use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of...

Use of a Cyclophosphamide-InductionMethotrexate-Maintenance Regimen for the

Treatment of Wegener’s Granulomatosis: ExtendedFollow-up and Rate of Relapse

Carol A. Langford, MD, MHS, Cheryl Talar-Williams, MPH, Karyl S. Barron, MD,Michael C. Sneller, MD

PURPOSE: To determine the relapse rate and outcome in pa-tients with Wegener’s granulomatosis treated with daily cyclo-phosphamide and glucocorticoids to induce remission followedby methotrexate for remission maintenance.METHODS: We performed an open-label prospective study in42 patients with active Wegener’s granulomatosis. All patientswere treated with a standardized regimen. Outcomes were as-sessed using predetermined definitions based on clinical char-acteristics and pathologic, laboratory, and radiographic find-ings.RESULTS: All patients achieved disease remission. The me-dian time to remission was 3 months, and the median time todiscontinuation of glucocorticoids was 8 months. During a me-

dian of 32 months of follow-up, 1 patient died (of a myocardialinfarction not related to vasculitis). Two patients (5%) had towithdraw from the study because of medication toxicity. Twen-ty-two patients (52%) relapsed, with glomerulonephritis occur-ring in 16 patients. Of these 16 patients, 4 had an increase of�0.2 mg/dL in serum creatinine level. All 4 patients returned totheir prior level of renal function with treatment. None of the 22relapses met the criteria for severe disease.CONCLUSION: The use of cyclophosphamide and glucocor-ticoids for induction and methotrexate for maintaining remis-sion is an effective and well-tolerated therapeutic approach inpatients with active Wegener’s granulomatosis. Am J Med.2003;114:463– 469. ©2003 by Excerpta Medica Inc.

Daily cyclophosphamide and glucocorticoids is aneffective treatment for Wegener’s granulomato-sis (1,2). Unfortunately, disease relapse is com-

mon, and prolonged use of cyclophosphamide can resultin substantial toxicity. For this reason, we initiated a pro-spective standardized study in 1994, in which patientswith active Wegener’s granulomatosis were treated ini-tially with daily cyclophosphamide and glucocorticoidsuntil remission, at which time methotrexate was substi-tuted for cyclophosphamide for remission maintenance.

In an initial analysis of 31 patients who were followedfor a median of 16 months, all patients survived andachieved remission. Two patients had to withdraw fromthe study because of medication toxicity, and 5 had dis-ease relapse (3). Despite these encouraging results, theconcern remained that with longer follow-up, additionalrelapses might occur, ultimately resulting in organ dam-age. To address this, we reexamined the outcome and rateof relapse in the 42 patients in this study.

METHODS

PatientsBetween November 1994 and July 1999, 60 patients whomet the eligibility criteria for enrollment in this studywere evaluated by physicians at the National Institute ofAllergy and Infectious Diseases. Of these, 18 had activebut not immediately life-threatening disease and were en-rolled in other protocols that used methotrexate as theprimary cytotoxic agent to induce remission. The re-maining 42 patients are the subjects of this study. Thirty-nine of these patients had biopsy-proven Wegener’sgranulomatosis with necrotizing vasculitis, granuloma-tous inflammation, or both, in a typical organ system.The remaining 3 patients were diagnosed on the basis ofhaving all of the following features: a positive antineutro-phil cytoplasmic antibody (ANCA) test directed againstproteinase 3, upper airways disease, an active urine sedi-ment including red blood cell casts, and involvement ofone or more additional major organ systems (i.e., lowerairways, nervous system, or eye) in which infection hadbeen ruled out. All patients met the American College ofRheumatology 1990 criteria for the classification of We-gener’s granulomatosis and had active disease requiringtherapy (4). Patients were excluded if they had chronicliver disease; excessive alcohol intake (�14 ounces of100-proof liquor or equivalent per week) or ongoing al-cohol use that could not be discontinued; pregnancy; in-fection with the human immunodeficiency virus; or

From the National Institute of Allergy and Infectious Diseases, NationalInstitutes of Health, Bethesda, Maryland.

