High rate of renal relapse in 71 patients with Wegener's granulomatosis under maintenance of remission with low‐dose methotrexate

Objective

To examine the long‐term efficacy of low‐dose intravenous methotrexate (MTX) with and without concomitant glucocorticoids (GC) for remission maintenance in patients with generalized Wegener's granulomatosis (WG) in an open‐label, prospective, standardized trial.

Methods

After induction of remission by cyclophosphamide and GC, 71 patients (41 males, 30 female) with initially generalized WG received low‐dose methotrexate at 0.3 mg/kg body weight once weekly. At study‐start 55 of 71 (77.5%) patients were on low‐dose GC (mean 5.9 mg/day) which was tapered during the study. All patients underwent interdisciplinary staging at 3‐month (and later at 6‐month) intervals to assess disease activity and extent as well as side effects. End points were the first relapse or the end of study (January 2001).

Results

Within a mean followup period of 25.2 months, 26 patients (36.6%) experienced a relapse after a mean of 19.4 months. Seventeen (65.4%) of these 26 patients had terminated GC therapy at the time of relapse. There was no difference in relapse rates among patients with and without concomitant GC at study start. Relapses occurred mainly in the initially involved organ systems, preferentially in the ear, nose and throat tract in 18 of 26 patients and the kidney in 16 of 26 patients. One renal relapse presented as rapid, progressive glomerulonephritis with lethal outcome. Further, 14 relapses were accompanied by a significant rise in creatinine values. In 15/26 patients the relapse was paralleled or preceded by a significant rise of antineutrophil cytoplasmic antibody titer. Two patients ceased MTX prematurely because of persistent leukopenia.

Conclusion

Weekly MTX is a well tolerated therapy for long‐term maintenance of remission. However, one‐third of the patients relapsed during ongoing MTX treatment, irrespective of whether they were still receiving GC. Because more than half of the relapses affected the kidney, close monitoring is indispensable.

     

The treatment of wegener's granulomatosis with glucocorticoids and methotrexate

Objective. To identify alternatives to daily low-dose cyclophosphamide (CYC) in the treatment of Wegener's granulomatosis (WG). Methods. An open-label pilot study of weekly low-dose methotrexate (MTX) plus glucocorticoids (GC) for treatment of patients with WG was performed. Twenty-nine patients who did not have immediately life-threatening disease were included. Outcome was determined by clinical characteristics, pathologic findings, course of illness, laboratory and radiographic findings, and successful withdrawal of GC therapy. Results. Weekly administration of MTX (at a mean stable dosage of 20 mg) and GC resulted in marked improvement in 76% of the 29 patients. Remission was achieved in 69% of the patients, 7% improved but had intermittent smoldering disease that precluded total withdrawal of GC, and 17% had progressive disease within 2–6 months of starting the study treatment. Two patients who initially achieved remission later had relapses after GC was discontinued. Of those who remain in remission (mean followup time 14.5 months), 72% have not required GC for a mean period of 10 months. Conclusion. Although standard therapy for WG (daily CYC and GC) has dramatically improved outcome in this often-fatal disease, treatment morbidity has led to attempts to identify effective interventions that have less toxicity. Weekly low-dose MTX was shown in this study to be a feasible alternative to CYC in patients whose illness was not immediately life-threatening or in whom prior CYC treatment was ineffective or produced serious toxicity. Although these results are preliminary, they are encouraging and justify further studies in which MTX, CYC, and other alternative therapeutic approaches are compared concurrently.     

