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Clinical Reviews in Allergy and Immunology © Copyright 2005 by Humana Press Inc. 1080-0549/05/221–229/$30.00

Clinical Studies in Patients With Castleman’s Disease, Crohn’s Disease, and Rheumatoid Arthritis in Japan Norihiro Nishimoto

Abstract

Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University.

Interleukin (IL)-6 is a pleiotropic cytokine with a wide range of biological activities and regulates immunological reactions, inflammatory responses, and hematopoiesis. Overproduction of IL-6 has been shown to be pathologically involved in some inflammatory diseases, such as Castleman’s disease, Crohn’s disease, and rheumatoid arthritis. Clinical studies have been conducted to investigate a role of IL-6 and the therapeutic potential of anti-IL-6 therapy for these diseases using humanized anti-IL-6 receptor antibody (tocilizumab; currently known as MRA). Overall, tocilizumab was well-tolerated, and improvements of signs and symptoms were observed, confirming the pathological role of IL-6 and suggesting that the blockade of IL-6 could become a new and important treatment option in these refractory diseases.

Index Entries Interleukin-6; humanized anti-IL-6 receptor antibody; tocilizumab; MRA; Castleman's disease; Crohn's disease; rheumatoid arthritis.

Author to whom correspondence and reprint requests should be addressed. E-mail: [email protected]

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Introduction Cytokines are biologically active soluble factors that induce proliferation and differentiation of various cell types (including immunecompetent cells, hematopoietic cells, and neuronal cells) and regulate immune response and inflammatory reaction. Most cytokines play essential roles as a life-support system, and their actions are well-regulated both under cytokine networks and by the expression of regulatory molecules of cytokine signals. However, deregulated overproduction of cytokines sometimes causes disadvantages to a living body. Some malignant cells have a nature of dependency on a certain cytokine. Others show signs and symptoms associated with overproduction of some cytokines. Besides malignant diseases, some auto-immune inflammatory diseases (such as rheumatoid arthritis [RA] and Crohn’s disease) are shown to have deregulated overproduction of pro-inflammatory cytokines or disruption in the regulation of cytokine signaling as underlying mechanisms, although the exact causes remain obscure. Therefore, a new therapeutic strategy can be proposed to block the actions of the cytokines that are pathologically involved in these diseases. Monoclonal antibodies (MAbs) designed during the 1970s have been widely used for researches and clinical diagnoses, taking advantage of their specificity for recognizing target antigens. Additionally, clinical trials were conducted to investigate the efficacy or safety of MAbs as magic bullets for the therapy of some malignant diseases in the 1980s, although the majority of them were unsuccessful (1). The accumulation of knowledge about the functions and distributions of the target molecules in vivo, as well as the application of molecular biology techniques to design monoclonal antibodies as therapeutic agents, have facilitated the development of the therapeutic monoclonal antibodies. Specifically, MAbs against pro-inflammatory cytokines are ready to change Clinical Reviews in Allergy & Immunology

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the therapeutic strategies of some auto-immune inflammatory diseases refractory to conventional therapies, including corticosteroids and immune-suppressive agents. Interleukin (IL)-6 is a pleiotropic cytokine with a wide range of biological activities including pro-inflammatory activities. Overproduction of IL-6 has been observed in some inflammatory diseases and is believed to be pathologically involved. We have attempted to treat patients with inflammatory diseases, such as Castleman’s disease, Crohn’s disease, and RA, using a humanized anti-IL-6 receptor (IL-6R) antibody (tocilizumab; currently known as MRA). This article discusses clinical studies for Castleman’s disease, Crohn’s disease, and RA in Japan.

