Advances in rheumatology: new targeted therapeutics

Treatment of inflammatory arthritides - including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis - has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at east one of the above-named diseases are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Biologic agents with a different mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly effective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identification of early symptoms of inflammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules - for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) - to target other aspects of the inflammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice.


Introduction
Recent advances in the treatment of infl ammatory arthritides -which include rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) -have resulted from greater understanding of the pathogenesis of these diseases. Cellular-level and molecular-level research has revealed that these diseases share some common mechanisms [1]. Most critically, the proinfl ammatory mechanisms of these diseases are associated with progressive joint destruction early in the disease course [2].
In the present article, we review insights into the management of infl ammatory arthritides that have been gained from experience with the fi rst generation of TNF inhibitors. We then discuss newer biologic agents as well as novel targeted small molecules that act on signalling pathways, all of which are expanding our knowledge of infl ammatory arthritides and providing more comprehen sive management options.

Lessons learned from TNF inhibitors
Th e development of biologic agents that selectively block cytokines has provided a major advance in the treatment of infl ammatory arthritides [3,4]. TNF is a proinfl ammatory cytokine known to be present in higher concentrations in patients with RA, AS, and PsA. Th is cytokine plays a dominant role in the infl ammatory cascade under lying various infl ammatory disorders [5][6][7][8]. TNF is both an auto crine stimulator and a potent paracrine inducer of other infl ammatory cytokines, including the interleukin family [8].
To date, three TNF-targeting agents have dominated the biologic management of RA, AS, and PsA. Etanercept, a dimeric fusion protein, consists of the extracellular portion of the human p75 TNF receptor linked to the Fc region of human IgG 1 [9,10]. Infl iximab, a chimeric human-murine monoclonal antibody, binds to TNF and consists of human constant and murine variable regions. Adalimumab is a recombinant human monoclonal antibody specifi c to TNF [11,12]. All three anti-TNF therapies have well-demonstrated effi cacy in RA, AS, and PsA [9,11,12]. Th is section focuses on these three agents, for which the most data exist.

Abstract
Treatment of infl ammatory arthritides -including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis -has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at least one of the above-named diseases are etanercept, infl iximab, adalimumab, golimumab, and certolizumab. Biologic agents with a diff erent mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly eff ective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identifi cation of early symptoms of infl ammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules -for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) -to target other aspects of the infl ammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice.
In RA (for which most data have been accrued), early treatment with any one of these antagonists in combi nation with methotrexate (MTX) leads to low disease activity or remission in a considerable percentage of patients [13][14][15]. TNF inhibitors can potentially prevent radiological progression and thereby prevent disability. However, the pharmacokinetics and binding profi les of these agents are diff erent [1]. Nevertheless, randomised clinical trials (RCTs) in RA strongly suggest that all three TNF inhibitors eff ectively reduce signs and symptoms, improve physical function, and inhibit progression of structural damage.
According to the manufacturers, an estimated 1,136,000 patients have been exposed to infl iximab, 500,000 patients to etanercept, and 370,000 patients to adalimumab worldwide since these products became commercially available. Th e regular monitoring requirements for TNF inhibitors are less stringent than those required for many conventional disease-modifying antirheumatic drugs (DMARDs). TNF inhibitors are commonly used in combination with conventional DMARDs, however, so most patients will still require monitoring.

Safety
Bacterial infections, including sepsis and pneumonia, invasive fungal infections, and other opportunistic infections (for example, pneumocystosis, candidiasis, listeriosis, aspergillosis), have been reported with the use of TNF inhibitors [9,11,12]. Reactivation of latent tuberculosis following treatment has led to the introduction of preinitiation screening procedures, which have successfully reduced the number of reported cases [16,17]. Th e risk of reactivation of latent tuberculosis is, of course, dependent on the incidence of latent infection and is associated with all TNF inhibitors [18,19]. Some registry data, however, suggest that the risk may be lower with etanercept [20][21][22]. In RA patients, risk factors include active longstanding disease, age, country of origin, history of exposure to a person with tuberculosis, concomitant use of immunomodulators, and disease activity [23]. Physicians should remain alert to the development of symptoms related to tuberculosis or other infections.
Owing to adverse eff ects observed during clinical trials, patients with congestive heart failure should be closely monitored if they are receiving TNF inhibitors [9,11,12]. Other rarely reported conditions possibly related to use of TNF inhibitors include demyelinating disease, seizures, aplastic anaemia, pancytopaenia, and drug-induced lupus [9,11,12]. Physicians should remain vigilant for the development of these conditions [16].