Requests for reprints should be addressed to Carol A. Langford, MD,MHS, Laboratory of Immunoregulation, National Institute of Allergyand Infectious Diseases, National Institutes of Health, 10 Center Drive,MSC 1876, Building 10, Room 11B-13, Bethesda, Maryland 20892, [email protected].

Manuscript submitted July 10, 2002, and accepted in revised formDecember 10, 2002.

©2003 by Excerpta Medica Inc. 0002-9343/03/$–see front matter 463All rights reserved. doi:10.1016/S0002-9343(03)00077-9

chronic renal insufficiency with a serum creatinine level�2.5 mg/dL at the time of remission.

Treatment ProtocolAll patients received a standardized protocol regimen atthe initiation of therapy. In 24 patients, physicians at theNational Institutes of Health started treatment. Nine pa-tients had treatment initiated by their personal physicianand were referred for enrollment in our protocol withinthe first month while being treated with full doses ofprednisone and daily cyclophosphamide. The remaining9 patients were enrolled after being treated for more than1 month; all 9 had received daily cyclophosphamide andprednisone treatment at the doses and tapering scheduleoutlined in this protocol and had not yet achieved remis-sion. In our protocol, oral cyclophosphamide was begunat a dosage of 2 mg/kg/d as a single dose in the morning,together with 1 mg/kg/d of oral prednisone (1,3). If im-provement occurred after the first month of treatment, aprednisone taper was begun. Prednisone was tapered by5 mg on the alternate day at 1-week intervals, with thedosage being converted gradually to an alternate-dayschedule (3). Once remission was achieved (as definedbelow), cyclophosphamide was discontinued and meth-otrexate was started. The first dose of methotrexate wasgiven within 1 to 2 days after the last dose of cyclophos-phamide, provided the results of a complete blood countwas acceptable. Oral methotrexate was started at a dosageof 0.3 mg/kg, not to exceed 15 mg once a week. If thetreatment was well tolerated after 1 to 2 weeks, the meth-otrexate dosage was increased by 2.5 mg each week, up toa dosage of 20 to 25 mg each week and maintained at thatlevel. Patients were seen for follow-up once a month fromthe time of study entry through the first 3 months ofmethotrexate, and every 2 to 3 months thereafter. If re-mission was sustained for 2 years, the methotrexate wastapered by 2.5 mg each month until discontinuation.Four patients with immediately life-threatening diseasereceived initial treatment with methylprednisolone (1g/d) for 3 days, and 3 patients received plasmapheresis for5 days, methylprednisolone (1 g/d) for 3 days, and cyclo-phosphamide (4 mg/kg/d) for 3 days (1).

In addition, all patients received Pneumocystis cariniiprophylaxis with trimethoprim (160 mg)-sulfamethox-azole (800 mg), given as one tablet three times weeklywhile they were receiving either cytotoxic agent in com-bination with daily prednisone (5). While taking pred-nisone, patients received an osteoporosis prevention reg-imen consisting of either calcium carbonate and calcitriol(6) or calcium carbonate and etidronate (7). When pa-tients were switched to methotrexate, they were alsostarted on calcium leukovorin (5 to 10 mg) once a week,taken 24 hours after methotrexate. The study protocolwas approved by the Institutional Review Board andClinical Director of the National Institute of Allergy and

Infectious Diseases and the Director of the National In-stitutes of Health Clinical Center. All patients providedwritten informed consent.

