus cystitis (35 non-Japanese cases and 43 Japanese cases). Female patients accounted for 90.7%. The preceding gastrointestinal symptoms and subsequent urinary symptoms were the most frequent. Anti-double strand DNA antibody most often expressed in the 76.1% of the patients. Mean age and the prevalence of vomiting were significantly higher among Japanese patients compared to non-Japanese cases and the prevalence of CNS involvement was lower among Japanese patients (p=0.03, 0.04 and 0.001). We report a novel therapy (cetirizine hydrochloride) for lupus cystitis refractory to corticosteroid in one of the present cases. Conclusion Lupus enteritis, female gender, and positive anti-dsDNA antibody are risk factors for lupus cystitis. Japanese cases showed older age, a higher prevalence of vomiting and a lower prevalence of CNS involvement. We also report the efficacy of the novel use of cetirizine hydrochloride for lupus cystitis refractory to corticosteroid. Key words: systemic lupus erythematosus, lupus cystitis, anti-histamine, cetirizine hydrochloride (Intern Med 50: 961-968, 2011) (DOI: 10.2169/internalmedicine.50.4708) Introduction Lupus cystitis is a relatively rare manifestation of systemic lupus erythematosus (SLE), which was first reported by Nitze in 1907 (1). The incidence has been estimated as 0.01% with a female predominance of 92% (2). It is sometimes difficult to diagnose lupus cystitis without a delay. Earlier reports Introduction Lupus cystitis is a relatively rare manifestation of systemic lupus erythematosus (SLE), which was first reported by Nitze in 1907 (1). The incidence has been estimated as 0.01% with a female predominance of 92% (2). It is sometimes difficult to diagnose lupus cystitis without a delay. Earlier reports have suggested that this potentially serious condition was not diagnosed adequately due to a lack of recognition. Although several case series on lupus cystitis have been reported, the whole disease character has not been well described in the literature to date because of its rarity. The delay of the diagnosis can lead to irreversible renal damage secondary to hydronephrosis, but an appropriate diagnosis and immediate initiation of corticosteroid therapy usually prevent this tragic complication (3). Lupus cystitis is sometimes resistant to corticosteroid therapy. In such cases immunosuppressive agents are employed to control the disease. Mechanical devices such as a J-loop catheter might be introduced in the case of hydronephrosis due to lupus cystitis, although it is not a radical treatment and patients are exposed to radiation. In Japan lupus cystitis is not relatively rare compared to other countries. Some case reports have been described in Japanese literature, and unique manifestations of Japanese cases have been also reported. However there is a lack of systematic reports. Here, we report two cases of lupus cystitis and describe the characteristics of these patients. We also conducted a literature review to analyze the typical manifestations, concomitant symptoms, and risk factors of lupus cystitis. In addition we statistically compared the characteristics of lupus cystitis among Japanese patients and non-Japanese cases. Case Report Patient 1 A 32-year-old woman with systemic lupus erythematosus (SLE) presented with pollakiuria. Five months earlier she was admitted to our hospital for loss of appetite, nausea and vomiting. At that time she was diagnosed as having SLE based on malar rash, pleuritis, lymphopenia, positive antinuclear antibody (ANA) 1 : 320 with speckled pattern, positive anti-U1 ribonucleoprotein antibody (anti-U1 RNP antibody) and positive anti-Ro antibody. Gastrointestinal symptoms were not considered as a manifestation of SLE at that time. This time abdominal computed tomography (CT) showed bilateral hydronephrosis. Lupus cystitis was suspected and subsequently bladder wall biopsy via cystoscope was performed. She was diagnosed as having lupus cystitis based on histology findings, showing an invasion of lymphocytes and deposition of C3 on a small artery (Fig. 1, 2). Although the patient received corticosteroid therapy, three months later the patient underwent bilateral insertion of a J-loop catheter for bilateral hydronephrosis (Fig. 3). Eighteen months after the first placement of the catheter the patient was admitted to our hospital for lupus nephritis flare up. Steroid pulse therapy was initiated. The dose of PSL could not be reduced below 15 mg of prednisolone because of persistent urinary symptoms. Immunosuppressive treatment such as cyclophosphamide or myocophenolate mofetil (MMF) was not chosen because of her hope for pregnancy but repetitive radiation exposure for regular replacement of the catheters forced her to avoid conceiving. One month after the last exchange of J-loop catheter, 10 mg of cetirizine hydrochloride in addition to PSL was