THERAPY FOR THE MAINTENANCE OF REMISSION IN SIXTY-FIVE PATIENTS WITH GENERALIZED WEGENER S GRANULOMATOSIS

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1 2052 ARTHRITIS & RHEUMATISM Vol. 39, No. 12, December 1996, pp , American College of Rheumatology THERAPY FOR THE MAINTENANCE OF REMISSION IN SIXTY-FIVE PATIENTS WITH GENERALIZED WEGENER S GRANULOMATOSIS Methotrexate versus Trimethoprim/Sulfamethoxazole KIRSTEN DE GROOT, EVA REINHOLD-KELLER, EFSTRATIOS TATSIS, JENS PAULSEN, MARTIN HELLER, BERNHARD NOLLE, and WOLFGANG L. GROSS Objective. To compare the efficacy of low-dose intravenous (IV) methotrexate (MTX; 0.3 mg/kg once weekly), both with and without concomitant prednisone, versus daily oral trimethoprim/sulfamethoxazole (T/S; 160 mg of trimethoprim mg of sulfamethoxazole twice a day), with and without prednisone, in maintaining remission in patients with generalized Wegener s granulomatosis (WG). Methods. In this study, 65 patients with generalized WG whose disease had entered remission with cyclophosphamide (CYC) and prednisone therapy were started on one of the following remission-maintenance regimens: MTX alone (group A; n = 22), T/S alone (group B; n = 24), MTX plus conconlitant prednisone (group C; n = ll), and T/S plus concomitant prednisone (group D; n = 8). Clinical, radiographic, and seroimmunologic data were evaluated to assess the efficacy of the 4 regimens and to seek possible predictive factors concerning outcome in each group. Results. Partial or complete remission was maintained in 86% of the patients in group A, but in only 58% of those in group B (P < 0.05). In group C, 91% of patients remained in remission, which is in sharp contrast to group D, in which all patients experienced a relapse after a median of 14.5 months (P < 0.005). Side effects occurred twice as often with MTX (n = 12) as Kirsten de Groot. MD, Eva Reinhold-Keller, MD, Efstratios Tatsis, MD, Wolfgang L. Gross, MD: Medical University of Lubeck and Rheumaklinik, Bad Bramstedt GmbH, Germany; Jens Paulsen, MD, Martin Heller, MD, Bernhard Nolle, MD: University of Kiel, Kiel, Germany. Address reprint requests to Kirsten de Groot, MD, Medizinische Universitat Liibeck, Abteilung Klinische Rheumatologie, Oskar-Alexander-Strasse 26, D Bad Bramstedt, Germany. Submitted for publication March 11,1996; accepted in revised form June 28, with T/S (n = 6) treatment and could usually be resolved by supplemental folinic acid. Two patients taking MTX and 3 patients taking T/S were withdrawn from the study medication because of side effects. In none of the patients were the adverse effects life threatening. No statistically significant factors predictive of poor outcome emerged in any group. Conclusion. Low-dose MTX was found to be superior to T/S for the safe and effective maintenance of remission in patients with generalized WG. The use of concomitant prednisone was not associated with a worse outcome with MTX treatment. Since T/S, especially with concomitant prednisone, seemed to increase the chance of relapse, neither T/S alone nor T/S plus prednisone can be recommended for the maintenance of remission in patients with generalized WG. The capacity of continuous oral cyclophosphamide (CYC) plus prednisone (the Fauci scheme ) to induce remission in patients with generalized Wegener s granulomatosis (WG) is well established. This regimen has led to a 5-year survival rate of >80% (1). However, it is associated with substantial therapy-related morbidity and mortality (2). Despite this aggressive regimen, a cure for WG remains uncertain; the rate of relapse is between 10% and 50% (1-5). The relapse rate increases with the duration of the followup period and is independent of the therapy used (2,6). Hence, patients with generalized WG need long-term treatment for the prevention of relapse once remission has been induced by the standard regimen. Remissionmaintenance therapy requires a switch to an efficient but less toxic medication. Up to now, there has been no uniform consensus as to which medication best fulfills