An analysis of forty-two wegener's granulomatosis patients treated with methotrexate and prednisone

Objective. To determine the efficacy of low-dose methotrexate (MTX) plus prednisone in the treatment of Wegener's granulomatosis (WG). Methods. An open-label study of weekly low-dose MTX plus prednisone for the treatment of WG was performed. Forty-two patients who did not have immediately life-threatening disease were enrolled into the study. Outcome was determined by clinical characteristics and pathologic, laboratory, and radiographic findings. Results. Weekly administration of MTX and prednisone resulted in remission of disease in 30 of the 42 patients (71%). The median time to remission was 4.2 months. The estimated median time to relapse for all patients in whom remission was achieved was 29 months. Eight patients who had relapses were treated with a second course of MTX plus prednisone, and a second remission was induced in 6 of the 8 (75%). Conclusion. Weekly low-dose MTX was shown in this study to be an acceptable alternative form of therapy for selected patients with WG who do not have immediately life-threatening disease or who have developed serious cyclophosphamide-associated toxicity.     

The treatment of Wegener's granulomatosis with glucocorticoids and methotrexate.

OBJECTIVE. To identify alternatives to daily low-dose cyclophosphamide (CYC) in the treatment of Wegener's granulomatosis (WG). METHODS. An open-label pilot study of weekly low-dose methotrexate (MTX) plus glucocorticoids (GC) for treatment of patients with WG was performed. Twenty-nine patients who did not have immediately life-threatening disease were included. Outcome was determined by clinical characteristics, pathologic findings, course of illness, laboratory and radiographic findings, and successful withdrawal of GC therapy. RESULTS. Weekly administration of MTX (at a mean stable dosage of 20 mg) and GC resulted in marked improvement in 76% of the 29 patients. Remission was achieved in 69% of the patients, 7% improved but had intermittent smoldering disease that precluded total withdrawal of GC, and 17% had progressive disease within 2-6 months of starting the study treatment. Two patients who initially achieved remission later had relapses after GC was discontinued. Of those who remain in remission (mean followup time 14.5 months), 72% have not required GC for a mean period of 10 months. CONCLUSION. Although standard therapy for WG (daily CYC and GC) has dramatically improved outcome in this often-fatal disease, treatment morbidity has led to attempts to identify effective interventions that have less toxicity. Weekly low-dose MTX was shown in this study to be a feasible alternative to CYC in patients whose illness was not immediately life-threatening or in whom prior CYC treatment was ineffective or produced serious toxicity. Although these results are preliminary, they are encouraging and justify further studies in which MTX, CYC, and other alternative therapeutic approaches are compared concurrently.     

Treatment of glucocorticoid-resistant or relapsing takayasu arteritis with methotrexate

Objective. To identify the role of methotrexate (MTX) in the treatment of persistent or recurrent Takayasu arteritis that is refractory to treatment with glucocorticoids (GC) alone. Methods. An open-label pilot study of weekly low-dose MTX + GC treatment was performed. Outcome was evaluated according to clinical characteristics, laboratory abnormalities, findings on routinely performed angiographic studies, and ability to withdraw GC and MTX therapy. Eighteen patients entered the study; 2 dropped out, and 16 were followed up for a mean period of 2.8 years (range 1.3–4.8 years). Results. Weekly administration of MTX (mean stable dose of 17.1 mg) and GC resulted in remissions in 13 of 16 patients (81%). However, 7 patients (44%) had relapses as GC was tapered to or near discontinuation. Retreatment again led to remission, and 3 of 7 patients in this group have successfully stopped GC therapy. Of those patients who achieved remission, 8 (50%) have sustained remissions of 4–34 months (mean 18 months), and 4 of this group have not required GC or MTX therapy for 7–18 months (mean 11.3 months). Three patients experienced disease progression in spite of treatment. Conclusion. About half of all Takayasu arteritis patients have chronic active disease for which GC therapy alone does not provide sustained remissions that allow withdrawal of treatment. Weekly low-dose MTX is an effective means of inducing remission and minimizing GC therapy and toxicity in most of these patients. Further long-term studies will be required to assess the durability of remission and the need for maintenance MTX therapy in this subset of Takayasu arteritis patients.     

Therapy for the maintenance of remission in sixty-five patients with generalized Wegener's granulomatosis. Methotrexate versus trimethoprim/sulfamethoxazole

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 + 800 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 concomitant prednisone (group C; n = 11), 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 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.     