introduced as a novel therapy for lupus cystitis. Immediately bladder irritation showed dramatic improvement and the bilateral J-loop catheters were decannulated. Abdominal ultrasonography one month later revealed normal kidneys and ureter. Her condition has been stable with oral PSL 10 mg and cetirizine hydrochloride 10 mg daily and no relapse has been noted since then. Patient 2 A 64-year-old woman was admitted to our hospital for a recurrence of nausea immediately after the discharge from our hospital for a three-week evaluation of repetitive nausea. During the last admission, objective evaluation showed no abnormality including computed tomography of abdomen and her symptom was concluded as idiopathic. The symptom responded to bowel rest and intravenous fluid. This time the initial physical examination only showed epigastric tenderness. Otherwise physical examination was normal including cutaneous, joint, lymph nodes, cardiovascular and respiratory findings. Computed tomography of abdomen showed edema of small intestine, ascites, and localized thickness of intestinal wall (Fig. 4-6). Laboratory examination at admission showed: PT-INR 1.02 and APTT 66.0 sec. The patient was referred to rheumatology for prolonged activated PTT. Detailed review of her medical history via interview disclosed a history of multiple swollen joints and malar rash for a week in the second decade of her life and photosensitivity. Diagnostic abdominal paracentesis and blood examination were added for the further evaluation. Cystoscope was also performed to investigate the localized thickness of bladder detected by abdominal CT. Blood examination showed positive ANA 1:1280 (homo and speckled pattern), positive anti-dsDNA IgG antibody, positive anti-U1 RNP antibody, negative anti-Ro antibody, negative anti-La antibody, negative anti-caridiolipin antibody, low complements (C3 47 mg/dL, C4 1 mg/dL, CH50 12.1 mg/dL). Ascites was exudative with negative bacterial culture and negative cytology. The result of bladder wall biopsy showed invasion of lymphocytes to bladder wall, consistent with interstitial cystitis (Fig. 7). She was diagnosed as having SLE, manifesting lupus enteritis and lupus cystitis at that time. Intravenous methylprednisolone 20 mg three times a day was initiated. One day later, her symptom improved dramatically. She was discharged on the 8th day of admission. Steroid was tapered gradually and maintained at a dose of 10 mg of PSL daily at the outpatient clinic. Review and analysis of the literature We searched cases of lupus cystitis up to January 2008 with MEDLINE and ICHUSHI WEB (Japan Medical Abstract Society) by using the term “lupus cystitis”. Cases of interstitial cystitis without fulfilling the classification criteria of SLE were excluded. Only the cases of lupus cystitis with either hydronephrosis detected by image studies or the evidence of bladder histopathology consistent with interstitial cystitis were included. The patient demographic data and clinical data retrieved from the literature and the present 2 patients were analyzed. In total 76 cases fulfilling the above criteria were extracted. These cases consist of 41 Japanese cases and 35 non-Japanese cases. A total of 78 cases, including the present 2 cases, were analyzed. Collected clinical data included sex, age, presence or absence of the first symptom with urinary or gastrointestinal symptoms, order of symptoms, types of gastrointestinal symptoms (e.g. diarrhea, vomiting and ascites), types of specific autoantibodies (e.g. anti-dsDNA antibody, anti-RNP antibody, and anti-Ro antibody), presence or absence of hypocomplementemia, renal involvement, or central nerve involvement, and response to corticosteroid therapy. The symptoms not stated in each article were taken as negative symptoms and the cases in which laboratory data such as antibodies were not stated were excluded from the specific data analysis. The characteristics of 35 non-Japanese cases are summarized in Table 1; and those of the 43 Japanese cases including the present 2 cases are summarized in Table 2. In 62.7% of the patients, lupus cystitis was the initial manifestation of their SLE. Concurrent or subsequent development of lupus enteritis was also reported in 81.7% of cases, which suggests a strong association of these entities in the pathogenesis. As opposed to the gastrointestinal symptoms, dermatitis, arthritis and neuropsychiatric lupus were rarely seen in conjunction with cystitis. Renal involvement was documented in 61.3% of the cases but it was generally mild. A significant serological feature was positive anti-dsDNA antibody (76.1%). As for treatment, 59.4% of the cases were successfully treated with prednisolone alone. However, there are several reports of serious complications such as persistent bilateral hydronephrosis, end-stage renal failure, and secondary upper urinary