2 REMISSION MAINTENANCE THERAPY IN PATIENTS WITH WG 2053 maintenance of remission group A n = 22 MTX: 0.3 mg/kg/week i.v. I I m 65 patients, generalized WG induction of remission 58 x histology proven by Cyc 61 x canca + + Prd b I T/S: 2 x 960 mg/d p.0. I group C n= 11 MTX: 0.3 mg/kglweek i.v. + Prd b group D n=8 T/S: 2 x 960 mgld p.0. + Prd Figure 1. Therapeutic regimen in 65 patients with generalized Wegener s granulomatosis (WG), stratified according to remission-maintenance medication. canca = classic antineutrophil cytoplasmic antibody; Cyc = cyclophosphamide; Prd = prednisone; MTX = methotrexate; i.v. = intravenously; T/S = trimethoprim/sulfamethoxazole; p.0. = orally. this purpose and at what stage of the disease it is most beneficial. Among the candidates for use as remissionmaintenance therapy are low-dose methotrexate (MTX) and trimethoprim/sulfamethoxazole (T/S). Of these two, only T/S has been investigated in a standardized way. The results, however, were in conflict: one group reported a relapse rate of 42% (7); the other reported a rate of 20% (8). Only limited data are available on the use of MTX as a remission-maintenance medication (9). However, MTX has been used successfully in combination with rather high doses of prednisone to induce remission in 42 patients with generalized but not immediately life-threatening WG (10,ll). In the present study, we prospectively assessed the effectiveness of low-dose MTX in sustaining remission in 33 patients with generalized WG after induction of partial or complete remission by the Fauci scheme and compared the results with those in a previously prospectively studied cohort of 32 patients who were given T/S for the same purpose (7). Our primary aim was to measure the response rate in the different treatment groups. The remission-maintenance regimens were also evaluated to determine the relative frequency of side effects, and their capacity to further reduce the extent of disease, and to facilitate the reduction of steroid therapy. PATIENTS AND METHODS Patients. A total of 65 patients with generalized WG were included in the study. The term generalized denotes a state where the disease exceeds granulomatous manifestations of the upper and/or lower airways and is characterized by systemic vasculitic disease with or without renal involvement (12). All patients fulfilled the American College of Rheumatology 1990 classification criteria (13) and the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis 1992 definitions (14) for WG. To avoid toxicity from the study medications due to impaired renal function, no patients with a serum creatinine level >150 pmoles/liter were included in the study. Fifty-eight of the patients had biopsy-confirmed WG,

3 2054 DE GROOT ET AL Table 1. Baseline characteristics of 65 patients with generalized Wegener s granulomatosis treated with low-dose MTX or T/S with or without prednisone, as a remission-maintenance regimen MTX TIS (group A) (group B) Total no. of patients No. of males/females Age at diagnosis, median (range) years 48 (12-60) 48 (17-73) Months from symptom onset to diagnosis, 10.5 (1-140) median (range) 3 (0-115) Fauci scheme therapy before study No. (%) of patients 21 (96) 18 (75) Duration, median (range) months 27 (4-112)t 11.5 (4-58)t CYC pulse therapy before study No. of patients No. of pulses, median (range) (4-22) 18 6 (0-15) DEI score, median (range) At diagnosis 11 (6-17) 10 (4-15) At start of study canca titer, median (range) 4 (0-W 0 (0-7) At diagnosis 256 (0-1,024) 128 (0-512) At start of study 8 (0-1,024) 8 (0-512) sl2r level at start of study, median units/ml Months in study, median (range) 16 (5-30) 23 (4-73) 11 4/7 45 (31-67) 11 (0-134) 10 (91) 22 (5-64) 9 22 (2-42)$ 11 (7-17) 2.5 (2-6) 256 (0-1,024) 128 (8-1,024) (4-34) (21-63) 6 (0-24) 7 (88) 9 (3-36) (0-19)$ 8 (5-13) 3 (0-7) 128 (0-128) 16 (0-128) 1, (2-24) * MTX = methotrexate; TIS = trimethoprimlsulfamethoxazole; pred. = prednisone; CYC = cyclophosphamide; DEI score = Disease Extent Index score; canca = classic antineutrophil cytoplasmic antibody; sil-2r = soluble interleukin-2 receptor (serum). tp = $P = $P = with necrotizing vasculitis or granuloma, or both, in one or more organ systems, usually in the upper respiratory tract (n = 44), less often in the lung (n = 7), skin (n = 6), kidney (n = 5), or peripheral nervous system (n = 1). In the 7 patients in whom WG could not be confirmed histologically, the diagnosis was made on the basis of the typical history, characteristic clinical findings (especially in the ear, nose, and throat [ENT] areas, with sinusitis, saddle nose deformity, etc.), and a positive classic antineutrophil cytoplasmic antibody (canca) pattern on indirect immunofluorescence with antigen specificity for proteinase-3. Infections, malignant tumors, or other underlying systemic diseases were excluded. Sixty-one of the 65 patients were positive for canca, with antigen specificity for proteinase-3, the remaining 4 patients were ANCA negative. All 65 patients had received remission-inducing therapy consisting of either oral continuous CYC plus prednisone (starting with 2 mg/kg of CYC and 1 m ag of prednisone), pulse CYC plus continuous oral prednisone (median dose of 650 mg/m per pulse of