Assessment of Disease ActivityDisease activity was assessed using standardized defini-tions. Unequivocally active disease was defined by typicalhistological abnormalities seen on biopsy of a clinicallyinvolved major organ site. High probability of active dis-ease was defined as progressive lower airways or oculardisease in the absence of infection or other illness; pro-gressive renal impairment as determined by active uri-nary sediment including red cell casts (in the absence ofred cell casts, a rise in serum creatinine level would not beconsidered to be due to active disease unless there washistologic evidence of glomerulonephritis); or progres-sive polyneuropathy (nonvasculitic causes having beenruled out). Moderate probability of active disease was de-fined as an erythrocyte sedimentation rate more than twotimes the upper limit, symptoms/signs related to the up-per airways, constitutional symptoms, fever, or arthral-gias/myalgias not related to other diseases. Patients withunequivocal or high probability of active disease wereconsidered to have active Wegener’s granulomatosis.Those with moderate probability of disease were evalu-ated serially to ensure that their abnormalities did notrepresent an impending flare of overt major organ diseaseactivity. If another disease process was not identified, itwas assumed that these abnormalities were part of “smol-dering” or low-grade active Wegener’s granulomatosis,and further tapering of medication was delayed. Remis-sion was defined as the absence of unequivocally or highprobability of active disease, whereas relapse was definedas a return of these categories of disease after remissionhad been achieved. The return of features associated witha moderate probability of disease was considered a re-lapse if accompanied by the need to increase the dose ofprednisone, cyclophosphamide, or methotrexate. Test-ing for ANCA was performed by indirect immunofluo-rescence (8) at every follow-up visit.

Statistical AnalysisThe estimated cumulative percentages of patients withrelapse were determined by the Kaplan-Meier method(9). Remission and relapse data from 60 patients withWegener’s granulomatosis who had been treated at ourcenter (2) were used as controls. These patients met all ofthe following criteria: disease in at least one major organsystem; treatment with daily cyclophosphamide andprednisone using a dosage schedule identical to the in-duction regimen used in this study; precise informationon dates of remission and relapse was available; and cy-clophosphamide was given for at least 1 full year pastremission as has been previously described (1). Compar-isons were made using the log-rank test. Proportionswere compared with the chi-squared test.

A Cyclophosphamide-Induction Methotrexate-Maintenance Regimen for Wegener’s Granulomatosis/Langford et al

464 April 15, 2003 THE AMERICAN JOURNAL OF MEDICINE� Volume 114

RESULTS

About two thirds of the patients were men and about halfmet the criteria for severe disease at study entry (Table 1).Nearly all of the patients with severe disease had renalinvolvement (Table 2).

Clinical ResponseInduction treatment with prednisone and daily cyclo-phosphamide resulted in remission in all 42 patients. Themedian time to achievement of remission (and the dura-tion of cyclophosphamide treatment) was 3 months(range, 1 to 12 months). The median time to conversionfrom daily to alternate-day prednisone was 4 months(range, 2 to 8 months). All patients were able to stopprednisone treatment; the median time to complete dis-continuation of prednisone was 8 months (range, 5 to 22months).

The 42 patients have been followed for a median of 32months (range, 5 to 71 months) from remission. Therewere no significant differences in relapse-free survivalwhen patients were compared with a historical controlgroup treated with long-term cyclophosphamide (Fig-ure). All but 1 patient survived. The single fatality oc-

curred from a myocardial infarction not due to vasculitisafter being in remission for more than 2 years. One pa-tient was lost to follow-up 35 months after study entryafter declining to taper methotrexate below 7.5 mgweekly and withdrawing from the study. Two patientswere withdrawn from the study after developing metho-trexate pneumonitis.

Twenty-two patients (52%) in whom remission wasachieved have relapsed (Table 3). Although all relapsesinvolved a major organ system, none met the criteria forsevere disease as defined in this protocol (Table 1). Glo-merulonephritis was a manifestation of relapse in 16 ofthe 22 patients, including 6 with their first episode ofrenal involvement. Four of the 16 patients with glomer-ulonephritis at relapse had an increase in their serum cre-atinine level �0.2 mg/dL above baseline; the maximumincrease was 0.4 mg/dL. All 4 patients returned to theirprior level of renal function with treatment.

The median time from remission to relapse was 15months (range, 5 to 60 months). All of the patients haddiscontinued glucocorticoid therapy before relapse for amedian of 9 months (range, 2 to 54 months) when relapseoccurred (Table 3). Ten patients relapsed after the initialepisode of their disease, whereas the other 12 had previ-ous relapses. Six (30%) of the 20 patients who had severedisease at the time of study enrollment developed re-lapses. Ten (40%) of the 25 patients who had glomerulo-nephritis at study entry relapsed, as compared with 12(71%) of the 17 who did not have renal disease (P � 0.05).All 22 patients who relapsed were again able to achieveremission when treated through this or other NationalInstitute of Allergy and Infectious Diseases protocols.