Formation of antibodies
Th e formation of antibodies to biologic agents is a signifi cant issue because antibodies have the potential to reduce the effi cacy of the agent or to cause adverse events [10]. All three TNF inhibitors have been associated with the development of antibodies, although etanercept does not appear to generate neutralising antibodies [9][10][11][12][24][25][26]. Th e use of MTX in combination with TNF inhibitors appears to reduce the incidence of antibody for mation [10][11][12]24].
In a cohort study of 53 patients receiving etanercept for AS without MTX, mean etanercept levels in responders and nonresponders at 12 and 24 weeks were similar, and no antibodies to etanercept were detected [27]. No correlation was found among etanercept levels, formation of antibodies to etanercept, and clinical response. Conversely, in a 54-week cohort study of 38 patients receiving infl iximab for AS, detection of antibodies to infl iximab was associated with undetectable serum trough infl iximab levels and reduced response to treat ment [28].

Shared mechanisms
A look at the cellular and molecular levels of diseases in rheumatology demonstrates that such diseases share common mechanisms and may be more closely related than previously recognised. Rigorous studies have examined the mechanisms of action of the anti-TNF inhibitors, particularly infl iximab and etanercept; however, many questions remain unresolved [1]. For example, although both infl iximab and etanercept are useful in the treatment of peripheral arthritis and AS, there appear to be diff erences in their eff ects at the cellular level [29,30]. Moreover, while their actions in AS have yet to be fully elucidated, the long-lasting suppression of T-cell function apparent during treatment with infl iximab suggests that neutralisation of soluble TNF cannot be the only mechanism [29]. Possible mechanisms generally fall into two categories: those mediated by blockade of the TNF receptor, and those mediated by induction of transmembrane TNF. Several mechanisms probably act simul taneously.
To what extent various mechanisms contribute to drug effi cacy remains an open question. All of the anti-TNF agents bind to transmembrane TNF and could theoretically induce both complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, although at lower levels for etanercept compared with the anti-TNF agents infl iximab and adalimumab [1]. Th e roles of apoptosis and infl ammation reversal for reducing cellularity in rheumatoid synovial tissue during anti-TNF therapy are unclear [1]. A study by Wijbrandts and colleagues analysed apoptosis in peripheral blood and synovial tissue within 24 hours of treatment with infl iximab in patients with RA. Th ere were no signs of apoptosis induction in peripheral blood monocytes or lymphocytes after infl iximab treatment. Th ese results support the view that the rapid decrease in synovial cellularity observed after initiation of anti-TNF therapy cannot be explained by apoptosis induction at the site of infl ammation [31].

Routes of administration
Th e TNF inhibitors all require parenteral administration, either intravenously (infl iximab) or via subcutaneous injection (etanercept, adalimumab) [4]. Th e availability of diff erent formulations allows tailoring of treatment to the individual and ensures that the patient is receiving maximal benefi t with minimal negative impact on their quality of life. Although some patients appreciate the control off ered by self-administration of subcutaneous injections, others do not like to self-inject. Intravenous drugs can be inconvenient because of the need for regular hospital visits, but some patients desire regular contact with medical professionals. Th e decision on whether to use an intravenous or subcutaneous product should be based on the clinician's and patient's goals for treatment.
Intravenous administration allows high serum concentrations to be rapidly achieved, and therefore off ers the potential for fast, complete suppression of infl ammation [32,33]. Rapid improvement in signs and symptoms has been observed following the usual clinical dose of infl iximab (3 mg/kg) in RA patients [34]. Within 48 hours of administration, patients experienced signifi cant improvements in the mean duration of morning stiff ness, patient assessment of pain, physician global assessment of arthritis, and patient global assessment of arthritis compared with baseline measurements. Studies using a high-dose infu sion of infl iximab (10 mg/kg) in RA patients have shown signifi cant reductions in C-reactive protein levels [35,36], improvements in Disease Activity Score (DAS) and American College of Rheumatology (ACR) response [37], and signifi cant re duc tions in bone resorption as measured by β-CrossLaps, a predictor of annual bone loss in RA, as soon as 24 hours post infusion [37]. Th e benefi ts of higher doses, however, must be weighed against accompanying increases in side eff ects. Additionally, infl iximab therapy has demonstrated a reduction in the number of infl ammatory cells, including intimal and sublining macrophages, T cells, and plasma cells, in rheumatoid synovial tissue as soon as 48 hours after initiation of treatment [33]. Although unlicensed, intravenous administration of adalimumab also has demon strated a rapid onset of clinical eff ect [38]. Whether intravenous administration of TNF antagonists has a faster eff ect than subcutaneous administration is not known presently, as no direct comparisons have been published.
Subcutaneous agents may be appropriate for and preferred by some patients. Although drug absorption into the bloodstream is slower and a delay of several days is possible before maximal concentrations are reached, desired outcomes can be achieved. While a rapid onset of eff ect for intravenous administration has been established, there is on average no clear-cut diff erence in longterm overall effi cacy outcomes between subcutaneous and intravenous administration.

