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Klinik für Innere Medizin III
Klinische Abteilung für Rheumatologie
Rheumatoid arthritis (RA), the most severe and disabling joint disease, affects almost 1% of the general population. Although autoimmune mechanisms are considered to initiate the disease, no causative agent has yet been characterised and, thus, preventive therapy is still out of sight. Current therapy aims to control signs, symptoms and structural damage of RA. This includes symptomatic treatment and disease-modifying antirheumatic drugs (DMARDs).
During the past 10 years, research has focused on developing targeted cytokine inhibitors. Inhibition of tumour necrosis factor (TNF) and interleukin (IL)-1 is an effective tool to treat RA. TNF- and IL-1-blockers can either be antibodies (such as infliximab and adalimumab), soluble receptors (etanercept) or antagonistic proteins (anakinra). All these drugs are large molecules (“biologicals”), which need to be injected either subcutaneously or intravenously.
The main advance of the introduction of cytokine blockers for the treatment of RA is their ability to achieve clinical response in patients who have failed to respond to therapy with conventional DMARDs.(1–5) This allows control of the disease in a wider patient population. Furthermore, TNF- and IL-1-blockers are particularly effective in interfering with the structural damage caused by RA, which is considered the main factor for persistent loss of joint function.(1,2,6)
To date, most clinical studies on cytokine blockers have been performed on patients refractory to conventional DMARD treatment. These patients received either monotherapy with a cytokine blocker or placebo-controlled combination of the cytokine blocker with conventional DMARD treatment. Hence, it remains unclear from these studies whether cytokine blockers achieve better responses than conventional DMARDs, since no head-to-head comparison has been undertaken. Interestingly, although such head-to-head analyses are still scarce, these studies (Early RA [ERA] and Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes [TEMPO] trials) showed that both approaches may be equally effective in reducing signs and symptoms in RA patients.(1,7)
Methotrexate (MTX) and etanercept equally reduced signs and symptoms of MTX-naive patients with early and established RA. Considering the high treatment costs and precautions of long-term safety of cytokine blockers, these data clearly underline the role of conventional DMARD treatment in modern RA therapy.
Clinical studies have shown that remission of RA is not observed in a majority of patients treated with conventional DMARDs or with cytokine blockers.(1–5,8) A 20% improvement of the signs and symptoms of RA, defined according to the American College of Rheumatology (ACR) response criteria (ACR20), is usually achieved by 50–70% of patients in clinical studies. This ACR20 response has been designed to discriminate the specific effect of a drug from the placebo response.(9)
However, an ACR20 response cannot be regarded as an ambitious therapeutic goal. Major responses, such as a 50% (ACR50) or 70% (ACR70) improvement of the signs and symptoms of RA, are achieved in only 30–50% and 10–30% of patients, respectively. This means that at least two out of three patients with active RA fail to achieve part or full clinical remission, even when using modern antirheumatic drug therapy.
This situation still leaves plenty of opportunities for new therapeutic strategies, which should aim to induce a complete remission of the disease. It also implies a shift in the paradigm of antirheumatic therapy, from defining the degree of improvement in a patient to defining the number of patients that are achieving remission (“ACR100” response).
Three general trends for current and future management of RA that could significantly increase clinical response will now be discussed.
“The earlier the better”
The early and accurate selection of the individuals prone to develop the chronic and destructive disease from the heterogeneous entity of new-onset arthritis is a major diagnostic task. Tools to accomplish this include certain clinical patterns of disease (eg, polyarticular onset), established laboratory parameters (eg, high C-reactive protein) and new biomarkers (eg, antibodies against citrulline).(10–12) Better responses to treatment have been observed in clinical trials for patients with early disease, compared with patients with established RA.(13) In fact, the time window for achieving disease remission may be more narrow (3–6 months) than the common definition of early RA (less than one year).(14) This requires a tightly organised healthcare infrastructure, including standardised patient assessment and early referral to rheumatology specialists in the case of suspected early RA.
Such a policy is still not established in many European countries, which causes delayed therapeutic intervention. This means that, in addition to missing the therapeutic window of three months, the notion of early RA is not clearly defined. Furthermore, early diagnosis has to be followed by an aggressive therapy.
