Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis

Nijjar, J., Tindell, A., McInnes, I.B. and Siebert, S. (2013) Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis. Rheumatology, 52(9), pp. 1556-1562. (doi:10.1093/rheumatology/ket225) (PMID:23861534)

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Publisher's URL: http://dx.doi.org/10.1093/rheumatology/ket225

Abstract

The pathogenesis of RA is a complex and ever-changing landscape but amid the chaos of the disease process we have found effective treatment regimes. However, our current therapeutics, although targeting various components of both the innate and adaptive immune response, do not result in disease remission. Protein kinase inhibitors are attractive targets due to their ability to influence downstream signalling and their oral bioavailability. Fostamatinib (R788) inhibits spleen tyrosine kinase (Syk) and has been in clinical trials involving both MTX inadequate responders (MTX-IRs) and biologic inadequate responders. Studies on the MTX-IR population revealed ACR20 responses of 67-72% at higher doses (150 mg bd and 100 mg bd), ACR50 responses of 43-57% and ACR70 responses of 28-40%. The trial in the biologic non-responder population showed no efficacy, however, post hoc analyses of the data suggested that a further trial in this population is warranted. The most common adverse events included gastrointestinal effects, hypertension, neutropenia and transaminitis. Many adverse effects were dose responsive and hypertension was amenable to treatment. Upper respiratory tract infections were more likely at higher doses, but no serious infections with tuberculosis, fungi or opportunistic infections were reported. The oral availability of these agents makes them attractive treatment options for our patients, although the literature from the oncology field suggests that patients will only choose the oral route if efficacy is equivalent. Long-term follow-up studies are ongoing and will be critical for rare side effects. The role of these agents in our current arsenal is unclear and economic analyses are awaited.

Item Type:Articles
Keywords:Rheumatoid arthritis; Spleen tyrosine kinase; syk
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Tindell, Dr Alistair and Siebert, Dr Stefan and Nijjar, Dr Jagtar
Authors: Nijjar, J., Tindell, A., McInnes, I.B., and Siebert, S.
Subjects:R Medicine > RZ Other systems of medicine
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Rheumatology
Publisher:Oxford University Press
ISSN:1462-0324
ISSN (Online):1462-0332

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