Rheumatoid Arthritis: Tesser J

Schiff MH, DiVittorio G, Tesser J, Fleischmann R, Schechtman J, Hartman S, Liu T, Solinger AM. · Denver Arthritis Clinic, Colorado 80230, USA. · Arthritis Rheum. · Pubmed #15188350 links to  free full text

Abstract: OBJECTIVE: To determine in a placebo-controlled, double-blind trial the safety profile of daily anakinra (Kineret) use in patients with active rheumatoid arthritis (RA) and concurrent comorbid conditions. METHODS: In 169 centers in 9 countries, 1,414 patients with active RA were randomly assigned to receive either anakinra (100 mg) or placebo treatment (4:1 anakinra-to-placebo allocation ratio), with study drug administered by daily subcutaneous injection for 6 months. The current post hoc analysis assessed baseline comorbid conditions, and patients were considered at high risk for the occurrence of adverse events if they had a history of at least one of the following: cardiovascular event, pulmonary event, central nervous system-related event, infection, diabetes, malignancy, or renal impairment. Within each treatment group (anakinra or placebo), incidence rates were summarized for serious adverse events, infectious events, and serious infectious events in high-risk patients and compared with these incidence rates in patients without comorbid conditions. RESULTS: The majority of patients in the trial had one or more comorbid conditions. In these high-risk patients, there were no differences in the incidence of serious adverse events or infectious events between treatment groups. The incidence of serious infectious events with anakinra use was similar between high-risk patients (2.5%) and the entire study population (2.1%) and was not attributable to any single comorbidity. CONCLUSION: Results of the analysis of adverse events in patients with active RA and coexisting comorbidities suggest that the favorable safety profile of anakinra is maintained in a high-risk patient population.

Tesser J, Fleischmann R, Dore R, Bennett R, Solinger A, Joh T, Modafferi D, Schechtman J, Anonymous00214. · University of Arizona Health Sciences Center, Arizona Rheumatology Center, Phoenix, Arizona 85015-2160, USA. · J Rheumatol. · Pubmed #15088288 No free full text.

Abstract: OBJECTIVE: To examine the safety of anakinra when added to a background of standard rheumatoid arthritis (RA) medications in patients with RA with active disease. METHODS: This analysis further evaluates data from the first 6 months of a blinded, placebo controlled safety trial that had a subsequent 30 month, open label portion (not reported here). Patients with RA with a wide range of comorbid conditions, disease activity, and background medications were randomly assigned in a 4:1 allocation ratio to treatment with anakinra 100 mg or placebo administered daily by injection. Safety was assessed by comparing adverse event profiles between anakinra and placebo patients according to concomitant medications received. RESULTS: Anakinra patients (n = 1116) showed no difference in the incidence of upper respiratory infections or overall serious adverse events compared with placebo patients (n = 283). The anakinra group had more injection site reactions (72.6% vs 32.9% in placebo) and a small increase in serious infections (2.1% vs 0.4% in placebo). Anakinra's safety profile did not differ in patients receiving antihypertensive, antidiabetic, or statin drugs. CONCLUSION: This study indicates that anakinra has a good safety profile in patients typically seen in a rheumatology practice who are considered candidates for therapy with agents that are immunomodulatory and disease modifying. Except for injection site reactions and a nonstatistically although potentially clinically significant increase in serious infections in the anakinra versus the placebo groups, the addition of anakinra to a stable background regimen of RA medications introduced no other important safety risk in patients with RA.

Fleischmann RM, Schechtman J, Bennett R, Handel ML, Burmester GR, Tesser J, Modafferi D, Poulakos J, Sun G. · St. Paul University Hospital, Dallas, Texas 75235, USA. · Arthritis Rheum. · Pubmed #12687534 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety of anakinra (a recombinant human interleukin-1 receptor antagonist) in a large population of patients with rheumatoid arthritis (RA), typical of those seen in clinical practice. METHODS: A total of 1,414 patients were randomly assigned to treatment with 100 mg of anakinra or placebo, administered daily by subcutaneous injection. Background medications included disease-modifying antirheumatic drugs, corticosteroids, and nonsteroidal antiinflammatory drugs, alone or in combination. The primary end point was safety, which was evaluated by adverse events (including infections), discontinuation from study due to adverse events, and death. RESULTS: Safety was evaluated in 1,399 patients (1,116 in the anakinra group and 283 in the placebo group; 15 patients were randomized but did not receive any study drug) during the initial 6-month, double-blind, placebo-controlled phase of this long-term safety study. Baseline demographics, disease characteristics, and concomitant medications were similar between the 2 groups. The study group included patients with numerous comorbid conditions and a wide range of RA disease activity. Serious adverse events occurred at a similar rate in the anakinra group and the placebo group (7.7% and 7.8%, respectively). Serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group). The rate of withdrawal due to adverse events was 13.4% in the anakinra group and 9.2% in the placebo group. CONCLUSION: Results from this large, placebo-controlled safety study demonstrate that anakinra is safe and well tolerated in a diverse population of patients with RA, including those with comorbid conditions and those using multiple combinations of concomitant therapies. Although the frequency of serious infection was slightly higher in the anakinra group, no infection was attributed to opportunistic microorganisms or resulted in death.

