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- PATIENTS AND METHODS
The epidemiologic data of the 71 patients with WG included in this study are presented in Table 1. Within a mean observation period of 25.2 months (median 24 months, range 1–71), 26 (36.6%) of 71 patients with WG receiving maintenance treatment of weekly low-dose MTX with or without concomitant corticosteroids experienced a relapse after a mean of 19.4 months (median 19 months; range 1–49). Figure 1 shows the appearance of the relapses within the study period of 77 months. In the patients who relapsed, the mean DEI increased from 2.2 (median 2, range 0–6) at study start to 4.7 (median 4, range 2–9) at the time of relapse. At that time, all patients were still receiving MTX a mean dosage of 18 mg/week (median 15 mg/week; range 7.5–27.5). Seventeen (65.4%) of the 26 patients who relapsed had already discontinued their GC treatment (6 patients before the start of the study, and 11 during maintenance treatment with MTX). The remaining 9 patients were given a mean GC dose of 5.1 mg (median 4.5 mg, range 1–12 mg) at the time of relapse. Approximately one-third of the 55 patients who were still taking GC and one-third of the 16 patients who were not taking GC at the start of the study subsequently relapsed (36.4% versus 37.5%).
Figure 1. Cumulative probability of relapse in patients with Wegener's granulomatosis receiving treatment with intravenous methotrexate.
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Eighteen relapses were classified as major, 16 of which required a switch to CYC treatment. One patient was treated with local laser therapy and local GC injections for a severe subglottic stenosis. Another patient received an increased dose of MTX plus additional cyclosporin A. When this failed to control the disease he also received CYC pulses, instead of daily CYC, because of a CYC-induced cystitis due to previous CYC therapy. This patient subsequently died of uncontrollable disease (for details see below). All 18 patients with a major relapse were additionally given an increased dose of GC (0.5–1 mg/kg). Eight relapses were determined to be minor, because they could be controlled by an increase of the GC dose and/or the MTX dose alone. The mean followup time to major relapse was 16 months, whereas the mean time to a minor relapse was 27.1 months (P = 0.019).
Most relapses occurred in the ear, nose, and throat tract (18/26) and, surprisingly, in the kidney (16/26). Relapses occurred to a lesser extent in the lung (5/26), skin (2/26), the peripheral nervous system (2/26), and the eyes (1/26). Constitutional and rheumatic symptoms (i.e., arthralgias, arthritides, myalgias) reemerged in 11 of 26 patients, respectively (Table 2). Most relapses affected organ systems that were already affected by the initial manifestation of the disease. However, a case of glomerulonephritis and a case of cutaneous vasculitis were each observed in 2 patients for the first time in their disease course at relapse during MTX therapy. Also 3 patients displayed arthralgias and arthritides for the first time at relapse (Table 2).
Table 2. Organ manifestations in 26 patients at the time of relapse during maintenance of remission with low-dose MTX*
|Organ system according to DEI||Patients, n (%)||New organ manifestation at relapse receiving MTX, n|
|Upper respiratory tract||18 (69.2)||0|
|Rheumatic symptoms||11 (42.3)||3|
|Constitutional symptoms||11 (42.3)||0|
|Peripheral nervous system||2 (7.7)||0|
|Inflammatory eye involvement (no granulomatosus changes)||1 (3.8)||0|
|Gastrointestinal tract||0 (0)||0|
|Central nervous system||0 (0)||0|
Of note is the high number of renal relapses that occurred during MTX therapy. Of these 16 patients, 14 exhibited a rise in serum creatinine from normal values to 1.5–2 mg/dl plus a new nephritic sediment. One additional patient even developed a rapidly progressive glomerulonephritis (RPGN) combined with a severe pulmonary infiltration and pulmonary hemorrhage while receiving MTX and concomitant GC. He subsequently died of progressive disease that could not be controlled by an intensification of immunosuppressive therapy. One patient had a nephritic sediment only.
