Abstract: Rheumatoid arthritis (RA) is the most common inflammatory musculoskeletal disease and an important cause of diminished quality-of-life for the affected individuals and with a major impact on society because of decreased work-force participation. Treatment of RA has been advanced dramatically during the past two decades by the advent of biological therapies. A large number of such agents have been approved and several additional ones are in late-stage clinical developments. Because of the high price of biologics, pharmacoeconomical considerations have become an important part of the appraisal of such medications. Current therapeutic developments include the development of additional biologics with various specific targets, the development of small-molecule compounds with similar efficacies, and entirely new approaches to treat autoimmune inflammatory diseases such as RA.
Rheumatoid arthritis (RA) is a rather common chronic autoimmune disease causing inflammation in multiple joints of the hands, feet, and elsewhere in the body. The disease affects women more often than men and can occur in all age groups, with a peak incidence in the 4th and 5th decades of life. The prevalence in western societies is around 0.8%, making it the most common inflammatory musculoskeletal disease (osteoarthritis, which is more common, is considered a degenerative-metabolic disorder). Because of its chronic nature and its propensity to cause irreversible damage to the cartilaginous and bony structures in and around the joints, RA has a major impact on the quality of life of the patient. When inadequately treated, the course of the disease is typically chronic and undulating with progressively more joint destruction and increasing loss of physical function and handicap. The consequences for society are therefore also significant: RA is a major cause of long-term sick-leave and permanent disability, leading to very high costs to society from RA.
The treatment of RA has undergone dramatic developments over the past two decades, fueled to a large extent by the advent of biotechnology with the possibility of targeting specific molecules and cells that play key roles in the autoimmune inflammatory process. To understand these developments, more established therapies for RA and the key principles of their use must first be discussed.
Principles of Antirheumatic Treatment and Established Antirheumatic Agents
It is widely accepted that RA must be treated, in principle, with one or more specific antirheumatic drugs, usually referred to as disease-modifying antirheumatic drugs or DMARDs. Treatment with only analgesics and simple anti-inflammatory agents is not acceptable in the vast majority of cases. Because of a combination of generally satisfactory efficacy, acceptable toxicity, and patient convenience, methotrexate (MTX) emerged during the 1990’s as the first-line DMARD for most patients. However, only a minority of patients have an excellent result with MTX, and for most patients additional or alternative therapies must be sought. Medications such as sulfasalazine (Salazopyrin), (hydroxy)chloroquine, and several others were traditionally used as alternatives to MTX but combined use of DMARDs has also become accepted as a valid treatment option with additional benefit (O’Dell et al.., 1996). During the late 1990’s, leflunomide (Arava) was developed as an alternative to MTX with similar efficacy and toxicity profiles.
In addition to the use of DMARDs, glucocorticoids (corticosteroids) can and are often used in the treatment of RA. An important reappraisal of the role for glucocorticoids in the treatment of RA has occurred relatively recently. While Harris and coworkers had previously suggested in the 1980’s that low-dose glucocorticoids might decrease the progression of radiographical (structural) damage (Harris et al., 1983), evidence for this was only recently presented in three trials that demonstrated that not only radiographical (Kirwan et al., 1995) but also clinical outcomes are improved in patients who are treated with low-dose glucocorticoids when added to standard DMARD therapy (Svensson et al., 2005; Wassenberg et al., 2005).
A number of clinical trials have investigated the optimal strategies in the treatment of RA. The Finnish RA combination therapy trial FINRACO demonstrated that a strategy of initial multidrug combination and adjustment of the treatment every 3 months was clearly superior to the more usual monotherapy approach, even if the latter was also adjusted frequently (Möttönen et al., 1999). The TICORA study demonstrated that the combination of frequent (monthly) visits to the rheumatologist, the generous use of glucocorticoid injections, and the frequent adjustment of therapy led to superior results compared to a more conventional approach (Grigor et al., 2004); similar results were also found by the CAMERA study, which employed computerized algorithms to prescribe treatment changes in the intensified therapy group (Verstappen et al., 2007). The BeSt trial compared four different treatment strategies and concluded that more intensive initial therapies bring about faster changes and less radiographic damage. Recently we demonstrated in the SWEFOT trial that initial methotrexate followed within 3-4 months by escalation to anti-tumor necrosis factor (TNF) therapy might provide a useful strategy for the treatment of early RA (van Vollenhoven et al., 2009). This trial will be described in more detail below.