CYC plus 1 mgkg of prednisone at the beginning), or both regimens. At the beginning of complete or partial remission, patients were switched to maintenance medications, as follows (Figure 1 and Table 1). Group A consisted of 22 patients who received 0.3 mgkg of intravenous (IV) MTX once weekly, without concomitant medication. Group B was made up of 24 patients who received oral T/S alone (160 mg of trimethoprim mg of sulfamethoxazole twice a day) (7). If at the switch to maintenance medication, the patient still needed prednisone, the prednisone was continued and, if possible, the dosage was gradually tapered. Group C was composed of 11 patients who were given MTX at the same dosage as group A patients, plus low-dose prednisone (median dose 3 mg/day). Group D included 8 patients who were given T/S as in group B patients, plus low-dose prednisone (median dose 10 mglday) (7). Maintenance therapy with T/S was administered from 1986 to 1993, as reported earlier (7), with MTX between 1992 and September For evaluation of the efficacy of MTX versus T/S as remission-maintenance medication, group A was compared with group B and group C was compared with group D. Assessment of the extent and activity of disease. At 3-month intervals, all patients underwent a standardized set of interdisciplinary clinical and seroimmunologic examinations for the presence of vasculitis and granulomas. The same team of specialist clinicians in internal medicine, otorhinolaryngology, ophthalmology, neurology, etc. performed the examinations each time. The term granuloma signifies clinically and radiologically visible masses, especially in the upper and lower respiratory tract, attributable to granulomatous infiltrates, if considered histologically. Every 6-12 months, the patients were also subjected to imaging procedures, including cranial magnetic resonance imaging, which were evaluated as described elsewhere (15). The exrent of WG was assessed using the ELK classification (16), as extended by No11e et a1 (17) and compiled into a Disease Extent Index (DEI) by Reinhold-Keller et a1 (7,18,19). Applying this instrument, organ involvement was recorded as follows: E = upper respiratory tract (ENT), L = lung, K = kidney, Ey = inflammatory eye involvement (mostly episcleritis), H = heart (myocarditis, pericardial effusion, new arrhythmias, coronaritis seen by coronary angiogram), GI = gastrointestinal tract (new bloody diarrhea, histologic proof of

4 REMISSION MAINTENANCE THERAPY IN PATIENTS WITH WG 2055 Table 2. Treatment results in the 46 patients with generalized Wegener s granulomatosis treated with low-dose MTX or T/S, without prednisone, as a remission-maintenance regimen* Fauci scheme therapy before study No. of patients Duration, median (range) months No. of patients taking CYC pulse therapy before study DEI score, median (range) At diagnosis At start of study At study end No. in complete remission At start of study At study end canca titer, median (range) At diagnosis At start of study At study end sil-2r level, median units/ml At start of study At study end Months in study, median (range) * See Table 1 for definitions. tp < MTX (group A; n = 22) T/5 (group B n = 24) Responder Nonresponder Responder Nonresponder (n = 19; 86%)t (n = 3; 14%) (n = 14; 58%)t (n = 10; 42%) (4-112) 9 11 (7-17) 4 (0-6) 2 (0-4) (0-1,024) 16 (0-1,024) 32 (0-512) (6-30) (8-32) 1 9 (7-13) 2 (2-4) 4 (2-5) (2-512) 8 (0-64) 64 (0-128) (5-7) (4-58) (4-15) 0 (0-7) 0 (0-3) (8-512) 8 (0-128) 0 (0-128) (6-73) 6 9 (7-35) 7 9 (4-15) 1 (0-5) 5 (2-7) (0-512) 8 (0-512) 6 (0-4,096) 1, (4-58) vasculitis in a biopsy), S = skin, P = peripheral nervous system, C = central nervous system, A = rheumatic complaints, B = constitutional symptoms (fever, weight loss, fatigue, night sweats). All organ manifestations were allocated 2 points, except for constitutional symptoms, which received only 1 point. The maximum possible DEI score was 21 points. The activity of WG was assessed according to clinical, radiologic, and seroimmunologic data. Complete remission was arbitrarily defined as the absence of pathologic findings in these parameters, irrespective of the ANCA titer. Partial remission was defined as partial improvement in disease activity (1,7,18) in a state of unchanged, smoldering disease over a period of at least 3 months. The reemergence of clinical symptoms attributable to active WG after a phase of complete or partial remission was considered a relapse. ANCA titers were determined serially in all patients at 3-month intervals as described previously (17,20). Because the serum level of soluble interleukin-2 receptor (sil-2r) has previously been