BERLIN – The proteasome inhibitor bortezomib shows considerable promise as a novel treatment for refractory SLE, according to Dr. Reinhard E. Voll.
"I think it’s useful as an induction therapy; then you can go on with regular maintenance therapy," he said at the annual European Congress of Rheumatology.
Dr. Reinhard E. Voll
He presented a series of 13 patients with SLE refractory to conventional immunosuppressive drugs and antimalarials treated off label with bortezomib (Velcade) at three German university medical centers. Ten patients had refractory active lupus nephritis.
All patients responded to bortezomib with significant reductions in anti–double-stranded DNA antibody titers and SLE Disease Activity Index (SLEDAI) scores. Proteinuria decreased within 6 weeks in all patients with active lupus nephritis, one of whom achieved normal protein excretion by 4 months, according to Dr. Voll, a rheumatologist at the University of Freiburg (Germany).
The mean baseline SLEDAI score was 14.3, dropping to 5.2 after two to a maximum of four courses of bortezomib. In the three patients with the highest baseline SLEDAIs of 20 or 21, their scores at the end of bortezomib therapy were 4, 6, and 7.
Patients remained on mycophenolate mofetil and antimalarials during treatment with bortezomib. Once the patients displayed marked improvement, the proteasome inhibitor was stopped. During 6 months of follow-up post bortezomib, SLEDAIs remained the same as, and in some cases lower than, at the time bortezomib was stopped.
Bortezomib is approved for the treatment of relapsed multiple myeloma and for mantle cell lymphoma.
The SLE patients received bortezomib intravenously at a dose of 1.3 mg/m2 of body surface area on days 1, 4, and 8, and in some cases also on day 11 of a given treatment cycle. Patients typically received 20 mg of dexamethasone together with bortezomib. Up to four cycles could be given, with 10-14 days in between.
Dr. Voll said he limits himself to three treatment days per cycle because three of the seven patients who got a fourth dose on day 11 at other centers developed peripheral polyneuropathies, the drug’s major side effect. Bortezomib-induced peripheral neuropathy resolves upon treatment discontinuation. But the problem didn’t occur in patients treated on three days per cycle.
One patient developed a moderate transient thrombocytopenia after four treatment cycles, but no other hematologic toxicities occurred.
Because of concern that a drug that depletes pathogenic antibodies might also lower protective vaccine antibody titers, the investigators measured titers to hepatitis B surface antigen and tetanus toxoid before and after bortezomib. Vaccine antibody titers dropped by up to 50% but still remained in the protective zone.
In an interview, Dr. Voll explained that he grew interested in investigating bortezomib because of a conviction he shares with others that one of the major reasons SLE and other antibody-mediated diseases can become highly refractory to conventional therapies is that affected patients have long-lived plasma cells secreting copious quantities of pathogenic antibodies. These self-perpetuating plasma cells are resistant to conventional SLE medications, including intravenous pulsed-dose cyclophosphamide, rituximab, and antimalarials (Nat. Rev. Rheumatol. 2011;7:170-8).
"We thought bortezomib might be toxic not only to myeloma cells, but to normal plasma cells. We moved to mouse models of lupus and found we could deplete the long-lived plasma cells very nicely with bortezomib. And we could also resolve lupus nephritis," he recalled, citing his earlier published study (Nat. Med. 2008;14:748-55).
The rheumatologist speculated that the proteasome inhibitor might also be useful in very severe cases of allergic disease. A colleague treated a patient with food allergies so severe that the patient had been unable to eat solid food for 2 years and was becoming suicidal as a result.
"After the second course of bortezomib, he could eat one solid meal per day, and his IgE antibody titers went way down. It was really amazing," Dr. Voll said.
In light of the highly promising 13-patient series, the next logical step would be a formal clinical trial of bortezomib in refractory SLE. Bortezomib’s manufacturer, Millenium Pharmaceuticals, has a related drug with less associated peripheral neuropathy that’s well along in development; the company has indicated interest in sponsoring a clinical trial of the new drug in refractory SLE, according to the rheumatologist.
The bortezomib used in the 13-patient series was paid for by the German health care system. Dr. Voll reported having no relevant financial conflicts.