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.     

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.     

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.     

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.     

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.     

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 μmoles/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.

     

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.     

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.     

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.

     

Influence of disease manifestation and antineutrophil cytoplasmic antibody titer on the response to pulse cyclophosphamide therapy in patients with wegener's granulomatosis

Objective. To assess the effectiveness of pulse cyclophosphamide (CYC) in the treatment of Wegener's granulomatosis (WG) and to identify the patients who are responsive to the treatment. Methods. The prospective study included 43 patients with biopsy-proven WG. Clinical, radiographic, laboratory, and immunologic data were evaluated for predicitive values regarding the outcome of pulse CYC therapy. Results. Only 42% of the patients showed complete or partial remission that lasted at least 6 months after cessation of pulse CYC therapy. These responders had a higher frequency of disease activity limited to the upper and lower respiratory tract (39%, versus 8% in the nonresponder group; P < 0.05) and had lower titers of classic antineutrophil cytoplasmic antibody (cANCA) prior to treatment (<1:64 42%, versus 6% in the nonresponder group; P < 0.05). In the 58% of patients who did not respond to pulse CYC treatment, there was both systemic disease involving more than 4 organ systems (mainly, the heart, nervous system, eye, and skin) and constitutional symptoms. Serious side effects induced by pulse CYC occurred in only 1 patient. Conclusion. Based on these findings, pulse CYC therapy appears to be effective in WG patients with moderate disease activity and low titers of cANCA, but of little benefit in patients with severe WG. Pulse CYC should therefore not be used as first-line therapy in patients with severe and rapidly progressing forms of WG associated with high titers of cANCA.     

Mycophenolate mofetil for remission maintenance in the treatment of Wegener's granulomatosis

OBJECTIVE: To examine the safety of mycophenolate mofetil (MMF) for remission maintenance in patients with Wegener's granulomatosis (WG) who had been treated with daily cyclophosphamide (CYC) and glucocorticoids to induce remission. METHODS: Fourteen patients were treated for active WG using a standardized regimen of CYC and glucocorticoids for induction of remission and MMF for remission maintenance. Outcome was assessed using predetermined definitions based on clinical characteristics and pathologic, laboratory, and radiographic findings. RESULTS: Remission occurred in all 14 patients (100%) at a median time of 3 months. The median time to discontinuation of glucocorticoids was 8 months. No patients died during protocol treatment and 6 patients (43%) relapsed at a median of 10 months after achieving remission. MMF was well tolerated and no patients had to be withdrawn as a result of medication toxicity. CONCLUSION: The use of CYC and glucocorticoids for induction of remission and MMF for remission maintenance was well tolerated, but disease relapses were observed.     

Brief Report: Long‐term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody–associated vasculitis

Objective

The NORAM (Nonrenal Wegener's Granulomatosis Treated Alternatively with Methotrexate [MTX]) trial demonstrated that MTX can replace cyclophosphamide (CYC) as remission‐inducing treatment for patients with newly diagnosed early systemic antineutrophil cytoplasmic antibody–associated vasculitis. Duration of relapse‐free survival was longer among CYC‐treated patients than among MTX‐treated patients during short‐term followup. The aim of the present study was to describe the long‐term outcome in patients enrolled in the randomized clinical trial.

Methods

Outcome questionnaires were sent to investigators who had recruited patients for the NORAM trial. Patients treated with MTX for induction of remission (n = 49) were compared to CYC‐treated patients (n = 46) with respect to immunosuppressive therapy during followup, relapse‐free survival, mortality, and occurrence of other clinical events.

Results

The median duration of followup was 6 years (range 0.1–10.8 years). One patient developed end‐stage renal disease, and 11 died. The number of patients affected by serious infection, malignancy, or severe organ failure did not differ between treatment groups, and no difference in survival rate was observed. The duration of corticosteroid therapy was longer in the MTX group during the 18 months of the trial (P = 0.005). During subsequent followup, patients who were in the MTX group in the NORAM trial received corticosteroids, CYC, and other immunosuppressive agents (azathioprine, MTX, and/or mycophenolate mofetil) for longer periods than those who were in the CYC group (P = 0.004, P = 0.037, and P = 0.031, respectively). The cumulative relapse‐free survival tended to be lower in the MTX group (P = 0.056).

