Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis

• Published in: Annals of the rheumatic diseases Vol. 73; no. 5; pp. 871 - 882
• Main Authors: Salgado, Eva, Maneiro, Jose R, Carmona, Loreto, Gomez-Reino, Juan J
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.05.2014
• Subjects: Antirheumatic Agents - adverse effects; Arthritis, Rheumatoid - drug therapy; Cytokines; Diarrhea; Drug dosages; Enzymes; Fibroblasts; Growth factors; Humans; Kinases; Nausea; Neutropenia; Pathogenesis; Protein Kinase Inhibitors - adverse effects; Proteins; Studies; Vomiting; Rheumatoid Arthritis; Autoimmune Diseases; Treatment
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2012-203116

Objective To summarise the adverse events (AE) reported in patients with rheumatoid arthritis (RA) treated with protein kinase inhibitors (PKi), and identify family and molecule-related AEs. Methods Systematic review of the PKi used in clinical trials (CTs) in RA. Medline, Embase, Cochrane Library, Web of Knowledge, and international abstracts of congress were reviewed, (up to 31 October 2012). Search was limited to interventional studies of PKi used in CTs in RA, written in English, and reporting frequencies of AE. Diseases with similar comorbidity burden also were included. Frequency of AE, serious AE (SAE), death and discontinuation due to  AEs (DCAE) were recorded. Risk of bias was assessed. Meta-analysis was carried using pooled relative risk (RR) with 95% CI as effect measure. Results The search produced 4410 hits. Forty-one articles reporting data on 21 PKi of the Janus kinase (JAK), SYK, p38 and cKit families were selected for detailed analysis. In patients treated with p38 inhibitors, RR for dizziness was 2.36 (1.20 to 4.63), and in patients treated with c-Kit inhibitors, RR for oedema was 3.43 (1.58 to 7.42). In patients treated with the JAK inhibitor tofacitinib, RR for hypercholesterolaemia was 1.70 (1.10 to 2.63) that was dose related. In patients treated with the Syk inhibitor fostamatinib, pooled RR for hypertransaminasaemia, hypertension, diarrhoea and neutropenia were 2.93 (1.02 to 8.43), 2.80 (1.58 to 5.99), 5.20 (3.19 to 8.49) and 9.24 (2.22 to 38.42), respectively. Serious infections and malignancies were not significantly more frequent in PKi-treated patients than in comparator groups. Conclusions Event rates of serious infections and malignancies with PKi are not different from biologics. In addition, PKi have a unique safety profile related to target and off-target inhibition of kinases, at times dose related.