Proteasome Inhibitors as Therapeutics of Autoimmune Diseases
Proteasome Inhibitors as Therapeutics of Autoimmune Diseases
Other than for malignant diseases and in the setting of graft-versus-host disease, clinical application of BTZ or next-generation PIs in the treatment of autoimmune diseases is still at an early stage. Moran and colleagues discussed a few case reports describing clinical experience with BTZ in immune-mediated diseases. These include reports of patients with autoimmune diseases such as SLE and refractory autoimmune hemolytic anemia (chronic cold agglutinin disease) where beneficial effects of BTZ were accompanied by improved laboratory findings consisting of reduced anti-extractable nuclear antigen levels, reduced anti-double-stranded DNA antibody levels, and normalization of complement levels and platelet count. These studies were further corroborated by Hiepe and colleagues, who reported that refractory SLE patients responded to BTZ therapy. Currently, there are only three registered clinical trials for BTZ in autoimmune diseases and these include refractory cold agglutinin disease, IgA nephropathy and proliferative lupus nephritis, the last of which has been withdrawn prior to initiation. Registered clinical trials for autoimmune diseases with next-generation PIs (for example, CFZ, oprozomib, delanzomib or ONX 0914) are still lacking.
Obviously, successful implementation of PI therapies in autoimmune diseases will be dependent on managing toxic side effects. In early clinical studies of BTZ treatment of multiple myeloma, peripheral neuropathy emerged as one undesirable side effect, though others were also documented - for example, pancytopenia, congestive heart failure, pulmonary edema, gastrointestinal hemorrhage, disseminated herpes zoster, sepsis and renal failure. Peripheral neuropathy appeared to be related to non-proteasomal inhibition by BTZ of HtrA2/Omi, a neuronal survival protease. Currently, modified schedules and routes of administration (subcutaneous versus intravenous) and (orally) available second generation PIs have improved their efficacy, safety and toxicity profiles.
Current Clinical Status of Proteasome Inhibitors in Autoimmune Disease
Other than for malignant diseases and in the setting of graft-versus-host disease, clinical application of BTZ or next-generation PIs in the treatment of autoimmune diseases is still at an early stage. Moran and colleagues discussed a few case reports describing clinical experience with BTZ in immune-mediated diseases. These include reports of patients with autoimmune diseases such as SLE and refractory autoimmune hemolytic anemia (chronic cold agglutinin disease) where beneficial effects of BTZ were accompanied by improved laboratory findings consisting of reduced anti-extractable nuclear antigen levels, reduced anti-double-stranded DNA antibody levels, and normalization of complement levels and platelet count. These studies were further corroborated by Hiepe and colleagues, who reported that refractory SLE patients responded to BTZ therapy. Currently, there are only three registered clinical trials for BTZ in autoimmune diseases and these include refractory cold agglutinin disease, IgA nephropathy and proliferative lupus nephritis, the last of which has been withdrawn prior to initiation. Registered clinical trials for autoimmune diseases with next-generation PIs (for example, CFZ, oprozomib, delanzomib or ONX 0914) are still lacking.
Obviously, successful implementation of PI therapies in autoimmune diseases will be dependent on managing toxic side effects. In early clinical studies of BTZ treatment of multiple myeloma, peripheral neuropathy emerged as one undesirable side effect, though others were also documented - for example, pancytopenia, congestive heart failure, pulmonary edema, gastrointestinal hemorrhage, disseminated herpes zoster, sepsis and renal failure. Peripheral neuropathy appeared to be related to non-proteasomal inhibition by BTZ of HtrA2/Omi, a neuronal survival protease. Currently, modified schedules and routes of administration (subcutaneous versus intravenous) and (orally) available second generation PIs have improved their efficacy, safety and toxicity profiles.
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