Background The safety profile of the protein kinase inhibitors (PKI) in trials for Rheumatoid Arthritis (RA) is unknown
Objectives To describe the safety profile of PKI in trials for RA.
Methods Systematic review of all published studies of eighteen PKI (AMG-548, ARRY-371797, BMS-582949, dilmapimod, doramapimod, pamapimod, PH-797804, SCIO-323, talmapimod, VX-702, VX-745, LY3009104, tofacitinib, ruxolitinib, fostamatinib disodium, imatinib mesylate, masitinib and ARRY-438162) was performed. Medline, Embase, Cochrane, and abstracts from the ACR and EULAR meetings were searched (up to September 2011). The search was limited to interventional studies in humans written in English reporting frequencies of adverse events (AE). Healthy subjects and diseases other than RA were included, with the exception of cancer or intensive care pathology. Two independent reviewers did the selection by title and abstract. MedDRA preferred terms were used for AE definition, and AE were categorized according to MedDRA classification. All AEs were collected. Risk of bias was assessed. Qualitative data analysis by drug and adverse event was performed. Pooled analysis of the raw frequencies of AE with the denominator as the n in all studies reporting the AE was performed.
Results The search produced 3276 hits. After selection by title and abstract and full reading of the text, 28 studies of 11 PKI with more than 3000 participants were included for detailed analysis. Frequencies of each AE are shown in table. Imatinib and masitinib were the PKI with higher rate of SAEs (44% and 20%, respectively). VX-702, tofacitinib and fostamatinib have the lower number of withdrawals related to AE (3%, 7% and 6% respectively).
Conclusions In RA, a unique safety profile seems related to the different PK inhibitors. Dizziness, rash and neutrophilia are related with p38 inhibition; cholesterol increase with JAK inhibition; mild transaminases increase, hypertension and diarrhea with Syk inhibition; and headache, rash, peripheral edema, nausea, vomiting and diarrhea with cKit inhibition.
Disclosure of Interest E. Salgado: None Declared, J. R. Maneiro: None Declared, L. Carmona Speakers Bureau: LC has received lectures fees from Abbott and Pfizer, J. J. Gomez-Reino Grant/Research support from: JJGR has received research grants from Roche and Schering-Plough, Consultant for: JJGR is on the Advisory Boards of BMS, Pfizer, Roche, Schering-Plough and UCB. SA, Speakers Bureau: JJGR has received lecture fees from BMS, Roche, Schering-Plough and Wyeth
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