ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2015; Early Online: 1–3 © 2015 Japan College of Rheumatology DOI: 10.3109/14397595.2015.1014153


A case of refractory polyarteritis nodosa successfully treated with rituximab Yu Seri, Hirofumi Shoda, Norio Hanata, Yasuo Nagafuchi, Shuji Sumitomo, Keishi Fujio, and Kazuhiko Yamamoto

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Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan



A 59-year-old man who presented with continuous fever, livedo reticularis, and left leg ischemia with multiple tibial artery stenosis and renal artery aneurysm, as demonstrated by arteriography, was diagnosed with polyarteritis nodosa (PAN) 6 years ago. Although he frequently relapsed in spite of intensive immunosuppressive therapies, the disease activity of PAN was controlled with repeated rituximab (RTX) therapies and steroid doses were tapered safely. Peripheral CD19⫹ Bcells disappeared soon after the 1st administration of RTX. Although CD19⫹ B-cells remained absent, 3.1% of CD3⫹CD20⫹ T-cells were observed in the peripheral blood prior to the 2nd administration of RTX. Recent studies have suggested the pathogenic role of CD3⫹CD20⫹ T-cells in autoimmune diseases in the context of RTX therapy; therefore, their roles in the pathogenesis of PAN also need to be considered.

B-cell, Polyarteritis nodosa, Rituximab, T-cell

Introduction Polyarteritis nodosa (PAN) is a rare autoimmune disease that is characterized by vasculitis in the medium- and small-sized arteries of multiple organs, including the lungs, kidneys, skin, and intestines [1]. Stenosis and aneurism on arteriograms are diagnostic features of PAN. Necrotizing vasculitis in medium- and smallsized arteries can also be diagnosed histopathologically. Steroid and immunosuppressive reagents, such as methotrexate and cyclophosphamide, are frequently used in the treatment of PAN; however, refractory and relapsed cases of PAN have been reported. Biological reagents may be good candidates for the treatment of refractory cases. The clinical efficacy of the anti-CD20 antibody, rituximab (RTX), has been demonstrated in many autoimmune diseases. We herein present a new case of refractory PAN that was successfully treated with RTX.

History Received 8 January 2015 Accepted 29 January 2015 Published online 11 March 2015

Although a histological analysis of medium-sized arteries revealed fibrous thickening of the inner and medial membranes, there was no evidence to suggest vasculitis or cellular infiltration. Moderatedose steroid therapy (prednisolone [PSL]: 0.5 mg/kg) was initiated with azathioprine (AZP). However, serum CRP levels were often elevated and ulcer exacerbation repeatedly occurred with a daily PSL dose of less than 15 mg. Therefore, tacrolimus and intravenous cyclophosphamide (IVCY) pulse therapy were attempted as a steroid-sparing effect. Necrosis and severe ulceration relapsed in the lower left leg 1 year before the patient was admitted during IVCY courses, resulting in amputation. Steroid pulse therapy was initiated following amputation, and IVCY was continued for 10 courses (the total dose administered was 8750 mg). Serum CRP levels subsequently decreased and skin ulcers healed. After completing IVCY, AZP was started for maintenance therapy and the PSL dose was tapered to 7 mg daily 3 months before his

Case report A 59-year-old man was admitted to our department due to a painful skin rash on his lower right leg and a prolonged elevation in C-reactive protein (CRP) levels. Six years prior to being admitted, he exhibited ischemic necrosis, ulcers, and livedo reticularis on his left lower leg. He also had myalgia in the lower legs and low-grade fever. Arteriography revealed multiple stenoses in the tibial artery and total occlusion of the pretibial artery (Figure 1A). Arteriography of the abdominal arteries also revealed an aneurysm in the left renal artery (Figure 1B). The patient was diagnosed with PAN in accordance with the American College of Rheumatology criteria [2]. The second toe on the left foot was amputated.

Correspondence to: Hirofumi Shoda, Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. Tel: ⫹ 81-3-3815-5411. Fax: ⫹ 81-3-3815-5954. E-mail: [email protected]

Figure 1. (A) Arteriography of the left leg. Total occlusion of the pretibial artery was indicated by the arrowhead. (B) Arteriography of the left renal artery. The aneurysm was indicated by the arrowhead.

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Y. Seri et al.

admission. A painful skin rash appeared again on his right lower leg 1 month before his admission and an increase in his serum CRP level (4.4 mg/dL) was noted. Although the daily dose of PSL was increased to 30 mg, his skin rash did not improve; therefore, he was referred to our department. On admission, his blood pressure was 152/98 mmHg, pulse rate was 82 beats per minute, and body temperature was 36.6°C. Livedo reticularis and a palpable painful skin rash were observed on his lower right leg. The dorsalis pedis artery pulse in the right foot was diminished. Laboratory data showed that inflammatory responses were increased (CRP: 0.61 mg/dL and erythrocyte sedimentation rate: 38 mm/hr). Blood cell counts revealed an elevation in white blood cell (11300/μL) and platelet (42.7 ⫻ 104/μL) counts and mild normocytic normochromic anemia (hemoglobin: 12.7 g/dL, mean corpuscular volume: 90.2 fl, mean corpuscular hemoglobin concentration: 31.4 g/dL, and reticulocytes: 1.2%). His liver and renal functions were maintained within normal levels throughout the course of his disease, and no serum autoantibodies, including anti-neutrophil cytoplasmic antibodies (ANCAs), rheumatoid factor, or anti-nuclear antibodies, were detected. Serum complements were increased (CH50: 60 U/mL, C3: 119 mg/dL, and C4: 23 mg/dL). Neither the serum hepatitis B antigen nor anti-hepatitis B and C antibodies were detected. Since we considered it difficult to control his disease using previous immunosuppressive therapies, RTX was initiated (375 mg/m2/week four times) with the consent of the patient and Ethical Committee of the hospital. The number of CD19⫹ B-cells in the peripheral blood decreased after the first course of RTX (43/μL to 1.7/μl) (Figure 2). Herpes zoster occurred 6 months after the induction of RTX and was treated with antiviral therapy. Although the activity of vasculitis was controlled for at least 1 year, a mild relapse of the skin rash was observed. An additional course of RTX therapy was initiated. Although the number of CD19⫹ B-cells in the peripheral blood did not recover, CD3⫹CD20⫹ T-cells were detected (111/μL, 3.1% of all CD3⫹Tcells). This CD3⫹CD20⫹ T-cell population disappeared following RTX therapy (Figure 2). Remission has been maintained for