Unmet needs in biologic therapy with TNF inhibitors
Although TNF inhibitors are currently the gold standard of biologics for patients with infl ammatory arthritides, there are still a number of outstanding questions regarding how to gain the maximum benefi t from these agents. Th e most recent ACR guidance stating that patients with early RA are not candidates for biologic therapy [18] is debatable. Th ere are convincing data indicating that the use of biologics early in the course of the disease can be highly effi cacious and may induce clinical remission in a certain percentage of patients [13,15,[39][40][41]. Additional data may spur modifi cation of guidelines and practice for those early RA patients who do not respond suffi ciently to conventional treatment. Of importance, a well-defi ned referral pathway within health care systems is needed to identify patients early in the course of the disease. Also, family physicians and other healthcare professionals must be educated about the early symptoms of infl ammatory arthritides, with an emphasis on the importance of early referral to rheumatologists for diagnosis and treatment [42].
Likewise, additional studies are needed to determine whether patients with co-morbidities or those taking concurrent medications require monitoring for specifi c toxicities [4]. Several registries have reported a high prevalence of co-morbid conditions in RA patients who are commencing biologic therapy in routine practice [43,44]. Oldroyd and colleagues compared 354 patients with AS from the Australian Rheumatology Association Database who were commencing biologic therapy with more than 1,000 enrolees from four RCTs involving biologic therapy. At baseline, patients from the Australian Rheumatology Association Database -considered representative of the general population seeking clinical care -were found to have much higher levels of comorbidity than the RCT subjects, as well as signifi cantly greater disease activity. Th ese fi ndings have important implications for patient monitoring [45].
In a broader sense, RA trial inclusion criteria may need to be less restrictive [46]. A comparison of 546 RA patients from the Dutch Rheumatoid Arthritis Monitoring registry with 1,223 RA patients from 11 RCTs showed much greater disease activity at baseline in RCT enrolees [47]. Th e effi cacy of TNF-blocking agents was lower in Dutch Rheumatoid Arthritis Monitoring registrants. For example, in 10 of the 11 comparisons, the ACR 20% improvement criteria (ACR20) response rate was lower in the registry cohort (again, representative of daily clinical practice) than in the RCT group, and the diff erence was signifi cant in fi ve of the 11 comparisons. Th ese data indicate a smaller, real-world eff ect of anti-TNF treat ment than the eff ect seen in trials. Th e discrepancy may be due to continued use of co-medication and selection toward greater disease activity in RCTs.
Zink and colleagues obtained similar results during their comparison of 1,458 patients from the Rheumatoid Arthritis Observation of Biologic Th erapy registry with data from fi ve major RCTs that led to approval of biologics for RA. Only 21 to 33% of Rheumatoid Arthritis Observation of Biologic Th erapy registrants would have been eligible for the trials, and this ineligible group demonstrated lower TNF inhibitor response rates than RCT enrolees who received biologic therapy. Th e investigators concluded that observational cohort studies, which include a full spectrum of patients (for example, with various co-morbidities, taking assorted concomitant medications), are essential to complement RCT data [46]. A study of 417 RA patients from the Danish Database for Biological Th erapies in Rheumatology further supports these clinical practice data. In the majority of these routine care patients, TNF antagonists were not successful in controlling disease, although they did achieve moderate overall success in controlling clinical infl ammation [48]. Clearly, a bridge is needed between trial results and real-world results.
Some studies have hypothesised that TNF inhibitors may have the potential to repair RA joint damage [49,50]. Th e data to support this notion are currently negligible, however, and tools to measure and evaluate repair must be developed before in-depth investigations can be launched.