Concerning predictive factors for relapse under maintenance of remission treatment with MTX, neither the DEI at diagnosis of the WG nor the DEI at the start of the study differed significantly between patients who relapsed and those that did not (mean values 10.3 versus 10.0, and 2.2 versus 2.0) (Table 3). Figure 2 illustrates that the cumulative probability to experience a relapse was lower for patients who were in complete remission (DEI = 0), compared with patients in a state of partial remission at study start, although this difference in probability failed to reach statistical significance. Table 3 also shows that there were no differences in pretreatment, mean GC dose at study start, and number of patients not taking GC at study start between patients who relapsed and those who did not. The median duration of pretreatment with CYC was 10 months in both groups. The only significant difference between the 2 groups was found in the mean ANCA titer at the start of the study, which was significantly higher in patients who subsequently relapsed compared with those who did not relapse (1/128 versus 1/32). Apart from a slightly more frequent vasculitic eye involvement at study start in patients with subsequent relapse (3/26 versus 0/45, P = 0.045, Fisher's exact test) there were no statistically significant quantitative differences in organ manifestation patterns either at diagnosis or at study start between patients who relapsed and those who did not. Seven of twenty-six patients (27%) who relapsed and 11 of 45 (24%) who did not relapse during therapy had exhibited previous relapses.
Table 3. Patients who relapsed compared with patients who did not relapse during maintenance of remission with low-dose MTX*
| ||Relapses (n = 26)||Nonrelapses (n = 45)||t-test|
|Male/female, n||17/9||24/21||Chi-square, NS|
|Age at diagnosis, mean ± SD (range) years||47.4 ± 12.6 (12–69)||49.9 ± 13.8 (25–77)||NS|
|CYC-duration, mean ± SD months||16.3 ± 14.3||12.4 ± 8.9||NS|
|CYC-duration, median (range) months||10 (5–66)||10 (3–50)|
|GC for remission induction, n (%)||25 (96.2)||45 (100)||NS|
|DEI at diagnosis, mean ± SD (range)||10.3 ± 2.1 (7–13)||10.0 ± 2.3 (7–15)||NS|
|DEI at start of study, mean ± SD (range)||2.2 ± 2.0 (0–5)||2.0 ± 1.6 (0–6)||NS|
|DEI = 0 at study start, n (%)||9 (35)||13 (20)||NS|
|GC-dose at study start, mean ± SD (range) mg/day||4.7 ± 4.9 (0–20)||4.5 ± 4.2 (0–25)||NS|
|Patients off GC at study start, n (%)||6 (23)||10 (22.2)||NS|
|Followup (= time to end-point), mean ± SD (range) months||19.4 ± 11.4 (1–49)||28.5 ± 15.2 (9–77)||P = 0.01|
|Weekly MTX dose at end-point, mean ± SD (range) mg||18.04 ± 6.5 (7.5–30)||17.6† ± 6.3 (7.5–30)||NS|
|Daily GD dose at end-point, mean ± SD (range) mg||1.7 ± 3.2 (0–12)||1.02 ± 1.9 (0–5)||NS|
|Off GC at end point, n (%)||17 (65)||34 (75)||NS|
|cANCA titer at study start, mean ± SD (range)||128 ± 2.7‡ (0–1024)||32 ± 3.7‡ (0–1024)||P = 0.024|
|cANCA negative at study start, n (%)||2/26 (8)||8/43 (19)||NS|
Figure 2. Cumulative relapse-probability for patients with Wegener's granulomatosis in complete remission (Disease Extent Index = 0) versus patients with Disease Extent Index > 0.
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In 15 of 26 patients who experienced a relapse while receiving MTX, the relapse was preceded or paralleled by a significant increase in ANCA titer by IFT (n = 6) or direct PR3-ELISA (n = 9). Only 3 patients showed a parallel increase in ANCA titer in both tests, including the patient who developed RPGN in the course of his fatal relapse.
In the group of patients who did not relapse, 34 of 45 could taper their GC dose to zero during the study period, and 22 of the patients could also cease their MTX medication because of complete remission. Complete remission was exhibited by 13 patients at study start and by 25 patients at study end, indicating that MTX has the potential to further suppress the disease activity. Among those who did not relapse, 12 of 45 (27%) experienced an increase of ≥2 titer steps in their cANCA titer by IFT during the study period (versus 6/26 [23%] of those who relapsed, see above), 13 of 45 (29%) exhibited a decrease of the ANCA titer to the same extent, and 7 of the latter group eventually became ANCA negative.
