The best use of drugs for rheumatoid arthritis

Prof Josef S Smolen

Chairman of the Department of Rheumatology,
Medical University of Vienna and Hietzing Hospital, Vienna, Austria

Prof Robert Landewé

Professor of Rheumatology, Maastricht University Medical Centre, the Netherlands

Rheumatoid arthritis (RA) is the most frequent chronic inflammatory rheumatic disease affecting about 0.5%–1% of the population in the industrialised world. It affects women twice as frequently as men and can occur at any age, peaking in the fifth to sixth decade of life. It is characterised by swelling and severe pain and stiffness of the joints, most frequently the joints of the hand (wrist, metacarpophalangeal and proximal interphalangeal joints), feet and knees.

While many joint diseases consist of swelling and pain, RA typically also leads to rapid and severe destruction of many of the involved joints and both the cartilage and the periarticular bone are often severely damaged. As a consequence of the painful condition, RA is associated with significant impairment of physical function and inability to work, and as a consequence of the accrued joint damage, physical disability becomes irreversible.

Importantly, joint damage becomes visible by radiography within the first year of the disease in most patients; with insufficiently effective treatment, destruction of the joints will frequently lead to severe incapacitation within few years.

Treatment measures
The treatment of RA involves a variety of measures. Symptomatic therapy such as with analgesics or non-steroidal anti-inflammatory drugs (NSAIDs), together with physio- and occupational therapy, may be helpful in alleviating certain signs and symptoms for some time, but will not affect the long-term course of the disease. Glucocorticoids alleviate signs and symptoms and interfere with the pathways to the disease, but their adverse effects preclude their long-term use.

Thus the most important therapeutic measures are the so called disease-modyifying antirheumatic drugs (DMARDs) which interfere with the disease process, including joint destruction, they improve signs and symptoms, as well as physical function and inhibit progression of structural joint changes. Until about ten years ago, a variety of chemical agents were available, foremost among them being methotrexate (MTX), but also leflunomide, sulfasalazine, gold salts and (hydroxy)chloroquine.

The advent of biologics
About ten years ago, the first biologic agents were introduced, the tumour necrosis factor- (TNF) inhibitors. Meanwhile, the family of biologics has been significantly expanded and today five TNF-blockers (adalimumab, certolizumab, etanercept, golimumab and infliximab) as well as three agents directed at other molecular targets are licensed, namely:

• 
Rituximab (anti-CD20, depletes B-lymphocytes)
• 
Abatacept (CTLA-4Ig, an inhibitor of T-cell co-stimulation)
• 
Tocilizumab, an anti-interleukin (IL)-6-receptor antibody.

In addition, a compound inhibiting IL-1, anakinra (an IL-1 receptor antagonist) is on the market, but its efficacy appears weaker than that of the other biological agents.1 Like other medicines, therapy with biologics can lead to adverse effects, since these agents interfere with important molecules involved in the immune response. Infections form the most prominent, though not frequent problem, which – aside from more classic bacterial infections – comprise the reactivation of tuberculosis (especially with TNF-inhibitors) and opportunistic infections. Other adverse effects are mentioned in detail in the package inserts.

Eight principles gleaned from research
The approach to treating RA has changed dramatically over the past two decades and several insights have materialised. These are:

1. 
It has been recognised that early diagnosis and treatment with DMARDs can prevent or at least reduce the long-term sequelae of RA2
2. 
It has been realised that progression of joint damage is highly associated with joint swelling. But also laboratory surrogates of the underlying cytokine production, the acute phase reactants – and here foremost C-reactive protein levels – and also that the presence of autoantibodies, such as rheumatoid factor or antibodies to citrullinated peptides, are associated with more severe joint damage3,4
3. 
Consequently, it has been found that optimal outcome of the disease requires maximal reduction of disease activity and that even more profound responses, such as 50% reduction of disease activity, are not sufficient to prevent joint damage, but rather low disease activity or remission should be attained5
4. 
Several research groups have shown that using composite measures of disease activity allows clinicians not only to determine improvement of disease activity but also the disease activity state achieved6
5. 
Using such composite measures, and adapting treatment if a target of low disease activity or remission was not attained, proved to result in better outcomes in comparison to not following such tight control strategies7
6. 
Most biologics as monotherapy are not superior than MTX monotherapy, while the combination of biologics with DMARDs, particulary MTX, conveys better efficacy than either monotherapy8
7. 
Irrespective of the type of treatment, the probability to attain a good clinical outcome in the longer term, such as at one year, can be reliably determined after three to six months of treatment.9

With all the information detailed above, the definition of a ‘treat-to-target’ approach to RA therapy that encapsulates both a tight control of clinical disease activity and rapid treatment adaptation within 3–6 months aiming at attaining an optimal disease activity state was a logical consequence.10 By having at least five synthetic and nine biologic agents available, and a ‘treat-to-target’ concept available, the need to develop recommendations for the management of RA with synthetic and biologic DMARDs was apparent. So the European League Against Rheumatism (EULAR) convened a large group of experts and patients to address this task.