Potential for eff ectiveness of TNF antagonists in early rheumatoid arthritis
In one study, a small number of patients experiencing RA symptoms for <12 months but considered to have a poor prognosis were randomised to receive either infl iximab plus MTX (n = 10) or placebo plus MTX (n = 10) for 1 year [51]. Patients receiving infl iximab experienced signifi cant improvements in all measures at the end of year 1 compared with those receiving placebo. Th e infl iximab patients then received MTX alone for an additional year, and 70% of patients maintained the infl iximab responses, as measured by the C-reactive protein level, DAS in 28 joints (DAS28), and Health Assessment Questionnaire results [51].
van der Kooij and colleagues recently compared the clinical and radiological effi cacy of initial (n = 117) versus delayed (n = 67) treatment with infl iximab plus MTX in patients with early RA in a post hoc analysis of the BeSt study [52]. After 3 years of treatment, patients receiving initial infl iximab plus MTX demonstrated more improve ment in functional ability over time, as measured by the Health Assessment Questionnaire, and were less likely to have radiological progression than patients treated with delayed infl iximab plus MTX. Th ese results suggest that initial treatment with a biologic-plus-DMARD combi nation in patients with recent-onset RA is more benefi cial than reserving such treatment for patients in whom traditional DMARDs have failed [52].
Th e PREMIER study compared the effi cacy of early intervention with a combination of adalimumab and MTX versus either agent used alone as monotherapy in patients with early, aggressive RA [15]. Th e primary end points in this 2-year, double-blind, controlled study (n = 799) were the percentage of patients in whom an ACR50 response was achieved and the mean change from baseline in the modifi ed Total Sharp Score, which assesses bone erosion and joint space narrowing on radiographs. Combination therapy was superior to adalimumab and MTX mono therapy in all outcomes measured. At year 1, patients treated with combination therapy had a mean increase in Total Sharp Score of 1.3 units compared with 3.0 units in those receiving adalimumab monotherapy (P = 0.002) and of 5.7 units in those receiving MTX monotherapy (P <0.001). At year 2, patients receiving combination therapy continued to have signifi cantly less radiographic progression (mean change 1.9 Sharp units) compared with those treated with either adalimumab (5.5 units) or MTX (10.4 units) monotherapy (P <0.001 for both comparisons). Although ACR responses were comparable in the two monotherapy arms, there was signifi cantly less progression in the adalimumab arm compared with the MTX arm at 6 months (2.1 vs. 3.5), 1 year (3.0 vs. 5.7) and 2 years (5.5 vs. 10.4) (P <0.001 for all comparisons). Th is is another study suggesting the value of combination therapy in early RA [15].
Van der Heijde and colleagues have hypothesized that therapeutic intervention early in the disease course has a disproportionate benefi t on outcome if treatment is started early in the disease course [51]. Additionally, drug-free remis sion may be a realistic goal in some patients with early RA. In the BeSt study, 19% of patients who received infl iximab plus MTX in a DAS-steered, tightly controlled manner were in drug-free remission at 5 years, for a mean duration of 22 months. Infl iximab had been successfully discontinued in 58% of patients, while 18% were still receiving combination therapy. Furthermore, compared with other treatment strategies, initial tem porary treatment with infl iximab plus MTX resulted in signifi cantly better functional ability over 5 years [53]. Th ese studies raise the possibility that if aggressive treatment to induce remission is instituted very early in the course of RA, more conservative management strategies may be suffi cient to maintain that remission.
Th e use of TNF blockers for early-stage PsA is currently under discussion. For early-stage AS, one study showed infl iximab to be highly effi cacious in patients who were positive for HLA-B27, had recent-onset infl ammatory back pain, and had early sacroiliitis demonstrated by mag netic resonance imaging [54].

Prediction and discontinuation of TNF antagonists
Additional unmet needs include: the ability to predict clinical response so that these drugs, which are expensive and have the potential for serious toxicity, can be targeted to patients who would most benefi t [55]; an understanding of acquired drug resistance to anti-TNF agents [56]; a full explanation for why patients with spondyloarthritis (a group of disorders that includes AS and PsA) have a 20% lower probability of discontinuing TNF antago nists than patients with RA [57]; and an understanding of reasons for and predictors of discontinuation.
Relative to the fi rst point, the search for predictors of response is important in the context of personalised medicine, with the aim of increasing the percentage of patients exhibiting a robust response to a given treatment. Wijbrandts and colleagues recently studied arthroscopic synovial tissue in 143 patients with active RA prior to initiating treatment with infl iximab [58]. Th eir analysis confi rmed that the baseline level of TNF expression may be a signifi cant predictor of response to anti-TNF therapy. At baseline, TNF expression in the intimal lining layer and synovial sublining was signifi cantly higher in responders than in nonresponders (clinical response determined at week 16) (P = 0.047 and P = 0.008, respectively). Th e number of macrophages, macrophage sub sets, and T cells was also signifi cantly higher in respon ders than in nonresponders [58]. Th e relationship between synovial lymphocyte aggregates and the clinical response to infl iximab has also been studied in RA patients [59]. Synovial tissue biopsy samples were obtained from 97 patients with active RA before initiation of infl iximab treatment. Lymphocyte aggregates were counted and graded for size, and logistic regression analysis identifi ed whether the presence of lymphocyte aggregates could predict clinical response at week 16. Th e majority (57%) of RA synovial tissues contained lymphocyte aggregates. Additionally, aggregates were found in 67% of clinical responders compared with 38% of nonresponders. Th e presence of aggregates at baseline was a highly signifi cant predictor of the clinical response to anti-TNF treatment (P = 0.008), demonstrating that RA patients with synovial lymphocyte aggregates may have a better response to infl iximab treatment than those with only diff use leucocyte infi ltration [59].
Relative to the fourth point, 21 to 35% of patients discontinue TNF-blocking agents within the fi rst year [60]. Reasons for discontinuation appear to include lack of response, loss of response, development of intolerance, partial effi cacy, and adverse events [61,62]. Switching to a diff erent TNF inhibitor may be an option for some patients [63]. One limited study with 31 enrolees suggested that when etanercept is not effi cacious, infl iximab may off er gains, and that when infl iximab fails due to adverse events, etanercept may allow continuation [61]. Another larger study (complete data for 197 patients) in RA suggested that a second TNF inhibitor may be eff ective after failure of the fi rst inhibitor, regardless of the reason for discontinuation of the fi rst agent [60]. Conceivably, effi cacy of a second TNF blocker may be lower in primary nonresponders to a fi rst TNF blocker (response being defi ned at 12 to 16 weeks after initiation of treatment). Switching to a diff erent mechanism of action and agent, such as rituximab, abatacept, or tocilizumab, is also an option (see below).
Identifying predictors of discontinuation would be valuable in managing disease and targeting therapies to patients most likely to benefi t. Currently, treatment choices are dominated by patient and physician preference, side-eff ect profi les, and cost [64]. A cohort (n = 503) from the Brigham Rheumatoid Arthritis Sequen tial Study was examined to identify clinical predictors associated with discontinuation of TNF inhi bi tors [64]. In this study, 210 out of 503 patients (42%) discontinued therapy. Unfortunately, only 63 patients gave a reason; the investigators therefore shifted to a model-based analysis. Th e results showed that higher risk of discontinuation was associated with prior use of another TNF agent. Lower risk of discontinuation was associated with longer disease duration, prior use of DMARDs, and longer MTX use.
More information is clearly needed with regard to individualising physician/patient decision-making about initiating anti-TNF agents, switching agents, and predicting effi cacy and tolerability. Lowering the discontinua tion rates is an important current goal.

