□ CASE REPORT □ Successful Treatment with Rituximab in a Patient with TTP Secondary to Severe ANCA-Associated Vasculitis Yukari Asamiya 1, Takahito Moriyama 1, Mari Takano 1, Chihiro Iwasaki 1, Kazuo Kimura 1, Yukako Ando 1, Akiko Aoki 1, Kan Kikuchi 2, Takashi Takei 1, Keiko Uchida 1 and Kosaku Nitta 1 Abstract We report a case of thrombotic thrombocytopenic purpura (TTP) secondary to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis treated by rituximab. TTP secondary to ANCA-associated vasculitis is very rare and has a high mortality rate. We employed rituximab and successfully treated TTP secondary to ANCA-associated vasculitis, because standard therapies, such as steroid therapy, intravenous pulse cyclophos- phamide, and repeated plasma exchange (PE), did not suppress her disease activity. This is the first report to suggest that rituximab can achieve complete remission of TTP secondary to ANCA-associated vasculitis. Key words: ANCA-associated vasculitis, TTP, rituximab, renal failure, intrapulmonary hemorrhage, hemo- dialysis (Inter Med 49: 1587-1591, 2010) (DOI: 10.2169/internalmedicine.49.3135) pies such as steroids and therapeutic PE (4-6). However, ri- Introduction tuximab was employed mainly against idiopathic TTP, and there were few reports discussing treatment of secondary Antineutrophil cytoplasmic antibody (ANCA)-associated TTP; in particular, TTP with ANCA-associated vasculitis vasculitis is recognized as a multisystem autoimmune dis- was rare. Here, we report a patient with TTP secondary to ease characterized by ANCA production and small vessel in- myeloperoxidase-antineutrophil cytoplasmic antibody (MPO- flammation (1). It’s typical clinical manifestations are rap- ANCA) associated vasculitis who was treated using rituxi- idly progressive glomerulonephritis and the occasional de- mab combined with steroid pulse, IVCY and repeated PE. velopment of intrapulmonary hemorrhage, which is poten- This is the first report of the successful use of rituximab tially fatal (2). against TTP secondary to ANCA-associated vasculitis. Thrombotic thrombocytopenic purpura (TTP) is a life- threatening disease. TTP secondary to ANCA-associated Case Report vasculitis is very rare; to the best of our knowledge, only nine cases have been reported. Those nine cases all received In 2002, a 59-year-old woman was admitted to our hospi- intensive therapies such as steroid pulse therapy, intravenous tal because of marked rapidly progressive renal impairment pulse cyclophosphamide (IVCY), and plasma exchange [creatinine level, 1.56 mg/dL (normal 0.48-0.79 mg/dL)], (PE), however, 56% of them died. Among these previous re- proteinuria and microscopic hematuria, interstitial pneumo- ports, none of the cases were treated using rituximab (3). nia and an elevated MPO-ANCA level of 490 EU (normal < Rituximab is a chimeric monoclonal antibody that targets 20 EU). Although a renal biopsy was not performed because the B cell-specific CD20 calcium channel, resulting in the of hydronephrosis caused by a urinary calculus, she was di- depletion of peripheral B cells. Recently, rituximab has been agnosed as having MPO-ANCA-associated vasculitis based reported in the treatment of TTP resistant to standard thera- on the diagnostic criteria of the Ministry of Health, Labor １Department of Medicine, Kidney Center, Tokyo Women’s Medical University, Tokyo and ２Shimoochiai Clinic, Tokyo Received for publication November 10, 2009; Accepted for publication March 1, 2010 Correspondence to Dr. Takahito Moriyama, [email protected] 1587 Inter Med 49: 1587-1591, 2010 DOI: 10.2169/internalmedicine.49.3135 Urinalysis Serological test total bilirubin was increased. On day 11, her platelet count Protein 2+ IgG 821 mg/dL 4 4 Occult blood 3+ IgM 128 mg/dL started to decrease to 11.6×10 /μL from 15.0-19.0×10 /μL, Red blood cells 30-49/HPF IgA 280 mg/dL LDH increased, her renal dysfunction showed signs of pro- White blood cells 5-9/HPF Serum CH50 48.8 U/mL gression (creatinine level, 4.3 mg/dL; blood urea nitrogen Serum C3 104.6 mg/dL Complete blood cell counts Serum C4 27.1 mg/dL level, 114 mg/dL) and fluid overload occurred. Then she be- White blood cells 11750/μL Annuclear anbody 1 : 160 gan receiving intermittent hemodialysis. On day 14, her Neut 90.1% MPO-ANCA 119 EU MPO-ANCA level decreased to 14 EU. The thrombocy- Lymph 6.1% PR3-ANCA < 10 EU Red blood cells 297 ×104/μL An-GBM anbody < 10 EU topenia was continuously progressive, her platelet count de- Hemoglobin 8.9 g/dL creased further to 5.0-8.0×104/μL. On day 19, her hemoglo- Platelet 17.3 ×104/μL bin level decreased to 9.2 g/dL from 11.2 g/dL, a Coombs Chemical analysis test was negative, serum haptoglobin level was undetectable. Total protein 5.7 g/dL Drug-induced hemolytic anemia and thrombocytopenia were Albumin 3.1 g/dL AST 27 U/L clinically negative and hemodialysis-induced hemolytic ane- LDH 216 U/L mia and thrombocytopenia