Mod Rheumatol, 2015; Early Online: 1–3

Figure 2. Peripheral lymphocytes analyzed by flow cytometry.

1.5 years and the daily steroid dose was tapered to 6 mg. The disease course is summarized in Figure 3.

Discussion Three non-virus-related cases of PAN that were treated with RTX have been reported to date. Sonomoto et al. described a 47-yearold male patient with PAN who had cutaneous and neurological lesions. His disease was refractory to steroids, IVCY, IV gammaglobulin, and leukocytapheresis, whereas RTX was effective [3]. Ribeiro presented a case of a 71-year-old man with PAN, in which coronary artery involvement and skin ulcers were resolved by RTX [4]. Rees also described a case of cutaneous PAN in which clinical remission was maintained for 28 months with repeated RTX therapy [5]. On the other hand, RTX-refractory PAN has also been reported [6]. In our case, intensive therapy with repeated IVCY could not maintain long-term remission; difficulties were associated with tapering the steroid dose. However, the initiation of RTX

Figure 3. Summary of the clinical course.

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DOI 10.3109/14397595.2015.1014153

successfully controlled the activity of vasculitis and the steroid dose was tapered safely. The clinical efficacy of RTX in the treatment of ANCAassociated vasculitis has been demonstrated previously [7–8]. The mechanisms underlying B-cell depletion therapy are considered to involve in the removal of pathogenic ANCAs. In some cases, vasculitis relapsed without elevations in ANCAs, and the removal of infiltrated B-cells in inflamed organs was also considered to be the mechanism of action of RTX. In contrast, the importance of B-cells has not been established in the pathogenesis of PAN, and PAN-associated autoantibodies have not yet been discovered. Although infiltrating cells in the vascular lesions of PAN patients are mainly macrophages and T-lymphocytes, B-cells also infiltrate into lesions and may be a target of RTX therapy [9]. B-cells can activate immune responses by promoting the secretion of cytokines and antigen presentation [10]. The depletion of B-cells may suppress pro-inflammatory cytokines such as interleukin-6, or modify T-cell differentiation [10]. CD3⫹CD20⫹ T-cells were observed in the minor relapse period before the 2nd course of RTX, and subsequently disappeared after RTX. A CD3⫹CD20⫹ T-cell population was recently identified in patients with rheumatoid arthritis and multiple sclerosis, and is considered to play pathological roles [11,12]. In the case of multiple sclerosis, peripheral CD3⫹CD20⫹ T-cells were previously observed before the administration of RTX, were clearly depleted after RTX, and then gradually recovered [12]. Unfortunately, we did not find out CD3⫹CD20⫹ T-cell counts before the first RTX administration; therefore, it was difficult to demonstrate the pathological importance of CD3⫹CD20⫹ T-cells in the present case. However, minor relapse occurred without the recovery of peripheral CD19⫹ B-cells, suggesting that CD3⫹CD20⫹ T-cells were involved in the relapse of vasculitis and were a target of RTX therapy in PAN. In our case, histological findings in the arteries were mainly fibrous and chronic lesions. We attributed this to long-term vascular inflammation with modifications by steroid therapy. Since we did not determine how RTX exerted its effects in our case, the precise mechanisms of action of RTX in the treatment of PAN need to be elucidated in more detail in future studies. Taken together, we reported a new case of refractory PAN that was successfully treated with the repeated administration of RTX. CD3⫹CD20⫹ T-cells were observed before an additional RTX course, which disappeared after therapy. Although the clinical efficacy of RTX has not yet been established in the treatment of PAN, RTX can be considered as an alternative therapy for refractory PAN in view of the difficulties associated with treating active vasculitis, especially for maintaining long-term remission and sparing steroid doses.

Treatment of refractory polyarteritis nodosa with rituximab 3

Conflict of interest Y.K. received financial support or fees from AbbVie, Astellas, BMS, Daiichi-Sankyo, MitsubishiTanabe, Pfizer, Sanofi, Santen, Takeda, Teijin., Boehringer Ingelheim, Chugai, Eisai, Ono, Taisho Toyama, UCB, ImmunoFuture, Asahi Kasei, and Janssen. K.F. received financial support or fees from Astellas, BMS, Daiichi-Sankyo, MitsubishiTanabe, Pfizer, Santen, Takeda, Chugai, Eisai, Taisho Toyama, UCB, and Janssen. All other authors declare no competing financial interests.

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A case of refractory polyarteritis nodosa successfully treated with rituximab.

A 59-year-old man who presented with continuous fever, livedo reticularis, and left leg ischemia with multiple tibial artery stenosis and renal artery...
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