Newly discovered mechanisms of action
More than 100 cytokines and chemokines have been identifi ed in the infl ammatory cascade associated with infl ammatory arthritides [1]. Although TNF is a key player in the proinfl ammatory cytokine cascade, the complex interconnectivity and dynamics of cytokine biology mean that relationships between cytokines may be better visualised as a network within a cascade ( Figure 1) [1,65].
Increased understanding of the pathophysiology of RA has led to the identifi cation of new therapeutic targets, including proinfl ammatory cytokines, T cells and B cells, adhesion molecules, chemokines, and intracellular and extracellular signalling pathways. Th e fi rst stage in the pathogenesis of RA is thought to be the activation of T cells via the T-cell receptor complex [66]. Th e second stage involves interaction between co-stimulatory molecules on T cells and molecules on antigen-presenting cells, providing more targets for intervention [66]. Fibroblast-like synoviocytes are resident mesenchymal cells of the synovial joints and are increasingly recognised as key players in the pathogenesis of RA. Activation of fi broblast-like synoviocytes produces a broad array of cell surface and soluble mediators that help to recruit, retain, and activate cells of the immune system and resident joint cells, leading to the promotion of ongoing infl ammation and tissue destruction [67].
Cytokines such as IL-6, IL-12, IL-15, IL-17, IL-18, IL-21, IL-23, IL-33, and IFNγ provide potential targets for modulation [68], as do the signal transduction systems that follow the binding of cytokines to cell receptors, typically sequences of protein kinases such as mitogen-activated protein kinase [69]. Factors that modulate the transcription of genes following cytokine stimulation, such as NF-kB, provide more targets for modulation of cytokine pathways [70,71].
B cells are also important in the pathophysiology of RA, although their role is not as well understood as that of T cells. B cells produce autoantibodies, may act as antigen-presenting cells, secrete proinfl ammatory cytokines such as IL-6, and regulate T cells. In addition to possibly acting as antigen-presenting cells, B cells produce immunoglobulins and secrete cytokines, perpetuating infl ammation. Depletion of B cells is a logical therapeutic strategy that should provide a reduction in immunoinfl ammatory components [72,73]. B-cell-related potential targets include B-lymphocyte stimulator and the proliferation-inducing ligand APRIL. Both assist the survival, proliferation, and antigen presentation of B cells. An exploratory phase IB trial of the recombinant fusion protein atacicept, which binds and neutralises B-lymphocyte stimulator and APRIL, was recently completed [74]. B cells also exhibit a regulatory capacity by controlling dendritic cell and T-cell function through cytokine production [75,76]. B-cell signalling pathways are emerging as potential therapeutic avenues. Targets include Bruton tyrosine kinase, which plays a key role in B-cell development and activation, and B-lymphocyte stimulator, which is important to B-cell survival and maturation [77].
Autoantibodies, such as anticitrullinated peptide antibodies and rheumatoid factor, serve as diagnostic and prognostic markers of RA. Th eir presence in a variety of autoimmune diseases suggests that they may also be valuable therapeutic targets. For example, blockade of Bcell traffi cking may inhibit formation of autoantibodies [77]. Th is is an area ripe for investigation.
Other areas of research include modulating complement activation to prevent the infl ux of infl ammatory cells into the synovium and inhibiting chemokines [78] to prevent the degradation of cartilage and bone [66]. Th e receptor activator of NF-κB/receptor activator of NF-κB ligand pathway is also being targeted with the aim of regulating the formation and activation of osteoclasts [79].
Lastly, although it is still unclear whether patients who fail one TNF blocker should switch to another TNF blocker or to a drug with a diff erent mechanism of action, in RA in the recent past it has been common to try another TNF blocker after treatment with the fi rst TNF blocker has failed [80]. However, it is possible that TNF is not the crucial cytokine instigating RA in primary nonresponders (patients with no response 12 to 16 weeks after initiation of therapy) to anti-TNF therapy [58,80]. Initial evidence that primary nonresponders are less likely to respond to a second TNF blocker may accelerate the search for non-TNF targets [80]. Consistent with this notion, lower synovial TNF expression and fewer TNFproducing infl ammatory cells are, on average, present in primary nonresponders [58]. Pharmacokinetics and pharmaco genetics are expected to elucidate these concepts [81].