A staged approach to the treatment of Wegener's granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance

OBJECTIVE: To determine the efficacy of a daily cyclophosphamide (CYC) and glucocorticoid induction and methotrexate (MTX) remission-maintenance regimen for the treatment of Wegener's granulomatosis (WG). METHODS: An open-label, prospective, standardized trial for the treatment of WG was performed using CYC and glucocorticoids for remission induction and MTX for remission maintenance. Thirty-one patients were enrolled in this study. Outcome was assessed using predetermined definitions based on clinical characteristics and pathologic, laboratory, and radiographic findings. RESULTS: The use of CYC and glucocorticoids for remission induction and MTX for remission maintenance resulted in disease remission for all 31 patients. The median time to remission was 3 months and the median time to discontinuation of glucocorticoids was 8 months. No patients have died, and 5 patients (16%) have had disease relapses at a median of 13 months after achieving remission. Only 2 patients (6%) have had to withdraw from the trial as a result of medication toxicity. CONCLUSION: The use of CYC and glucocorticoids for remission induction and MTX for remission maintenance was shown by this study to be an acceptable alternative therapy for patients with active WG, including those with severe disease at onset.     

Treatment of non-life threatening Wegener's granulomatosis with methotrexate and daily prednisone as the initial therapy of choice.

OBJECTIVE: To examine our experience with methotrexate (MTX) and daily prednisone (PRED) as the initial treatment of Wegener's granulomatosis (WG). METHODS: Between November 1992 and November 1997, we treated 19 patients with non-life threatening WG with the combination of oral weekly MTX (starting at 7.5-10.0 mg/week) and daily PRED (median starting dose 40 mg/day, range 20-60). The MTX dose was increased to 15 mg/week by the end of the first month, and then by 2.5 mg/week until the disease was controlled. We attempted to taper PRED to 20 mg/day by the end of the second month, but did not use alternate day corticosteroids. Before treatment with this regimen, no patient had received previous treatment for WG. RESULTS: At presentation, the average number of organ systems involved was 3.6. Nine of the 19 patients (47%) had glomerulonephritis, but none had a serum creatinine > 1.2 mg/dl at presentation. Only 37% of the patients were hospitalized at presentation. Seventeen of 19 patients (89%) improved with treatment, and 14 (74%) achieved remission. However, half those who achieved remission suffered relapses, and no patient achieved a durable, complete remission (disease-free status free of all medications). Fifteen patients (79%) were able to taper PRED to < 10 mg/day. Seven of 8 disease relapses responded to increases of MTX and/or PRED. Only one patient developed glomerulonephritis while receiving treatment and required a change of therapy to cyclophosphamide. There were no deaths among patients in this series. Treatment with MTX and PRED was well tolerated: only 2 (11%) of the patients stopped treatment because of side effects (major liver function test abnormalities in both cases). No patient suffered permanent morbidity from MTX treatment. CONCLUSION: In selected patients with WG, the combination of MTX and daily PRED effectively controls the disease. However, chronic disease courses are the rule with this treatment regimen, and the likelihood of disease relapse is high. In our experience, the use of MTX and PRED in WG was safer than previously described, despite the use of daily corticosteroids.     

Efficacy and tolerance of methotrexate in a real-life monocentric cohort of patients with giant cell arteritis