IL-6 and IL-6R System IL-6 is produced by various types of cells, such as T-cells, B-cells, monocytes, fibroblasts, endothelial cells, and several kinds of tumor cells (2). IL-6 as a B-cell differentiation factor induces the differentiation of activated B-cells to produce immunoglobulins (3). IL-6 acts on hematopoietic stem cells synergistically with IL-3 to support the formation of multilineage blast cell colonies (4,5) and differentiates megakaryocytes to produce platelets (6). IL-6 is also a differentiation factor not only for T-cells (7,8) but also for macrophages (9,10). IL-6 is a hepatocyte-stimulating factor that induces acute phase protein production, such as C-reactive protein (CRP), fibrinogen, α1-antitrypsin, and serum amyloid A (SAA), while simultaneously suppressing production of albumin (11–13). It induces leukocytosis and fever when it is administered in vivo (14). Additionally, IL-6 induces the differentiation of osteoclast precursor cells to authentic osteoclasts characterized by the presence of tartrate-resistant acid phosphatase (TRAP) activity, calcitonin receptors, and pit formation in dentine slices in the presence of soluble IL-6R (sIL-6R) (15). Therefore, overproduction of IL-6 may explain the Volume 28, 2005

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appearance of some signs and symptoms of Castleman’s disease, Crohn’s disease, and RA. The pleiotropic actions of IL-6 are mediated by a unique IL-6R system. The IL-6R system consists of two functional membrane proteins: an 80-kDa ligand-binding chain (IL-6R, IL-6R αchain, CD126; ref. 16) and a 130-kDa nonligandbinding but signal-transducing chain (gp130, IL-6R β-chain, CD130; refs. 17 and 18). When bound to the cell surface IL-6R, IL-6 induces the homodimerization of gp130 and produces a high-affinity functional receptor complex of IL-6, IL-6R, and gp130. Because a very short intracytoplasmic portion of IL-6R containing only 82 amino acids is not essential for signal transduction, sIL-6R, which lacks the intracytoplasmic portion of IL-6R, is also capable of signal transduction as a ligand-binding receptor (18). A considerable amount of sIL-6R is observed both in the serum and in the synovial fluids (19,20). Therefore, it is required to block both cell surface IL-6R and sIL-6R to inhibit IL-6 signal transduction. Tocilizumab is obtained by grafting the complimentary-determining regions from the murine anti-IL-6R MAb into human immunoglobulin (Ig)G1, thereby creating a functioning antigen-binding site in a reshaped human antibody (21). This humanization reduces antigenicity of tocilizumab in vivo in humans and, therefore, decreases the emergence of neutralizing antibodies and prolongs the half-life, even when administered to patients in repeated doses. Furthermore, tocilizumab can bind both cell surface IL-6R and sIL-6R and can inhibit the formation of IL-6–IL-6R complex. It inhibited the growth of IL-6-dependent human myeloma cells with an affinity similar to the original mouse antibody and polyclonal antiIL-6R antibody (21,22).

Clinical Studies for Castleman’s Disease Castleman’s disease is an atypical lymphoproliferative disease with benign hyperplastic Clinical Reviews in Allergy & Immunology

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lymph nodes. Castleman’s disease is classified (according to the histology of affected lymph nodes) into plasma cell type, hyaline-vascular type, or a mixed type. The patients with plasma cell type or a mixed type have chronic inflammatory manifestations and immunological disorders, such as general fatigue, fever, anemia, an increased erythrocyte sedimentation rate (ESR), elevated levels of acute phase proteins (such as CRP, fibrinogen, and SAA), and polyclonal hyper-γ-globulinemia (23,24). Based on the number of affected lymph nodes, Castleman’s disease is also classified into either localized or multicentric Castleman’s disease. For the localized disease, the disease improved by excision of the affected lymph node, whereas for multicentric disease or patients to whom surgical excision cannot be applied, corticosteoroids and chemotherapy are treatment options but are often refractory. Although the exact causes of this disease are not known, uncontrolled IL-6 overproduction from the affected lymph nodes is observed (25). Signs and symptoms of patients with localized lymphadenopathy were completely abolished by resection of the affected lymph node, associated with normalization of serum IL-6 levels. This suggests that specific blockade of IL-6 action may constitute a new therapeutic strategy for this disease. In fact, it was reported that treatment with a murine anti-IL-6 antibody ameliorated signs and symptoms associated with Castleman’s disease (26). Clinical study of tocilizumab in seven patients with Castleman’s disease was first conducted with the approval of the ethics committee of Osaka University. Treatment with 50 to 100 mg of tocilizumab per body either once or twice weekly immediately improved systemic symptoms such as fever and malaise. Serum levels of CRP, fibrinogen, SAA, albumin, hemoglobin and hyper-γ-globulinemia were remarkably alleviated within a few weeks (27). Additionally, histopathological examination of the lymph node revealed that treatment with tocilizumab reduced follicular hyperplasia Volume 28, 2005