The First Three Biologic Antirheumatic Agents for RA
The term biologic agents or biologics refers to complex protein molecules, created by using molecular biology methods, and produced in prokaryotic or eukaryotic cell cultures. Their biological activities can be predefined and are usually directed towards a specific cytokine or cell surface molecule, making it possible to predict a range of activities both in terms of efficacy and toxicity - although predictions of the latter have not always been correct. The biologic agents have opened up new therapeutic horizons in RA, but have also confronted regulatory issues on quality control, and prompted health-care payers to deal with high costs.
The FDA approval of etanercept and infliximab in 1998 and 1999, respectively, for the treatment of RA heralded a new era in RA therapy. Some years later, adalimumab was also approved. Development of anti-TNF agents as therapies for RA was based on the original observations by Brennan et al. that TNF appeared to be a more upstream, dominant cytokine in the rheumatoid synovium than IL-1 (Brennan et al., 1989). The remarkable efficacy of blocking TNF in the clinic would have been hard to predict, however, based on in vitro or animal data. The efficacy of anti-TNF agents has now been demonstrated in many controlled trials. The initial trials with each agent showed efficacy compared to placebo in groups of patients who had an inadequate response to methotrexate (and might have failed other DMARDs as well) (Elliott et al., 1993; Weinblatt et al., 1999; Weinblatt et al., 2003). The use of methotrexate as an ‘anchor drug’ proved to be important both in terms of avoiding immunogenicity, primarily with infliximab, and also in achieving radiographical results that were, perhaps unexpectedly, even better than the clinical results. Thus, in the patients treated with methotrexate plus an anti-TNF, almost complete inhibition of joint destruction at the group level was achieved. Later studies also supported the use of anti-TNF agents in combination with methotrexate in patients with early RA (Breedveld et al., 2006) or in patients with established RA who had not yet been treated with methotrexate (Klareskog et al., 2004).
Remarkably, few trials directly compared the efficacy of anti-TNF agents to other reasonable therapeutic options. In the TEMPO trial, which involved patients with established RA who had not yet been treated with methotrexate, the combination of methotrexate plus etanercept was superior to methotrexate monotherapy both clinically and radiographically, whereas etanercept as a monotherapy was clinically similar to methotrexate monotherapy and radiographically an intermediate between the groups of methotrexate plus etanercept and methotrexate monotherapy (Klareskog et al, 2004). In the BeSt trial, the immediate initiation of methotrexate plus an anti-TNF agent proved to be better than the initial monotherapy with MTX alone but was not superior to MTX plus SSZ plus initial high-dose glucocorticoids (Goekoop-Ruiterman et al., 2005). In our SWEFOT trial, the patients with early RA were first given MTX, and only after failing this agent were they randomized to one of two ‘reasonable’ therapy strategies: the addition of SSZ plus hydroxychloroquine, or the addition of infliximab (Figure 1) (van Vollenhoven et al., 2009). After one year, 25% of patients with the former combination, and 39% of patients with the latter had achieved a European League Against Rheumatism good response, the difference being statistically significant (Figure 2). Other key clinical outcomes also showed superiority for the biologic treatment over the conventional alternative, and recently, we presented radiographical data (you may list the abstract as a reference) that also favored the former treatment. Nonetheless, the superiority of anti-TNF over conventional combination therapy is only one of three important conclusions from this trial. The other two are that some patients do have very good responses to conventional medications, and the other that even with anti-TNF medications, some patients do not improve. The clear conclusion is that we are still in need of better ways to determine which treatment would serve each patient the best, that is, to individualize treatment.
Newer Biologic Agents for the Treatment of RA
Although ‘new’ is a relative term, I will discuss here agents that were approved in the past several years and/or where major new data have recently emerged regarding their use.
Anakinra is the recombinant form of the naturally occurring IL-1 antagonist IL1-RA and was approved for the treatment of RA on the basis of trials showing efficacy when compared to placebo. In practice, the results were not as impressive as with anti-TNF biologic agents, and this fact, perhaps combined with the less patient-friendly dosing (daily subcutaneous injections), led to the drug being used infrequently for RA. Interestingly, anakinra has become an important niche-drug for rare but devastating inborn syndromes characterized by high IL-1 production, such as neonatal onset multisystem inflammatory disease (NOMID) and chronic infantile neurological, cutaneous, and articular (CINCA) syndrome and Muckle-Wells syndrome (Lovell et al., 2005), and might even have an important role in the treatment of the systemic form of juvenile inflammatory arthritis (Still’s disease) (Lequerre et al., 2008). Moreover, a randomized trial is currently underway in the Nordic countries to compare anakinra to conventional DMARDs in adult-onset Still’s disease.