ObjectivesTo assess the indications, efficiency and tolerance profiles of methotrexate (MTX) in patients with giant cell arteritis (GCA) in a real-life setting.MethodsFrom a monocentric database of >500 GCA patients, we retrospectively selected 49 patients who received MTX between 2010 and 2020. Cumulative glucocorticoid (GC) doses, the number of relapses and GC-related adverse events were recorded before, during and after MTX. We separately analyzed the 3 main indications of MTX, i.e., disease relapse, GC-sparing strategy, and GCA presentation.ResultsWith a median follow-up of 84 [10–255] months, 25 (51%) and 18/41 (44%) patients relapsed during MTX treatment and after its discontinuation, respectively. Among the 40 patients who relapsed before MTX, 26 (65%) experienced a new relapse after MTX introduction. Once MTX was introduced, 24 (49%) patients were able to discontinue GC after 20.5 [7–64] months. No significant difference in cumulative GC doses were noted before and after MTX introduction with a total GC dose of 14.7 [1.05–69.4] grams. At the last follow-up, MTX was discontinued in 41 patients, including 13 (32%) due to clinicobiological remission, 12 (30%) due to treatment failure and 15 (36%) due to side effects.ConclusionOur real-life study showed a modest beneficial effect of MTX on relapse in patients with GCA. However, we did not observe any GC-sparing effect in this study. Other studies are needed to assess the GC-sparing effect in patients in whom GC management is adapted from recent recommendations.     

Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis

OBJECTIVES: Results from open-label trials suggest that methotrexate (MTX) and leflunomide (LEF) are effective for maintenance of remission in Wegener's granulomatosis (WG), but data from randomized controlled clinical trails are not yet available. METHODS: In this multicentre, prospective randomized controlled clinical trial, patients with generalized WG were treated either with oral LEF 30 mg/day or oral MTX (starting with 7.5 mg/week reaching 20 mg/week after 8 weeks) for 2 yrs following induction of remission with cyclophosphamide. The primary endpoint was the incidence of relapses. Secondary outcome parameters were DEI, BVAS, SF-36, cANCA-titre, ESR and CRP. RESULTS: Fifty-four patients were included in the study, 26 in the LEF-limb, 28 in the MTX-limb. In the LEF-group, six patients relapsed after a median time of 7 months, thereof one major relapse with a new pulmonary manifestation. In the MTX-group, 13 relapses occurred in 6 months, of which seven were major: rapidly progressive glomerulonephritis (n = 4), pulmonary haemorrhage (n = 2) and one cerebral granuloma. The significantly higher incidence of major relapses in the MTX-limb (P = 0.037) led to premature termination of the study. In the LEF-limb, four patients were withdrawn due to hypertension (n = 2), peripheral neuropathy (n = 1) and leucopenia (n = 1). CONCLUSION: LEF at a dosage of 30 mg/day appears to be effective in the prevention of major relapses in WG, however, this is associated with an increased frequency of adverse events. Further studies testing other dosing regimens of lower doses of LEF are needed to confirm these promising results in larger patients cohorts.     

Wegener's granulomatosis in India: clinical features, treatment and outcome of twenty-five patients

OBJECTIVE: To report our clinical experience on Wegener's granulomatosis (WG). METHODS: A retrospective review of case records of all patients with WG in our Rheumatology Clinic during the period July 1988 to June 2000 was carried out and the details of demography, clinical and laboratory data, treatment and outcome were obtained and analysed. RESULTS: Twenty-five patients (16 females and 9 males) were found eligible for inclusion in the study. The mean age and duration of symptoms at presentation were 33.5 years and 5.5 months, respectively. Two patients had limited WG. Twenty-two patients with generalized WG were treated with standard regimen comprising oral prednisolone (1 mg/kg/day) and oral cyclophosphamide (2 mg/kg/day). Cyclophosphamide was continued for at least one year after the patient attained remission. One patient was treated with intravenous cyclophosphamide regimen. The two patients with limited WG were treated with oral prednisolone and methotrexate (10-12.5 mg as a single dose per week). Remission was achieved in 24 patients after a median time of six months. The median follow-up of patients was five years (range 4 months-11 years). Five patients were lost to follow-up. Eight patients suffered a relapse. The mean time for relapse was 34 months after the initial remission. Seven out of eight patients remitted again after reinstitution of the initial induction regimen. One patient died of diffuse pulmonary haemorrhage despite early institution of therapy. CONCLUSION: WG is being increasingly diagnosed in India now because of greater awareness and diagnostic aids. Although remissions are easy to achieve, relapses continue to pose a challenge to the treating physician.     

