Substitution of Methotrexate for Cyclophosphamide in Wegener Granulomatosis

Abstract

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 <or=500/mm3, sustained over a median time of 4 (quartiles: 1, 8.5) months, were 3.8 times more likely to achieve a sustained remission (p = 0.015). Conversely, following remission, an absolute lymphocyte count of >1000/mm was associated with a hazard ratio for relapse of 3.0, although the latter diffe...

Lymphocyte counts in patients with ANCA-associated vasculitis

“…In the context of AAV, our data-on a cohort level-are in-line with the plausible notion stemming from a relatively large study stating that lymphocyte counts inversely associate with sustained remission [7]. However, by combining cohort-derived data and analyses in individual patients, our results indicate that the value of individual lymphocyte counts in reXecting treatment-eYciency is limited.…”

“…How circulating lymphocyte counts relate to disease activity, however, remains controversial. One study reported that treatment-induced lymphopenia (·0.5 £ 10 9 /L) is associated with a high likelihood to achieve sustained remission [3,7]. By contrast, another group suggested that, analogous to patients with systemic lupus erythematodes, lymphopenia in AAV reXects disease activity, with lymphocyte counts actually increasing in patients achieving remission [8,9].…”

Cyclophosphamide as induction therapy for Wegener's granulomatosis and microscopic polyangiitis

“…These have included an open-label study of MTX after daily CyP induction in which a 3·7% mortality rate was seen, in which sustained remission occurred in 78% of patients and serious infections in 17% [10]. A randomized trial comparing AZA to MTX for remission maintenance showed that these agents had a comparable rate of toxicity and relapse in eligible patients without contraindications to these agents [11].…”

Combination therapy to treat Churg-Strauss syndrome: Corticosteroids with short- or long-term cyclophosphamide pulses

“…Both minor and major relapse rates were high in both regimens and associated with increases in CS and CYC therapy and also the use of several others immunosuppressive agents. The high relapse rate observed is also reminiscent of the clinical response to immunosuppressive therapy observed in other vasculitic disorders [6]. CSS is a much rarer vasculitic disorder that may have also played a role in the inability of the investigators to reach the number of patients (n = 110) needed for statistical power.…”