Presentation: Limited Utility of Rapamycin in Severe, Refractory Wegener’s Granulomatosis (WG) (2007)

2018 Limited Utility of Rapamycin in Severe, Refractory Wegener’s Granulomatosis (WG)

Purpose:
New therapeutics that can induce and maintain remission without incurring substantial toxicity are needed in the treatment of WG. WG is a disease in which enhanced macrophage, neutrophil, T cell, and B cell activation plays an important role in pathogenesis. Rapamycin, a macrocyclic lactone, inhibits T and B cell proliferation and activation by inhibiting the function of mammalian target of rapamycin (mTOR). We report our experience with the use of rapamycin in 8 patients who failed to achieve sustained remission or developed substantial toxicities from conventional therapy.
Methods:
A retrospective chart review was conducted on 8 patients who fulfilled the 1990 ACR criteria for WG and received oral rapamycin between February 1, 2004 and April 1, 2007. To have received rapamycin, patients had to have developed toxicities precluding the use of conventional therapeutics or failed to achieve remission after receiving a cytotoxic agent plus prednisone at doses of <10mg/day.
Results:
Eight patients with WG were treated with oral rapamycin for a median of 40.5 weeks (range 29-153) with maximum doses of 2 - 4 mg/d. The median time from disease onset to the start of rapamycin was 6.5 years (range 1-14). Patients had previously received a median of 4.5 (range 3-8) different immunosuppressive agents in addition to corticosteroids prior to the initiation of rapamycin. As of April 1, 2007, 3 of 8 patients continued to take rapamycin. Only one had a sustained remission defined as no features of active disease while receiving <10mg/day of prednisone. Another patient had a stable but persistent lung nodule with no other features of active disease while a third patient had a disease relapse after 45 weeks of rapamycin therapy. Even though no patient was able to discontinue prednisone without relapse, all three were able to taper to <10mg/day. For 5 of 8 patients in which rapamycin was discontinued, two patients stopped the drug due to continued disease activity. One continued to have progressive lung nodules and later developed invasive pulmonary aspergillosis. The other had progressive orbital WG. Two patients stopped rapamycin after developing cancer (melanoma and myxofibrosarcoma). A fifth patient developed pseudomonas pneumonia while receiving rapamycin therapy. Of the three patients who had a relapse while on rapamycin, each required additional immunosuppression to induce remission. Other adverse events included elevated liver function tests (1), oral ulcers (1), and leukopenia (1). All improved once the dose of rapamycin was reduced.
Conclusion:
For theoretical reasons, rapamycin would appear to be a promising agent in the treatment of WG. Although our treatment group was small and our patients resistant to more conventional treatment, toxicities were numerous and consistent proof of efficacy was not seen.

  C.L. Koening, Vasculitis Clinical Research Consortium (1 U54 RR019497-01) and the Cleveland Clinic Center for Vasculitis Care and Research, 9; J. Hernandez-Rodriguez, None; E.S. Molloy, None; T. Clark, None; C.A. Langford, None; G.S. Hoffman, None.