Advances in biologic therapy
Th ere are many agents in development for the treatment of infl ammatory arthritides. Th is is a highly competitive arena due to the complexity of interrelated pathways contributing to infl ammatory arthritis pathogenesis [66]. Establishing the exact role of diff erent treatments and identifying which patients will benefi t most from them are the challenges now facing rheumatologists.

Rituximab
Rituximab, a chimeric anti-CD20 monoclonal antibody, was the fi rst B-cell agent approved for treatment of RA [82]. Th is antibody was approved in combination with MTX in the United States and Europe in 2006 for adult patients with, respectively, moderate to severe active RA or severe active RA, after the failure of at least one TNF inhibitor. Th e agent targets B cells, rather than the entire immune system, and is administered by intravenous infusion to patients with an inadequate response to TNF inhibitors [83]. Rituximab has been shown to inhibit progression of structural damage in RA over 2 years, and continues to inhibit joint damage with long-term treatment [39,84].
In the event of inade quate effi cacy with a TNF inhibitor, some have suggested that switching patients to rituximab is a more eff ective management strategy than switching to another TNF inhibitor [85]. A prospective cohort study of 318 RA patients found that when the motive for switching to rituximab was TNF inhibitor ineff ectiveness, disease improvement was signifi cantly better than with an alternative TNF inhibitor [85]. If the reason for switching is not lack of effi cacy (for example, adverse events, patient preference), there is no advantage in switching to rituximab [85].
Immunoglobulin levels have been found to be lower in patients receiving rituximab in the long term for RA [86]. An initial apparent trend toward higher rates of serious infection in this population may have been discounted by an open-label study of 1,039 RA patients [87]. Th e serious infection rate was 5.0 per 100 patient-years, similar to that for etanercept, infl iximab, and adalimumab (5.3 per 100 patient-years) [88]. Th ere also have been reports of psoriasis and PsA developing in RA patients receiving rituximab [89]; however, the same is true for TNF inhibitors [90]. Th e development of progressive multifocal leukoencephalopathy or hepatitis B reactivation during rituximab treatment for RA is very rare.

Abatacept
Abatacept is a T-cell co-stimulation modulator administered by intravenous infusion. Th e modulator is thought to prevent the activation of T lymphocytes, including naïve T cells [91,92]. Abatacept was approved in the United States and Europe in 2005 for treatment of RA in adult patients with an inadequate response to DMARDs or TNF inhibitors. In January 2010 it was approved in Europe for moderate-to-severe active polyarticular juvenile idiopathic arthritis in patients 6 years of age and older. Because abatacept was the fi rst therapy targeting the inhibition of co-stimulatory signals to prevent T-cell activation, its use in early disease [93] and in biologicnaïve patients with active RA [94] has generated particular interest and investigation [91,[95][96][97]. Th ese data may support the use of abatacept in biologic-naïve patients with early disease who have had an inadequate response to MTX.
Th e magnitude of abatacept's eff ect appears to increase over time. According to the initial report of the Abatacept in Inadequate Responders to Methotrexate, Abatacept or Infl iximab versus Placebo, a Trial for Tolerability, Efficacy, and Safety in Treating Rheumatoid Arthritis study, clinical response and disease activity were not only maintained from 6 to 12 months, but also appeared to improve [98]. Th e report containing 2-year results is currently only in abstract form but shows that reduced disease activity was maintained with ongoing abatacept treatment [94,99]. Abatacept has also demonstrated an increasing and signifi cant degree of inhibition of structural damage progression in patients receiving treatment for 2 years [95]. Abatacept may have an increasing disease-modifying eff ect on structural damage over time in the majority of patients who respond to treatment. To date, this is a unique observation among biologic treatments for RA.
Th e long-term effi cacy and safety of abatacept have been demonstrated over 5 years with a dose of 10 mg/kg [97]. In a long-term extension trial, abatacept was well tolerated and provided durable improvements in disease activity, with no unique safety events reported. Th ese data, combined with relatively high retention rates, confi rm that abatacept provides sustained clinical benefi ts in RA. Additionally, abatacept has been shown to provide clinical benefi ts in patients with RA who have previously failed TNF inhibitor treatment, regardless of the previous TNF inhibitor(s) used or the reason(s) for treatment failure [100]. Th is fi nding suggests that switching to abata cept may be a useful option for patients who fail TNF inhibitor treatment.