Conclusion

In the NORAM cohort, no difference in occurrence of major adverse events was observed between treatment groups during long‐term followup. However, first‐line treatment with MTX was associated with less effective disease control than CYC‐based induction therapy.

     

A prospective,multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized wegener's granulomatosis

Objective. To investigate the effectiveness and side effects of oral versus pulse cyclophosphamide (CYC) in combination with corticosteroids (CS) in the treatment of systemic Wegener's granulomatosis (WG). Methods. Patients with newly diagnosed systemic WG were enrolled in a prospective, randomized trial. At the time of diagnosis, prior to randomization, every patient received a daily injection of methylprednisolone for 3 days, followed by daily oral prednisone (1 mg/kg/day) and a 0.7-gm/m² pulse of CYC. Patients were then randomly assigned to receive either prednisone plus intravenous pulse CYC (group A) or prednisone plus oral CYC (group B) as first-line treatment. CYC was given for at least 1 year and was then progressively tapered and discontinued. Results. Fifty patients were included in the study: 27 in group A and 23 in group B. At 6 months, 24 group A patients (88.9%) were in remission, versus 18 group B patients (78.3%). At the end of the trial, 18 group A patients (66.7%) and 13 group B patients (56.5%) were in remission. In group A, 66.7% of the patients experienced side effects, versus 69.6% in group B. Infectious side effects were significantly more frequent in group B (69.6%) than in group A (40.7%) (P < 0.05). The incidence of Pneumocystis carinii pneumonia was higher in oral CYC-treated patients (30.4%) than in pulse CYC-treated patients (11.1%). Nine group A patients (33.3%) and 10 group B patients (43.5%) died. Actuarial curves showed that relapses were significantly more frequent in group A (59.2%) than in group B (13%) (P = 0.02). Conclusion. Our results indicate that pulse CYC is as effective as oral CYC in achieving initial remission of WG and is associated with fewer side effects and lower mortality. However, in the long term, treatment with pulse CYC does not maintain remission or prevent relapses as well as oral CYC.     

Discontinuation of etanercept after achievement of sustained remission in patients with rheumatoid arthritis who initially had moderate disease activity—results from the ENCOURAGE study,a prospective,international, multicenter randomized study

Objectives: To investigate the efficacy and safety of etanercept (ETN) in patients with rheumatoid arthritis (RA) with moderate disease activity and the possibility to discontinue ETN after achieving remission.

Methods: Multicenter, randomized, and open-label study was conducted in Japan and Korea. RA patients (disease duration?<5 years) with moderate disease activity despite methotrexate (MTX) treatment were allocated to either MTX or ETN?+?MTX (Period 1) for 12 months. Patients who achieved sustained remission defined as DAS28?<?2.6 at both 6 and 12 months in the ETN?+?MTX group, were randomized to either continue or discontinue ETN for 12 months (Period 2).

Results: A total of 222 patients were enrolled in Period 1 and clinical remission was achieved in 106/157 (67.5%) and 5/28 (17.9%) patients in the ETN?+?MTX and MTX groups, respectively. In Period 2, sixty-seven patients were randomized and finally 28/32 (87.5%) and 15/28 (53.6%) patients who continued or discontinued ETN maintained clinical remission. Baseline disease activity and the presence of comorbid diseases influenced the maintenance of remission after ETN discontinuation.

Conclusions: ETN?+?MTX was efficient for RA patients with moderate disease activity into remission. After achieving sustained remission, a half of the patients who discontinued ETN could maintain remission for 1 year.     

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.     