Methotrexate treatment in juvenile idiopathic arthritis: when is the right time to stop?

OBJECTIVES: To investigate whether prolonged methotrexate (MTX) treatment after induction of remission influences the subsequent duration of remission in patients with juvenile idiopathic arthritis (JIA), and to analyse the usefulness of myeloid related proteins 8 and 14 (MRP8/MRP14) as predictive markers for the stability of remission at the time when MTX is withdrawn. METHODS: Twenty five patients with oligoarticular and polyarticular JIA who received MTX to induce remission were followed up. MTX treatment was stopped after a mean of 3.8 months (group 1) or 12.6 months (group 2) after remission was documented. Differences in the number of relapses between these groups were looked for. Additionally, MRP8/MRP14 were analysed by ELISA in 22 patients. RESULTS: No difference was found in the number of relapses between patients with prolonged or early discontinued MTX treatment. Patients who were in stable remission had significantly lower MRP levels when MTX was discontinued than patients with relapses. With a cut off point for MRP8/MRP14 at 250 ng/ml, sensitivity and specificity were 100% and 70%, respectively. CONCLUSION: Longer duration of MTX treatment after induction of remission does not generally improve the status of remission in patients with JIA. Residual synovial inflammation seems to influence the rate of relapses after discontinuation of MTX treatment. MRP8/MRP14 indicate residual activity even in the absence of other laboratory or clinical signs of continuing inflammation. Normal serum concentrations of MRP8/MRP14 in clinical inactive arthritis may help to identify patients in whom MTX can be safely withdrawn after remission is achieved.     

Comparison of two schedules for administering oral low-dose methotrexate (weekly versus every-other-week) in patients with rheumatoid arthritis in remission: a twenty-four week, single blind, randomized study.

OBJECTIVE: To compare the efficacy of 2 low-dose oral methotrexate (MTX) schedules in maintaining remission in patients with rheumatoid arthritis (RA). METHODS: Patients with RA were included if they were receiving treatment with weekly MTX for at least 9 months and the RA was in remission (defined by American College of Rheumatology [ACR] criteria) for at least 6 months. Patients were stratified by treatment and randomly assigned to weekly or every-other-weekly (EOW; reducing their monthly dose by half) treatment with MTX. Patients were evaluated by a rheumatologist (blinded to the treatment schedule) at baseline and at 6, 12, and 24 weeks. The evaluations included joint counts, Ritchie Articular Index, Health Assessment Questionnaire Disability Index, physician's and patient's global health assessments, visual analog scale for pain, and incidence of adverse effects. Laboratory evaluations were done at baseline and at week 24. RESULTS: Fifty-one patients were included (26 taking weekly MTX, 25 taking EOW MTX). Baseline comparisons showed no differences between the groups. The mean duration of RA was <3 years in both groups, and they had been started on weekly MTX treatment early after diagnosis. After 24 weeks, >90% of the patients in both groups continued in remission. Evaluations of disease activity at 6 and 12 weeks showed no between-group differences. EOW MTX patients who experienced relapse were switched back to weekly MTX, and after a few weeks, their RA was again controlled. The incidence of adverse effects was slightly higher in the weekly MTX group, although the difference did not reach statistical significance. The observed laboratory values were very similar for both groups, except for the serum aspartate aminotransferase and alanine aminotransferase levels, which decreased in the EOW MTX group and were statistically significant at week 24 (P = 0.04 and P = 0.006, respectively). CONCLUSION: EOW MTX represents a valid therapeutic alternative for a specific subgroup of RA patients, as outlined by the ACR remission criteria. Patients with a short disease duration who were treated early after disease onset with weekly MTX and who achieve sustained remission have a higher probability of success with the EOW MTX schedule.     

Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience

We conducted a retrospective review to assess outcomes of therapy in patients with newly diagnosed Wegener granulomatosis (WG) using methotrexate (MTX) for mild to moderate disease and short-term treatment with cyclophosphamide (CYC) followed by MTX for severe disease. Patients with WG were included if their initial plan of therapy and subsequent care were directly supervised by the Cleveland Clinic Center for Vasculitis Care and Research. Severe disease (immediately life-threatening or involving critical organs) was initially treated with CYC and glucocorticoids. Mild to moderate disease was initially treated with MTX and glucocorticoids if serum creatinine was less than 2 mg/dL. Following initial improvement of severe disease, treatment was changed to MTX if serum creatinine was originally less than 2 mg/dL or had diminished to less than 2 mg/dL. Disease activity was determined at each visit and later converted to a Birmingham Vasculitis Activity Score, as modified for Wegener granulomatosis (BVAS/WG). Laboratory monitoring of disease and treatment toxicity was initially weekly and never less than monthly.Eighty-two (32%) of 253 patients with WG referred to the Center for Vasculitis Care and Research met eligibility criteria. Ineligible patients did not have new-onset disease or were not able to be followed principally in our center. Seventy percent of patients (57/82) initially had severe disease and received a short course of CYC for remission induction. In over half of these patients, illness was judged to be severe because of pulmonary hemorrhage; rapidly progressive glomerulonephritis, including need for dialysis; or neurologic abnormalities.All patients improved: remission was achieved in 50% (41/82) of patients within 6 months and in 72% (59/82) within 12 months. Sustained remission (BVAS/WG = 0 for at least 6 consecutive months) was ultimately achieved in 78% (64/82) of patients. Among the 75 (91%) patients who achieved remission of any duration, 45% relapsed within 1 year and 66% relapsed within 2 years following remission. Eighty-two percent of relapsed patients achieved subsequent remissions after additional treatment. About three-quarters of relapses were mild and promptly responded to treatment.Seventeen percent of patients developed serious infections. CYC-associated cystitis or bladder cancer did not occur in any patients. At least 1 form of permanent morbidity from WG alone was noted in 74.0% of patients. Three patients (3.7%) died over a median follow-up period of 4.5 years; no deaths were due to active disease.Although treatment was primarily directed toward achieving clinical improvement and not calculated to achieve marked lymphopenia, patients in whom treatment produced lymphocyte counts of 1000/mm was associated with a hazard ratio for relapse of 3.0, although the latter difference was not statistically significant.In patients with WG, a strategy that limits or avoids CYC therapy produced a frequency of remission comparable to that achieved with conventional CYC protocols, excellent survival, and avoidance of long-term CYC toxicity. However, relapses were common and incremental permanent morbidity occurred in most patients. While not a goal of therapy, when treatment produced marked lymphopenia, prolonged remissions were more likely.     

Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis

OBJECTIVE: Standard therapy for antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) with cyclophosphamide (CYC) and prednisolone is limited by toxicity. This unblinded, prospective, randomized, controlled trial was undertaken to determine whether methotrexate (MTX) could replace CYC in the early treatment of AASV. METHODS: Patients with newly diagnosed AASV, with serum creatinine levels <150 mumoles/liter, and without critical organ manifestations of disease were randomized to receive either standard oral CYC, 2 mg/kg/day or oral MTX, 20-25 mg/week; both groups received the same prednisolone regimen. All drug treatments were gradually tapered and withdrawn by 12 months. Followup continued to 18 months. The primary end point was the remission rate at 6 months (noninferiority testing). RESULTS: One hundred patients were recruited from 26 European centers; 51 patients were randomized to the MTX group and 49 to the CYC group. At 6 months, the remission rate in patients treated with MTX (89.8%) was not inferior to that in patients treated with CYC (93.5%) (P = 0.041). In the MTX group, remission was delayed among patients with more extensive disease (P = 0.04) or pulmonary involvement (P = 0.03). Relapse rates at 18 months were 69.5% in the MTX group and 46.5% in the CYC group; the median time from remission to relapse was 13 months and 15 months, respectively (P = 0.023, log rank test). Two patients from each group died. Adverse events (mean 0.87 episodes/patient) included leukopenia, which was less frequent in the MTX versus the CYC group (P = 0.012), and liver dysfunction, which was more frequent in the MTX group (P = 0.036). CONCLUSION: MTX can replace CYC for initial treatment of early AASV. The MTX regimen used in the present study was less effective for induction of remission in patients with extensive disease and pulmonary involvement and was associated with more relapses than the CYC regimen after termination of treatment. The high relapse rates in both treatment arms support the practice of continuation of immunosuppressive treatment beyond 12 months.     

