15-Deoxyspergualin in Patients with Refractory ANCA- Associated Systemic Vasculitis: A Six-Month Open-Label Trial to Evaluate Safety and Efficacy

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1 J Am Soc Nephrol 14: , Deoxyspergualin in Patients with Refractory ANCA- Associated Systemic Vasculitis: A Six-Month Open-Label Trial to Evaluate Safety and Efficacy RAINER BIRCK,* KLAUS WARNATZ, HANNS M. LORENZ, MIRA CHOI, MARION HAUBITZ, MATHIAS GRÜNKE, HANS H. PETER, JOACHIM R. KALDEN, URSULA GÖBEL, JOHANNES M. DREXLER, OSAMU HOTTA, # RAINER NOWACK,* and FOKKO J. VAN DER WOUDE* *Department of Nephrology, University Hospital Mannheim, Mannheim, Germany; Department of Nephrology, Berlin-Buch, Germany; and Department of Nephrology, Hannover, Germany; Department of Clinical Immunology and Rheumatology, University Freiburg, Freiburg, Germany; Department of Rheumatology, Erlangen-Nürnberg, Germany; Euro Nippon Kayaku GmbH, Frankfurt, Germany; and # Department of Nephrology, Sendai Shakaihoken Hospital, Japan. Abstract. The combination of cyclophosphamide (CYC) and oral corticosteroids is effective in the majority of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AASV), but it carries substantial risk of drug-related morbidity and mortality. New regimens are desired, especially in refractory cases. The immunosuppressant 15-deoxyspergualin (DSG) is effective in experimental autoimmune disease and transplantation as well as in acute kidney transplant rejection in humans. To assess the efficacy and safety of DSG, an open label multicenter trial was conducted in patients with AASV who were either unresponsive or had contraindications for standard immunosuppressants. Included were 19 cases of Wegener granulomatosis and one case of microscopic polyangiitis. Nine of them had received CYC shortly before study entry without apparent therapeutic success. DSG (0.5 mg/kg per d) was given for 2 to 3 wk until the WBC count dropped to 3000/ l followed by a rest until at least a WBC of 4000/ l was reached again. This was repeated up to six cycles. During the study, no other immunosuppressants besides steroids were allowed. Disease improvement during treatment with DSG was achieved in 70% of cases (six cases of complete remission; eight cases of partial remission). Leucopenia occurred in each patient in a regular pattern during the cycles and was transient without exception. No mortality or septicemia was observed. Mild to moderate infections mainly in the respiratory tract were observed but resolved under adequate treatment without sequel. It is concluded that treatment with DSG is successful in patients with refractory Wegener granulomatosis under careful monitoring of WBC count. Antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis (AASV) is the most common primary small-vessel vasculitis in adults, encompassing Wegener granulomatosis (WG), microscopic polyangiitis (MPA), and the Churg-Strauss syndrome. The introduction of the combination of cyclophosphamide (CYC) and oral corticosteroids (OCS) for the treatment of active WG in the early seventies changed a formerly almost invariably fatal disease with a lethality rate of 82% in the first 12 mo (1) into a treatable condition of a more chronic-relapsing nature associated with a 5-yr survival rate of 80% (2). Despite the efficacy of the above-mentioned Received July 28, Accepted October 22, Correspondence to Dr. Rainer Birck, Fifth Department of Medicine, (Nephrology/Endocrinology/Rheumatology), University Hospital Mannheim, Theodor- Kutzer-Ufer 1-3, D Mannheim, Germany. Phone: ; Fax: ; rainer.birck@med5.ma.uni-heidelberg.de / Journal of the American Society of Nephrology Copyright 2003 by the American Society of Nephrology DOI: /01.ASN regimen in the majority of patients, up to 25% achieve no complete remission (2) and relapses are seen in up to 50% (3). Moreover, it is associated with serious treatment-related risks in 42% of patients, including severe infections, increased incidence of malignancies, as well as gonadotoxicity (3). Thus, new treatment strategies combining less toxicity with comparable efficacy are warranted, especially in frequently relapsing or refractory cases or in patients suffering from severe side effects of CYC. 15-Deoxyspergualin (DSG; 1-amino-19-guanidino-11-hydroxy-4, 9, 12-triazanona-decane-10, 1 3-dione; generic name, Gusperimus) is a synthetic analogue of spergualin, a natural product of the bacterium Bacillus laterosporus (4). Spergualin, a peptidomimetic compound containing a spermidine-moiety within its structure, was discovered in 1981 by Umezawa et al. in a culture filtrate while screening for natural products that inhibit the transformation of chicken embryo fibroblasts through Rous sarcoma virus (5). Although initially developed as an anti-cancer drug (6), strong immunosuppressive properties were discovered and studied in several animal models of transplantation (7 8) and of autoimmune disease (9 10). In

2 J Am Soc Nephrol 14: , Deoxyspergualin and Vasculitis 441 clinical trials including patients with recurrent kidney transplant rejections, DSG led to remission in 79% of cases (11). Moreover, in a randomized trial in patients with steroid-resistant kidney transplant rejections, DSG was as effective as the monoclonal antibody OKT3, showing reversal of acute rejection in 59% respectively 62% (12). Recently, Hotta et al. (13) demonstrated that DSG shows therapeutic efficacy in patients with crescentic proliferative glomerulonephritis. From preclinical and clinical data, DSG appears to be a potent immunosuppressant with a favorable side effect profile exerting no renal, liver, or diabetogenic toxicity and only reversible bone marrow suppression (11 14). To assess the efficacy and tolerability of DSG, we conducted a pilot trial in patients with active WG or MPA refractory or with contraindications to standard immunosuppressants. Materials and Methods Patients In this open-label multicenter trial, three nephrology and two rheumatology departments in tertiary care centers within Germany participated. Eligible were patients with WG, MPA, or renal limited vasculitis with or without histologic confirmation and c- or p-anca positivity with specificity for proteinase 3 (PR-3) or myeloperoxidase (MPO). ANCA-negative cases could be included if confirmed histologically. Furthermore, these patients had to have a history of intractable course, severe side effects, frequent relapses, or constantly grumbling disease under standard immunosuppressants or denied to be treated with cytostatics. Exclusion criteria were a leukocyte count 4000/ l, pregnancy and lactation, the presence of uncontrolled acute or chronic infections, anticonvulsive treatment, and inadequate contraception. The study was in accordance with the Declaration of Helsinki as well as the requirements of Good Clinical Practice (GCP). All patients gave written informed consent before inclusion, and ethical approval was obtained in each participating center. Reliability of the data in the record books was checked throughout the study by a professional monitoring company (Omnicare Clinical Research GmbH, Germany). Treatment Protocol After entry to the study, all but three patients were given DSG in a dosage of 0.5 mg/kg daily by subcutaneous injection. Patients 1 to 3 received the first week of treatment by intravenous injection with the same dosage. The aim within each cycle was to reach a leukocyte nadir of 3000/ l. WBC were therefore monitored every other day. Treatment was then discontinued for 2 wk to allow the leukocyte number to recover, and the cycle was repeated up to six times. Treatment was continued by subcutaneous injection by the patient in the same dosage to facilitate therapy in an outpatient setting. Besides steroids, no other immunosuppressive drugs were allowed during the study period. The steroid regimen was not restricted by the study protocol and was chosen individually by each investigator on clinical grounds. Assessment of Disease Activity The definitions for refractory disease, remission, and relapse as well as the use of the Birmingham Vasculitis Activity Score (BVAS) (15), the Vasculitis Damage Index (VDI) (16) and the Short-Form-36 (SF-36) (17), were adopted from the criteria used within the therapeutic trials of the European Vasculitis Study Group (EUVAS) (18). The primary endpoint of the study was the remission rate after six cycles of DSG respectively after study termination. Complete remission was indicated by complete absence