Low-dose interleukin-2 induced remission of the main symptoms of hepatitis C virus–related vasculitis in 8 of 10 patients participating in a phase I/phase II clinical trial, according to results reported in the Dec. 1 issue of the New England Journal of Medicine.
The remission of purpura, arthralgia, and nephropathy was accompanied by a 420% increase in the potently suppressive regulatory T cells known as Tregs, which are abnormally decreased in patients who have mixed cryoglobulinemic vasculitis induced by chronic infection with hepatitis C virus, said Dr. David Saadoun of the Université Pierre et Marie Curie, Paris, and his associates (N. Engl. J. Med. 2011;365:2067-77).
The interleukin-2 immunotherapy did not activate other T cells and did not cause any adverse events related to immune activation. The treatment appeared to reduce HCV viral load modestly.
"Further studies are needed to determine whether this intervention could be further modified and whether it would also be effective in the treatment of other inflammatory and autoimmune diseases, such as atherosclerosis or type 1 diabetes," the authors noted.
Dr. Saadoun and his colleagues recently found "a quantitative defect in Tregs" among patients with HCV-induced mixed cryoglobulinemia vasculitis, which was reversed when the vasculitis in those patients was cured.
"We therefore reasoned that induction of Tregs could have beneficial effects for patients with HCV-induced vasculitis that is resistant to HCV therapy," the researchers noted. That prompted them to conduct an open-label phase I/ IIa trial to assess the safety as well as the immunologic and clinical effects of repeated administration of low-dose interleukin-2 in HCV-infected patients who had associated autoimmunity, they added.
The prospective, single-center study included five men and five women with a median age of 58.5 years and a mean duration of HCV infection of 30 years. Eight patients had purpura, eight had neuropathy, six had asthenia, three had arthralgia, and one had kidney involvement. The vasculitis had been refractory to conventional antiviral therapy, rituximab therapy, or both.
The patients underwent an initial 5-day course of subcutaneous interleukin-2 injections (1.5 million IU per day, or half the target dose) with safety monitoring. "This dose led to a significant increase of Treg percentages in all patients; adverse events were minor and transient," the researchers said.
After a washout period, all the subjects received three more 5-day courses at the target dose of 3 million IU per day, separated by washout periods. During each treatment period, the percentage of Tregs increased. "We do not know whether this increase was consequent to the increased dosage, to the repetition of treatment, or both," the investigators noted.
The researchers selected the primary end point – an absolute increase of 4 percentage points in the proportion of circulating Tregs at the end of treatment – because it was the mean increase seen in earlier patients whose vasculitis was cured by standard HCV treatment. All 10 patients reached that end point.
"Notably, Treg proportions had increased by approximately a factor of 2 after the first 5-day course of 1.5 million IU of interleukin-2 per day, continued to increase during the washout period between courses, and were further boosted after the administration of subsequent courses," Dr. Saadoun and his associates said.
The median peak value corresponded to a 420% increase in Tregs. The proportion of Tregs remained significantly elevated for 130-150 days of follow-up, at twice the baseline value. That level is within the normal range for healthy adults.
Tests of the functionality of the Tregs induced by the interleukin-2 therapy demonstrated that they were "highly suppressive," the study authors said.
Serum levels of cryoglobulin decreased during treatment, and the HCV viral load decreased modestly but significantly, even though patients were not receiving antiviral therapy.
Concomitantly with those biologic improvements, the HCV-induced mixed cryoglobulinemic vasculitis also improved in 8 of 10 patients. Purpura resolved in all eight patients who had had it at baseline, and arthralgia resolved in all three patients who had had it at baseline. Neuropathy remitted in all but two patients. Measures of kidney function normalized in the one patient who had had nephropathy.
Clinical improvement was noted after the first or second course of treatment, simultaneously with the peak increases in Tregs.
Only the two patients who had presented with neuropathy as their sole vasculitis symptom failed to show clinical improvement, the investigators said.
The French Agency for Research on AIDS and Viral Hepatitis funded the study, with additional support from the authors’ institutions. Dr. Saadoun had no disclosures but his associates reported ties to numerous industry sources.