The B-cell depleting agent rituximab was approved on the basis of several trials showing efficacy in patients with RA, and in particular, in patients who had failed to respond to one or more anti-TNF agents (Emery et al., 2006; Cohen et al., 2006). The clinical results seen in these trials were similar to those with anti-TNF agents, but with somewhat reduced radiographical efficacy. Several clinical trials have shown that rituximab is effective in patients who have at least one of the two types of autoantibodies associated with RA, rheumatoid factor and anti-citrullinated peptide antibodies, whereas efficacy in patients lacking these antibodies has not been clearly demonstrated. The fact that rituximab treatment results in long-lasting near-complete B-cell depletion from the peripheral blood led to initial concerns regarding the long-term safety; however, extensive longitudinal follow-up data have demonstrated reasonable safety and tolerability profiles in line with those established for other antirheumatic drugs (Keystone et al., 2007). Recently, a few isolated cases of progressive multifocal leukoencephalopathy, a rare and frequently fatal viral disorder of the central nervous system, have been reported in RA patients treated with rituximab.
This biologic agent is the recombinant dimerized form of the natural inhibitor of T-cell activation molecule CTLA-4 and was shown in several randomized trials to be clinically and radiographically superior to placebo both in anti-TNF-agent naïve patients (Kremer et al., 2003) and in patients who had failed to respond to anti-TNFs (Genovese et al., 2005). Generally, the clinical results are similar to those achieved with anti-TNF agents, while the radiographical results are perhaps somewhat less impressive. Abatacept appears to have a slower onset of action than the anti-TNF agents. Interestingly, a randomized controlled trial demonstrated that over a 1-year period, abatacept achieved clinical results that were superior to infliximab at the recommended minimum dosage (3 mg/kg), and the abatacept-treated patients had fewer adverse events including fewer infections (Schiff et al., 2008).
The anti-IL-6 receptor blocker tocilizumab was approved in Europe in 2009 and has also been approved recently in the US. It was studied in several large controlled trials, which showed clinical efficacy in patients who had previously failed to respond to DMARDs (Maini et al., 2006) and/or anti-TNF agents (Emery et al., 2008). The efficacy appeared comparable to that seen with anti-TNF agents, although the frequency of remission with tocilizumab was higher in some of these trials than in comparable trials with anti-TNF agents (conceptually, remission is the complete absence of disease activity; it is often defined by a value of the disease activity score called DAS28 below a threshold of 2.6). The high rate of remission may in part be explained by a direct inhibition of tocilizumab on the blood tests used to gauge disease activity, including C reactive protein but there may also be a true unique benefit of this mechanism of action in a sizeable subset of patients. My own observations in a small group of patients treated at our clinic are not inconsistent with the latter possibility.
The safety data from the clinical trials and longitudinal follow-up of treatment with tocilizumab are in some respects similar to those seen with other biologic agents: some infusional adverse events, a slightly increased rate of common infections, and the infrequent occurrence of more serious adverse events. Tocilizumab treatment might be uniquely associated with decreases in neutrophil and thrombocyte counts, although these rarely reach clinically relevant levels. An increase in total and LDL cholesterol levels has also been demonstrated, and this might be explained in part by decreased inflammation, as similar observations have been reported for infliximab, but could also be linked more directly to IL-6 antagonism. In tocilizumab trials, HDL cholesterol level was also increased, and the atherogenic index was largely unchanged. The long-term implications of these observations are at this time not clear.
During the past year, two additional anti-TNF biologic agents, certolizumab pegol (Cimzia) and golimumab (Simponi), have been approved in both the USA and Europe.
