Objective. To preliminarily evaluate the safety and efficacy of different dose levels and dosing frequencies of recombinant human interleukin-1 receptor antagonist (rHuIL-1Ra) in the treatment of patients with rheumatoid arthritis (RA).Methods. One hundred seventy-five patients with active RA were enrolled in a randomized, double-blind trial of rHuIG1Ra administered by subcutaneous injection. There were 9 treatment groups in the trial. During the initial 3-week treatment phase, patients were treated with 20, 70, or 200 mg rHuIL-lRa, administered either once, 3 times, or 7 times per week, followed by a 4-week maintenance phase, during which all patients received the treatment-phase dose once per week. To maintain the blindness of the study, patients received daily injections of either rHuIL-1Ra or placebo on the days rHuIClRa was not administered.Results. Recombinant HuIL-1Ra was well tolerated. The most frequent adverse event was injection-site reactions, which were reported in 62% of patients and caused 8 patients (5%) to withdraw prematurely from the study. Five patients (3%) developed serious adverse reactions unrelated to dose or dosing frequency. Due to the lack of a placebo arm and to the multiple small treatment groups, a definitive statement regarding efficacy could not be made. However, by the end of the 3-week treatment phase, daily dosing appeared more effective than weekly dosing when assessed by the number of swollen joints, the investigator and patient asSupported by Synergen Inc.

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Prior studies have shown that patients with seropositive rheumatoid arthritis (RA) In 1975, Alspaugh and Tan reported the discovery of an antibody in patients with seropositive rheumatoid arthritis (RA) that precipitated with extracts of human B lymphoblastoid cell lines containing the genome of the Epstein-Barr virus (EBV) (1). It was shown by indirect immunofluorescence that the antigen was confined primarily to the cell nucleus, and the antigen was therefore designated the rheumatoid arthritis nuclear antigen (RANA) (2). RANA is closely related to another nuclear antigen, the Epstein-Barr nuclear antigen (EBNA), detected by anticomplement immunofluorescence (3). RANA and EBNA seem to be biochemically dissimilar by their differing solubilities in ammonium sulfate and different susceptibilities to digestion by the enzyme deoxyribonuclease (1, 4). Individual sera have been found with antibodies exclusively to one or the other (1, 2). RANA and EBNA are B cell neoantigens distinct from the viral capsid antigen (VCA) present in the virion of the EBV (5).Previous serologic studies (6-8) found no evidence for a role for EBV in RA. Comparable titers of antibody to VCA were found in normal individuals and RA patients (6-8), and no evidence of increased anti-VCA was found in RA synovial effusions relative to paired RA sera (9). The findings by Alspaugh et al. (1, 2) of the high frequency of anti-RANAt in RA, however, raised anew the question of a role for EBV. The aim of our study was (i) to investigate in normal individuals positive and negative for anti-RANA the titers of antibodies to EBNA and (ii) to determine the anti-EBNA titers in RA and normal persons.MATERIALS AND METHODS Sera. Forty-seven sera were obtained from patients with classical or definite RA, all seropositive by latex fixation testing (titer 80 or greater). Sera were also obtained from 48 normal subjects and from 21 patients who fulfilled the provisional criteria for systemic lupus erythematosus (SLE) (10). All were assayed for anti-RANA, anti-EBNA, and anti-VCA antibodies. Selected sera were also assayed for antibodies to other human herpes viruses.Cell-Free Extract for RANA. The human diploid B lymphoblastoid cell line Wil-2 is EBV genome-positive. It originally derived from a patient with hereditary spherocytosis. It was grown in Eagle's minimum essential medium supplemented with 2 mM each of glutamine, sodium pyruvate, and nonessential amino acids (Flow Laboratories, McLean, VA). The medium also contained heat-inactivated 10% fetal calf serum, 10 ml of antibiotic/antimycotic (GIBCO) per liter, and was adjusted to a final pH of 7.2 with 5.6% NaHCO3. The cells were incubated at 37°C on a gyratory shaker and were grown to a concentration of 1-2 X 106/mm3. The cells were then centrifuged at 350 X g at 40C and the medium was removed. The packed cells were resuspended in medium without calf serum and centrifuged as before. After three washes, the cells were resuspended in phosphate-buffered saline at pH 7.4 to a final volume 1.5 times that of ...