shown to correlate with disease activity in WG and to be a marker of imminent relapse in patients in remission (21), serum levels of sil-2r were measured using a commercially available sandwich enzyme-linked immunosorbent assay kit (T Cell Sciences, Cambridge, MA). Normal values (420 -t 30 units/ml) were determined in a cohort of healthy control subjects (21). Response to treatment was defined as successful maintenance of preexisting partial or complete remission for at least 6 months. Any relapse was considered a nonresponse to remission-maintenance therapy and led to withdrawal from the maintenance regimen, and thus, from the study. Statistical analysis. Data are reported as median values. Analysis of significance was performed using Wilcoxon s rank test, the Kruskal-Wallis test, and the Latin square. In all statistical tests, a P value less than 0.05 was considered significant. RESULTS We compared the efficacy of MTX versus T/S, each with and without concomitant prednisone, in maintaining remission in 65 patients with generalized WG (Figure 1 and Table 1). Group A patients (MTX alone). Nineteen of the 22 patients (86%) receiving MTX alone remained without signs of relapse for a median of 16 months (range 6-30 months). In these 19 responders, the median DEI score decreased from 4 to 2 over the study period. At study initiation, only 3 of these patients were in complete remission; a further 3 patients went from partial to complete remission while taking MTX. In 10 of these responders, the MTX dose could be reduced, and in 4, the MTX could be stopped completely after 6 months in complete remission with the MTX. During the treatment period, the median ANCA titer in the 19 responders rose by 1 titer, and the serum sil-2r level increased insignificantly (Table 2). Three patients (14%) had to discontinue MTX treatment after a median of 7 months (range 5-7 months) because of a relapse. In these patients, the

5 2056 DE GROOT ET AL Table 3. Treatment results in the 19 patients with generalized Wegener s granulomatosis treated with low-dose MTX or T/S, with prednisone, as a remission-maintenance regimen* MTX + pred. (group C; n = 11) T/S + pred. (group D; n = 8) Responder Nonresponder (n = 10; 91%)t (n = I; 9%) Fauci scheme therapy before study No. of patients 9 1 Duration, median (range) months 20 (5-64) 35 No. of patients taking CYC pulse 8 1 therapy before study DEI score, median (range) At diagnosis 10 (5-13) 11 At start of study 2.5 (2-6) 4 At study end l(0-4) 7 Complete remission At start of study 0 0 At study end 4 0 canca titer, median (range) At diagnosis 128 (32-512) - At start of study 128 ( ) 32 At study end 64 (0-128) 32 sil-~r, median At start of study At study end Responder Nonresponder (n = 0; O%)t (n = 8; 100%) 7 9 (3-36) 5 8 (5-13) 3 (0-7) 5.5 (2-15) (0-128) 16 (0-128) 32 (0-512) 1, Concomitant prednisone dose, 3 (1-4) 5 median (range) mgfday Months in study, median (range) 22 (5-34) (2-24) * See Table 1 for definitions. t P < median DEI score rose from 2 to 4, and the median canca titer rose from 1:s to 1:64. Their sil-2r serum levels also rose slightly, but did not differ significantly from those of the responders (Table 2). At study initiation, there were no significant differences in DEI scores, ANCA titers, or sil-2r levels between the responders and the nonresponders (by Wilcoxon s rank test). Group B patients (T/S alone). Only 14 of these 24 patients (58%) who were receiving T/S alone sustained remission during a median treatment period of 36.5 months (range 6-73 months). Ten patients (42%) relapsed after a median of 13 months, and their medication was changed to a more aggressive regimen, usually CYC. The 24 patients in group B entered the study with a median DEI score of 0, which remained unchanged in the 14 responders but rose to a median score of 5 (range 2-7) in the 10 nonresponders. At study initiation, responders and nonresponders had the same canca titer, and the nonresponders had higher serum sil-2r levels, but the difference in sil-2r levels was not statistically significant (Table 2). Comparison of groups A and B. The results in groups A and B patients can be summarized as follows. Remission in WG was sustained in a statistically significantly higher percentage of patients in group A (MTX alone) than in group B (T/S alone) (86% versus 58%; P < 0.05). The two groups did not differ significantly in terms of age, type of remission-inducing medication (CYC), DEI score, or ANCA titer at the initial diagnosis of WG, or in the duration of remission-maintenance treatment. The sole distinction between the two groups was the significantly longer remission-induction