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.