Tocilizumab
Tocilizumab is a humanised anti-IL-6-receptor monoclonal antibody administered by intravenous infusion. Th is antibody inhibits signals through both membrane and soluble IL-6 receptors [101]. Tocilizumab has received approval in Europe and the United States (January 2009 and 2010, respectively) for the treatment of moderate to severe RA in adult patients who have responded inadequately or have been intolerant to previous therapy with one or more DMARDs or TNF antagonists.
Tocilizumab used as monotherapy or in combination with MTX has demonstrated superiority over MTX mono therapy in reducing disease activity in RA over 24 weeks [102,103]. Furthermore, tocilizumab has resulted in signifi cant improvements compared with placebo in physical function, fatigue, and physical and mental health scores over 24 weeks in patients who fail to respond to conventional DMARD therapy alone [104]. Tocilizumab has also demonstrated effi cacy in RA patients who fail to achieve an adequate response with or became refractory to TNF inhibitors [105].
Th ere is a close relationship between normalisation of serum IL-6 levels following treatment with tocilizumab and clinical remission. In the phase III SATORI trial, patients whose serum IL-6 levels became normal tended to achieve DAS28 remission. Normal IL-6 levels may therefore provide a good marker to identify patients who can stop tocilizumab treatment without the risk of fl aring [106,107].
In the 3-year extension of the SAMURAI study, patients with early RA treated with tocilizumab exhibited strongly suppressed radiographic progression [108]. Further more, radiographic progression was more eff ectively suppressed in patients who received tocilizumab at the start of the trial than in those who received conventional DMARDs at the start. Early introduction of tocilizumab treatment may therefore be more eff ective in preventing joint damage. Th e LITHE study in 1,196 patients who had inadequate responses to MTX further supports the potential for tocilizumab to suppress radiographic pro gression [109]. Patients also demonstrated improvements in physical function.
Tocilizumab has a well-characterised safety profi le, with infections being the most common adverse event in trials [101,109]. Safety data pooled from fi ve pivotal tocilizumab studies demonstrate rates of serious infection of 3.5 per 100 patient-years for the 4 mg/kg dose and of 4.9 per 100 patient-years for the 8 mg/kg dose compared with 3.4 per 100 patient-years for the comparator groups over a median 3.1 years' treatment duration [109]. Physicians should also monitor for decreased neutrophil counts and increased lipid or liver enzyme levels, and manage appropriately [101,109].

Certolizumab pegol
Certolizumab is a pegylated Fab fragment of a humanised anti-TNF monoclonal antibody that neutralises the activity of TNF [66]. Certolizumab was approved for treatment of RA in combination with MTX in the United States and Europe in 2009. Th e use of pegylation increases the half-life of the molecule and eliminates the chimeric Fc portion. It is therefore hoped that adding poly ethylene glycol will produce a longer-lasting compound with fewer side eff ects, although it remains to be established whether pegylation does indeed confer these advantages in clinical practice [66].
Subcutaneous administration of 400 mg certolizumab every 4 weeks as monotherapy has demonstrated a rapid onset of response and reduction in RA disease activity as early as week 1 [110]. When used in combination with MTX, certolizumab (400 mg at baseline weeks 2 and 4, then 200 or 400 mg every 2 weeks) reduces radiographic progression compared with MTX alone over 1 year, and the diff erence is already signifi cant at 6 months [111].

Golimumab
Golimumab is a fully human anti-TNF IgG 1 monoclonal antibody that targets and neutralises both the soluble and membrane-bound forms of TNF [66]. Golimumab was recently approved for monthly subcutaneous treatment of adults with RA, PsA, and AS. A randomised, doubleblind, placebo-controlled dose-ranging study compared subcutaneous injections of golimumab with placebo in patients with active RA despite treatment with MTX [112]. In this study, greater effi cacy was demonstrated for golimumab 50 mg every 4 weeks in addition to MTX compared with MTX plus placebo in terms of ACR responses. Furthermore, 20% of patients receiving golimu mab achieved DAS28 remission at week 16, compared with only 5.7% (P = 0.074) of patients receiving MTX alone. Over a 52-week treatment period, all clinical responses achieved at week 16 were maintained and/or improved, and no unexpected safety issues were observed [112].
Th ese results have been further confi rmed in a phase III study in patients with established RA and disease activity despite treatment with MTX monotherapy [113]. Additionally, golimumab demonstrated effi cacy in patients with established RA who had previously received other TNF inhibitors and in MTX-naïve patients [114,115].
Effi cacy has also been demonstrated in patients with PsA and AS treated with golimumab [116], similar to that for currently available TNF inhibitors [117,118]. Furthermore, golimumab is capable of increasing function in patients with AS [118]. In PsA, golimumab has also demonstrated improvements in psoriatic skin and nail disease [116].