phase with continuous oral CYC in group A than in group B (27 months versus 11.5 months; P = 0.006) (Table 1). This did not, however, result in a lower median DEI score in group A. Moreover, patients in group B had a significantly lower median DEI score at the start of the study than did patients in group A (0 versus 4; P = 0.003) and still had a higher rate of relapse during the remissionmaintenance period compared with the patients in group A. Group C patients (MTX plus prednisone). Ten of the 11 patients (91%) receiving T/S plus prednisone remained in remission for a median treatment period of 22 months (range 5-34 months) (Table 3). The median DEI score in the responders decreased from 2.5 to 1; the median canca titer and serum sil-2r level remained largely unchanged. None of the patients were in complete remission at study initiation, while at study completion, 4 were (Table 3). In all 10 responders, the

6 REMISSION MAINTENANCE THERAPY IN PATIENTS WITH WG 2057 prednisone dosage could be reduced during the study; in 7, the MTX dosage could also be reduced. In the 4 patients whose WG was in complete remission, prednisone was discontinued. One of the 11 patients did not respond to MTX plus prednisone, and he died of a fulminant relapse after 5 months of remission-maintenance medication. At the outset of the study, his canca titer and serum sil-2r level did not differ significantly from those of the responders. His DEI score at that time, however, was slightly higher (4 versus 2.5) (Table 3). Group D patients (T/S plus prednisone). All 8 patients taking T/S plus low-dose prednisone experienced recurrence of disease activity after a median of 14.5 months (range 2-24 months). This was accompanied by a rise in the median DEI score from 3 to 5.5 (Table 3). Comparison of groups C and D. The results in groups C and D were similar to those in the other two groups. A statistically significantly higher percentage of patients in group C (MTX plus prednisone) than in group D (T/S plus prednisone) remained in remission (91% versus 0%; P < 0.005) (Table 3). The duration of maintenance treatment did not differ significantly between the two groups. At the initial diagnosis of WG, the two groups had the same sex ratio, age, type of remission-inducing drug, DEI score, and canca titer. The difference in the median duration of pretreatment with the Fauci scheme at study entry (9 months in group D versus 22 months in group C) was not statistically significant, but the patients in group C had significantly more CYC pulses than those in group D (P = 0.01) (Table 1). This is because in group C, there was a higher incidence of leukopenia and hemorrhagic cystitis during treatment according to the Fauci scheme, which forced a change to pulse CYC treatment. Still, both groups had similar median DEI scores and canca titers at study entry. The median sil-2r level in group D was higher than that in group C (1,039 versus 240 units/rnl at study entry). This difference failed to reach statistical significance. The median concomitant daily prednisone dose was also higher in group D than in group C (Table 3). Response of specific disease manifestations. Treatment with MTX, with or without concomitant prednisone (groups A and C), was very efficient in sustaining remission in WG patients and even resulted in a further decrease in the median DEI score in the responders, most of whom had not been in complete remission at the start of the remission-maintenance regimen (Figures 2A and B). The disease manifestations that responded most frequently to this treatment were DEI A < Change in DEI under MTX alone B ~ / DEI months of treatment Change in DEI under MTX + Prd months of treatment Figure 2. Changes in the Disease Extent Index (DEI) score during remission-maintenance treatment in A, 22 patients taking methotrexate (MTX) alone and B, 11 patients taking MTX plus prednisone (Prd). the rheumatic complaints (system A on the DEI) and the activity in the ENT system (system E on the DEI) in 11 and 7 patients, respectively. Still, 57% of the 33 patients taking MTX (groups A and C) showed ENT manifestations indicative of active WG (actively inflamed lesions, seen by an ENT specialist, most also biopsy-proven) at study completion, compared with 79% at study initiation. Additionally, with MTX treatment, there was resolution of pulmonary manifestations in 4 patients, renal (nephritic sediment without deterioration of renal function) in 1, ophthalmologic in 1, and vasculitic polyneuropathy in 3 patients. Bearing in mind that slightly more patients who were taking T/S were in complete remission at study initiation, the manifestations that resolved under T/S were ENT symptoms in 4 of 10 patients, polyneuropathy