of clinical signs of disease activity. Partial remission was defined as absence of acute or newer clinical activity, although minor persistent activity was allowed to be present. Relapse was defined as recurrence or first appearance of typical organ involvement characteristic of the underlying disease. ANCA titers were irrelevant for the purpose of this protocol. The effect of treatment on disease activity, further organ-damage, and on functional aspects was also assessed before and after each cycle with the BVAS, before the first and after the third and the sixth cycle with the VDI, and before the first and after the sixth cycle with the SF-36 functional assessment questionnaire. The scores were used as secondary endpoints within this trial, adding to the clinical judgment of the responsible physicians but not restricting it. The BVAS is calculated from new or deteriorated symptoms and signs within the previous month attributable to active vasculitis in nine separate organ systems that are weighed according to their relative contribution on mortality and morbidity of systemic vasculitis. Chronic irreversible organ damage attributable to systemic vasculitis was scored by the VDI. To count for VDI, the signs or symptoms had to be present for at least 3 mo. All patients were also reevaluated 6 mo after study termination with respect to efficacy and safety of prior DSG treatment. Due to the low patient number, mainly descriptive statistical analyses were performed with respect to variables like BVAS scores, steroid dosages, demographic characteristics, etc. For comparing means between BVAS scores and steroid dosages at the beginning and the end of the study the paired t test was used. P 0.05 was considered to be significant. Results Treated Patients Clinical characteristics and demographic details of the included 20 patients are summarized in Tables 1, 2, and 3. Seventeen patients were enrolled in the official study according to GCP from May 1999 to July Before the official study, three patients (patients 1, 2, and 6) were treated on compassionate-use basis with commercial DSG (from May 1998 to September 1999), and their treatment modalities and evaluations were performed according to the same protocol. In this report, those 17 and 3 patients were summed up and used for safety and efficacy analysis. Nineteen patients had WG, and one patient (patient 17) suffered from MPA. All patients with exception of two (patient 7: no biopsy results available; patient 13: nonspecific inflammation) had biopsy-proven necrotizing vasculitis, granulomatous inflammatory changes, or both in a typical organ system during their disease history. Fifteen of nineteen WG patients were canca /PR3 at entry, and the MPA case was panca /MPO. Mean age at study entry was 51.3 yr (range, 34 to 78 yr), mean disease duration was 5.54 yr (range, 0.25 to 25.3 yr) and mean number of relapses before study entry was 4.3 (range, 0 to 13) times. Previous immunosuppressive medications had been taken by all patients (for details, please see Table 1). The mean cumulative CYC dosage in patients ever receiving CYC (18 of 20) was 78 g (range, 4.5 to 199 g).

3 442 Journal of the American Society of Nephrology J Am Soc Nephrol 14: , 2003 Table 1. Clinical and demographic characteristics a Patient Age (yr)/ Gender Pretreatment History (with Cumulative CYC Dosage) VDI BVAS Scores are given at entry IS/OCS at Entry (in mg/d p.o. Unless Otherwise Indicated) 1 37/m CYC 4.5 g, AZA, MMF, IVIG, PPS, MTX 5 12 MTX 15 s.c. weekly/mp /f CYC 34 g, AZA, MMF 3 19 MMF 2000/MP /m CYC 68 g 3 12 CYC 75/MP /m CYC 46 g, CyA, MTX, MMF, AZA 7 10 MMF 1000, AZA 100/MP /f CYC 73 g, AZA, MTX, CyA 7 6 CYC 100/PREL /m CYC 90 g 4 25 PREL /f CYC 90 g, AZA, MTX 9 11 MTX 15 s.c. weekly/prel /f CYC 64 g, MMF 4 9 MMF 1000/MP /m CYC 50 g, AZA 3 7 CYC 100/ /m CYC 96 g 3 5 CYC 150/PRED /f CYC 138 g, MTX 1 12 MTX 25 s.c. weekly/mp /f MTX 1 13 MTX 15 s.c. weekly/pre /f CyA, MTX 1 5 CyA 300/PRED /f CYC 36 g 5 6 CYC 75/PRE /f CYC 189 g 3 3 CYC 25/PRED /m CYC 9 g 2 7 CYC 750/m 2 i.v. monthly/mp /m CYC 79 g, MMF 5 11 CYC 1000/m 2 i.v. monthly, MMF 2000/PRE /f CYC 199 g, MTX, AZA 8 3 CYC 50/PRE /f CYC 85 g, MTX, CyA, AZA 4 8 AZA 100/PRE /m CYC 50 g 4 12 MP 80 a BVAS, Birmingham Vasculitis