Of the 16 remaining patients, 15 have tapered frommethotrexate and have remained in remission withoutimmunosuppressive medication for a median of 16months (range, 3 to 40 months). The other patient hasbeen in remission for more than 2 years and is taperingmethotrexate. The median follow-up time since remis-sion of these 16 patients is 48 months (range, 30 to 71months).

ToxicityAdverse effects of treatment are summarized in Table 4.Protocol discontinuation due to drug toxicity was re-quired in only 2 patients (5%) who developed methotrex-ate pneumonitis.

Results of ANCA TestingOf the 37 patients who had a cytoplasmic staining ANCA(cANCA) at study entry, 15 (41%) have remainedcANCA positive throughout their treatment course, in-cluding 8 patients who have remained in remission. Ofthe 22 patients whose ANCA titers became undetectableat some point in the study, all but 2 have since becomepositive; 14 (70%) of these 20 patients eventually re-lapsed. Of the 13 patients who had undetectable ANCA

Table 1. Characteristics of 42 Patients with Wegener’s Granu-lomatosis Treated with a Cyclophosphamide- and Glucocorti-coid-Induction and Methotrexate Remission-MaintenanceRegimen

CharacteristicNumber (%) or

Mean � SD (Range)

Male sex 27 (64)Age (years) 38 � 17 (10–66)Enrolled during first episode of disease 24 (57)Enrolled during relapse 18 (43)Severe disease at study entry* 20 (48)More than three involved organ sites

at study entry18 (43)

Site of active disease at study entrySinus 25 (60)Lung 29 (69)Kidney 25 (60)Joints (arthritis) 11 (26)Eye/orbit 11 (26)Nerves 4 (10)Skin 7 (17)

cANCA positive 37 (88)pANCA (myeloperoxidase) positive 5 (22)

* Defined by the presence of one or more of the following features: renalfailure resulting in a serum creatinine level �2.5 mg/dL; rise in serumcreatinine level �0.5 mg/dL above baseline; pulmonary hemorrhage;arterial PO2

�70 mm Hg or carbon monoxide diffusing capacity �70%of predicted; or central nervous system disease believed to be due toactive Wegener’s granulomatosis.cANCA � antineutrophil cytoplasmic antibodies, cytoplasmic pattern;pANCA � antineutrophil cytoplasmic antibodies, perinuclear pattern;PO2

� partial pressure of oxygen.


April 15, 2003 THE AMERICAN JOURNAL OF MEDICINE� Volume 114 465

titers at the time of the switch from cyclophosphamide tomethotrexate, 9 (69%) have relapsed, as compared with13 (54%) of the 24 who had detectable ANCA titers at thetime of switching to methotrexate (P � 0.37).

Overall, 31 patients had a fourfold rise in ANCA titerbetween two serial measurements. Nineteen (61%) ofthese patients relapsed at a median time of 12 months(range, 0 to 46 months) following the rise in ANCA titer.The other 12 patients remained in remission at a mediantime from the rise in titer to last follow-up of 33 months(range, 0 to 55 months).

DISCUSSION

A prior analysis of this group of patients (3) suggestedthat a staged regimen using cyclophosphamide for induc-

tion and methotrexate for remission maintenance waseffective and associated with a favorable toxicity profile ata median follow-up of 16 months. Based on previousstudies of daily cyclophosphamide regimens (2), how-ever, we expected more relapses, and perhaps more treat-ment adverse effects, to occur with longer follow-up.

