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.