Activity Score; VDI, vasculitis damage score; OCS, oral steroids; PRE, prednisone; PREL, prednisolone; PRED, prednylidene; MP, methylprednisolone; CYC, cyclophosphamide; AZA, azathioprine; MTX, methotrexate; MMF, mycophenolate mofetil; ATG, anti-thymocyte globulin; PPS, plasmapheresis; IVIG, intravenous immunoglobulin; CyA, cyclosporine A; IS, immunosuppressant; f, female; m, male. Treatment Directly before Study Entry Immediately before initiation of DSG therapy, all patients had received immunosuppressants (for details, Table 1) that either failed to control disease activity or could not be continued due to severe side effects. Nine of these patients (patients 3, 5, 9, 10, and 14 to 18) received CYC either orally (n 7; mean dosage, 82 mg/d; range, 25 to 150 mg) or intravenously (n 2; mean dosage, 875 mg/m 2 monthly; range, 750 to 1000 mg/m 2 ) directly before the study entry without sufficient therapeutic effect. CYC was contraindicated in four patients due to hemorrhagic cystitis (patients 7, 8, 10, and 15) and in one patient due to toxic hepatitis (patient 1). At study entry, the mean daily oral steroid dosage was 27.2 mg (range, 0 to 100 mg). One patient (patient 12) received during cycle 1 pulse intravenous steroids up to 500 mg. Individual steroid dosages are given in Table 1. Treatment Effects Six (30%) of twenty patients went into complete remission, and 8 (40%) of 20 showed partial remission after study termination. Thus, 14 (70%) of 20 patients showed improvement after DSG treatment. Of the remaining six patients, three (patients 4, 14, and 16) relapsed in cycle 6 under DSG treatment despite achieving partial or complete remission in the previous cycle. One patient (patient 8) did not respond at all to DSG treatment showing disease progression. Of the nine patients on CYC treatment (patients 3, 5, 9, 10, 14 to 18) right before the study entry, one patient (patient 5) achieved complete remission, and four patients (patients 9, 10, 15, and 17) achieved partial remission. Beneficial effects of DSG treatment were observed in all organ systems typically affected by systemic vasculitis. Thus, regression or resolving of pulmonary lesions (Figure 1) and subglottic granuloma, reversal of nephritic urinary sediment and improvement of proteinuria and renal function (data not shown), as well as disappearance of palsies and constitutional signs were noted. The mean BVAS showed a significant improvement from to (P 0.002) in responders and an increment in nonresponders from 8 3to during the study being congruent to the investigators clinical judgment in almost all patients. Responsiveness to DSG was also associated with a decreased usage of OCS. In responding patients, the mean daily oral steroids dosage could be significantly reduced from mg at entry to mg/d at study termination (P 0.029). Individual numbers of the BVAS and the concomitant OCS treatment in each patient at study entry and at study termination as well as 6 mo thereafter are given in Tables 1, 2, and 3. The VDI was constant, indicating no further

4 J Am Soc Nephrol 14: , Deoxyspergualin and Vasculitis 443 Table 2. Treatment and outcomes in responders a Patient Cycles Treated (n) Outcome at Study Termination/6 mo later Clinical BVAS OCS (mg/d) Therapy during the 6 mo Follow-Up after Study Termination 1 6 CR/CR 0/na MP 8/3 Maintenance with DSG 2 6 CR/CR 6/na MP 4/2 Maintenance with DSG 5 6 CR/CR 3/na PRE 7.5/5 Maintenance with DSG 6 6 PR/REL 7/na PREL 4 Maintenance with DSG; PREL could be tapered off completely; relapse in month 6; switch to CYC and high-dose steroids 7 6 PR/CR 4/na PREL 10/7.5 Maintenance with OCS 9 6 PR/CR 4/na PREL 20/5 Maintenance with AZA 10 6 PR/PR 10/na PRED 3/3 Maintenance with AZA 11 6 PR/PR 5/na MP 6/4 Maintenance with MTX 12 6 CR/REL 1/na PRE 5 Maintenance therapy with AZA, after 2 mo severe renal relapse; switch to CYC and high-dose steroids; then fatal pneumocystis carinii pneumonia 13 6 CR/CR 5/na PRED 6/6 Maintenance with MTX 15 2 PR/PR 3/na PRED 6/4 Maintenance with MTX 17 6 PR/PR 5/na PRE 10/5 Maintenance with AZA 19 2 CR/REL 3/na PRE 10 Maintenance with AZA, MMF; relapse after 6 mo; switch to CYC and high-dose steroids 20 6 PR/CR 7/na MP 6/0 Maintenance with AZA a PR, partial remission; CR, complete