Ustekinumab
Ustekinumab is a human monoclonal antibody directed against the p40 subunit of IL-12/IL-23 that has demonstrated effi cacy in PsA [119]. In a parallel-group crossover study involving 146 patients, a signifi cantly higher proportion of ustekinumab-treated patients achieved a response using ACR criteria compared with placebotreated patients at week 12. Ustekinumab was approved in 2009 in both the United States and Europe for treatment of patients with moderate-to-severe plaque psoriasis. Ustekinumab has not been approved for PsA.

Kinase targets in development
Kinases such as Janus kinase 3 are intracellular molecules that play a pivotal role in signal transduction of interleukins. CP-690550 is an oral Janus kinase inhibitor developed to interfere with these enzymes. In a recent study, 264 patients were randomised equally to receive placebo, 5 mg CP-690550, 15 mg CP-690550, or 30 mg CP-690550 twice daily for 6 weeks and were followed for an additional 6 weeks after treatment. Th e primary effi cacy endpoint was the ACR20 response rate at 6 weeks [120]. Response rates were 70.5%, 81.2%, and 76.8%, respectively, in the groups receiving 5 mg, 15 mg, and 30 mg CP-690550 twice daily compared with 29.2% in the placebo group (P <0.001). Th is study also assessed pain, physical functioning, and health status using 100-mm visual analogue scales, the Health Assessment Questionnaire -Disability Index, and the selfadministered Short-Form 36 [121]. Treatment with CP-690550 resulted in clinically meaningful and statistically signifi cant patient-reported improvements by week 1 of treatment. Th e incidence of blood lipid elevations and neutropaenia is concerning, however, and much longerterm studies are needed.
Also of interest are data indicating that spleen tyrosine kinase could serve as a novel and promising target for immune intervention in rheumatic diseases. R788, a novel and potent small-molecule spleen tyrosine kinase inhibitor, recently demonstrated the ability to ameliorate established diseases in lupus-prone NZB/NZW F1 mice and MRL/lpr mice, and also signifi cantly reduced clinical arthritis in collagen-2-induced arthritis models [122,123]. In a recent 12-week double-blind study, 142 patients with active RA despite MTX therapy received R788 at concurrent doses of 50 mg, 100 mg, or 150 mg twice daily; 47 patients received MTX plus placebo [124]. Th e primary endpoint, an ACR20 response at week 12, was achieved by the majority of patients receiving 150 mg or 100 mg twice daily (72% vs. 65%; P <0.01). Around one-half of the patients achieved an ACR50 response (57% vs. 49%), and more than one-quarter of patients achieved an ACR70 response (40% vs. 33%). Th ese results suggest that spleen tyrosine kinase inhibition is worthy of more in-depth study.

Conclusion
New approaches to infl ammatory arthritides are challenging the rheumatologist. Th e advent of biologic therapies has revolutionised treatment and has allowed us to further infl uence the progression of these diseases as well as their symptoms. Development of the fi rst biologics, TNF inhibitors, expanded our knowledge of the pathogenesis of infl ammatory conditions. As TNF inhibitors have been available to rheumatologists for more than a decade, a large body of data has accumulated regarding their safety and effi cacy. More recently, biologics with a distinct mechanism of action (rituximab, abatacept, and tocilizumab) have been approved. Numerous other targets within the infl ammatory cascade continue to be identifi ed, and biologic and nonbiologic agents to modulate/inhibit the associated pathways are either in the pipeline or have already been developed. Th e relative effi cacy of these agents remains to be established, and, in time, head-to-head trials will be required to determine the best treatment options for patients.
An international task force comprising more than 60 rheumatology experts and a patient recently developed recommendations for achieving optimal therapeutic outcomes in RA. Using a Delphi-like procedure, the members discussed, amended, and voted on evidence derived from a systematic literature review as well as expert opinion. Th e resulting initiative, called Treat-to-Target, shares information and strategies in an eff ort to determine the best options for patients [125].
In the meantime, the prospect of preventing radiographic damage has led to a re-evaluation of how patients with infl ammatory arthritides are managed, with early diagnosis and referral becoming increasingly important. Additionally, researchers are acknowledging specifi c subgroups of patients who are more likely to derive benefi t from certain treatments. Before off ering treatment options, the rheumatologist needs to be able to identify patients who are likely to respond to a particular treatment. Th is ability would allow optimal treatment to be initiated sooner, thereby potentially reducing the costs and the risks to patients and preventing radiological progression.
Th e search continues for biomarkers and molecular networks that can help us better understand the variable response to targeted therapy. Today, the key challenge facing rheumatologists is how best to integrate the advanced therapies into daily practice.

Competing interests
PPT has served as a consultant to Abbott, BMS, Merck-Serono, Pfi zer, Roche, Schering-Plough and Wyeth. JRK has served as a consultant to Wyeth for Europe, and he lectures on behalf of Abbott, Pfi zer, Roche and Wyeth.