Areas for systematic literature review
Since it is EULAR’s general policy to develop recommendations in the course of a two-step procedure that involves a systematic literature review (SLR) to provide underlying evidence and a consensus-finding process to amalgamate the evidence; with patient and expert views, the process started with a total of five SLRs devoted to the topics:

1. 
Synthetic DMARDs and DMARD combination therapy excluding combination with glucocorticoids111
2. 
Glucocorticoids including combination of one or more synthetic DMARDs with glucocorticoids12
3. 
Biological DMARDs13
4. 
Treatment strategies14
5. 
Economic aspects.15

All these SLRs informed the EULAR task force on the current state of evidence.16 In the subsequent consensus-finding process, the RA patients and experts – mostly rheumatologists, but also an infectious disease specialist and a health economist – developed the three overarching principles and 15 management recommendations which were ultimately amended for wording details and voted upon.16 The 15 recommendations are encapsulated in the algorithm shown in Figure 1, which is divided into three phases. Importantly, the recommendations set forth the treatment target for all phases which should be remission or, when remission is not achievable, at least low disease activity, and should be reached within six months from start of therapy.

Following the treatment map
Treatment should be started with synthetic DMARDs, especially MTX and, if necessary, in combination with glucocorticoids to achieve most rapid reduction of disease activity. If patients fail to reach the treatment goal, they should be stratified according to their risk on a bad outcome. Those without such a risk should switch to another synthetic DMARD (in combination with glucocortiocids), but adding the new DMARD to the previous one is also an option; if the next DMARD fails, one could switch to a third one or consider a biologic agent.

In contrast, patients who have a high risk of developing rapid joint damage should receive a biologic; in this regard it is stated that current practice is to use a TNF-blocker, but also tocilizumab and abatacept are licensed in this indication. Again, the treatment target should be reached within three to six months. If that is not the case, then another biologic should follow (another TNF-inhibitor, abatacept, rituximab or tocilizumab), whereby the SLR did not reveal any superiority of one regimen over another. The biologics should generally be applied in combination with MTX or other DMARDs, but for tocilizumab data suggest that its efficacy as monotherapy is superior to that of MTX.16

Taken together, the EULAR RA management recommendations can be used by physicians to compare their current therapeutic approach with this consensus view and to discuss their treatment strategy better with their patients. It can help patients to obtain information on the 2010 state of RA management, and it provides regulators and payers with the current state of evidence that they may have to consider when developing their policies.

While the recommendations are mainly based on evidence, certain items were developed by consensus, since evidence simply is not available. Therefore, the task force has formulated a long research agenda to address the need to clarify a variety of questions. With accruing information on parts of this research agenda, results of new clinical trials on existing and the evolution of new agents, it is expected that the recommendations will be updated in about three years.

References

1. 
Smolen JS et al. Lancet 2007;370:1861-1874.
2. 
van der Heide A et al. Ann Intern Med 1996;124(8):699-707.
3. 
van Leeuwen MA et al. J Rheumatol 1994;21(3):425-429.
4. 
Scott DL et al. Lancet 1987;1(8542):1108-1111.
5. 
Aletaha D et al. Arthritis Rheum 2008;58:2622-2631.
6. 
van der Heijde DM et al. Ann Rheum Dis 1992;51:177-181.
7. 
Grigor C et al. Lancet 2004;364:263-269.
8. 
Breedveld FC et al. Arthritis Rheum 2006;54:26-37.
9. 
Aletaha D et al. Arthritis Rheum 2007;56(10):3226-3235.
10. 
Smolen JS et al. Ann Rheum Dis 2010;69(4):631-637.
11. 
Gaujoux-Viala C et al. Ann Rheum Dis 2010;69(6):1004-1009.
12. 
Gorter SL et al. Ann Rheum Dis 2010;69(6):1010-1014.
13. 
Nam JL et al. 
Ann Rheum Dis 2010;69(6):976-986.
14. 
Knevel R et al. Ann Rheum Dis 2010;69(6):987-994.
15. 
Schoels et al. 
Ann Rheum Dis 2010;69(6):987-994 .
16. 
Smolen JS et al. Ann Rheum Dis 2010;69(6):964-975 .
17. 
Jones G et al. Ann Rheum Dis 2010;69(1):88-96; published Online First 17 March 2009.