remission; REL, relapse; OCS, oral steroids; PRE, prednisone; PREL, prednisolone; PRED, prednylidene; CYC, cyclophosphamide; AZA, azathioprine; MTX, methotrexate; MMF, mycophenolate mofetil; DSG, 15-deoxyspergualin; na, not applicable. progress in organ damage and the short-form 36 showed no significant changes (data not shown). When the same cohort was reevaluated 6 mo after study termination, in 11 of the 14 patients initially responding to DSG, the achieved clinical condition was sustained respectively, even further improved (Table 2). Only three patients experienced a relapse. Five patients did not complete six cycles of DSG due to premature study termination. Patient 3 developed severe but transient thrombocytopenia during cycle 1 and discontinued the treatment. Patient 8 did not respond to DSG, showing a primary treatment failure and was switched to another therapy after three cycles. Patient 15 showed recurrent urinary tract infection with bleeding episodes from preexisting teleangiectasias and discontinued the treatment after two cycles while in partial remission. Patient 18 discontinued the treatment after two cycles, as infection had mimicked vasculitis activity at entry. Patient 19 reached complete remission after cycle 2 and was lost to follow-up. Treatment duration within the cycles was determined by the time necessary to reach target leucopenia levels. Cycles lasted on average 20.0 d (range, 8 to 37 d). Duration of treatment and leucopenia did not change significantly during the whole study period. In all cases, leucopenia was transient and followed a foreseeable course without any signs of an accumulation effect. DSG affected mainly neutrophil counts; the changes in lymphocyte counts were NS (Figure 2). A dose decrease in one patient (patient 5) and a dose increase in another (patient 9) were necessary to comply with the treatment protocol. Slight decreases in hemoglobin levels and thrombocytes were also noted, but they were clinically insignificant with the exception of the above-mentioned patient 3 (data not shown). This patient developed thrombocytopenia during the first cycle, but thrombocytes recovered to baseline levels again after stopping the treatment. This patient was 78 yr old, had been pretreated with 68 g of CYC, and had moderate thrombocytopenia already before initiation of DSG treatment. The major side effects encountered during the study were mainly infections of the upper respiratory tract, which quickly resolved with the use of antibiotics without further sequel. There were also some cases of oral candidiasis and one infection with herpes zoster, which necessitated antifungal or antiviral therapy. The infections were not related to the neutropenic phases during the cycles within the study. Besides the above-mentioned side effects, local and systemic tolerability of DSG was excellent, and most patients were basically willing to continue on DSG after study termination. Details concerning adverse events encountered during the study are shown in Table 4. Discussion The present study was conducted to evaluate the safety and efficacy of DSG for refractory patients with ANCA-associated vasculitis. It shows that DSG is able to stabilize disease or to induce complete remission in patients with active ANCA-

5 444 Journal of the American Society of Nephrology J Am Soc Nephrol 14: , 2003 Table 3. Treatment and outcomes in nonresponders Patient Cycles Treated (n) Outcome at Study Termination Clinical BVAS OCS (mg/d) Comments 3 1 OTHERS 7 MP 32 During the first DSG cycle transient thrombocytopenia, switch to CYC and PREL; disease progress; adding plasmapheresis; partial remission; then lost to follow-up 4 6 REL 18 MP 14 Switch to CYC and high-dose steroids; then still grumbling disease under maintenance with DSG, MMF, and leflunomide with progression to endstage renal failure 8 3 OTHERS 15 MP 4 Initially disease progression under DSG; switched to ATG and high-dose steroids; partial remission; maintenance with steroids, MMF, and etanercept 14 6 REL 11 PRE 5 Switched to CYC and high-dose steroids; maintenance with MTX 16 6 REL 7 MP 150 Switched to CYC and high-dose steroids; death 2 mo later due to cerebral granuloma and septicemia 18 2 OTHERS 4 PRE 20 Infection