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1.  Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors 
The long-term treatment of rheumatoid arthritis (RA) most often involves a sequence of different therapies. The response to therapy, disease progression and detailed knowledge of the role of different therapies along treatment pathways are key aspects to help physicians identify the best treatment strategy. Thus, understanding the effectiveness of different therapeutic sequences is of particular importance in the evaluation of long-term RA treatment strategies. The objective of this study was to systematically review and quantitatively evaluate the relationship between the clinical response to biologic treatments and the number of previous treatments with tumor necrosis factor α (TNF-α) inhibitors.
A systematic search was undertaken to identify published, peer-reviewed articles that reported clinical outcomes of biologic treatment among RA patients with an inadequate response to TNF-α inhibitors. Data were systematically abstracted. Efficacy rates were estimated for groups of patients who differed in the number of prior TNF-α inhibitors used. End points included American College of Rheumatology (ACR)-, European League Against Rheumatism (EULAR)- and Disease Activity Score 28 (DAS28)-based response criteria.
The literature search identified 41 publications, of which 28 reported biologic treatment outcomes for RA patients with prior exposure to TNF-α inhibitors. Seven publications reported outcomes obtained in randomized clinical trials, while the remaining consisted of observational studies. The likelihood of responding to a subsequent biologic treatment decreased as the number of previous treatments with TNF-α inhibitors increased for six of the seven response criteria examined.
For patients with prior exposure to TNF-α inhibitors, the likelihood of response to subsequent treatment with biologic agents declines with the increasing number of previous treatments with TNF-α inhibitors.
PMCID: PMC3241369  PMID: 21324169
2.  Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis 
CP-690550 is a small molecule inhibitor of Janus kinase 3 (JAK3), a critical enzyme in the signaling pathway of multiple cytokines (interleukin (IL)-2, -7, -15 and -21) that are important in various T cell functions including development, activation and homeostasis. The purpose of this study was to evaluate CP-690550 in murine collagen-induced (CIA) and rat adjuvant-induced (AA) models of rheumatoid arthritis (RA).
CIA and AA were induced using standard protocols and animals received the JAK3 inhibitor via osmotic mini-pump infusion at doses ranging from 1.5–15 mg/kg/day following disease induction. Arthritis was assessed by clinical scores in the CIA models and paw swelling monitored using a plethysmometer in the AA model until study conclusion, at which time animals were killed and evaluated histologically.
CP-690550 dose-dependently decreased endpoints of disease in both RA models with greater than 90% reduction observed at the highest administered dose. An approximate ED50 of approximately 1.5 mg/kg/day was determined for the compound based upon disease endpoints in both RA models examined and corresponds to CP-690550 serum levels of 5.8 ng/ml in mice (day 28) and 24 ng/ml in rats (day 24). The compound also reduced inflammatory cell influx and joint damage as measured histologically. Animals receiving a CP-690550 dose of 15 mg/k/d showed no histological evidence of disease.
The efficacy observed with CP-690550 in CIA and AA suggests JAK3 inhibition may represent a novel therapeutic target for the treatment of RA.
PMCID: PMC2374467  PMID: 18234077

Results 1-2 (2)