The following side effects were observed during therapy with MTX: leukopenia in 9 of 71 patients, leading to temporary dose reduction of MTX in 7 and withdrawal from MTX in 2 patients, and one infectious episode in 7 of 71 patients. Five of the infections were bacterial, specifically: 2 urinary tract infections caused by Escherichia coli, 1 upper airway infection caused by Staphylococcus aureus, and upper airway infections caused by Pseudomonas aeruginosa that occurred twice in 1 patient with preexisting bronchiectases. All bacterial infections required antibiotic treatment. In two other patients segmental herpes zoster occurred, requiring antiviral therapy. In no case did the patient need to be hospitalized because of the infection or its treatment. None of the observed infections were serious. Pneumocystis carinii pneumonia, cytomegalovirus infections, mucositis, or MTX-induced pneumonitis did not occur. Apart from the 2 withdrawals mentioned above, there were no further cessations of MTX therapy due to adverse effects.
- Top of page
- PATIENTS AND METHODS
We have followed 71 patients with initially generalized WG, after induction of remission with CYC and GC, under low-dose MTX therapy for maintenance of remission. This is the largest reported cohort of patients with WG treated with MTX. Just over one-third of the patients experienced a relapse, mostly comprising several organ systems (during the maintenance phase after a mean time of 19.4 months from study start). Alarmingly, in almost two-thirds of the relapses the kidneys were involved, including a rise in creatinine in almost all patients.
Today's challenge in treating WG lies in the prevention of relapses rather than in the achievement of the first remission. In the literature, relapse rates for patients with WG are variable but generally unsatisfactorily high: 50% in 8 years (1), 71% after a followup of more than 5 years (2), 44% after 18 months from diagnosis of the disease (15), and 46% after a median of 27 months in a cohort consisting of patients with WG and microscopic polyangiitis (5). In our cohort of 71 patients with WG, we observed a slightly lower relapse rate (36.6% after a mean period of 19.4 months from start of the maintenance regimen) that corresponds to a mean of 35.7 months from diagnosis. In accordance with the literature (5), all our relapses occurred while the patients where still taking MTX, although two-thirds of them had already discontinued taking GC.
In the attempt to minimize toxicity from long-term treatment with CYC (1), low-dose MTX has successfully been introduced into the therapy of WG for induction (1, 6, 9, 10) and maintenance of remission (7, 8). All reports including the present showed correspondingly that MTX was a relatively safe drug in terms of adverse effects. In addition, the occurrence of opportunistic infections appeared to be related to the dose of concomitant corticosteroids rather than attributable to MTX alone. This can be seen by comparing 2 cohorts of WG patients treated with similar regimens of low-dose MTX but different doses of GC, one low (7) and one higher (6).
However, as opposed to a group from the NIH who used MTX successfully in WG patients with active glomerulonephritis for induction and maintenance of remission (8, 9), we have seen an alarming number of renal relapses (16/26 = 61.5%) under maintenance of remission with MTX. It must be emphasized that all but one of these patients had a rise in serum creatinine from normal values to 1.5–2 mg/dl; one patient even experienced a RPGN and subsequently died. This happened despite a regular, thorough, and meticulous disease assessment program for activity and extent in our center every 3–6 months. Furthermore, this was combined with patient education in order to train them to detect warning signs of an imminent relapse as early as possible.
If one compares our patient cohort with Langford's (8) whose study has a similar set-up (induction with CYC, maintenance with MTX), one can state that the patients in Langford's cohort are significantly younger (37 versus 49 years, P = 0.000), and have a lower DEI at initiation of induction of remission treatment with CYC and GC (mean DEI 5.4 versus 10.1, P = 0.000). The percentage of renal involvement prior to induction of remission was insignificantly lower in Langford's cohort, compared with ours (17/31 patients, [54.8%] versus 51/71 patients [71.8%]; P = 0.444). Whether the advanced patient age and the higher DEI in our cohort could account for a higher renal relapse rate compared with that in Langford's cohort remains speculative. So far there are no published data showing that these parameters would be associated with a higher relapse rate. However, as Langford stated, the severity of the disease and the presence of glomerulonephritis were not associated with a higher frequence of relapse in their cohort consisting of a total of 31 patients (8), which is probably too small of a number of representative statistic calculations. In our significantly larger cohort there was no difference between patients who did and did not relapse in terms of DEI and age at diagnosis, nor was the incidence of renal involvement different in the 2 groups, either at diagnosis, or at start of the study.