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and vascularity. In this study, the treatment with tocilizumab was well-tolerated, and only a transient and mild leucopenia was observed. Therefore, the pathological significance of IL-6 in Castleman’s disease was confirmed, and the blockade of the IL-6 actions by tocilizumab can constitute a new therapy. These encouraging preliminary results led to the initiation of a phase II clinical trial in a larger number of patients with Castleman’s disease that confirmed the results of the previous trial (28). Tocilizumab showed a significant effect on most of the 28 treated patients (Nishimoto N, Kanakura Y, Aozasa K, et al., in press). An extension study is being conducted to determine the long-term safety and efficacy of tocilizumab for multicentric Castleman’s disease.

Clinical Studies for Crohn’s Disease Crohn’s disease is a chronic granulomatous inflammatory bowel disease (IBD) of unknown etiology. The peak incidence of Crohn’s disease is in early adulthood. Conventional therapy using corticosteroids, 5-amino salicylic acid, and immunosuppressive drugs ameliorates the symptoms, but there is no curative therapy for Crohn’s disease. Pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and IL-1 have been shown to play a key role in the disease (29). Indeed, the anti-TNF-α chimeric antibody infliximab showed a remarkable therapeutic effect for the disease. The therapy not only improves the disease activity of Crohn’s disease but also maintains the improvement and even introduces patients into remission (30,31). Anti-TNF-α chimeric antibody therapy also has a potential to induce endoscopic mucosal healing and closure of draining abdominal or perianal fistulas (32). The importance of IL-6 signaling in the pathophysiology of Crohn’s disease has been suggested. Serum and colonic mucosal IL-6 levels are elevated and correlated with disease activity and degree of macroscopic inflammation (33–35). IL-6 is produced in mucosal tisClinical Reviews in Allergy & Immunology

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sue, lamina propria mononuclear cells, and colonic epithelial cells (35,36), evidenced by overexpression of messenger RNAs (mRNAs) for IL-6 in the inflamed mucosa (37,38). Colonic mucosal macrophages were also reported to produce IL-6 and sIL-6R, especially in those with active diseases (39). Therefore, IL-6 is believed to play a crucial role in the pathogenesis of Crohn’s disease. In murine colitis models established by grafting CD45RBhigh CD4+ T-cells from normal mice to congenic severe combined immunodeficient (SCID) mice, colitis similar to Crohn’s disease and wasting occurs. IL-6 blockade using rat antimouse IL-6R antibody inhibits the development of this T-helper (Th)-1 cell-mediated colitis and wasting through induction of apoptosis of lamina propria T-cells (40). The treatment prevents both macroscopic and histological lesions of colitis. The number of Mac1-positive and intercellular adhesion molecule (ICAM)-1-positive macrophages is decreased, and the expression of ICAM-1 and vascular cell adhesion molecule (VCAM)-1 in the intestinal vascular endothelium is suppressed (41). It also reduced colonic expression of TNF-α, IL-1β, interferon (IFN)-γ, and mRNA without affecting the production of transforming growth factor-β, IL-4, or IL-10 (42). This evidence led us to investigate the role of IL-6 blockade in this disease. A pilot placebo-controlled study of tocilizumab for patients with Crohn’s disease was conducted to investigate the pharmacokinetics, safety, and efficacy in Japan (43). Thirty-six patients with Crohn’s disease activity index (CDAI) greater than 150 and with abnormal CRP levels were randomly assigned to receive an intravenous infusion of either placebo alone, tocilizumab at a dose of 8 mg/kg every 2 wk, or a dose of 8 mg/kg every 4 wk for a total of 12 wk. Patients were required to have stable treatment for doses of corticosteroids, salazosulfapyridine, azathioprine, 5-amino salicylic acid, metronidazole, or elementary diet during the study period. Patients treated with cycloVolume 28, 2005