mimicking vasculitis at entry; retrospectively no active disease; maintenance with AZA; PRE reduced to 5 a REL, relapse; PRE, prednisone; PREL, prednisolone; PRED, prednylidene; MP, methylprednisolone; CYC, cyclophosphamide; AZA, azathioprine; MTX, methotrexate; MMF, mycophenolate mofetil; DSG, 15-deoxyspergualin. Figure 1. Lung computed tomography scans showing a pulmonary nodule on the right side as indicated by the arrow before (left panel) and after two cycles of 15-deoxyspergualin (DSG) treatment (right panel) in patient 19. associated vasculitis, even when prior immunosuppressive agents, including CYC, have failed. This was an open-label trial in patients pretreated with a variety of immunosuppressive drugs and no restrictions concerning concomitant steroids usage; therefore, a postponed effect of the other immunosuppressants given before study entry or of initially increased steroid

6 J Am Soc Nephrol 14: , Deoxyspergualin and Vasculitis 445 Figure 2. A representative differential white blood cell count (patient 11) is shown during the study period (ordinate gives 1000 leukocytes/ l). Start and end points denote beginning and end of DSG treatment. dosages in many patients cannot be excluded. However, the patients included were chosen by investigators who were all experienced in the field of vasculitis on the assumption that the current immunosuppressive medications of the patients were either not sufficiently effective or contraindicated due to severe side effects. Thus, it seems unlikely that steroids alone or a standard immunosuppressant given shortly before study entry would stabilize vasculitis over the treatment time of six cycles (6 to 8 mo) in such a cohort of refractory patients. Moreover, in most patients responding to DSG, the beneficial effects were sustained as indicated by the follow-up results 6 mo after study termination. Noteworthy, in a recent open-label study with a derivative of DSG, anisperimus, in patients with persisting or relapsing primary systemic vasculitis (mostly AASV), preliminary results showed beneficial effects in a substantial amount of included patients (30), thereby confirming our novel therapeutic approach. Treatment with DSG, given subcutaneously or intravenously at dosages of 0.5 mg/kg per day until the target leukocyte count of 3000 cells/ l is reached was feasible and safe. For treatment of acute kidney rejection, DSG is normally used in doses ranging from 3 to 5 mg/kg per d intravenously infused for 5 to 10 d (11 12,14). However, on the basis of the data from animal experiments (19) as well as on the basis of clinical experience from patients with various forms of crescentic proliferative glomerulonephritides (13), the efficacy of DSG may rather be dependent on the duration of application than on the absolute amount given. Despite the significant reduction in neutrophil counts within each cycle, all experienced infections were of mild to moderate intensity and resolved after adequate treatment. No signs of cumulative toxicity of the drug after repeated cycles were seen since the pattern and duration of leukocyte depression did not change over time in the patients. In phase I studies in patients with advanced cancer, DSG was well tolerated at doses ranging from 20 to 500 mg/m 2 per d by 3-h infusion or from 80 to 2792 mg/m 2 per d (2 to 75 mg/kg per d) by 24-h infusion for 5 d. The main adverse effects were reversible hypotension and transient perioral numbness at the higher dose ranges. Mild myelosuppression was also observed. Importantly, DSG showed no diabetogenic, hepatotoxic, or nephrotoxic properties in this setting (20 22). Excellent tolerability of DSG was also reported in a randomized double-blind controlled study in multiple sclerosis including 236 patients where DSG was given in doses of 2 mg/kg or 6 mg/kg intravenously in five 4-d courses at 4-wk intervals. During the follow-up of 2 yr, the number and severity of adverse effects did not significantly differ from the placebo-treated groups. Within the treatment phases, a mild and transient myelosuppression with anemia and leucopenia was noted (29). These data are also in accordance with an adverse side effect report to the Japanese health authorities in 1998, where in 385 cases of acute renal rejection a total of 38 infections were described without any severe septicemia (29). Noteworthy, in contrast to current immunosuppressive drugs in preclininical toxicology studies used for registration, in Japan in 1994, DSG revealed no mutagenicity, teratogenicity, or

