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LS Martin-Martin,1 F Giovannangeli,2 E Bizzi,2 U Massafra,2 E Ballanti,2 M Cassol,3 A Migliore2 1Department of Internal Medicine, Regina Apostolorum Hospital, 2Operative Unit of Rheumatology, 3Department of Internal Medicine, San Pietro Fatebenefratelli Hospital, Rome, Italy Background: Biologic agents are currently the strongest immunosuppressive drugs able to induce remission in rheumatoid arthritis (RA). One of the objectives of the medical scientific community now is how to maintain remission or low disease activity (LDA). The aim of this trial is to evaluate the contribution of low-dose sequential kinetic activation (SKA) IL-4, IL-10, and anti-IL-1 antibodies (10 fg/mL) in patients affected by RA in maintaining LDA or remission obtained after biological therapy. Method: This is a randomized, open, active-controlled, prospective, Phase IV trial. Disease activity score (DAS28), clinical disease activity index, simplified disease activity index, erythrocyte sedimentation rate and C-reactive protein levels, global health assessment, and pain visual analog scale were evaluated at baseline visit and then every 3 months together with an assessment of side effects till 12 months. Thirty-nine RA patients were enrolled and randomized to continue disease-modifying antirheumatic drugs (DMARDs) therapy or to receive a combination of SKA low-dose cytokines formulated in concentration of 10 fg/mL orally administered at a dose of 20 drops/d for 12 consecutive months. Results: The rate of maintenance of LDA at 12 months was superior in the group treated with low-dose cytokines compared with patients treated with DMARDs, 66.7% and 42.1%, respectively; however, the difference between the groups was not statistically significant. Noside effects were reported in both groups. Conclusion: This is the first study using a combination of three low-dose cytokines in RA, after data published on psoriasis. These data suggest that the use of a combination of low-dose SKA cytokines may be an opportunity to explore in the management of RA. Keywords: RA, low-dose cytokines, low-dose antibodies, SKA, biological agents, low disease activity

Background: High and intermediate IL-2 regimens are difficult to recommend because of great toxicity and efficacy is not sufficient. We suggest that a combination of very low-dose cytokines is effective and safe in metastatic renal cell carcinoma (MRCC) patients (pts). A prospective randomized study was started in 2003. The primary end-point was a response rate. Methods: The eligibility criteria included histopathologically confirmed MRCC, ECOG PS 0-2, no autoimmune diseases, no brain metastases, and normal organ function. All pts were randomized in three arms: IL-2 alone, 1.5 MIU, iv, t.i.w., weeks 1—3 or IL-2 1.0 MIU, iv, t.i.w., weeks 1—3 plus IFN 5 MIU, sc, t.i.w, weeks 1—3 or biochemotherapy group 5-FU, 500 mg/m2, iv, once a week, weeks 1—3 plus IL-2 1.0 MIU, iv, t.i.w., weeks 1—3 plus IFN 5 MIU, sc, t.i.w., weeks 1—3. Courses were repeated every three weeks. A response was assessed according to the RECIST every 2 courses.Results: 64 pts were enrolled, of whom 63 were analyzed. Their median age was 55.4 years (range 16—74). 42.9% of the patients had pre- viously received chemo- or immunotherapy. 55.6 percent of the pts had poor prognosis (according to Motzer et al., 2002). Bone metastases were present in 52.4% of the pts. Sixteen patients treated with IL-2 alone showed no CR, PR, 2 SD, or 14 PD. Of 23 patients in the IL-2+IFN group, there were 5 PR, 8 SD, and 10 PD, with a response rate of 21.7%. Amongst 24 patients in the 5-FU+IL-2+IFN group, there were 1 CR, 3 PR, 10 SD, and 10 PD, with a response rate of 16.7%. One-year survival was 20.0%, 81.3% and 81.0%, respectively. The influenza-like syndrome was the most common side effect in the pts who received IFN (89.1%, grade 1, CTC). Hypotension associated with IL-2 (all groups) was seen in 56.3% (50%, grade 1 and 6.3%, grade 2). The other adverse reactions were 12.7% grade 1 neutropenia and vomiting in 4.7% pts (Group 3).Conclusion: All regimens are well tolerated. Small-dose IL-2 alone is ineffective. 5-FU does not improve the efficacy of a cytokine combination. Small-dose IL-2 and IFN demonstrate a reasonable efficacy and can be recommend for MRCC pts outside clinical trials.