Wegener's granulomatosis: long-term follow-up of patients treated with pulse cyclophosphamide

Treatment with daily oral cyclophosphamide (CY) has improved survival in Wegener's granulomatosis (WG), but is associated with severe and potentially lethal adverse effects. Less toxic treatment regimens, such as pulse CY, have been used, but the effect has been questioned. We have treated 11 patients with WG with pulse CY (15 mg/kg initially every second week, gradually increasing the pulse interval). After 4.5 yr follow-up and a total of 501 pulses of CY, one patient died and eight patients (73%) were in complete remission. Remission was induced in 91% of the patients after a median period of 3.5 months and relapses were seen in 60%. With the same treatment protocol, a new complete remission was induced in 75% of those relapsing. Except for one patient who died, no patient developed end-stage renal failure. Haemorrhagic cystitis was not observed and no malignancies recorded. Severe infections were seen in 36%, but none caused by Pneumocystis carinii. Nausea was the most frequent side-effect, seen in 64% of the patients. We conclude that treatment with pulse CY every second week is safe and effective in inducing remission and treating relapses in WG. The relapse rate seems to be higher than with low-dose oral CY, but the cumulative dose of CY is less.      

Maintenance of remission with leflunomide in Wegener's granulomatosis

OBJECTIVE: To investigate the safety and efficacy of leflunomide plus low-dose prednisolone for the maintenance of remission in Wegener's granulomatosis (WG). METHODS: This was a Phase II, single-centre, open-label clinical investigation of patients with generalized WG treated with leflunomide after the induction of complete (n = 4) or partial (n = 16) remission by cyclophosphamide/prednisolone combination therapy. Leflunomide treatment was initiated at 20 mg/day and increased to 30 mg/day after 12 weeks and, in patients with partial remission, to 40 mg/day after 24 weeks. Concomitant low-dose prednisolone (< or =10 mg/day) was allowed during the study. In addition to the frequency of relapse, treatment efficacy was assessed by the standard measures of disease activity/extent. RESULTS: A total of 20 patients were enrolled in the trial. During a treatment period of up to 2.5 yr (median 1.75 yr, range 1-2.5 yr), one patient had a major relapse and required retreatment with cyclophosphamide/prednisolone. Eight patients had minor relapses that were successfully treated by dose increases to 40 mg/day leflunomide. Disease activity remained unchanged for the duration of the study. The most frequently reported adverse events were mild respiratory infection (40%), arthralgia (35%) and hypertension (35%); dry skin, nail disorder and diarrhoea were each reported by 30% of patients. Despite the aggressive pretreatment with cyclophosphamide, adverse events with leflunomide treatment at the higher dose (30-40 mg/day) were comparable with those seen with the standard dose (20 mg/day) for rheumatoid arthritis patients. CONCLUSION: Leflunomide appears to be safe and well tolerated for the maintenance of complete or partial remission of WG. The results of this pilot study encourage further controlled trials comparing leflunomide with alternative remission maintenance therapies.     