7 446 Journal of the American Society of Nephrology J Am Soc Nephrol 14: , 2003 Table 4. Adverse events observed under treatment with 15-deoxyspergualin Adverse event Relationship (no. of patients) Definitely Probably Possibly Fever 5 Diarrhea 5 Headache 2 Bronchitis 5 Nausea 4 Upper respiratory tract infection 1 3 Anemia 1 5 Fatigue 3 Paresthesia 2 1 Sinusitis 3 Conjunctivitis 1 Infection 4 Oral moniliasis 4 Parageusia 4 Pharyngitis 1 Urinary tract infection 1 3 Coughing 2 Dyspnea 1 Injection pain 1 1 Renal function abnormal 3 Rhagades 3 Sore throat 3 Acne 1 1 Dysuria 2 Heartburn 2 Influenza-like symptoms 2 Vomiting 2 cancerogenicity (29). In the above-mentioned trial with its derivative anisperimus (30), cardiotoxicity was suspected in two cases due to some changes in left ventricular function as indicated by echocardiography (personal communication Dr. David Jayne, Cambridge, UK). However, the findings in both cases were not unequivocal; neither in the available literature (14,20 22,29) nor in our trial were any signs of cardiotoxicity noted. Thus, DSG appears, despite its considerable immunosuppressive properties, as a drug with a favorable side effect profile when compared with standard immunosuppressants. The precise mechanism of action of DSG, however, remains obscure. From the available data, it seems that it influences the immune system in quite a different way than standard immunosuppressants. It inhibits B cell differentiation and lightchain expression at the transcriptional level by blocking nuclear translocation of the transcription factor NF- B (23). Wang et al. (24) showed that DSG leads to an arrest of T lymphocyte maturation in the thymus during CD4 CD8 to CD4 CD8 transition as well as in preb cells in the bone marrow when the prereceptor complex containing Ig heavychain is expressed, thereby reducing the number of mature effector cells to 2% after a 14-d treatment period in mice. DSG also affects monocyte/macrophage/antigen-presenting cells. Thus, decreased generation of reactive oxygen species and hydrolytic enzymes (25), diminished expression of MHC class II antigens (26), as well as inhibition of proliferation and antigen processing/presentation have been observed (27 28). In conclusion, DSG appears as an effective and safe agent to treat patients with AASV refractory or with contraindications to standard immunosuppressants. The observed side effects were mainly infections of mild to moderate intensity, all of which could be controlled with appropriate therapy. Our proposed treatment regimen necessitates determination of blood cell counts in regular intervals to monitor the myelosuppressive effects of the drug. However, long-term treatment with subcutaneous injection on an outpatient basis was feasible and safe. Further studies are warranted to investigate DSG as secondary or even primary agent in patients with systemic vasculitis. Acknowledgment This study was sponsored by Euro Nippon Kayaku GmbH, Staufenstr. 4, D Frankfurt, Germany. References 1. Walton EW: Giant cell granuloma of the respiratory tract (Wegener s granulomatosis). Br Med J 2: , Fauci AS, Haynes BF, Katz P, Wolff SM: Wegener s granulomatosis: Prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 98: 76 85, Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS: Wegener s granulomatosis: An analysis of 158 patients. Ann Intern Med 116: , Maeda K, Umeda Y, Saino T: Synthesis and background chemistry of 15-deoxyspergualin. Ann NY Acad Sci 685: , Takeuchi T, Iinuma H, Kunimoto S, Masuda T, Ishizuka M, Takeuchi M, Hamada M, Naganawa H, Kondo S, Umezawa H: A new antitumor antibiotic, spergualin: Isolation and antitumor activity. J Antibiot 34: , Nishikawa K, Shibasaki C, Takahashi K, Nakamura T, Takeuchi T, Umezawa H: Antitumor activity of spergualin: A novel antitumor antibiotic. J Antibiot 39: , Itoh J, Takeuchi T, Suzuki S, Amemiya H: Reversal of acute rejection episodes by deoxyspergualin (NKT-01) in dogs receiving renal allografts. J