ABSTRACT
Post-traumatic arthritis (PTA) is a rapidly progressive form of arthritis that develops due to joint injury, including articular fracture. Current treatments are limited to surgical restoration and stabilization of the joint; however, evidence suggests that PTA progression is mediated by the upregulation of pro-inflammatory cytokines, such as interleukin-1 (IL-1) or tumor necrosis factor-α (TNF-α). Although these cytokines provide potential therapeutic targets for PTA, intra-articular injections of anti-cytokine therapies have proven difficult due to rapid clearance from the joint space. In this study, we examined the ability of a cross-linked elastin-like polypeptide (xELP) drug depot to provide sustained intra-articular delivery of IL-1 and TNF-α inhibitors as a beneficial therapy. Mice sustained a closed intra-articular tibial plateau fracture; treatment groups received a single intra-articular injection of drug encapsulated in xELP. Arthritic changes were assessed 4 and 8 weeks after fracture. Inhibition of IL-1 significantly reduced the severity of cartilage degeneration and synovitis. Inhibition of TNF-α alone or with IL-1 led to deleterious effects in bone morphology, articular cartilage degeneration, and synovitis. These findings suggest that IL-1 plays a critical role in the pathogenesis of PTA following articular fracture, and sustained intra-articular cytokine inhibition may provide a therapeutic approach for reducing or preventing joint degeneration following trauma.
Subject(s)
Arthritis, Experimental/drug therapy , Cartilage, Articular/drug effects , Delayed-Action Preparations/pharmacology , Interleukin 1 Receptor Antagonist Protein/pharmacology , Peptides/pharmacology , Amino Acid Sequence , Animals , Arthritis, Experimental/etiology , Arthritis, Experimental/metabolism , Cartilage Oligomeric Matrix Protein/metabolism , Cartilage, Articular/diagnostic imaging , Cartilage, Articular/injuries , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/chemistry , Drug Delivery Systems/methods , Elastin/chemistry , Injections, Intra-Articular , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Interleukin 1 Receptor Antagonist Protein/chemistry , Interleukin-1/antagonists & inhibitors , Interleukin-1/metabolism , Male , Matrix Metalloproteinase 3/blood , Matrix Metalloproteinase 3/metabolism , Mice, Inbred C57BL , Molecular Sequence Data , Peptides/administration & dosage , Peptides/chemistry , Synovial Fluid/drug effects , Synovial Fluid/metabolism , Temperature , Time Factors , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , Wounds and Injuries/complications , X-Ray MicrotomographyABSTRACT
OBJECTIVE: Women with multiple sclerosis are often diagnosed and treated during their reproductive years. Limited data are available on the safety of treatment during pregnancy. The Betaseron Pregnancy Registry prospectively monitored women exposed to interferon ß-1b (IFNß-1b) during pregnancy to estimate the rates of birth defects, spontaneous abortions (SABs) and other negative outcomes in this population. DESIGN: From 2006 to 2011, this observational registry enrolled women exposed prior to conception or during pregnancy (but prior to or without abnormalities on prenatal screening). Follow-up continued from enrolment through the 4-month paediatric visit. SETTING: Patients in the USA who met these criteria were enrolled in the registry. RESULTS: The registry enrolled 99 pregnant women; 3 were lost to follow-up. The earliest exposure to IFNß-1b occurred during the first trimester for 95 pregnancies and in the third trimester for 1 pregnancy. There were 99 birth outcomes (3 twins), including 86 (86.9%) live births, 11 (11.1%) SABs and 2 (2%) stillbirths. Birth defects were reported in five (5.1%) cases. Rates of birth defects and SAB were not significantly different from population comparators. No developmental concerns were identified at the 4-month paediatric visit. CONCLUSIONS: The small sample size limits the ability to draw definitive conclusions; however, there was no pattern to suggest increased negative outcomes with IFNß-1b. CLINICAL TRIALS REGISTRATION NUMBER: NCT00317564.