were also considered negative BUN 72.6 mg/dL because drugs and dialyzer had not been changed during Creanine 3.9 mg/dL C-reacve protein 16.4 mg/dL this therapeutic period. Disseminated intravascular coagula- tion (DIC) was negative based on the diagnostic criteria of the MHLW of Japan (8). On the other hand she had the Figure 1. Laboratory and chest X-ray findings on admis- transient neurological symptoms including headaches, emo- sion. Chest X-ray image showed a diffuse alveolar pattern. tional disturbance and personality disorder. A brain CT scan Neut: neutrophilic leukocyte, Lymph: lymphocyte, AST: revealed no abnormal findings. The diagnosis of TTP was aspartate aminotransferase, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, MPO-ANCA: myeloperoxidase- made based on microangiopathic hemolytic anemia with antineutrophil cytoplasmic antibody, PR3-ANCA: proteinase schistocytes on the peripheral blood smear, high LDH lev- 3-antineutrophil cytoplasmic antibody, Anti-GBM antibody: els, and thrombocytopenia, in addition to clinical features anti-glomerular basement membrane antibody such as fever, organ dysfunctions of renal insufficiency and neurological deficits. Although the patient’s condition showed an improvement of ANCA-associated vasculitis, her and Welfare of Japan (7) and treated with high-dose oral renal disease was progressive, therefore we regarded that her prednisolone. Prednisolone was gradually tapered, and she renal disease was progressed with complicated TTP. PE was was treated with a maintenance dose of prednisolone of 10 started on day 21, which was replaced with 25-30 units of mg per day and her serum creatinine level was 2.50-2.87 fresh-frozen plasma three times a week, and the ADAMTS mg/dL in 2008. 13 activity was decreased at 37.8% (normal 70-120%), In February 2009, at the age of 66 years, she was admit- ADAMTS13 inhibitor level of <0.5 Bethesda Units (BU)/ ted with symptoms of a lack of appetite, fever and respira- mL on same day. On day 26, black tarry stools appeared, tory distress. Her laboratory examinations showed the fol- her blood pressure dropped to 70/42 from 116/66 mmHg lowing values: white blood cell count, 1,1750/μL (normal and she required blood transfusion. The upper esophagogas- 4,000-8,600/μL); hemoglobin level, 8.9 g/dL (normal 12-16 troduodenoscopy and colonoscopy could not be performed g/dL); platelet count 17.3×104/μL (normal 15-35×104/μL), C- immediately, because the patient’s general condition was not reactive protein (CRP), 16.4 mg/dL (normal <0.33 mg/dL); good. Contrast-enhanced CT scans of her chest, abdomen MPO-ANCA level, 119 EU; creatinine level, 3.89 mg/dL; and pelvis were performed and revealed no acute abnormali- lactate dehydrogenase (LDH) 216 U/L (normal 119-229 U/ ties except for diffuse thickening of the gastroduodenal wall. L); intense proteinuria and microscopic hematuria (Fig. 1). We suspected that disease activity of TTP and ANCA- A chest X-ray image showed a diffuse alveolar pattern associated vasculitis was not suppressed by the steroid ther- (Fig. 1). The clinical course of the patient is shown in apy and PE, thus intravenous pulse cyclophosphamide Fig. 2. On hospital day 2, a bronchoscopy was performed (IVCY) (cyclophosphamide, 200 mg) was administered on and the patient was diagnosed as having severe pulmonary day 28. The upper esophagogastroduodenoscopy was per- alveolar hemorrhage. Steroid pulse therapy (methyl- formed on day 29 and colonoscopy was performed on day prednisolone, 500 mg/day×3 days) was immediately started 35, both of them were negative of active bleeding of diges- followed by 40 mg (1.0 mg/kg body weight) per day of oral tive tract. Eight days after initiation of PE treatment, the prednisolone based on the guideline of Ministry of Health, ADAMTS13 activity increased to 70.1% (normal 70-120%) Labor and Welfare of Japan (7). On day 7, the chest com- and ADAMTS13 inhibitor level was <0.5 BU/mL. However, puted tomography (CT) scan revealed that pulmonary hem- her platelet count decreased further and remained at 3.5- orrhage tended to be improved, and her CRP level decreased 5.5×104/μL during the subsequent 10 days. As before, drug- to 0.4 mg/dL. On the same day fragmented red blood cells induced or hemodialysis treatment-induced thrombocy- (FRC) (schistocytes) were observed in her peripheral blood topenia, or DIC were considered also negative. Conse- smear for the first time and she had a high fever. On day 8, quently, the PE treatment could not be stopped because of 1588 Inter Med 49: 1587-1591, 2010 DOI: 10.2169/internalmedicine.49.3135 mPSL pulse IVCY Prednisolone (mg/day) 40 30 20 15 10 Rituximab CD19 (%) 0.5 0.4 0.2 0.1 0.1 CD20 (%) 0.8 0.1 0.1 0.1 0.2 Platelet LDH (×104/μL) PE 3 (mes/week) 2 (U/L) Hemodialysis 3 (mes/week) 20 leaving hospital 500 400 15 300 10 200 5 100 Platelet LDH 0 0 0 20406080110 140 Days from hospitalizaon Figure 2.