Golimumab is a fully human anti-TNF IgG and is dosed at 50 mg subcutaneously once per month. Its efficacy was demonstrated in RA patients who had previously failed or had incomplete response to MTX, and also in patients who had failed another anti-TNF agent (golimumab is also approved for ankylosing spondylitis and psoriatic arthritis). The overall results of these trials suggest that golimumab’s clinical efficacy is in the same range as with the original three anti-TNFs. The radiographical data (efficacy against the progression of joint damage) are somewhat less clear, partly because progression in the control groups was minimal. Safety and tolerability profiles are similar to other anti-TNFs, and golimumab carries the same warning that applies to all anti-TNFs regarding the need to screen for latent tuberculosis prior to their use. On balance, golimumab appears to offer similar benefits and risks to the other anti-TNFs. The monthly dosing adds a measure of patient convenience. A key question is whether the efficacy is truly maintained during the full >4 weeks between two contiguous injections.
Certolizumab pegol is the pegylated Fab’ fragment of a humanized anti-TNF IgG molecule. Because of its smaller size, its lack of ability to cross-link, and its lack of the Fc based effector functions, one might have been inclined to predict that this molecule could have lower efficacy and/or fewer toxicities compared to the other anti-TNFs. However, data from multiple large randomized trials support the contrary view, namely that it has the same efficacies and the same toxicities/risks as the other anti-TNFs (Keystone et al., 2008; Smolen et al., 2009). With regards to the latter, tuberculosis screening is required. Certolizumab pegol is approved for dosing at 200 mg subcutaneously every 2 weeks, but also, as monotherapy, at 400 mg every 4 weeks (Fleischmann et al., 2009). Animal data indicate that it has better uptake in inflamed joints for this molecule by virtue of its smaller size and/or its being pegylated. And indeed, the onset of clinical efficacy in the clinical trials was also very rapid, but it is not possible to determine with certainty whether there is a true difference in the response kinetics between the different anti-TNFs.
|Table 1. Approved Biologic Agents for Rheumatoid Arthritis.|
|Agent||Brand Name||Structure||Pharmacology||Usual Dosage||Specific Side Effects and Risks|
|Abatacept||Orencia||Recombinant CTLA4 molecule dimerized on Ig-frame||T-cell co-stimulation blocker||500-1000 mg i.v. monthly||Infusional reactions, infections|
|Adalimumab||Humira||Human monoclonal||TNF blockade||40 mg s.c. biweekly||Injection site reactions, infections including tuberculosis|
|Anakinra||Kineret||Recombinant IL-1 receptor antagonist||IL-1 receptor blockade||100 mg s.c. daily||Injection site reactions, infections, neutropenia|
|Certolizumab pegol||Cimzia||Pegylated Fab’ fragment from humanized monoclonal||TNF blockade||200 mg s.c. biweekly or 400 mg s.c. monthly||Injection site reactions, infections including tuberculosis|
|Etanercept||Enbrel||Recombinant TNF receptor (p75) dimerized on Ig-frame||TNF blockade||50 mg s.c. weekly||Injection site reactions, infections including tuberculosis|
|Golimumab||Simponi||Human monoclonal||TNF blockade||50 mg s.c. every 4 weeks||Injection site reactions, infections including tuberculosis|
|Infliximab||Remicade||Chimeric monoclonal||TNF blockade||3-10 mg/kg i.v. every 4-8 weeks||Infusional reactions, infections including tuberculosis|
|Rituximab||MabThera (EU), Rituxan (US)||Chimeric monoclonal||B-cell depletion||1000 mg, 2 i.v. infusions 2 weeks apart||Infusional reactions, infections|
|Tocilizumab||Actemra (US), RoActemra (EU)||Humanized monoclonal||IL-6-receptor blockade||8 mg/kg i.v. every 4 weeks||Infusional reactions, infections, cytopenias, elevated cholesterol|
Future Agents: Introduction
Because of the medical and commercial successes of anti-rheumatic therapies, a large number of therapeutic agents are currently in early- and late-stage development for the RA indication. While some of these are similar to existing drugs in terms of mechanism of action (”me-too drugs”), some conceptually novel drugs are also being developed, and some entirely new approaches have been proposed.
Future agents in late-stage development
Ofatumumab and ocrelizumab are both anti-CD20 molecules and therefore very similar to rituximab in their basic mechanism of action. Because both have fewer mouse-protein sequences in their molecular content than rituximab the expectation is that allergic reactions will occur less frequently. In other respects the differences would most likely be small, and clinical trial results to date generally have supported this view.