Antibiot 41: , Reichenspurner H, Hildebrandt A, Human PA, Boehm DH, Rose AG, Odell JA, Reichart B, Schorlemmer HU: 15-Deoxyspergualin for induction of graft nonreactivity after cardiac and renal allotransplantation in primates. Transplantation 50: , Nemoto K, Hayashi M, Sugawara Y, Ito J, Abe F, Takita T, Nakamura T, Takeuchi T: Biological activities of deoxyspergualin in autoimmune disease mice. J Antibiot 41: , Lan HY, Zarama M, Nikolic-Paterson DJ, Kerr PG, Atkins RC: Suppression of experimental crescentic glomerulonephritis by deoxyspergualin. J Am Soc Nephrol 3: , Amemiya H, Suzuki S, Ota K, Takahashi K, Sonoda T, Ishibashi M, Omoto R, Koyama I, Dohi K, Fukuda Y, et al: A novel rescue drug, 15-deoxyspergualin. First clinical trials for recurrent graft rejections in renal recipients. Transplantation 49: , Okubo M, Tamura K, Kamata K, Tsukamoto Y, Nakayama Y, Osakabe T, Sato K, Go M, Kumano K, Endo T: 15-deoxysper-

8 J Am Soc Nephrol 14: , Deoxyspergualin and Vasculitis 447 gualin rescue therapy for methylprednisolone-resistant rejection of renal transplants as compared with anti-t cell monoclonal antibody (OKT3). Transplantation 55: , Hotta O, Furuta T, Chiba S, Yusa N, Taguma Y: Immunosuppressive effect of deoxyspergualin in proliferative glomerulonephritis. Am J Kid Dis 34: , Amemiya H: Deoxyspergualin: Clinical trials in renal graft rejection. Japan Collaborative Transplant Study of Deoxyspergualin. Ann N Y Acad Sci 685: , Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, Savage C, Adu D: Birmingham vasculitis activity score (BVAS) in systemic necrotizing vasculitis. Q J Med 87: , Exley AR, Bacon PA, Luqmani RA, Kitas GD, Gordon C, Savage CO, Adu D : Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum 40: , Luqmani RA, Exley AR, Kitas GD, Bacon PA: Disease assessment and management of the vasculitides. Baillieres Clin Rheumatol 11: , Jayne DR, Rasmussen N: Treatment of antineutrophil cytoplasm autoantibody-associated systemic vasculitis: Initiatives of the European Community Systemic Vasculitis Clinical Trials Study Group. Mayo Clin Proc 72: , Yuh DD, Morris RE: The immunopharmacology of immunosuppression by 15-deoxyspergualin. Transplantation 55: , Tamura K, Niitani H, Oguro M, Ohno R, Sanpi K, Majima H, et al: Phase I study of NKT-01. Cancer Chemother Pharmacol 36: , Havlin KA, Kuhn JG, Koeller J, Boldt DH, Craig JB, Brown TD, Weiss GR, Cagnola J, Phillips J, Harman G, et al: Deoxyspergualin: Phase I clinical, immunologic and pharmacokinetic study. Anti-Cancer Drugs 6: , Kaufman DB, Gores PF, Kelley S, Grasela DM, Nadler SG, Ramos E: 15-Deoxyspergualin: Immunotherapy in solid organ and cellular transplantation. Transplant Rev 10: , Tepper MA, Nadler SG, Esselstyn J, Sterbenz C: Deoxyspergualin inhibits kappa light chain expression in 70Z/3 pre-b cells by blocking lipopolysaccharide induced NF-kappaB activation. J Immunol 155: , Wang B, Benoist C, Mathis D: The immunosuppressant 15- deoxyspergualin reveals commonality between pret and preb cell differentiation. J Exp Med 183: , Dickneite G, Schorlemmer HU, Sedlacek HH: Decrease of mononuclear phagocyte cell functions and prolongation of graft survival in experimental transplantation by 15-deoxyspergualin. Int J Immunopharmacol 9: , Nikolic-Paterson DJ, Tesch-GH, Lan HY, Foti R, Atkins R: Deoxyspergualin inhibits mesangial cell proliferation and major histocompatibility complex class II expression. J Am Soc Nephrol 5: , Kerr PG, Nikolic-Paterson DJ, Lan HY, Rainone S, Tesch G, Atkins RC: Deoxyspergualin suppresses local macrophage proliferation in renal allograft rejection. Transplantation 58: , Hoeger P, Tepper MA, Faith A, Higgins J, Lamb J, Geha R: The immunosuppressant deoxyspergualin inhibits antigen processing in monocytes. J Immunol 153: , Stegemann CA, Birck R: New immunosuppressants: mycophenolate and 15-deoxyspergualin. In: Disease-Modifying Therapy in Vasculitides, edited by Kallenberg CGM, Cohen Tervaert JW, Basel, Birkhäuser Verlag, 2001, pp Jayne DW, for the LF Vasculitis Study Group: Efficacy and safety of LF (Anisperimus) in persistent or relapsing primary systemic vasculitis [Abstract]. Cleve Clin J Med Suppl 2, 69: SII1-191, 2002 Access to UpToDate on-line is available for additional clinical information at