infection resulting in death. We also compared the characteristics of non-Japanese cases with Japanese cases (t-test for mean age and chisquared analysis for others). Mean age, prevalence of vomiting and prevalence of CNS involvement showed a statistically significant difference by the utility of SAS Enterprise Guide 4. (p=0.03, 0.04 and 0.001). Japanese cases exhibited older age, a higher prevalence of vomiting and a lower prevalence of CNS involvement (Table 3). Discussion We report 2 cases of lupus cystitis in SLE patients. This has been the largest such case series reported to date. In the above-mentioned patient 1, prolonged bilateral Jloop catheter placement was necessary and the radiation exposure during the procedure rendered the patient unable to conceive. The patient had a J-loop catheter for over two years with several bouts of upper urinary tract infection. Cetirizine hydrochloride was chosen for the treatment because of the safety profile for pregnancy. After the initiation of certirizine no urinary obstruction or infection has been observed without catheters. The dose of prednisolone was also tapered from 25 mg/day to 10 mg/day over one year without any flare. Anti-histamine, such as cetirizine hydrochloride, has been successfully used in interstitial cystitis without lupus erythematosus. Preceding studies reported the effectiveness antihistamine agents for interstitial cystitis without SLE (60). QOL score has been reported to be improved after treatment with hydroxyzine (61). Theoharides reported the effectiveness of hydroxyzine for interstitial cystitis through the inhibition of mast cell and neuronal secretion (62). We presume that cetirizine hydrochloride suppresses local inflammation for lupus cystitis, but further study is needed to determine the mechanism of drug action. Cetirizine hydrochloride belongs to FDA (Food and Drug Administration) pregnancy category B. Adverse events and anomalies due to drugs among humans have not been reported. Administration of cetirizine hydrochloride for women who hope to become pregnant would be a novel therapy for lupus cystitis. As for the above-mentioned patient 2, it took time to reach the diagnosis but fortunately glucocorticoid was initiated properly, which led to remission. Both of our cases were female patients manifesting gastrointestinal symptoms. They are consistent with the typical characteristics of lupus cystitis drawn from our analysis of the literature review. The results of case series including the present two cases have shown that the preceding gastrointestinal symptoms accounted for a large proportion (36.6%, 26/71). We should note this symptom for the early diagnosis of lupus cystitis. Appropriate initial therapy by steroid was effective. This response rate was 59.4% (41/69). Early diagnosis by preced gastrointestinal symptoms and therapy by steroid was essential for a good prognosis. Moreover, it is important to know that the manifestations of enteritis or urinary symptoms are commonly the first sign of SLE. To diagnose SLE, we should focus on gastrointestinal manifestation and urinary symptoms. As for biomarkers, we have to pay attention to positive of anti-dsDNA antibody cases. In our findings 76.1% (51/67) cases were positive. Patients who had preceding gastrointestinal symptoms and urinary symptoms with positive antidsDNA antibody have a significantly higher risk of lupus cystitis and SLE. When we compared Japanese cases with non-Japanese cases, Japanese cases showed advanced age, a higher prevalence of vomiting and a lower prevalence of central nerve involvement. The results would depend on environmental and genetic factors. Similarly, Japanese Behcet’s disease shows a higher prevalence of the pathergy reaction, severe eye involvement and inflammatory bowel disease (63). These special findings would depend on environmental and genetic factors. In the near future, further studies are needed to determine any difference between Japanese and non- Japanese manifestation of lupus cystitis. To avoid irreversible or serious consequences, we should recognize that lupus enteritis, female gender, and positivity of anti-dsDNA are risk factors for lupus cystitis. Moreover, we should know the manifestation is commonly the first sign of SLE. Conclusion Lupus cystitis is one of the important manifestations of SLE, which should be more widely recognized to avoid irreversible or serious consequences. Lupus enteritis, female gender, and positive anti-dsDNA antibody are risk factors of lupus cystitis. Among the reported Japanese cases, old age, a higher prevalence of vomiting and a lower prevalence of CNS involvement seemed different from the reported non- Japanese cases. We report the efficacy of Cetirizine hydrochloride for lupus cystitis refractory to corticosteroid at the first time. The authors state that they have no Conflict of Interest (COI).