Our observation of sustained remission in eight of our thirteen patients suggests that maintenance of TCZ therapy may be feasible following attempts to increase the spacing of infusions. Indeed, six patients successfully transitioned to long-term maintenance with tapered TCZ infusions. Four patients developed a secondary failure after beginning the spacing of infusions, while one patient developed severe neutropenia associated with TCZ. The age of patients may influence the success of long-term maintenance on TCZ, as younger patients were more likely to experience a successful transition and less likely to experience secondary failure. Moreover, RF and ACPA positive RA patients experienced more episodes of flares during our follow-up, underscoring a greater severity of the disease.
Guidelines concerning initiation of bDMARDs and how to induce remission are well established [2, 16]. However, data on patient responses to therapy once remission is reached are scarce. Stopping bDMARDs after achieving remission is challenging due to a potential tradeoff between the important health economic impact that could be achieved on one hand and the potential risk of recurrence on the other . New EULAR recommendations propose that clinicians consider changes in therapy, either through changes in dose or increasing the spacing between treatments, especially for patients in long-term remission in association with csDMARDs . However, recommended strategies are not yet clearly defined and the consequences of such changes are not well understood. Cost-analysis studies clearly demonstrate that decreasing doses of bDMARDs decreases costs . What remains unclear are the consequences for patients, both in terms of identifying the long-term consequences of extending dosing (radiographic changes, flares ...) as well as determining characteristics that may aid clinicians in identifying patients in which down-titration or discontinuation of bDMARDs may be possible .
Several studies have examined the discontinuation or changing the spacing of bDMARDs in RA patients with prolonged remission. Results suggest that discontinuation of anti-TNF-α agents does not allow a sustained remission in most drug-free patients [7, 19]. Indeed, the prospective observational study of Van der Mass et al. found that discontinuation of anti-TNF-α therapy was feasible for only 16% of their patients . The PRESERVE study compared three strategies of RA drug management (maintenance, half dose reduction and complete discontinuation of etanercept) in a randomized controlled trial of RA patients showing sustained remission in the past year . After 1 year, low disease activity (LDA) was observed in 46% of patients in the placebo group versus 82.6% in patients maintained on etanercept therapy. In addition, the ADMIRE study with adalimumab , CERTAIN study with certolizumab pegol  and DOSERA study with etanercept  all demonstrated that withdrawing anti-TNF-α therapy did not allow maintenance of patients in sustained remission, with rates of sustained remission of 13, 17 and 13% respectively. In light of these results, others have tried down-titration of bDMARDs, rather than discontinuation, to maintain RA patients in sustained remission. In the PRESERVE study, Smolen et al. found that the risk of relapse and structural damage progression in patients switched to a half dose was statistically indistinguishable from those maintained with a full dose after one year . The recent STRASS study of RA-patients in remission (DAS28 < 2.6) found that relapse was observed more frequently in patients placed on a progressively increased spacing of TNF-blockers injections than those maintained on their previous dosing regimen (76.6% vs 46.5%, p = 0.0004), however the equivalence of the two strategies could not be demonstrated due to an underpowered trial . Most recently, the TARA (TApering strategies in Rheumatoid Arthritis) study, the first randomized controlled study comparing a de-escalation strategy with reduction and discontinuation of synthetic DMARDs versus TNF-blockers, highlighted the importance of first reducing treatment with bDMARDs prior to initiation of synthetic DMARDs therapy .
Concerning TCZ tapering, several strategies have been tried, including discontinuation TCZ infusions [12, 13], and gradually increasing the RTI to a fixed interval (eg. 6-weeks) [14, 25,26,27]. We conducted the present study to determine if tapering TCZ by progressively increasing the spacing of infusions would be a better strategy to maintain TCZ-treated patients in remission. This approach was adopted because we believed that it might be the best therapeutic option for our patients as well as from a medico-economical standpoint. A recent study extending the dosing interval of TCZ infusions to 6 weeks for RA patients in sustained remission for the previous 3 months appeared to provide an acceptable option, with 88% retaining remission after 54 weeks . Similarly, Saiki et al. published two studies on extending the RTI for TCZ infusions. In the first, they showed the feasibility of 5-week or 6-week spacing in patients with low disease activity, with a therapeutic maintenance rate of 90% at two years . In the second study, 60% of patients who passed directly to a treatment interval of 6 weeks remained on treatment two years later . In another Dutch study, testing the strategy first reducing infusion doses to 4 mg/kg and then progressively increasing the spacing between treatments, 42% of patients responded positively to TCZ de-escalation at one year . By contrast, sustained remission following cessation of TCZ treatment was much lower: in the DREAM study , drug free remission or LDA was present in 35.1, and 13.4% of patients after 24 and 52 weeks respectively following cessation of TCZ used in monotherapy, and in the ACT-RAY study, the remission rate dropped to 16% after stopping TCZ . In our study, we observed that a majority (61.5%) of our patients remained in remission at month 24 and 46.1% had successful long-term maintenance following the tapering of TCZ infusions, results that are comparable to those of previous studies [14, 25, 26].
Some factors contributing to prolonging the duration of DAS28 remission and LDA after discontinuation or tapering of biologics have been previously identified. A lack of disease severity factors may act as selection criteria for informing decisions about whether or not to increase spacing of TCZ infusions . In the BeST study and in early arthritis cohorts, successful discontinuation was associated with the absence of ACPA, male gender, rapid achievement of remission, non-smoking and absence of an HLA shared epitope [9, 29]. A shorter disease duration, better functional ability at discontinuation, and shorter symptom duration before starting any treatment were also predictive of successful discontinuation of bDMARDs . Our analysis of various clinical, radiological, biological and immune variables (Plasma TCZ level and ADAb), identified only the absence of RF and ACPA as being significantly associated with fewer flares.
Our study is mainly limited by the small number of included patients. As such, this preliminary analysis represents a “proof of concept”. In addition, our cohort was composed of patients with very severe disease (more than 75% with erosions, and long disease duration), none of whom had started TCZ as a first line of bDMARD. We also chose a very strict definition of remission in order to reduce the risk of relapse. The risk of relapse could likely be reduced by slowly tapering infusions. Indeed, the relatively quick tapering we adopted may have been responsible for some of the observed relapses. For example, three of the five patients (P10, P11, and P12) who had to switch to a new biotherapy showed a flare (Table 2) within 3 months after increasing treatment spacing. Saiki’s recent study showing the maintenance of a response rate greater than 90% in patients where treatment spacing was progressively increased initially to 5 weeks and then to 6 weeks also supports our contention . Conversely, if TCZ is reduced directly from 4 to 6 weeks, the maintenance of a low activity level drops to about 60% . We also found that plasma levels of TCZ, as well as ADAs, were not useful to predict flares after TCZ tapering.