Emerging protein kinase inhibitors for the treatment of rheumatoid arthritis

ABSTRACT

Introduction:

Protein tyrosine kinase inhibitors are emergent drugs in the treatment of rheumatoid arthritis (RA); they block the signal transduction in immune cells preventing the production and release of pro-inflammatory cytokines.

Areas covered:

The current research aims to review the role of Janus, Bruton’s and spleen kinase inhibitors for the treatment of RA. Mechanism of action, rationale for usage, and the main efficacy and safety outcomes in phase II and III clinical trials are described.

Expert opinion:

In RA, the development of Bruton kinase inhibitors was interrupted because they failed to demonstrate superiority versus placebo. The spleen kinase inhibitors had their development deprioritized because their risk/benefit profile was unfavorable compared to janus kinase inhibitors (JAKi). JAKi proved to be effective in treatment naïve patients and in those with previous failure to methotrexate and/or biological therapy. There still remain important points about JAKi that need more studies: the clinical importance of JAKi selectivity should be further evaluated in head-to-head trials and the safety profile of JAKi, mainly regarding the risk of malignancy and thromboembolic events, must be analyzed in long-term real-life studies.

KEYWORDS:

• Arthritis
• rheumatoid
• Bruton kinase inhibitors
• drug evaluation
• janus kinase inhibitors
• protein kinase inhibitors
• spleen kinase inhibitors

Declaration of interest

PE Palominos serves as consultant for Janssen and UCB, receives budget for conducting clinical trails for Pfizer and Novartis and received a Master Program sponsored by Abbvie. RM Xavier serves as a consultant for Abbvie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and UCB. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed grant/research support from: Abbvie, Asahi-Kasei, Boehringer, Chugai, Eisai and Mitsubishi-Tanabe; is a consultant for: Abbvie, Astellas, Boehringer, Eli Lilly, Gilead Sciences, Janssen, Novartis, Sanofi, UCB; and received speakers bureau fees from: Abbvie, Asahi-Kasei, Astellas, BMS, Chugai, Eisai, Eli Lilly, Gilead Sciences, Janssen, Mitsubishi-Tanabe, Novartis and Pfizer. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

List of abbreviations

RA	=	Rheumatoid arthritis
ATP	=	Adenosine triphosphate
DMARDS	=	Disease modifying antirheumatic drugs
csDMARDs	=	Conventional synthetic disease modifying antirheumatic drugs
bDMARDs	=	Biological disease modifying antirheumatic drugs
TNFi	=	Tumor necrosis factor inhibitors
TNF	=	Tumor necrosis factor
IL-6	=	Interleukin 6
EULAR	=	European League against Rheumatism
JAK	=	Janus kinase
JAKi	=	Janus kinase inhibitors
DAS28CRP	=	Disease Activity Score for 28-joints based on the C-reactive protein
CDAI	=	Clinical Disease Activity Index
IL-1	=	Interleukin-1
BTK	=	Bruton’s tyrosine kinase
BTKi	=	Bruton’s tyrosine kinase inhibitors
SYK	=	Spleen tyrosine kinases
SYKi	=	Spleen tyrosine kinases inhibitors
TYK2	=	Tyrosine kinase 2
STAT	=	Signal transducer and activator of transcription
ACR 20	=	20% improvement in the American College of Rheumatology Criteria
NCT	=	National clinical trial number
HAQ-DI	=	Health Assessment Questionnaire Disability Index
hsCRP	=	High-sensitivity C-reactive protein
MTX	=	Methotrexate
SAEs	=	Serious adverse events
LDL	=	Low-density lipoprotein
HDL	=	High-density lipoprotein
ALT	=	Alanine aminotransferase
AST	=	Aspartate aminotransferase
CK	=	Serum creatine phosphokinase
MACE	=	Major cardiovascular events
CI	=	Confidence interval
BID	=	Twice a day

Additional information

Funding

This paper was not funded.