Use of methotrexate and glucocorticoids in the treatment of Wegener's granulomatosis. Long-term renal outcome in patients with glomerulonephritis

OBJECTIVE: To determine the long-term renal outcome in patients with Wegener's granulomatosis (WG) and active glomerulonephritis who were treated with methotrexate (MTX) and glucocorticoids. METHODS: An open-label, prospective standardized trial using weekly low-dose MTX and glucocorticoids for the treatment of WG was performed. Forty-two patients were enrolled into the study, of whom 21 had active glomerulonephritis as a disease manifestation. The mean pretreatment level of serum creatinine in the patients with glomerulonephritis was 1.4 mg/dl. The extent of renal function in these patients at the time of their last followup was subsequently examined. RESULTS: Overall, 20 of 21 patients achieved renal remission. At 1 month and 6 months following study entry, the serum creatinine level in all patients either remained stable or improved. The 20 patients have now been followed up for a median time of 76 months (range 20-108 months). Only 2 patients have had a rise of >0.2 mg/dl in their creatinine level from the time of enrollment to the most recent followup examination. Of the remaining 18 patients, 12 have had stable renal function and 6 have had improvement in their creatinine levels by more than 0.2 mg/dl. CONCLUSION: In this study, the use of MTX and prednisone as initial therapy for patients with WG-related glomerulonephritis and a normal or near-normal level of serum creatinine was not associated with a long-term decline in renal function.     

Use of methotrexate in refractory Crohn's disease: the Edinburgh experience

BACKGROUND: In the two benchmark controlled trials in Crohn's disease (CD) supporting its use, methotrexate (MTX) was used as the immunosuppressant of choice in immunomodulatory-naive patients. However, in daily clinical practice MTX is used generally after thiopurine analogs have failed. METHODS: The data are reported using intramuscular (IM) MTX (25 mg/week) in the induction of remission and oral MTX (15 mg/week) in 39 CD patients with a median age of 32 years, assessed retrospectively. In all, 97% patients had failed azathioprine and/or mercaptopurine therapy due to lack of efficacy in 14 (36%) and side effects in 24 (61%) patients; 21 patients (53%) were steroid-dependent with a median dose of 27.5 mg prednisolone/day for over a year. RESULTS: In all, 72% of patients tolerated an induction regimen of 25 mg/week of IM MTX; 10% managed a reduced dose and 18% were intolerant. Remission was achieved in 71% of patients at 16 weeks. In the patients taking corticosteroids, withdrawal was achieved in 26% of patients and reduction in 47% at 16 weeks. Oral MTX therapy was continued in 22 patients after induction. In this group the probability of relapse was 78% at 50 weeks of oral therapy. CONCLUSIONS: Parenteral MTX therapy is efficacious in inducing remission in steroid-dependent CD patients, although its use is limited by side effects in approximately 30% of patients. Low-dose oral therapy does not maintain long-term remission and is not a suitable alternative.     

Wegener's granulomatosis: clinical features and prognosis in 37 patients

:Thirty-seven patients (21 female, 16 male) with Wegener's granulomatosis (WG)were reviewed. Patients were followed for a mean six years after diagnosis; 14 were followed for more than seven years. The clinical features were similar to those in previous studies. In this series, only 13 patients (35%) had renal disease at presentation and the cumulative incidence of renal involvement was 51%. Thirty-one patients received treatment which included cyclophosphamide (CP). The case fatality rate of the six patients not treated with CP was 83% (five deaths). By contrast, all CP treated patients improved and 21 (68%) had complete remissions. Nine (29%) were in complete remission for a mean 4.9 years after discontinuing all treatment. Two were disease free for over ten years. The actuarial probability of survival for these patients was 97% at one year and 71% at ten years. Only three CP treated patients (10%) progressed to end-stage renal disease. The case fatality rate was 26% (eight patients) and sepsis was the cause of death in five. Fourteen patients (45%) treated with CP had at least one relapse of vasculitis and seven (23%) had multiple (two or more) relapses. These data indicate that CP is effective in inducing remissions and prolonging survival in patients with WG; however, relapses are frequent. (Aust NZ J Med 1993; 23: 168–175.)