7 2058 DE GROOT ET AL Table 4. Frequency of side effects in 65 patients with generalized Wegener s granulomatosis treated with low-dose MTX or T/s, with or without prednisone. as a remission-maintenance regimen* Nausea Leukopenia Rise in transaminase levels Pancytopenia Mucositis Rise in creatinine levels MTX pneumopathy Additional folinic acid Opportunistic infections Total groups A + C (MTX 2 pred.) (n = 33) Total groups B + D (T/S 2 pred.) (n = 32) Dosage reduction due to side 6 - effects Withdrawal due to side effects 2 3 * See Table 1 for definitions. in 1, and renal symptoms (nephritic sediment) in 2 patients. Side effects. Adverse effects were observed in 12 of 33 patients taking MTX (groups A and C) (Table 4). The most frequent were nausea in 6 patients and transient leukopenia in 5, followed by mild stomatitis in 3 patients (not shown in Table 4). In order to resolve these symptoms, 11 patients were treated with additional folinic acid; 6 also had their MTX dosage transiently reduced. Despite the the administration of folinic acid, the MTX therapy in 1 patient had to be stopped during complete remission because of severe mucositis of the upper gastrointestinal tract in conjunction with pancytopenia. Another patient was taken off MTX at another hospital because an MTX-induced pneumopathy was suspected but could not be clearly differentiated from a possible relapse; bronchoalveolar lavage was not performed. Side effects with T/S treatment (groups B and D) were rare (Table 4), occurring in only 6 of the 32 patients. The side effects were a mild leukopenia in 5 patients and a mild rise in serum creatinine levels in 4. The simultaneous occurrence of both symptoms in 3 patients led to their withdrawal from T/S treatment, and thus, from the study. All patients had been in complete remission at this point. DISCUSSION Treatment of generalized WG remains a problem despite a remarkably increased chance of remission. The median survival time of 5 months in the 1950s (22) has improved to a 93% chance of remission today, primarily because of the use of the Fauci treatment scheme (daily CYC plus prednisone) (1). One major drawback to that regimen, however, is its high therapy-related morbidity and mortality (2). Furthermore, this aggressive treatment, which was designed to be given for as long as 1 year after complete remission was attained before being tapered (l), cannot prevent relapses despite a high initial rate of remission. Fauci and coworkers (1) observed relapses in 25 of 85 patients with generalized WG, all of which occurred during tapering of CYC, and therefore still under conditions of immunosuppressive treatment. In a more recent study, Hoffman et a1 (2) found that after initiation of standard treatment in 133 patients with WG, complete remission could be achieved in 75% of them, of whom 50% experienced a relapse within a mean followup period of 8 years. Gordon and coworkers (6) described a relapse rate of 44% in patients with generalized WG within a median period of 18 months after initial diagnosis, irrespective of the particular therapeutic regimen or any other predictive factor. Continued use of CYC plus prednisone according to the Fauci scheme once remission is achieved, therefore, does not seem to be warranted. First reports on the use of less toxic regimens such as T/S (7,8), azathioprine (l), and MTX (9) for remission maintenance in generalized WG have now appeared. The capacity of MTX in conjunction with high-dose prednisone to induce remission in WG (10) prompted us to study the potency of MTX in sustaining remission in generalized WG and to compare it with the efficacy of T/S in the same situation, as recently reported by Reinhold-Keller et a1 (7). In contrast to previous studies (lojl), MTX in the present study was given parenterally. This was to ensure that the full effects of MTX were possible by avoiding differences in efficacy caused by the substantial interindividual differences in gastrointestinal resorption of the drug (23). We were concerned that subcutaneous or intramuscular injections might carry a higher risk of infections at the injection site, as compared with IV injections. Thus, we chose the IV route for this study. Our results demonstrate that low-dose IV MTX, with or without concomitant prednisone, is more potent at maintaining remission than the similar regimens employing T/S. With T/S, all patients taking concomitant prednisone experienced a relapse (group D), as did almost half (42%) of the patients receiving T/S alone (group B). By contrast, almost all patients responded to MTX, irrespective of concomitant prednisone treatment