Mason U, Aldrich J, Breedveld F, Davis CB, Elliott M, Jackson M, Jorgensen C, Keystone E, Levy R, Tesser J, Totoritis M, Truneh A, Weisman M, Wiesenhutter C, Yocum D, Zhu J. · GlaxoSmithKline Pharmaceuticals, Greenford, Middlesex, UK. · J Rheumatol. · Pubmed #11838838 No free full text.

Abstract: OBJECTIVE: Double blind studies were conducted with the anti-CD4 monoclonal antibody (Mab) keliximab in patients with active, stable rheumatoid arthritis (RA), to confirm preliminary evidence of efficacy and safety from open. uncontrolled studies. METHODS: We enrolled 136 and 186 patients into 2 consecutive, randomized, double blind trials, with similar populations [apart from inclusion of disease modifying antirheumatic drug (DMARD)-naïve patients in Study 2]. Patients received 4 weeks intravenous placebo or keliximab [40, 80, 120, or 140 mg twice weekly (bw), or 240 mg once weekly (ow)].The primary endpoint was the American College of Rheumatology (ACR) 20 response criteria, one week after the end of treatment. RESULTS: ACR 20 response rates in Study I were 19%, 42%, 51%*, and 69%* (*p < 0.05 compared to placebo), with placebo, 40, 80, or 140 mg keliximab bw, respectively. The response rates in Study 2 were 30%, 39%, 46% and 47% with placebo, 80 or 120 mg bw, or 240 mg keliximab ow, respectively. In the 2 studies, there was a dose dependent increase in peripheral blood CD4+ T cell coating with keliximab, but a different pattern of CD4 depletion was seen. While only 12% of keliximab treated patients in Study I had CD4 counts below 250 cells/mm3 at the end of the treatment period, 47% fell below this level in Study 2. Clinical response was not correlated with CD4 depletion, but was correlated with CD4+ T cell coating with keliximab. CONCLUSION: Coating of peripheral blood CD4+ T cells with keliximab, but not CD4 depletion, is a determinant of clinical response.

Moreland L, Gugliotti R, King K, Chase W, Weisman M, Greco T, Fife R, Korn J, Simms R, Tesser J, Hillson J, Caldwell J, Schnitzer T, Lyons D, Schwertschlag U. · Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Arthritis Res. · Pubmed #11438043 links to  free full text

Abstract: Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of cytokine and nitric oxide production. In animal models of arthritis, treatment with recombinant human IL-11 (rhIL-11) reduces both the level of synovitis and the histologic lesion scores in the joints.The goal of this phase-I/II study in adults with rheumatoid arthritis (RA) was to evaluate the safety and clinical activity of different doses and schedules of rhIL-11 in patients with active RA for whom treatment with at least one disease-modifying antirheumatic drug had failed.This was a multicenter, randomized, placebo-controlled trial that evaluated the safety and tolerability of rhIL-11 in 91 patients with active RA. rhIL-11 was administered subcutaneously; patients were randomized into one of five treatment groups (ratio of rhIL-11 to placebo, 4:1). Patients were treated for 12 weeks with either 2.5 or 7.5 microg/kg of rhIL-11 or placebo twice per week or 5 or 15 microg/kg of rhIL-11 or placebo once per week. The status of each subject's disease activity in accordance with the American College of Rheumatology (ACR) criteria was assessed before, during, and after completion of administration of the study drug.Administration of rhIL-11 was well tolerated at all doses and schedules. The most frequent adverse event was a reaction at the injection site. The data suggest a statistically significant reduction in the number of tender joints (P < 0.008) at the 15 microg/kg once-weekly dose schedule but showed no overall significant benefit at the ACR criterion of a 20% response.The trial showed rhIL-11 to be safe and well tolerated at a variety of doses and schedules over a 12-week treatment period in patients with active RA. The only adverse event clearly associated with rhIL-11 administration was reaction at the injection site.