Anti-IL-17. Two different anti-IL-17 molecules have entered phase II/III development. Because of the central role of IL-17 in certain autoimmune processes a more specific activity might be expected in a disease such as RA. The first small-scale studies with these compounds did suggest efficacy, although perhaps not at par with anti-TNF approaches. An interesting question is whether anti-IL-17 could be used in combination with other targeted approaches and whether it would be possible to identify prospectively those patients most likely to benefit from this new mechanism of action.
Since the advent of biologics it has been clear that a major advance would be the development of small-molecular agents with the same mechanism of action. The hope would be that the efficacy of anti-cytokine therapies could be replicated with such a molecule, having the advantage that it could be administered orally and at a more sustainable cost. However, direct blockade by a small molecule of the interaction between cytokines and their receptors, which involves large areas of protein surface contact, has not so far been possible. A number of alternative approaches to developing such small-molecular compounds have been attempted, including inhibitors of MAP p38 kinase and of the TNF converting enzyme TACE, but without success. Recently, however, two small-molecular compounds have reached late-stage development for RA.
Tasocitinib (CP 690-550) is an inhibitor of the protein kinase JAK-3, a key molecule in the intracellular activation cascade that occurs when various cytokines bind to leucocytes. The first large-scale trials with tasocitinib have indeed suggested excellent efficacy compared to placebo, well in line with anti-TNFs. The side-effect profile that has emerged from these trials may in part be related to the fact that tasocitinib is not 100% specific for JAK-3 and it could also block JAK-2, which could lead to neutropenia, thrombocytopenia, and anemia. In the trials to date these side-effects were mostly mild and manageable. Other observed side-effects of tasocitinib were gastrointestinal symptoms and elevations of blood pressure and of serum lipids in some patients. Large phase III studies are currently ongoing.
Fostamatinib disodium (R788) is a small-molecular inhibitor of the protein kinase SyK, which plays a role quite similar to that of JAK-3 described above. Phase II clinical trials have supported an acceptable safety profile similar to that described for tasocitinib, and efficacy was encouraging in some but not all trials.
Additional biologics targeting other cytokines (IL-12/23, IL-15, IL-18, G-CSF, GM-CSF, BlyS, and APRIL), chemokines, or cell surface markers (CD19 and CD22) are or have been in development for RA or other rheumatological indications. In addition, some entirely novel approaches are also being developed in early-stage trials. For instance, it may be possible to elicit anti-cytokine immune responses in the patient that would, in a more natural manner, block excessive cytokine activity. Such ‘vaccination’ approaches are being tested in phase I/II. Another possibility is to utilize the regulation of immunological processes by the nervous system. It has been proposed that selective vagal stimulation using an electric device might down-regulate autoimmune inflammatory processes. Recruiting the natural regulators of immune responses, regulatory T-cells, or dendritic cells in order to down-regulate pathogenic immune responses could be other future approaches. In an even bolder proposal, it was suggested that the immune system in RA, which at the molecular level shows signs of premature aging (immunosenescence), could benefit from approaches that would rejuvenate it, ‘resetting’ the pathogenic immune responses.
Because treatment of RA must often be given for very long periods of time or indefinitely, because the patient population is rather large, because the disease often starts during middle age, and because the cost of biologic agents is so much higher compared to conventional therapies, the appraisal of these drugs in health-economic terms has emerged as a major issue. Nonetheless, formal health-economic assessments have generally determined the cost per quality-adjusted life year for biologics to be well within the accepted range. Moreover, it must be emphasized that the cost of not adequately treating RA is also enormous, and in order to have a correct assessment of the cost/benefit ratio of antirheumatic treatments, the impact of the disease must be analyzed in all its dimensions. An observational study using data from the Stockholm anti-TNF follow-up registry (STURE) showed that treatment with anti-TNF medications was associated with significant increases in work-force participation (Augustsson et al., 2009). In a controlled trial of early RA, combination treatment with methotrexate and the TNF-antagonist adalimumab provided significantly better improvements in work-force participation and home-activity than methotrexate alone (van Vollenhoven et al., 2010). And an analysis based on trials with certolizumab pegol in RA demonstrated significant improvement in patients’ home and workplace productivity and participation in social activities (Kavanaugh et al., 2009). Thus, the fact that modern therapeutics are considerably more expensive than older ones may, to a very important extent, be off-set by indirect benefits to society through greater participation by patients with RA in the workplace, in the home, and in other societal contexts.
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