ON the horizon rheumatoid arthritis

Treatment of rheumatoid arthritis: current and future SPL

Oliver Foot MB BS is core medical trainee year 2; Anshuman Malaviya MD, MRCP, MRCP (Rheumatology) is consultant rheumatologist at Mid Essex Hospital NHS Trust, Broomfield, Chelmsford

Rheumatoid arthritis (RA) is a chronic systemic inflammatory condition characterised by an erosive arthropathy and other extraarticular manifestations. It affects approximately 1 per cent of the population1 and the incidence is three times higher in women than men, peaking between the ages of 40 and 70 years. The disease has a significant impact on the quality of life of patients as well as on society at large and effective treatments are highly sought after. Although biologic therapies have transformed the management of RA, there is still scope for newer therapies and treatment strategies continue to evolve. This review will focus on the presently available treatments, the current unmet need and the future therapeutic strategy with a focus on some of newer molecules that show promise.

E

arly aggressive treatment of rheumatoid arthritis (RA) is associated with much better outcomes and the current strategy is to ‘treat to target’.2 This involves regular monitoring of disease activity and escalation of therapy, aiming to achieve disease remission as early as possible. Current NICE guidelines in the UK recommend use of conventional DMARDs (including 8 future prescriber vol 14 (2)

Although biologic therapies have transformed the management of RA, 30–50% of patients do not have an appropriate clinical response to these drugs

methotrexate and at least one other conventional DMARD plus shortterm glucocorticoids) as first-line treatment.1 In addition, a number of biologic therapies have been licenced for use in RA. NICE recommends the use of these drugs in patients that have failed conventional DMARD therapy. There are currently nine such biologic agents licensed for use in RA (see Table 1). The ‘unmet need’ Despite their profound impact on the management of RA current biologic therapies have some limitations. Despite their efficacy, approximately 30–50% of patients do not have an appropriate clinical response to these drugs.3 This may in part be due to the fact that they only target specific pro-inflamma-

tory cytokines and their receptors, a strategy not always successful in the complex dysregulation of the immune system seen with RA. In addition, their use is often limited by side-effects and indeed approximately 14% of subjects withdrawing from clinical trials do so due to the adverse effects of these drugs.4 Another significant factor that influences adherence and acceptance of these drugs is the mode of administration. The fact that biological agents require administration by injection is seen as undesirable by many when compared with traditional drugs.5 Cost of therapy is also an important issue. The higher cost of these therapies (often in excess of £10 000 per annum in the UK) in the short-term is not always perceived to offset the long-term costs w w w. f u t u r e p r e s c r i b e r. c o . u k

on t h e h o r i z o n rheumatoid arthritis

Generic name

Dosing schedule

Current licence

NICE guidance1,4

(trade name) Tumour necrosis factor inhibitors infliximab

iv infusion every 6–8 weeks

RA, PsA, AS



active RA (DAS 28 > 5.1) despite 6 months treatment with 2 conventional DMARDs in combination with MTX in patients with severe RA, inadequate response to at least

etanercept

weekly sc injections

1 TNF inhibitor, who cannot receive rituximab

RA, pJIA, AS, PsA active RA (DAS 28 > 5.1) despite 6 months treatment with 2 conventional DMARDs



in combination with MTX in patients with severe RA, inadequate response to at least



1 TNF inhibitor, who cannot receive rituximab monotherapy in patients with severe RA, inadequate response to at least 1 TNF

adalimumab

fortnightly sc injections

RA, PsA



inhibitor, who cannot receive rituximab or methotrexate active RA (DAS 28 > 5.1) despite 6 months treatment with 2 conventional DMARDs in combination with MTX in patients with severe RA, inadequate response to at least



1 TNF inhibitor, who cannot receive rituximab monotherapy in patients with severe RA, inadequate response to at least 1 TNF



inhibitor, who cannot receive rituximab or MTX

certolizumab

fortnightly sc injections

RA

active RA (DAS 28 > 5.1) despite 6 months treatment with 2 conventional DMARDs

golimumab

monthly sc injections

RA, AS, PsA

active RA (DAS 28 > 5.1) despite 6 months treatment with 2 conventional DMARDs

B cell depletion rituximab

iv infusion every 6 months

RA

in combination with MTX in patients with severe RA, inadequate response to at least



1 TNF inhibitor

Inhibition of T cell co-stimulation abatacept

monthly iv infusions

RA, pJIA



in combination with MTX in patients with severe RA, inadequate response to at least 1 TNF inhibitor, who cannot receive rituximab