Fleischmann RM, Tesser J, Schiff MH, Schechtman J, Burmester GR, Bennett R, Modafferi D, Zhou L, Bell D, Appleton B. · University of Texas Southwestern Medical Center at Dallas, Radiant Research, 5939 Harry Hines Boulevard, Dallas, TX 75235, USA. · Ann Rheum Dis. · Pubmed #16396977 links to  free full text

Abstract: OBJECTIVE: To determine the safety profile of anakinra after extended exposure in a diverse clinical trial population of patients with rheumatoid arthritis. METHODS: A six month, randomised, double blind phase comparing anakinra (100 mg/day) with placebo was followed by open label anakinra treatment for up to three years in patients with rheumatoid arthritis. Concomitant non-steroidal anti-inflammatory drugs, corticosteroids, and other disease modifying antirheumatic drugs were permitted. RESULTS: In all 1346 patients with rheumatoid arthritis received anakinra for up to three years. Patients had varying levels of disease severity, concomitant drug use, and comorbid conditions. Cumulative, exposure adjusted event (EAE) rates for all adverse events (AEs), serious AEs, and deaths were similar during each year of anakinra treatment; the overall rate (0 to 3 years) was similar to that observed for controls during the blinded phase. The most frequent AEs were injection site reactions (122.26 events/100 patient-years), rheumatoid arthritis progression (67.80 events/100 patient-years), and upper respiratory infections (26.09 events/100 patient-years). The EAE rate of serious infections was higher for patients treated with anakinra for 0 to 3 years (5.37 events/100 patient-years) than for controls during the blinded phase (1.65 events/100 patient-years). However, if the patient was not receiving corticosteroid treatment at baseline, the serious infection rate was substantially lower (2.87 event/100 patient-years). The overall incidence of malignancies was consistent with expected rates reported by SEER. Neutralising antibodies developed in 25 patients, but appeared to be transient in 12; neutralising antibody status did not appear related to occurrence of malignancies or serious infections. There were no clinically significant trends in laboratory data related to anakinra. CONCLUSION: Anakinra is safe and well tolerated for up to three years of continuous use in a diverse population of patients with rheumatoid arthritis.

Bergstrom L, Yocum DE, Ampel NM, Villanueva I, Lisse J, Gluck O, Tesser J, Posever J, Miller M, Araujo J, Kageyama DM, Berry M, Karl L, Yung CM. · University of Arizona, Tucson, 85724, USA. · Arthritis Rheum. · Pubmed #15188373 links to  free full text

Abstract: OBJECTIVE: To describe a group of patients who were treated with tumor necrosis factor alpha (TNF alpha) antagonists and who developed coccidioidomycosis, and to test the hypothesis that patients with inflammatory arthritis receiving TNF alpha antagonist therapy are at higher risk for developing symptomatic coccidioidomycosis. METHODS: Cases of coccidioidomycosis were identified and reviewed from among patients receiving TNF alpha antagonist therapy from May 1998 through February 2003 in 5 practices within the areas endemic for coccidioidomycosis (Arizona, California, and Nevada). In addition, the relative risk of developing symptomatic coccidioidomycosis was calculated in patients with inflammatory arthritis who were receiving treatment with infliximab, in comparison with patients with inflammatory arthritis who were not receiving infliximab, from January 2000 to February 2003 in a single medical center. RESULTS: Thirteen cases of documented coccidioidomycosis were associated with TNF alpha antagonist therapy. Twelve cases were associated with the use of infliximab and 1 case with etanercept. Among the cohort of patients from a single medical center, 7 of the 247 patients receiving infliximab and 4 of the 738 patients receiving other therapies developed symptomatic coccidioidomycosis (relative risk 5.23, 95% confidence interval 1.54-17.71; P < 0.01). CONCLUSION: Patients with inflammatory arthritis who are undergoing treatment with infliximab appear to be at higher risk for developing symptomatic coccidioidomycosis as compared with those not receiving infliximab.