With extended follow-up, the survival rate of this co-hort has remained high (41 of 42 patients), with a singledeath from a myocardial infarction not related to vascu-litis. This low mortality rate is similar to other studies inwhich daily cyclophosphamide was used for remissioninduction (2,10). There have also been no additional oc-currences of serious infection, methotrexate pneumoni-tis, or cyclophosphamide-induced bladder injury. Theinfection rate has been low compared with other series(11), and likely reflects prevention of leukopenia through

Table 2. Clinical Characteristics of 20 Patients with Wegener’s Granulomatosis Who Had Severe Disease at Study Entry

PatientNumber

Sites of Active Disease at Study Entry

Clinical ManifestationsUpper

Airways Lung Kidney Joints Skin Ocular Nerves

1 X X Multiple pulmonary nodules and infiltrates;hypoxia, PO2

53 mm Hg2 X X X X Alveolar hemorrhage, hemoglobin 6.7 mg/

dL; creatinine 1.3 mg/dL3 X X X X X Bilateral pulmonary infiltrates, scleritis,

creatinine 6.1 mg/dL4 X X Creatinine 1.7 mg/dL (baseline: 1.0 mg/dL)5 X X X X Bilateral pulmonary infiltrates, creatinine

2.0 mg/dL6 X X Alveolar hemorrhage, creatinine 1.9 mg/dL7 X X Alveolar hemorrhage, hemoglobin 9.8 g/dL;

creatinine 1.7 mg/dL8 X X X X X Retinal vasculitis, mononeuritis multiplex,

creatinine 2.0 mg/dL9 X X X Episcleritis, creatinine 1.7 mg/dL (baseline:

0.7 mg/dL)10 X X X X Alveolar hemorrhage, hemoglobin 6.4 g/dL11 X X Creatinine 1.6 mg/dL (baseline: 1.0 mg/dL)12 X X Pulmonary nodules and infiltrates; hypoxia,

PO263 mm Hg at entry

13 X X X Pulmonary nodules and infiltrates; hypoxia,PO2

58 mm Hg at entry14 X X X Alveolar hemorrhage, cutaneous vasculitis,

creatinine 1.5 mg/dL15 X X Creatinine 1.7 mg/dL (baseline: 1.0 mg/dL),

cutaneous vasculitis16 X X X X Alveolar hemorrhage, mechanical

ventilation, creatinine 2.7 mg/dL17 X X X X Creatinine 2.7 mg/dL18 X X Creatinine 15.3 mg/dL requiring transient

dialysis19 X X X Alveolar hemorrhage20 X X X X X Alveolar hemorrhage, mechanical

ventilation, mononeuritis multiplex

PO2� partial pressure of oxygen.



close monitoring of blood counts and the regular use oftrimethoprim-sulfamethoxazole for Pneumocystis pro-phylaxis. The 5% rate of cystitis (2 of 42 patients) in thisstudy is much lower than has been observed with thestandard cyclophosphamide regimen (12).

To date, 22 patients (52%) have relapsed. Severity ofdisease at enrollment and the presence of glomerulone-phritis were not associated with a higher rate of relapse.The observed rate of relapse was similar to that of patients

from our institution who were treated with the standardcyclophosphamide regimen (Figure). However, only arandomized trial can assess the comparative efficacy ofdifferent therapeutic approaches. The study of agents forremission maintenance is complicated by the ability ofdaily cyclophosphamide and prednisone to maintain re-mission in 90% of patients at 1 year (3). Thus, a random-ized trial comparing cyclophosphamide with anotheragent for remission maintenance requires a large sampleand an extended follow-up, which are difficult to achievein this rare disease (13). This study was therefore de-signed to be open-label to determine whether a stagedregimen could lessen toxicity and to help in planning fu-ture randomized trials.

Figure. Kaplan-Meier plot of the time to disease relapse in 42 patients with Wegener’s granulomatosis treated with a cyclophosph-amide- and glucocorticoid-induction and methotrexate remission–maintenance regimen (black line) and in 60 historical patientswith Wegener’s granulomatosis (see Methods) treated with a cyclophosphamide and glucocorticoid regimen in which cyclophos-phamide was given for 1 year after remission (gray line).

