title: Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis.
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.
authors.affiliation: College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK. jagtar.nijjar@glasgow.ac.uk
authors.forename: Jagtar Singh
authors.initials: JS
authors.lastname: Nijjar
authors.forename: Alistair
authors.initials: A
authors.lastname: Tindell
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.forename: Stefan
authors.initials: S
authors.lastname: Siebert
mesh_terms: D000631:Aminopyridines; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D009025:Morpholines; D010078:Oxazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines; D000072377:Syk Kinase; D016896:Treatment Outcome
chemical_list: D000631:Aminopyridines; D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C523665:fostamatinib
keywords: DMARD; R406; R788; biologic non-responder; fostamatinib; kinase; methotrexate; rheumatoid arthritis; spleen tyrosine kinase