Role of oral cyclophosphamide in the treatment of giant cell arteritis

Objective. Glucocorticoid (GC)-related adverse events greatly contribute to the outcome in giant cell arteritis (GCA). CYC was investigated as a steroid-sparing agent in GCA. Methods. Nineteen patients treated with CYC were retrospectively analysed. CYC was administered in 15 of the 19 patients after failure of high doses of GC or relapse during medium to high doses of GC, with or without MTX, while CYC was used ab initio in 4 of the 19 patients, all with type 2 diabetes. Follow-up ranged from 1 month to nearly 9 years after the end of CYC treatment. Results. The efficacy of CYC was observed in 15 of the 19 patients, and remission was still present 6-12 months after CYC suspension in 12 of the 13 patients. GCs were suspended in 6 of the 15 patients, and they were continued at a dose ≤5?mg/day of prednisone in all the remaining responders. Relapse occurred in 4 of the 15 patients, usually >12 months after CYC suspension. Suspension of GC daily dose or reduction to ≤5?mg/day of prednisone occurred within the first 6 months of follow-up after the beginning of CYC in 10 of the 15 patients. Ten adverse events were registered in nine patients, with recovery usually soon after the suspension of CYC or dose reduction. However, one death occurred due to acute hepatitis. Disappearance of the inflammatory infiltrate could be demonstrated when temporal artery biopsy was repeated 3 months after CYC in one patient. Conclusion. CYC may represent a useful option for patients requiring prolonged medium- to high-dose GC therapy and at high risk of GC-related side effects.     

Wegener-Granulomatose und mikroskopische Polyangiitis

Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA) are primary systemic small vessel vasculitides, associated with a positive C/PR3-ANCA in WG and P/MPO-ANCA in MPA. The most prominently involved organs are the upper (only in WG) and lower respiratory tract and the kidneys. The diagnostic work-up is an interdisciplinary approach assessing disease stage and extent. Treatment is adapted to disease stage and extent and relies on a combination of a cytotoxic plus a tapering regimen of corticosteroids. Induction of remission in “early systemic” disease can be achieved with low-dose methotrexate. In severe generalized vasculitis cyclophosphamide (CYC) is the mainstay of therapy, in rapidly progressive glomerulonephritis in combination with plasmapheresis. After 3–6 months of induction CYC is switched to a maintenance treatment with azathioprine. Alternatives are leflunomide, mycophenolate or methotrexate (creatinine < 150 µmol/l). Age ≥ 50 at diagnosis, renal dysfunction and pulmonary involvement are associated with higher mortality rates. The relapse rate is approximately 50% within 5 years, being higher in WG than MPA.     

Efficacy and Safety of a Combination Therapy of Methotrexate, Chloroquine and Cyclophosphamide in Patients with Refractory Rheumatoid Arthritis: Results of an Observational Study with Matched-Pair Analysis

The efficacy and safety of a combination of methotrexate (MTX), chloroquine (CQ) and cyclophosphamide (CYC) were studied in patients with refractory rheumatoid arthritis. A single-centre, matched-pair observational study with prospectively gathered data was performed. Fifty-six patients who had previously failed with MTX were treated with 15 mg MTX per week, 50 mg CYC three times a week and 250 mg CQ per day (group A). A 50% improvement of the swollen joint count was required to continue therapy. Data were compared with the results of the previous MTX therapy in the same group and with a matched-patient cohort receiving MTX monotherapy for the first time (group B). In group A, the combination therapy resulted in a significant decline of the swollen joint count after 1 year, in contrast to the previous MTX monotherapy in the same group. Complete remission of joint swelling was achieved in 13 patients (23%), compared with 26 patients in group B (47%). The median duration of effective combination treatment in group A was significantly longer than preceding therapies with MTX alone (19 vs 13 months, p <0.05). However, patients in group B could be treated for a median of 57.5 months (p <0.0001 compared with group A). Side-effects were comparable in both groups. The applied DMARD combination is safe and beneficial in a significant proportion of patients if MTX monotherapy is ineffective. Received: 6 March 1998 / Accepted: 5 October 1998     

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.