Although Langford et al did not specify the mean GC dose accompanying MTX, the dose seems comparable with that used in our study. In the Langford et al study supplemental folinic acid was given in doses of 5–10 mg (8) whereas our patients received folic acid in the same dose as MTX. Studies have confirmed a positive effect of folic or folinic acid in preventing side effects of MTX (16–19). Van Ede et al showed that patients who received folate supplementation needed slightly higher doses of MTX to obtain the same clinical effect as patients who did not receive folic acid supplementation (17). Ortiz et al did not confirm differences in folic acid dose in their meta-analysis, however similar conclusions were drawn by Endresen and Husby (18) and by Shiroky (19). It therefore seems unlikely that different doses of folic or folinic acid were responsible for the different results between our study and that of Langford et al. In addition, MTX was administered intravenously in all patients in our study, leading to a higher bioavailability compared with an oral application of MTX in the NIH study.
In our own preceding study (7) with a much smaller number of patients (who were not enrolled in this study) the relapse rate of patients receiving MTX as maintenance of remission medication was lower than the one presented here. However, the mean followup time was also shorter than in the cohort presented here, and it seems likely that the incidence of relapse is a function of time. This would also be supported by the preliminary results of a prospective, randomized, controlled European Vasculitis Study Group (EUVAS) trial CYCAZAREM, where the relapse rates under CYC and azathioprine were 17% and 16% respectively, but followup was only up to month 18 from diagnosis (20).
The question remains: what is the value of the continued use of a maintenance of remission medication and for how long should it be given? In the attempt to use CYC for as short a time period of time as possible, the maintenance of remission medication aims at consolidating the achieved remission, including conversion of a partial remission into a complete remission. This happened in 9 responders in our cohort, who were in partial remission at study start and finished the study in complete remission. Whether immunosuppression beyond the function of consolidation of the first remission carries more benefit than risks (infections, bone marrow suppression, permanent damage) awaits further assessment. This is the aim of the randomized, prospective, controlled EUVAS trial REMAIN. It tests the hypothesis that prolonged maintenance therapy with low-dose prednisolone and azathioprine reduces long-term morbidity in systemic vasculitis by reducing the frequency of relapse, when compared with cessation of therapy in the second year (3). Conversely, prolonged immunosuppression, even with drugs that are less aggressive than CYC may enhance the risk of myelodysplastic syndrome and lymphoma, which in turn renders potent immunosuppression in case of a relapse impossible (21).
Unfortunately, there are still no reliable predictors available that identify patients who have an increased risk for relapse, which would facilitate the decision of prolonged immunosuppression. In our present cohort, apart from a significantly higher median ANCA titer at study start in the cohort of patients who relapsed, there were no differences concerning age, sex, and disease extent at diagnosis, study start, or pretreatment between the 2 groups, that would indicate that either was at higher risk for relapse. Patients with a DEI = 0 at study start experienced fewer relapses than patients with a DEI > 0, but this difference failed to reach statistical significance. Even serial ANCA testing, at least in our hands, has not proven to be a reliable tool to identify patients at risk for imminent relapse. The relapse was preceded or paralleled by an increase in ANCA titer in only 57.7% of the patients, and this figure resulted from the addition of the results of 2 ANCA tests (the IFT and direct PR3-ANCA ELISA). Therefore, in order to reach that percentage one would have to do at least 2 tests serially, which is expensive and time-consuming. In summary, serial ANCA testing with a single-test system as used in daily practice was not sufficient to predict relapses.
In conclusion, MTX with and without concomitant GC is a safe medication for maintenance of remission in WG. However, 36.6% of the 71 study patients experienced a relapse at the end of the second year of treatment. In almost two-thirds of the patients, the relapse was with renal involvement, among them 1 patient with RPGN. Patients that are not in complete remission and have a high ANCA titer at the time of switch from CYC to MTX may be at higher risk for a future relapse. We still recommend the use of MTX as maintenance of remission medication for patients with generalized WG following remission induction with CYC. However, we emphasize that close monitoring, including urinary sediment, is mandatory in order to treat a relapse as early as possible, because the most frequently involved organ in relapse in our cohort was the kidney. This is a major problem, because this situation usually requires a switch back to CYC and is associated with a poorer prognosis. Since the use of MTX is impossible in patients with moderately to severely impaired renal function, a promising alternative drug for maintenance of remission may be leflunomide, because it does not accumulate with decreased renal function. In a preliminary pilot study for maintenance of remission in 20 WG patients after a median followup of 24 months, 9 minor relapses but only 1 major relapse was observed (22). Recently, a prospective, randomized, controlled, multicenter German study to compare MTX with leflunomide for maintenance of remission in WG has been started. The identification of risk factors that predict a future relapse is one of the major issues for future studies in order to design more individual maintenance of remission strategies.