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sporine, methotrexate, or tacrolimus within 12 wk before the first administration of study drug and those who had surgery or total parenteral nutrition up to 4 wk before the first administration of study drug were excluded. The efficacy analysis was a comparison of clinical response rate, defined as a reduction of CDAI more than 70. At the final evaluation, tocilizumab administered both every 2 and every 4 wk significantly reduced the CDAI, and 8 mg/ kg administered every 2 wk was superior to 8 mg/kg administered every 4 wk. Whereas only 31% of the placebo group showed a clinical response, 80% of patients treated with tocilizumab every 2 wk showed a clinical response. Furthermore, 20% of the patients treated with 8 mg/kg of tocilizumab every 2 wk could be introduced into remission (defined as a CDAI <150), whereas none of the placebo group was introduced into remission. Additionally, the quality of life (assessed by the IBD questionnaire) significantly improved in the patients in the tocilizumab groups. The score increased over the course of treatment. In the laboratory test, all the inflammatory markers, such as ESR, CRP, SAA, and fibrinogen, were normalized within 2 wk of first administration of 8 mg/kg of tocilizumab. Anemia and thrombocytosis were also ameliorated. Histologically, an increase in the number of apoptotic mononuclear cells was observed in patients treated with 8 mg/kg of tocilizumab every 2 wk, whereas no remarkable difference was observed in the biopsy specimens from a placebo-treated patient; however, the histological study was conducted in a limited number of patients. The treatment was generally well tolerated, and there was no difference in the incidence of adverse events between the groups. They were common cold, nausea, pharyngolaryngeal pain, headache, itching, vomiting, and insomnia. There were five serious adverse events reported, but neither obvious causal relation to the tested drug nor differences in the incidences among groups was found. No serious infusion reaction was observed. Therefore, humanized anti-IL-6R Clinical Reviews in Allergy & Immunology

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antibody therapy can be a new therapeutic strategy for active Crohn’s disease.

Clinical Studies for RA RA is one of the most frequently observed auto-immune diseases. In Japan, about 700,000 patients suffer from RA. The characteristic features of RA are hyperplasia of synovial tissues, destructive change of bone and cartilages in multiple joints, and emergence of rheumatoid factors (44). In the affected joints, there are T- and Bcells infiltrating the synovial tissues. A high amount of IL-6 is produced by T- and B-cells and macrophages, as well as synovial cells (45– 47), under the stimulation of TNF-α and IL-1, and these are responsible for the synovitis and destruction of the joints through activating osteoclasts. Hyperplastic synovial tissues of the affected joints also show increased angiogenesis, which is necessary to oxygenate the tissue (48). IL-6 is also involved in the angiogenesis through induction of vascular endothelial growth factor production from synovial cells synergistically with TNF-α and IL-1β (49). Elevated levels of IL-6 are also observed (45,50–52) in the serum and are responsible for systemic inflammatory manifestations, such as general fatigue, fever, anemia, an increase in ESR, elevated levels of acute phase proteins (such as CRP, fibrinogen, and SAA), and immunological disorders, such as polyclonal hyper-γ-globulinemia and emergence of autoantibodies (including rheumatoid factors). Indeed, serum IL-6 levels are reported to correlate with the disease activity of RA (51,52). Wendling et al. (53) reported that the administration of mouse antihuman IL-6 MAb to patients with RA resulted in improvement of symptoms and laboratory findings of RA. This confirmed that IL-6 plays a crucial role in this disease and suggested that blockade of IL-6 action could constitute a new therapy for the disease. This concept was also supported by the results of experiments using animal models. Volume 28, 2005