Although rapid initiation of DMARD therapy, dose escalation (when necessary) and tight monitoring of disease activity and therapeutic response are important, they are still not always implemented adequately.
Combination of DMARDs
Simultaneous administration of more than one DMARD increases therapeutic response. This is true for combinations of conventional DMARDs and combinations of conventional DMARDs with cytokine blockers. One example is the combination of salazopyrine, methotrexate and chloroquine, which gives better results than salazopyrine alone.(15) Similarly, the TEMPO trial showed increased efficacy of the combination methotrexate–etanercept compared with each of the single treatments.(7) Combination of DMARDs may be used either as a “step-up” approach, adding another DMARD if response is incomplete,(16,17) or as a “step-down” approach, by starting with a combination and removing drugs if sufficient response is obtained. An example for the latter is the COBRA trial, in which it was demonstrated that an induction regimen with methotrexate, salazopyrine and prednisolone was superior to salazopyrine alone.(18)
Furthermore, recent data from the BEST trial suggest that “step-down” approaches are superior to “step-up” approaches or monotherapies, regardless of whether combination partners are conventional DMARDs only or conventional DMARDs with cytokine blockers.(19)
Unlicensed drugs, alone or in combination with established DMARDs, may improve the clinical outcome of RA in the future.
TNF and IL-1 inhibitors constitute a first group of drugs in clinical development. Several molecules, such as pegylated anti-TNF antibody (CDP870), pegylated soluble TNF-R1 (pegsunercept), TNFR1:Ig (onercept) and IL-1R:Fc fusion protein (IL-1 trap), are being tested.(20–23) Whether these drugs have an advantage over currently available TNF and IL-1 blockers remains to be determined, but, in any case, such drugs will further increase our therapeutic repertoire. This is important, as patients who have failed on one TNF-blocker can have a significant clinical response to another TNF-blocker.
In addition, IL-1-blockers with a longer half-life, and thus a more beneficial pharmacokinetic profile, could lead to a stronger clinical response in patients with RA. The optimal way to inhibit TNF is currently unknown, and it is unclear whether an increase of efficacy of TNF blockade would result in an unfavourable benefit–risk ratio.
A second group of drugs, which do not involve cytokine blockade, have reached phase II clinical trials, where they demonstrated efficacy. This group comprises CTLA-4 and rituximab. CTLA-4, which is synthesised as an Fc fusion protein and is an inhibitor of T-cell activation that interferes with T-cell costimulation (CD80/86–CD28 interaction). Phase II trials have shown the efficacy of CTLA4 as a monotherapy as well as in combination with methotrexate, and a phase III trial is underway.(24) Rituximab is a chimeric monoclonal antibody (MAb) against CD20, a cell surface marker for B-cells. Rituximab leads to depletion of B-cells and has shown efficacy to treat RA in phase II clinical trials, alone or in combination with methotrexate.(25)
A third group of drugs has shown highly promising results in several animal models of arthritis; some of the compounds in this group have already entered clinical trials.(26) These drugs can target synovial inflammation; they can be inhibitors of interleukin-converting enzyme, such as pralnacasan, adhesion molecules (eg, alefacept for LFA3 or vitaxin for avb3), p38 protein kinase (with various small molecules in development), VEGF (eg, anti-VEGF MAb) and various interleukins (eg, anti-IL-6R MAb).
Another group of new molecules aims to protect against cartilage damage, and, to date, inhibitors of matrix metalloproteinases are the most intensively studied drug entity in this respect. Finally, specific inhibition of bone erosion via blockade of osteoclasts (osteoprotegerin, bisphosphonates) is an emerging therapeutic tool of antirheumatic therapy. This approach is backed by arthritis models in osteoclast-free mice, which show complete uncoupling of synovial inflammation from bone erosion. (27,28)
Disease remission is an ambitious goal in the treatment of RA. The introduction of cytokine blockers has clearly been a major step in that direction. Early and adequate use of approved conventional DMARDs and cytokine-blockers may push clinical responses further towards full disease remission. Step-down therapeutic approaches, with an initial induction phase combining several conventional DMARDs and/or cytokine blockers, are interesting new strategies in the management of RA.
Finally, a large group of antirheumatic drugs, some of which may induce a second revolution in RA treatment, are in development.