Investigators:
Alexandra Villa-Forte, MD and Gary S. Hoffman, MD

Location:
Center for Vasculitis Care and Research, Cleveland Clinic Foundation Cleveland, Ohio

Timeline:
February 1, 2002 – February 28, 2003

Abstract
Background: Cyclophosphamide (CP) is the most effective therapy for Wegener’s Granulomatosis (WG). Drug toxicity limits long-term CP therapy. Dr. Hoffman and others have stressed the limitations of CP. Since becoming Chairman of Rheumatic and Immunologic Diseases (1992) at the Cleveland Clinic Foundation (CCF), Dr. Hoffman has provided care for over 200 patients with WG. The protocol employed for severe WG has included induction of remission with CP, followed by maintenance therapy with either Methotrexate (MTX) or Azathioprine (Aza).

Objective
To utilize a single practitioner’s large patient cohort to determine whether short-term CP therapy, followed by either MTX or Aza, provides less morbidity and mortality than conventional approaches for WG.

Specific aims
1. Determine efficacy and toxicity of short-term (3-6 months) CP, followed by an alternate remission-maintenance therapy. Comparisons with conventional therapy will be facilitated because of the senior investigator’s (GSH) role as the principal investigator for the NIH WG-CP and MTX protocols.

2. Determine whether different initial clinical presentations of WG correlate with ong-term prognosis.

3. To test the hypothesis that sustained lymphopenia is associated with increased treatment effectiveness. The finding of a significant association between the presence of lymphopenia and efficacy would result in new guidelines for monitoring and modifying drug therapy.

What this means for patients

This study will help determine answers to the following questions:

1. Will the milder agent, MTX, be associated with fewer long-term remissions?

2. If relapses are more common after MTX has been started, will patients still do better because of fewer side effects from less prolonged use of CP (3-6 months vs. 18 or more months)?
Treatment and outcomes-related data gathered from this study will be compared to results that have been obtained by others, who have utilized similar and dissimilar treatment approaches.

3. Will only certain patients with specific types (subsets) of WG benefit from this approach? A related goal in this analysis is to determine whether certain initial features (or combinations of features) of disease, such as persistent sinusitis vs. joint, muscle, skin, lung or kidney disease, are associated with different ultimate outcomes.

4. Does the effect of therapy on reducing the numbers of certain types of white blood cells (lymphocytes) determine the likelihood of staying in remission?

It is known that one of the most striking effects of CP, MTX or other “chemotherapy”-type drugs is in reducing lymphocyte counts and suppressing lymphocyte functions. These effects may persist more than 1 year after the treatment has been discontinued. It is very possible that the risk of WG relapse is increased if the lymphocyte count is never adequately reduced or if a patient’s counts return to normal soon after remission.

Depending on the answers, the knowledge derived may change and improve therapy.

VF Funded Research

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