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Collagen-induced arthritis (CIA) in DBA/1J mice is an experimental model widely used for human RA studies. IL-6 gene knockout mice obtained a constitution resistant to CIA (54,55). Antimouse IL-6R antibody treatment also suppressed both the incidence and severity of CIA and prevented destruction of the joints (56) by suppressing both T- and B-cell functions against type II collagen. Similarly, tocilizumab prevented CIA in cynomolgus monkeys because it crossreacted with monkey IL-6R (57). Additionally, tocilizumab treatment significantly decreased the volume of synovial tissues from patients with RA implanted into SCID mice, as well as the number of infiltrating inflammatory cells, matrix metalloproteinase-9-positive cells, and TRAP-positive osteoclasts (58). Initially, tocilizumab was compassionately used in patients with RA that was completely refractory to conventional therapy using various disease-modifying antirheumatic drugs (DMARDs) after obtaining the permission of the ethical committee of the institute (59). Eleven patients were treated with tocilizumab, and improvement was observed in both clinical signs and laboratory values. On the basis of this experience, the role of IL-6 blockade in adult RA was explored in the phase I/II clinical trials in both the United Kingdom and Japan (60,61). The phase I/II clinical trial in the United Kingdom was a double-blinded, placebo controlled trial of a single dose of 0.1, 1, 5, or 10 mg/kg of tocilzumab or placebo (60). The efficacy was assessed according to American College of Rheumatology (ACR) criteria at 2 wk after the administration of the study drug. In the group administered 5 mg/kg, 55.6% of patients achieved ACR20, whereas none of the group administered placebo achieved ACR20. However, no statistically significant improvement was observed for the groups administered other dosages. No serious adverse reactions related to the treatment were reported. In Japan, 15 patients repeatedly received intravenous infusion of 2, 4, or 8 mg/kg of tocilClinical Reviews in Allergy & Immunology

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izumab every 2 wk for a total of 6 mo (61). At 6 wk, 60% of the patients achieved ACR20, and at 24 wk, more than 80% achieved ACR20 and 33% achieved ACR50. CRP and SAA were normalized within 6 wk, provided that the serum trough concentration of tocilizumab was detectable. The serum concentrations of tocilizumab decreased in a nonlinear manner with the dose range from 2 to 8 mg/kg. In the groups given 2 and 4 mg/kg, serum tocilizumab was always detectable in 7 of 10 patients; in the other three patients, it was not detectable in the trough level. Biweekly treatment with 8 mg/kg was enough to maintain the serum concentration of tocilizumab. The t 1/2 increased as the dose increased. Multiple infusions also prolonged the t1/2, and after the third injection in the group administered 8 mg/kg, t1/2 reached 241.8 ± 71.4 (mean ± standard deviation [SD]) hours. The mean area-under-the-curve increased as the dose increased, and the value was 10.66 ± 4.07 (mean ± SD) mg/hr/mL in the group given 8 mg/kg. A total of 70 adverse reactions were reported, but none were serious. Increase in total cholesterol was observed in 10 of 15 patients. Without use of methotrexate or immunosuppressive agents, no antinuclear antibody, anti-DNA antibody, or anti-tocilizumab antibody appeared in this monotherapy study (61). Double-blind, randomized, placebo-controlled phase II studies for RA were conducted in both Japan (62) and Europe (63) in 2001 through 2002. In the Japanese phase II study, 164 patients with refractory disease were randomized to receive either placebo or 4 or 8 mg/kg of tocilizumab every 4 wk for a total of 3 mo, and the clinical responses were measured using the ACR criteria (62). The efficacy was apparent at week 4 and became most pronounced at the end of treatment (week 12). At final observation, 78% of the patients in the group administered 8 mg of tocilizumab and 57% in the group administered 4 mg of tocilizumab met the ACR20 criteria, whereas only 11% in the group Volume 28, 2005

