Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist

360

199

for the 990757 Study GroupObjective. 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, doubleblind, 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, placebocontrolled 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.

Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

See 1 more Smart Citation

Anakinra, a recombinant human interleukin‐1 receptor antagonist (r‐metHuIL‐1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo‐controlled trial

Fleischmann¹,

Schechtman²,

Bennett

et al. 2003

360

199

“…Indeed, the assessment of biochemical markers of bone metabolism in RA suggests an increase in bone resorption as the dominant pathophysiologic mechanism (14,(19)(20)(21). Although therapeutic approaches to blocking TNF, IL-1, and IL-6 have been developed, and although such therapies are effective in slowing or even arresting local bone resorption as well as inhibiting inflammation (22,23), their potential to interfere with generalized bone loss in RA has not been sufficiently analyzed.…”

mentioning

confidence: 99%

Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice

Schett¹,

Redlich²,

Hayer³

et al. 2003

139

Objective. To investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade.Methods. We investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis.Results. Osteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (؊37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (؊85%) compared with wild-type controls. Osteoclast-covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly elevated, suggesting increased osteoclast-mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNFmediated bone loss by increasing BMD (؉89%) and bone volume (؉647%). Most strikingly, formation of primary spongiosa was dramatically increased (؉563%) in hTNFtg mice after OPG treatment. Osteoclastcovered bone surface and serum levels of deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast-mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin-1␤ (IL-1␤), and IL-6. However, OPG decreased bone formation parameters (osteoblast-covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti-TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti-TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG.Conclusion. OPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.

“…In patients with rheumatoid arthritis (RA), 2 critical proinflammatory cytokines are interleukin-1 (IL-1) and tumor necrosis factor ␣ (TNF␣) (3). Inhibition of IL-1 and/or TNF␣ reduces the extent of inflammation in RA (4,5) and lessens inflammation and bone destruction in various experimental models of arthritis (6)(7)(8)(9)(10)(11)(12). Therefore, therapeutic agents that inhibit the action of these 2 cytokines are gaining rapid acceptance as early, aggressive treatments for RA.…”

mentioning

confidence: 99%

Inhibition of interleukin‐1 but not tumor necrosis factor suppresses neovascularization in rat models of corneal angiogenesis and adjuvant arthritis

Coxon¹,

Bolon²,

Estrada³

et al. 2002

Objective. To assess the capacities of the cytokine inhibitors interleukin-1 receptor antagonist (IL-1Ra; anakinra) and PEGylated soluble tumor necrosis factor receptor I (PEG sTNFRI; pegsunercept) to suppress neovascularization.Methods. A corneal angiogenesis assay was performed by implanting nylon discs impregnated with an angiogenic stimulator (basic fibroblast growth factor or vascular endothelial growth factor) into one cornea of female Sprague-Dawley rats. Animals were treated with IL-1Ra or PEG sTNFRI for 7 days, after which new vessels were quantified. In a parallel study, male Lewis rats with mycobacteria-induced adjuvant-induced arthritis were treated with IL-1Ra or PEG sTNFRI for 7 days beginning at disease onset, after which scores for inflammation and bone erosion as well as capillary counts were acquired from sections of arthritic hind paws.Results. Treatment with IL-1Ra yielded a dosedependent reduction in growth factor-induced corneal angiogenesis, while PEG sTNFRI did not. IL-1Ra, but not PEG sTNFRI, significantly reduced the number of capillaries in arthritic paws, even though both anticytokines reduced inflammation and bone erosion to a similar degree.Conclusion. These data support a major role for IL-1, but not TNF␣, in angiogenesis and suggest that an additional antiarthritic mechanism afforded by IL-1 inhibitors, but not anti-TNF agents, is the suppression of the angiogenic component of pannus.