8 REMISSION MAINTENANCE THERAPY IN PATIENTS WITH WG 2059 (86% in group A and 91% in group C). This was the case even though only 3 of the 33 patients in the MTX groups (A and C) were in complete remission at study initiation compared with 17 of the 32 in the T/S groups (B and D). Patients given MTX alone (group A) entered the study with a significantly higher median DEI score than patients given T/S alone (group B) (4 versus 0; P= 0.003) and still showed better treatment results. Interestingly, in their preliminary report Stegeman and coworkers (8) describe much better remission maintenance with T/S alone. In a placebo-controlled trial involving 81 patients with generalized WG, 8 of 41 patients (20%) receiving T/S experienced a relapse, compared with 16 of 40 patients (40%) in the placebo group. Our relapse rate with T/S alone (42% in group B) equaled that of the placebo group in Stegeman's cohort. One explanation for this discrepancy could be that the patient cohorts in the 2 studies may have been assessed differently, thus producing disparate results. Until recently, there were no uniform, internationally valid standards for the assessment of disease activity and extent of WG, nor were there definitions of remission and relapse. A European vasculitis study group (ECSYSVASTRIAL [see ref. 241) was able to achieve, for the first time, a consensus concerning uniform assessment of these parameters based on the Birmingham vasculitis activity score (25) and the DEI score (18). It has been reported that chronic nasal carriage of Staphylococcus aureus may be an independent risk factor for relapse in WG (26). It is not known, however, which strain is relevant and whether there are local differences in the occurrence of S aureus strains that could explain regional differences in relapse rates of WG during therapy with T/S. In this study, MTX treatment resulted in a further decrease in the median DEI score. This was observed to a lesser extent with T/S treatment. Disease manifestations such as rheumatic complaints (DEI system A) and, less often, polyneuropathy (DEI system P), nephritic urinary sediment without deterioration of renal function (DEI system K), and inflammatory eye lesions (DEI system EY) vanished. Among the symptoms whose activity partially improved during MTX treatment were lesions in the ENT tract and lungs. These findings reveal the immunosuppressive potency of MTX and explain its favorable rates of response as a remission-inducing medication for WG, at least when used in conjunction'with rather high doses of prednisone (10,ll). There is an increasing consensus that MTX, which is indisputably the number 1 drug for the therapy of rheumatoid arthritis (27), will become increasingly important for the treatment of vasculitic disorders. This potential is demonstrated by its success in treating giant cell (temporal) arteritis (28) and Takayasu arteritis (29). No clear-cut, statistically significant factors predictive of relapse were found in any of the 4 treatment groups. It is striking that nonresponders in both T/S groups showed a tendency toward higher serum sil-2r levels at study entry compared with the responders to T/S and with all of the patients taking MTX. While this phenomenon was not statistically significant, it may be clinically relevant. The importance of elevated sil-2r as a predictor of possible relapse is consistent with previous findings (21,30). Furthermore, patients in group D, who were taking T/S, needed a slightly higher median concomitant prednisone dosage than patients in group C, who were taking MTX (10 mg versus 3 mg). The higher initial serum sil-2r levels and the need for a higher prednisone dosage may indicate a higher risk of relapse during remission maintenance with T/S. We found no factor predictive of relapse with MTX therapy that clearly distinguished the responders from the nonresponders to MTX. In view of the small number of relapses that occurred with MTX, this may be less important than the detection of such predictive factors for T/S, with its higher rate of relapse. Other serum markers have been evaluated for their predictive value regarding relapse in WG. While levels of soluble CD4 and CD8 have not shown any significant value (30), the prognostic value of a rise in ANCA titer is a subject of controversy (31,32). Relapses in our patient cohort were not necessarily associated with an increase in the ANCA titer. Interestingly, although patients receiving T/S (groups B and B) had undergone a shorter pretreatment period with the Fauci scheme than patients