Table 3. Characteristics of 22 Patients with Wegener’s Granu-lomatosis Treated with a Cyclophosphamide- and Glucocorti-coid-Induction and Methotrexate Remission-MaintenanceRegimen Who Experienced Disease Relapse

Characteristic Number (%)

Sites of active organ diseaseSinus* 4 (18)Lung 7 (32)Kidney 16 (73)Joints (arthritis)* 6 (27)Eye/orbit 3 (14)Heart (pericarditis) 1 (5)Skin* 4 (18)

Medications at the time of relapsePrednisone 0 (0)Maintenance methotrexate

(in remission �2 years)14 (64)

Tapering methotrexate(in remission �2 years)

4 (18)

No immunosuppressive therapy 4 (18)

* The manifestations were accompanied by disease activity involving amajor organ site.

Table 4. Drug Adverse Effects in 42 Patients with Wegener’sGranulomatosis Treated with a Cyclophosphamide- and Glu-cocorticoid-Induction and Methotrexate Remission-Mainte-nance Regimen

Adverse Effect Number (%)

Leukopenia requiring dosage reductionCyclophosphamide 4 (10)Methotrexate 4 (10)

Elevation in serum aminotransferase level 1 (2)Methotrexate pneumonitis 2 (5)Cystitis 2 (5)Avascular necrosis 1 (2)Cataracts 1 (2)Diabetes mellitus 1 (2)Cutaneous herpes zoster 4 (10)Bacterial pneumonia 2 (5)



None of the relapses met the criteria for severe diseasedefined in this protocol. Of the 22 patients who relapsed,16 had active glomerulonephritis, including 6 who devel-oped renal disease for the first time. These results areconsistent with previous observations, in which glomer-ulonephritis was a presenting manifestation in 15% to20% of patients but developed later in 75% to 80% duringthe course of disease (2,10). Importantly, the serum cre-atinine level returned to baseline in all patients followingtreatment.

Reinhold-Keller and colleagues contrasted our previ-ous results to those from a study performed at their insti-tution (14). In that study, 14 of 16 patients who relapsedwith glomerulonephritis had a marked increase in theirserum creatinine level, whereas none of the 16 patientswith renal relapse in our study had more than a 0.4-mg/dL rise above baseline. Although there are differencesin the design of the two studies— especially in the dura-tion of cyclophosphamide treatment, which ranged intheir study from 3 to 66 months—we concur with theirconclusion that close monitoring of patients with Wege-ner’s granulomatosis is essential, no matter the treatmentregimen. Glomerulonephritis in these patients is typicallyasymptomatic, can occur at any point in the diseasecourse, and can progress rapidly. We perform monthlylaboratory evaluations, including a complete bloodcount, erythrocyte sedimentation rate, renal function,and urinalysis. Microscopic hematuria should prompt acareful examination of a fresh urine specimen for evi-dence of glomerular hematuria, such as dysmorphic redblood cells or red cell casts.

Disease relapse remains a problem in managing Wege-ner’s granulomatosis, and to date there are no identifiedmarkers that predict which patients are at higher risk ofrelapse. Although some investigators have suggested thatANCA titers may be a useful indicator of disease activityand relapse, this was not supported by our results. Of 31patients who had a fourfold rise in cANCA titers, 12 didnot relapse. In the remaining 19 patients, the median timefrom rise to relapse was 12 months. The presence ofcANCA at the time of the transition to methotrexatetreatment was also not associated with relapse, andshould not affect the decision about when to stop cyclo-phosphamide and switch to methotrexate.

Because of the propensity for relapse, repeated treat-ment courses will be necessary in most patients. The de-velopment of bladder or bone marrow injury can preventa patient’s further use of cyclophosphamide, therebyeliminating the ability to use the most effective therapyfor severe manifestations of Wegener’s granulomatosis.Regimens that shorten the duration of cyclophospha-mide exposure decrease toxicity, thereby maintaining fu-ture therapeutic options. The main limitation of the reg-imen used in this study was that some patients were notable to take methotrexate because of renal insufficiency

or hepatic disease. Preliminary results from a randomizedtrial in Europe suggest that azathioprine can maintainremission following induction with cyclophosphamide(15), which may provide a means of reducing the lengthof cyclophosphamide use in patients who are unable totake methotrexate.