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administered placebo achieved ACR20 criteria. The ACR50 and ACR70 response rates in the 8-mg group were also significantly higher compared with those in the placebo group. Tocilizumab treatment significantly improved all measures for disease activity on the ACR core set. CRP was completely normalized in 76% of the patients in the group administered 8 mg, whereas it was only 1.9% in the placebo group. Good or moderate response rate according to the disease activity score 28 improvement criteria was 91% in the group given 8 mg of tocilizumab, whereas it was 72% in the group given 4 mg of tocilizumab and 19% in the placebo group. Tocilizumab considerably improved the levels of hemoglobin, platelet, fibrinogen, SAA, and albumin, as well as rheumatoid factors. Tocilizumab also significantly increased bone formation markers such as serum osteocalcin and carboxyterminal propeptide of type-I procollagen levels, and it simultaneously decreased bone absorption markers such as urinary pyridinoline and deoxypyridinoline. The overall incidences of adverse events were 56, 59, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and were not dosedependent. In the laboratory findings, increase in nonfasting total cholesterol, as well as in high-density lipoprotein (HDL) cholesterol was frequently observed in the patients treated with tocilizumab, but these increases did not continue. There was no increase in antinuclear antibodies or anti-DNA antibodies. Antitocilizumab antibodies were detected in only two patients, although no methotrexate or immunosuppressive agents were used. Therefore, the treatment with tocilizumab was generally well-tolerated and significantly reduced the disease activity of RA. Moreover, a clinical phase II study has also been conducted in Europe, and similar results were obtained (ref 63; see also the article written by Smolen et al. in this issue). Phase III studies are being conducted both in Japan and worldwide. Clinical Reviews in Allergy & Immunology

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Future Studies Clinical studies of tocilizumab in Japan indicate that there are potential therapeutic benefits of this new agent for the treatment of chronic inflammatory diseases, such as Castleman’s disease, Crohn’s disease, and RA. However, there are some issues that need to be addressed or investigated during the further development of this agent. First, the long-term safety in a larger number of patients needs to be established. Because IL-6 is essential for the host defense, infection and malignant diseases are potential concerns, as has been reported with other biologics. Additionally, it has been noted that tocilizumab treatment often increases total cholesterol with a concurrent increase in HDL cholesterol. Because DMARDs, as well as anti-TNF-α therapy have also been reported to increase total cholesterol, this phenomenon is believed to be related to the anti-inflammatory activity. Although we should carefully examine the possiblity of cardiovascular diseases, it should be noted that there is accumulated evidence demonstrating that IL-6 is involved in the pathogenesis of cardiovascular diseases. Therefore, blocking IL-6 may be of potential benefit to the cardiovasucular disease. Second, there is no firm evidence indicating whether tocilizumab can prevent joint destruction in patients with RA.This is being investigated in the ongoing phase III trials. Third, the production cost for this kind of drug is a common problem among biologics. This should be resolved in the near future. Finally, the mechanism of the actions regarding how IL-6 blockade shows its therapeutic effect is not fully understood. Furthermore, etiological causes of these diseases remain unclear. Further studies are required to establish the safe and most effective therapy for these refractory diseases. These studies should be investigated in the near future. Volume 28, 2005

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Conclusion The results of a series of clinical studies have shown that inhibition of IL-6 with tocilizumab constitutes an interesting approach for the treatment of inflammatory immunological diseases such as Castleman’s disease, Crohn’s disease, and RA. Although the results of the treatment of Castleman’s disease supported the filing of tocilizumab for this indication in Japan, the worldwide ongoing phase III program in adult RA will confirm the efficacy and safety profile of tocilizumab in this disease.

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Volume 28, 2005