Certolizumab in Pregnancy

Certolizumab is a PEGylated Fab fragment of a humanized TNF inhibitor monoclonal antibody. It is effective in the treatment of moderate-to-severe Crohn’s disease, axial spondyloarthropathy psoriatic arthritis, and rheumatoid arthritis. Studies have shown that that certolizumab does not cross the placenta during pregnancy.

CRIB was a pharmacokinetic (PK) study conducted among women ≥30 weeks pregnant receiving commercial CZP for an approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords, and infants at delivery; and from infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 μg/mL). Sixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0–49.4] μg/mL). Of the 16 infants, two were excluded from the per-protocol set: one due to missing data at birth and one due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 μg/mL), and one had a minimal CZP level of 0.042 μg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, one was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 μg/mL).

The conclusion of this study was that no to minimal placental transfer of CZP occurs from mothers to infants, suggesting lack of in utero fetal exposure during the third trimester. These results support the continuation of CZP treatment during pregnancy when considered necessary. Currently, the phase 2 IMPACT study (IMProve Pregnancy in APS With Certolizumab) is ongoing. This treatment trial evaluates the addition of an anti-tumor necrosis factor-alpha drug, certolizumab, to usual treatment (a heparin agent and low-dose aspirin) in pregnant women (18–38 years) with APS and repeatedly positive tests for lupus anticoagulant to determine whether this regimen will improve pregnancy outcomes. In mouse models, tumor necrosis factor-alpha blockade during pregnancy restores angiogenic balance, normalizes placental vascularization, and rescues pregnancies. All enrolled patients will receive certolizumab, and pregnancy outcomes will be compared to those of women with APS and repeatedly positive tests for LAC enrolled in a previous study by the investigators. It would be interesting to see the results of this study, as almost 44% of APS pregnant women may have adverse pregnancy outcomes despite a combination of aspirin (Promise study N=724).

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Bortezomib in Scleroderma

Scleroderma is still a difficult-to-treat disease due to the availability of limited treatment options. A few new molecules are being studied in clinical trials. Bortezomib is undergoing a trial in scleroderma with ILD patients.

Bortezomib inhibits the ubiquitin–proteasome proteolytic pathway, which degrades most short-lived intracellular proteins involved in cellular processes such as the cell cycle, differentiation, and death, DNA repair, transcription, signal transduction, morphogenesis, metabolism, and antigen presentation. It is licensed for the treatment of multiple myeloma and mantle cell lymphoma and is under investigation for the treatment of solid tumors.

Bortezomib has immunomodulatory effects involving immune cells, tumor-associated ligands, lymphocyte-activating receptors, and cytokine signaling pathways. In a mouse model, bortezomib promoted normal repair and prevented the development of skin and lung fibrosis after injury, a process related to inhibition of TGF-β1-mediated target gene expression. A phase 2, placebo-controlled study of bortezomib plus MMF vs. MMF is currently recruiting. Eligible patients have diffuse or limited SSc and evidence of pulmonary fibrosis at high risk of progression, with or without progressive skin disease. The primary endpoints were safety and tolerability, with secondary endpoints including QoL (Promis-29, 36-item Short Form and SGRQ dyspnea score), mRSS, FVC, and serum biomarkers at 48 weeks.

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