No abstract

Rituximab is a chimeric anti-CD20 monoclonal B cell-depleting antibody indicated for certain hematologic malignancies and active rheumatoid arthritis with inadequate response to tumor necrosis factor antagonists. Despite counseling to avoid pregnancy, women may inadvertently become pregnant during or after rituximab treatment. Using the rituximab global drug safety database, we identified 231 pregnancies associated with maternal rituximab exposure. Maternal indications included lymphoma, autoimmune cytopenias, and other autoimmune diseases. Most cases were confounded by concomitant use of potentially teratogenic medications and severe underlying disease. Of 153 pregnancies with known outcomes, 90 resulted in live births. Twenty-two infants were born prematurely; with one neonatal death at 6 weeks. Eleven neonates had hematologic abnormalities; none had corresponding infections. Four neonatal infections were reported (fever, bronchiolitis, cytomegalovirus hepatitis, and chorioamnionitis). Two congenital malformations were identified: clubfoot in one twin, and cardiac malformation in a singleton birth. One maternal death from pre-existing autoimmune thrombocytopenia occurred. Although few congenital malformations or neonatal infections were seen among exposed neonates, women should continue to be counseled to avoid pregnancy for < 12 months after rituximab exposure; however, inadvertent pregnancy does occasionally occur. Practitioners are encouraged to report complete information to regulatory authorities for all pregnancies with suspected or known exposure to rituximab. (Blood. 2011;117(5):1499-1506)

Aggrecan loss from cartilage in arthritis is mediated by aggrecanases. Aggrecanases cleave aggrecan preferentially in the chondroitin sulfate-2 (CS-2) domain and secondarily at the E 373 ↓ 374 A bond in the interglobular domain (IGD). However, IGD cleavage may be more deleterious for cartilage biomechanics because it releases the entire CS-containing portion of aggrecan. Recent studies identifying aggrecanase-2 (ADAMTS-5) as the predominant aggrecanase in mouse cartilage have not distinguished aggrecanolysis in the IGD from aggrecanolysis in the CS-2 domain. We generated aggrecan knockin mice with a mutation that rendered only the IGD resistant to aggrecanases in order to assess the contribution of this specific cleavage to cartilage pathology. The knockin mice were viable and fertile. Aggrecanase cleavage in the aggrecan IGD was not detected in knockin mouse cartilage in situ nor following digestion with ADAMTS-5 or treatment of cartilage explant cultures with IL-1α. Blocking cleavage in the IGD not only diminished aggrecan loss and cartilage erosion in surgically induced osteoarthritis and a model of inflammatory arthritis, but appeared to stimulate cartilage repair following acute inflammation. We conclude that blocking aggrecanolysis in the aggrecan IGD alone protects against cartilage erosion and may potentiate cartilage repair.

Objective. To characterize aggrecan catabolism and the overall phenotype in mice deficient in both ADAMTS-4 and ADAMTS-5 (TS-4/TS-5 ⌬-cat) activity.Methods. Femoral head cartilage from the joints of TS-4/TS-5 ⌬-cat mice and wild-type mice were cultured in vitro, and aggrecan catabolism was stimulated with either interleukin-1␣ (IL-1␣) or retinoic acid. Total aggrecan release was measured, and aggrecanase activity was examined by Western blotting using neoepitope antibodies for detecting cleavage at EGE 373 Conclusion. An aggrecanase other than ADAMTS-4 and ADAMTS-5 is expressed in mouse cartilage and is up-regulated by retinoic acid but not IL-1␣. The novel aggrecanase appears to have different substrate specificity from either ADAMTS-4 or ADAMTS-5, cleaving E-G bonds but not E-A bonds. Neither ADAMTS-4 nor ADAMTS-5 is required for normal skeletal development or aggrecan turnover in cartilage.Loss of aggrecan from cartilage is an early event in arthritis that precedes radiographic evidence of cartilage destruction. It is driven primarily by aggrecanases that cleave at a number of sites in the aggrecan core protein. In diseased tissue, the most important cleavage site is in the interglobular domain (IGD), between the N-terminal G1 and G2 globular domains. Aggrecan binding to hyaluronan via its G1 domain tethers aggrecan in the matrix, and cleavage in the IGD results in loss of the entire glycosaminoglycan-containing region, with an associated loss of aggrecan function. The term aggrecanase was first used to describe the activity that cleaves aggrecan in the IGD between E 373 and A 374 (1-3). Aggrecan fragments that are cleaved at this site have been identified in synovial fluid from patients with osteoarthritis, inflammatory joint disease, and/or knee injury (4,5). Matrix metalloproteinases (MMPs) cleave in the IGD between N 341 and F 342 (6), and fragments