receiving MTX (groups A and C), they still had a lower median DEI score and a higher number of complete remissions at study initiation (Tables 2 and 3). Nonetheless, they had a significantly higher number of relapses during remission-maintenance therapy. Gordon et a1 (6) could not find an association between the rate of relapse and the dosage of previous CYC treatment. The main reason patients in groups B and C tended to have had more CYC pulses than the patients in groups A and D is that ups, there was inadvertently a higher rance to continuous oral CYC treat- 'hemorrhagic cystitis). These data highlight the dilemma confronting the therapist: The londer the period of CYC treatment, the lower the likelihood of future relapses. But the longer the CYC treatment, the greater the toxicity, and thus the

9 DE GROOT ET AL greater the risk of permanent damage rendering further use of CYC impossible. As previous studies have shown, relapses in WG usually do not reach the same extent of disease as did the initial disease manifestation (6,7,18). Hence, it is probably advisable to keep the period of continuous oral CYC as short as possible, even if this means stopping after only partial remission is achieved. This may entail a higher risk of relapse while the patient is taking a different, less toxic remission-maintenance medication. However, it leaves open the option of future short-term CYC in the event of relapse. In our study, adverse drug reactions were rare and never fatal. It must be borne in mind, though, that the observation periods are still rather short. Moreover, patients with a serum creatinine value >150 mmoles/ liter were not included in our study in order to avoid toxicity caused by drug accumulation resulting from impaired renal function. Side effects were half as frequent during T/S treatment than during MTX treatment (Table 4). Most of the MTX-induced side effects were not serious and could be resolved by either supplemental folinic acid, transient dosage reduction of MTX, or both. Withdrawal of patients from the study because of adverse reactions was rare in all groups. In a study using MTX in 42 patients with generalized WG, mainly as a first-line drug for the induction of remission (ll), leukopenia was less frequent than in our cohort (7% versus 17%). Leukopenia was also very rare in a large cohort of patients receiving low-dose IV MTX for treatment of rheumatoid arthritis (3 of 100 patients) (27). The difference between these results and our own may be explained by the fact that our patients received MTX as second-line therapy after longstanding and potentially bone marrow-suppressing pretreatment with CYC, which was not the case in the other two studies. However, we did not see a single incidence of opportunistic infections during remission maintenance with low-dose IV MTX. This contrasts with the results published by Sneller et a1 (1 l), who observed 4 cases of Pneumocystis carinii pneumonia in 42 WG patients (9.5%) who were taking MTX and rather high doses of concomitant corticosteroids as a remission-induction regimen, with a fatal outcome in 2 of them. In our view, this can be attributed to the high doses of concomitant prednisone (50-60 mg/day) in 3 of the 4 patients, which is inevitable in the induction phase, rather than to the MTX itself. In summary, our results indicate that remission in generalized WG can be effectively sustained with weekly low-dose MTX. MTX seems to be more potent than T/S for this purpose. Patients need not be in complete remission at the start of MTX, and even a small concomitant prednisone dosage was not associated with a higher rate of relapse during MTX treatment. In view of these findings, we see a chance to shorten the induction treatment period with the Fauci scheme by switching to MTX as soon as partial remission is achieved. However, the Fauci scheme remains the therapeutic gold standard and is indispensable for the induction of remission in cases of severe generalized, possibly life-threatening WG. Since many vasculitic organ manifestations actually improved under remission-maintenance therapy with MTX, controlled studies are now needed to determine whether low-dose MTX can induce remission in generalized, non-life-threatening WG. Such a study is currently being conducted by the ECSYSVASTRIAL group. ACKNOWLEDGMENT The authors thank Dr. Hans-Jiirgen Friedrich (Institute of Medical Statistics, University of Liibeck) for his assistance with the statistical data. REFERENCES 1. Fauci AS, Haynes BF, Katz P, Wolff SM: Wegener s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. 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