IL-6 inhibition tocilizumab

monthly iv infusions

RA, pJIA, sJIA



in combination with MTX in patients with moderate to severe RA, inadequate response to at least 1 TNF inhibitor, who cannot receive rituximab

IL-1 inhibition anakinra

daily sc injections

RA

not recommended for the treatment of RA in the UK

RA rheumatoid arthritis, PsA psoriatic arthritis, AS ankylosing spondylitis, pJIA polyarticular juvenile idiopathic arthritis, sJIA systemic juvenile idiopathic arthritis Table 1. Biological therapies currently licensed in inflammatory arthritis

of the disease burden of RA. Newer therapies with similar efficacy and safety and with more favourable dosing schedules and modes of administration are currently being trialled. Newer therapies There is continued interest in the development of newer therapies for RA. In addition to modulaw w w. f u t u r e p r e s c r i b e r. c o . u k

tion of novel targets (both extracellular and intracellular) there also appears to be a move towards alternative modes of administration for drugs that already have an established place in the treatment of RA. Table 2 enumerates some of these newer therapies. Many of these have considerable supporting efficacy and tolerability data

and are likely to become available in the near future. Novel targets There is considerable interest in a new class of ‘small molecule’ immune modulators, compounds that can be administered orally with apparently lower manufacturing costs.19 Most of these agents future prescriber vol 14 (2) 9

ON the horizon rheumatoid arthritis

block kinases, such as mitogenactivated protein kinases (MAPKs) and nonreceptor tyrosine kinases – spleen tyrosine kinase (Syk) and janus kinases (JAKs). Such kinase targets are constituents of complex intracellular signalling pathways that mediate cell responses to external stimuli. MAPKs, through three subfamilies, c-Jun N-terminal kinase (JNK), extracellular signal-related kinase (ERK), and p38 MAPK, phosphorylate serine, threonine or tyrosine residues on intracellular proteins, regulating cell sur vival, cytokine synthesis and production of metalloproteases. Activation of this pathway is thought to play a role in the inflammation and destruction of tissue seen in RA, with p38, ERK and JNK all activated in the synovium of RA patients.3 Of the nonreceptor tyrosine kinases, spleen tyrosine kinase (Syk) binds to B cell receptors and the Fc-gamma receptors of macrophages, neutrophils and mast cells, subsequently activating downstream MAPKs, with upregulation of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and metalloprotease synthesis. Studies have shown increased phosphorylated Syk in RA synovial tissue, and mice deficient in Syk to be protected from autoantibodyinduced arthritis.19 The Janus activated kinases (JAKs), consisting of JAK-1, JAK-2, JAK-3 and TyK, activate signal transducers and activators of transcription (STAT), on receptor-ligand interaction. They play important roles in intracellular signalling pathways for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, critical for lymphocyte function and aspects of the immune response found to be activated in RA synovial tissue.14 10 future prescriber vol 14 (2)

Initial studies focused on MAPK inhibitors, specifically p38 inhibition with pamapimod and VX-702. These agents showed a lack of efficacy in clinical trials, possibly due to dosing being limited by adverse effects such as hepatotoxicity.6–8 Recent attempts to limit toxicity by targeting the downstream kinase, MAPKAPK5 (MAPK-activated protein kinase 5) in a phase 2 trial unfortunately once again showed no superiority of the study drug compared to placebo.9 Authors have suggested future targets on the MAPK pathway should be looked for upstream, with encouraging results from targeting the upstream kinases MKK-3 (MAPK kinase 3) and MKK-6 in mouse models of RA.20 More encouraging results have been seen in clinical trials of the nonreceptor tyrosine kinase inhibitors fostamatinib and tofacitinib. Fostamatinib, an oral Syk inhibitor, has been shown to produce significant clinical benefits in patients with active RA receiving MTX therapy, but with dose-dependent side-effects including hypertension and diarrhoea.10,11 Interestingly, in the only study looking at these newer agents’ effects on radiological outcomes, fostamatinib treatment resulted in significantly improved synovitis and osteitis scores on magnetic resonance imaging (MRI) compared to placebo at 12 weeks. 12 However, the same study failed to show a significant difference in American College of Rheumatology (ACR) response and thus further study of this agent is warranted. The JAK inhibitor tofacitinib has proven safety and efficacy clinical trials data in RA. The US Food and Drug Administration (FDA)

has recently approved its use in the treatment of moderate to severe RA in patients with an inadequate response to MTX.13–15,21 In a recent study, in addition to showing significantly greater ACR20 and Disease Activity Score 28 (DAS28) remission rates compared to placebo at six months (53 vs 28%, p