Abatacept vs Tocilizumab for the Treatment of RA in TNF Alpha Inhibitor Inadequate Responders

Rheumatoid arthritis (RA) is the most common inflammatory rheumatoid disease in France, affecting 0.3% of the general population. Without effective treatment, the persistent inflammation causes invalidating pain and joint destruction, leading to major functional disability.

Biological agents have been proposed for patients with RA who have the most severe form of the disease and that are inadequate responder patients to conventional synthetic Disease-modifying antirheumatic drugs (csDMARDs). TNF inhibitors (TNFi) are historically proposed as the first biological DAMRD for inadequate responder patients to csDMARDs. A diverse therapeutic arsenal has become available in recent years with the development of non-anti-TNFα drugs whose mechanisms of action are different from the classical TNFi. This new biotherapy class includes tocilizumab and abatacept, two drugs recently available for subcutaneous administration that enables ambulatory care for patients who would otherwise require repeated in-hospital care.

The role of these new treatments in the therapeutic strategy has been emphasized by studies that demonstrated their efficacy as first-line treatments. However, in clinical practice, TNFi remain the most common first-line treatment for the majority of patients, non-anti-TNFα biological agents being reserved for inadequate responder patients.

In second line, several studies have investigated therapeutic strategies for inadequate responder patients to TNFi. Current data suggest that it could be wise to change the therapeutic target after failure of a first-line treatment with TNFi.

Data about the comparative efficacy of different biologics proposed after failure of a first-line treatment with TNFi are in progress. Meta-analyses from registries and academic trials conducted in France and The Netherlands suggest that non-anti-TNFα agents would have equivalent or superior efficacy compared with a second TNFi. This finding suggests clinicians to switch for an alternate therapeutic target after failure of a first-line TNFi.

Data comparing different non-anti-TNFα biologics in inadequate responder patients to TNFi are scare. Industrial trials have demonstrated sustained biological efficacy of non-anti-TNFα biologics after failure of a TNFi. However, there is very little solid data on the direct comparison between them.

Rheumatoid arthritis (RA) is the most common inflammatory rheumatoid disease in France, affecting 0.3% of the general population. Without effective treatment, the persistent inflammation causes invalidating pain and joint destruction, leading to major functional disability as well as progressive structural damage resulting in major joint deformity.

Biologic agents are taking on an increasingly important role in the management of patients with an inadequate response to conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs).

Biological DMARD (bDMARD) therapy consists in the use of monoclonal antibodies or fusion proteins, administered intravenously or subcutaneously. The earliest developed biologic agents have been available for more than 15 years. Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, was the first cytokine successfully targeted by a biologic agent for RA treatment. TNF inhibitors (TNFi) are historically proposed as the first bDAMRD for inadequate responder patients to csDMARDs. More recently non-anti-TNFα drugs have emerged, with other biological targets such as interleukin-6 receptor (tocilizumab) or B- (rituximab) and T-lymphocytes (abatacept) that are implicated in the inflammatory response. Initially administered strictly intravenously, these drugs are now available in formulations adapted to subcutaneous administration, which allows ambulatory care for patients who otherwise would require repeated in-hospital care.

National and international guidelines, especially those issued in 2013 by the European League Against Rheumatism (EULAR) and also in 2013 by the French Society of Rheumatology now recommend first-line treatment not only with TNFi but also with non-anti-TNFα biologic agents. However, in routine practice, most clinicians preferably prescribe TNFi for the first-line regimen, reserving non-anti-TNFα drugs to TNFi inadequate responder patients.

There is a growing body of research focusing on first-line biologic agents but there is very little solid data on the direct randomized comparison between them. Actually, all three of the published studies have systematically compared a non-anti-TNFα biomedication versus TNFi (one study with a blinded design and two open studies).

The therapeutic strategy that should be adapted after failure of a TNFi regimen has also been investigated. Those studies favor non-anti-TNF drugs over an alternate TNFi.

There is adequate evidence of the efficacy of the different non-anti-TNFα biologic agents versus placebo after TNFi failure. In other hands, industrial trials have not provided any comparative data between drugs. An academic trial from The Netherlands using medico-economic performance as the primary outcome found no difference in efficacy between abatacept and rituximab (a non-anti-TNFα drug administered exclusively intravenously) after failure of a TNFi. Meta-analyses using data from care networks have not reported any difference between different non-anti-TNFα drugs after failure of a TNFi.

Data from national registries have provided interesting complementary information since in everyday practice these agents are generally used after failure of at least one TNFi. The Danish registry thus suggests that the therapeutic response would be better with tocilizumab than with abatacept. This observation was confirmed by an analysis of French registries data presented at the American College of Rheumatology (ACR) congress in November 2016 showing that tocilizumab exhibits superiority for treatment persistence over 2 years. These results were fully in agreement with the findings of the French ROC trial comparing intravenous administration of a second anti-TNFα drug versus a non-anti-TNFα agent after failure of an anti-TNFα drug that suggested a superiority of tocilizumab over abatacept in the subgroup of patients given a non-anti-TNFα agent. A recent Bayesian network meta-analysis showed better efficacy in the non-anti-TNFα groups for ACR20 in patients who responded insufficiently to an anti-TNFα.

Subcutaneous formulations have been recently developed for both tocilizumab and abatacept. Subcutaneous administration is important because it enables ambulatory care for a substantial number of patients who to date are recurrently hospitalized in day-care units for their intravenous infusions. Excepting specific situations, the subcutaneous formulation will be favored for a large majority of patients because of economic as well as practical considerations. Phase III trials have demonstrated the equivalence of the intravenous versus subcutaneous routes of administration focusing on efficacy and tolerance. The subcutaneous formulation is now also available for routine administration of both tocilizumab and abatacept. Nevertheless, despite large-scale industrial trials on drug equivalence, data issuing from clinical practice suggest a potential difference in the behavior of these two formulations which needs to be explored. Rituximab is apart in the treatment strategy because of its exclusive intravenous administration at spaced intervals and because it is used for specific patient profiles (extra-articular involvement, history of neoplasia, rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity). There is no perspective for the development of a subcutaneous formulation of rituximab for RA patients. Furthermore, the routine treatment schedule for rituximab (one-time injections at a mean interval of 9 months) would compromise comparison, especially short-term comparison, with other subcutaneous treatments.

These findings illustrate the need for a new multicentric, prospective, randomized trial designed to demonstrate the superiority of tocilizumab over abatacept in patients exhibiting inadequate response to a first anti-TNFα. A direct comparison of subcutaneous formulation is the need for the promising route of administration for future ambulatory care.

Eligibility Criteria:
Inclusion Criteria:

* age \>18 years
* RA according to the ACR/EULAR 2010 criteria
* inadequate response to a subcutaneously administered first-line TNFi defined as moderate to high disease activity (DAS28-ESR\>3.2 and CDAI\>10) after at least 3 months of treatment with a TNFi
* beneficiary of the French National Health Insurance Fund
* signed informed consent form
* for women of childbearing age: effective contraception during treatment period with engagement to continue such contraception for 14 weeks after last administration

Exclusion Criteria:

* counter-indication for one or other of the two drugs under study
* prior failure of the TNFi due to intolerance
* receiving ≥15 mg/day prednisone for more than 4 weeks
* pregnant or nursing women