In summary, our results suggest that patients with We-gener’s granulomatosis can be treated safely and effec-tively with a regimen using glucocorticoids and daily cy-clophosphamide to induce disease remission, followed byweekly methotrexate for remission maintenance. Al-though additional relapses have been observed since theprior analysis, these were not associated with an adverseoutcome and did not occur more frequently than wasseen in historical controls treated with the standard cy-clophosphamide regimen.

ACKNOWLEDGMENTThe authors wish to thank Kristen E. McCabe, RN, the clinicalfellows, and Clinical Center nursing staff at the National Insti-tute of Allergy and Infectious Diseases for the care of our pa-tients, and Dr. Anthony S. Fauci for his work in establishing theNational Institute of Allergy and Infectious Diseases VasculitisProgram.

REFERENCES1. Fauci A, Haynes B, Katz P, Wolff S. Wegener’s granulomatosis:

prospective clinical and therapeutic experience with 85 patients for21 years. Ann Intern Med. 1983;98:76 –85.

2. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis:an analysis of 158 patients. Ann Intern Med. 1992;116:488 –494.

3. Langford CA, Talar-Williams C, Barron KS, Sneller MC. A stagedapproach to the treatment of Wegener’s granulomatosis: inductionof remission with glucocorticoids and daily cyclophosphamideswitching to methotrexate for remission maintenance. ArthritisRheum. 1999;42:2666 –2673.

4. Leavitt RY, Fauci AS, Bloch DA, et al. The American College ofRheumatology 1990 criteria for the classification of Wegener’sgranulomatosis. Arthritis Rheum. 1990;33:1101–1107.

5. Sneller MC, Hoffman GS, Talar-Williams C, et al. An analysis offorty-two Wegener’s granulomatosis patients treated with metho-trexate and prednisone. Arthritis Rheum. 1995;38:608 –613.

6. American College of Rheumatology Task Force on OsteoporosisGuidelines. Recommendations for the prevention and treatment ofglucocorticoid-induced osteoporosis. Arthritis Rheum. 1996;39:1791–1801.

7. Adachi JD, Bensen WG, Brown J, et al. Intermittent etidronate ther-apy to prevent corticosteroid-induced osteoporosis. N Engl J Med.1997;337:382–387.

8. Kerr GS, Fleisher TA, Hallahan CW, et al. Limited prognostic valueof changes in antineutrophil cytoplasmic antibody titer in patientswith Wegener’s granulomatosis. Arthritis Rheum. 1993;36:365–371.

9. Kaplan E, Meier P. Non-parametric estimation from incompleteobservations. J Am Stat Assoc. 1958;53:457–481.

10. Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinaryapproach to the care of patients with Wegener’s granulomatosis:long-term outcome in 155 patients. Arthritis Rheum. 2000;43:1021–1032.



11. Guillevin L, Cordier JF, Lhote F, et al. A prospective, multicenter,randomized trial comparing steroids and pulse cyclophosphamideversus steroids and oral cyclophosphamide in the treatment of gen-eralized Wegener’s granulomatosis. Arthritis Rheum. 1997;40:2187–2198.

12. Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophospha-mide-induced cystitis and bladder cancer in patients with Wegenergranulomatosis. Ann Intern Med. 1996;124:477–484.

13. Cotch MF, Hoffman GS, Yerg DE, et al. The epidemiology of We-

gener’s granulomatosis. Estimates of the five-year period preva-lence, annual mortality, and geographic disease distribution frompopulation-based data sources. Arthritis Rheum. 1996;39:87–92.

14. Reinhold-Keller E, Fink COE, Herlyn K, et al. High rate of renalrelapse in 71 patients with Wegener’s granulomatosis under main-tenance of remission with low-dose methotrexate. Arthritis CareRes. 2002;47:326 –332.

15. Jayne D. Update on the European Vasculitis Study Group trials.Curr Opin Rheumatol. 2001;13:48 –55.



use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of...

Documents