- Top of page
The benefit of concommittant oral immunossupressive drugs with sheduled anti-TNF maintenance therapy has been established for infliximab (IFX), but remains unclear for adalimumab (ADA), although combination therapy is routinely used with all anti-TNF agents in rheumatological practice. Concommitant immunosuppressive (IS) drugs, including azathioprine (AZA), mercaptopurine (MP), or methotrexate (MTX), appear to reduce the risk of antibody formation to the drugs, which are associated with lower trough levels, shorter time to relapse and infusion reactions.[3, 4] In IS-naive patients with relatively early Crohn's disease treated with IFX, the prospective Study Of biologic and immunomodulator Naive patients In Crohn's disease (SONIC) trial clearly demonstrated the benefit of combination therapy with IFX and AZA. In patients with longer duration of Crohn's disease, many of whom had already been exposed to IS in clinical practice, a retrospective study from Paris also suggested a potential benefit of IFX+IS combination therapy, at what ever stage IS was combined with IFX. Few data are available for ADA. In the pivotal registration study of ADA (Crohn's trial of the fully Human Antibody adalimumab for Remission Maintenance, CHARM), post-hoc analysis did not detect any impact of IS co-treatment on the remission rate achieved at 1 year. The Leuven group also reported no more treatment failure in patients on ADA monotherapy than combination therapy, but a slightly shorter time to drug escalation. The aim of our study was to assess the impact of ADA+IS combination therapy on the rate of response to ADA induction, as well as its effect on flares of Crohn's disease or treatment failure during maintenance therapy with ADA in routine clinical practice.
- Top of page
Although the benefit of IS in patients treated with IFX has been clearly demonstrated both in IS naïve and IS exposed patients, the benefit of such combination therapy is not well documented with ADA. In this retrospective analysis, we could not show any benefit of ADA+IS for achieving induction success for clinical response and remission. In maintenance ADA therapy, we could also not show any decrease in semesters with flares during semesters with ADA+IS combination therapy. This is consistent with the results of the subanalysis of the CHARM trial, but at odds with the practice-based French study on IFX.
Nevertheless, there was a benefit of combination therapy (ADA+IS) when IS had been given during the first semester of ADA treatment. This was associated with half the rate of ADA failure over the subsequent semesters. Although this was quantatively small (from 10% to 5%), it is likely to be clinically as well as statistically significant. Furthermore, among these patients treated during the first semester with ADA+IS, there were fewer semesters with flares during subsequent maintenance treatment with ADA+IS compared with semesters on ADA monotherapy, suggesting a sustained benefit.
The large majority of semester flares were characterised by escalation in ADA dosage. On subanalysis, it was only prevention of dose escalation with ADA that benefited from continued ADA+IS combination therapy after having been treated by this combination in the first semester, not other definitions of flares, including new perianal complications or abdominal surgery, although numbers (19 and 18/195 semesters with abdominal operations and new perianal complications respectively) in the latter groups were very small. A similar benefit of ADA+IS was suspected by the Leuven group who noted a shorter time to ADA dose escalation, but no excess of treatment failure on ADA monotherapy.
Combination therapy with IS can reduce anti-TNF antibody formation and improve the pharmacokinetics of anti-TNF drugs.[11, 12] It has also been demonstrated that discontinuation of ADA due to treatment failure is associated with low ADA trough level concentrations. In our study, the benefit of combination therapy at the time of starting ADA, whether or not continued after the first semester, might be explained by early inhibition of anti-ADA antibody formation, leading to higher trough levels from the start of the therapy that could predict long-term efficacy of ADA. An alternative explanation might simply be better control of the inflammation on combination therapy from the onset of treatment that reduces the risk of relapse compared with ADA monotherapy. Prospective studies combined with anti-ADA antibody and ADA trough level measurements are required to validate these hypotheses.
Apart from combination therapy in the first semester, among the factors associated with flare semesters, were previous surgery and being treated in Liège. Although previous abdominal surgery is consistent with more severe disease, the association with Liège deserves a specific comment. In the current study, fewer in the Belgian cohort received IS than the British cohort, but weekly treatment with ADA was more common in Belgium. As the commonest reason for defining a flare was dose escalation on monotherapy, this treatment strategy is reflected in the increased rate of flares in Liège compared to Oxford. In contrast, surgery and perianal complications were more frequent in Oxford, but accounted for only a small proportion of flares. These results may reflect easier access to anti-TNF therapy in Belgium. Indeed, the Belgian healthcare system allows easier access to long-term anti-TNF therapy as well as dose escalation, whereas the British healthcare system encourages shorter treatment duration with a higher threshold for dose escalation. This might explain why, in similar clinical circumstances, patients may be treated in Belgium with weekly ADA monotherapy, but in the UK with ADA every other week in combination with IS or even surgery.
Our study was closely modelled on that of Sokol et al., who demonstrated a benefit of IS+IFX compared with IFX monotherapy using semester-based analysis. However, in their study, only patients receiving IFX+IS during the first semester were included, which corresponds to our subgroup of 45 patients (157 semesters) treated with ADA+IS during the first semester. In their study, IFX+IS was associated with fewer semesters with dose escalation or interval reduction compared with subsequent semesters on IFX monotherapy. In this respect, we confirm a similar result in those on ADA+IS during the first semester, with fewer needing ADA dose escalation in subsequent ADA+IS semesters compared with ADA monotherapy. The Sokol study also reported fewer perianal complications or switches in biological therapy in IFX+IS semesters, but no impact on the frequency of semesters with abdominal surgery. These events were too rare to analyse in our population. Furthermore, 70% of our patients had already been treated by another anti-TNF agent (usually IFX) before ADA; hence, switch biological therapy in the Sokol study might be compared with ADA failure in our study. Although Sokol et al. found a modest decrease in the need to switch to another biologic during IFX+IS semesters, we found no benefit of prolonged ADA+IS beyond the first semester. This is more comparable to the results in the Leuven cohort and IMID trial.
Our study has several limitations due mainly to its retrospective nature. First, the definition of the flare was retrospective and included different clinical situations (e.g. starting steroids, dose escalation, surgery, etc.). Second, patients were not randomised between ADA monotherapy and ADA+IS, hence these two populations are not strictly comparable. Third, there were no serum samples to measure trough levels or anti-ADA antibodies. Fourth, data on the intake and the dose of corticosteroid during the induction time with ADA were missing for half of the patients, although just 5% of all data in the induction group were missing. Although the available data did not show any influence of corticosteroids on the response to ADA induction, an effect cannot be excluded; hence, a lack of influence of steroids on response to ADA cannot be concluded. Nevertheless, in this retrospective analysis from the experience of two referral centers, q the benefit of ADA+IS appears limited to those co-treated at the start of ADA therapy. Combination therapy with ADA during the first semester slightly decreased the rate of ADA failure during maintenance therapy independently of whether ADA+IS was continued beyond the first semester. During maintenance therapy, ADA+IS was associated with a lower rate of ADA dose escalation.
We think our results may help clinicians decide whether to use ADA in monotherapy or combination therapy, particularly, with regard to the potential benefits from such combination at the start of ADA. Accordingly, it seems reasonable to start with the combination and then continue ADA monotherapy after about 6 months of combination therapy, as the need for dose escalation does not appear to be affected after the first semester. The choice of the treatment strategy needs to be balanced with potential risks of infection and cancer and also with the cost of the strategy. In older patients with high comorbidity, or younger male subjects at increased risk of hepatosplenic T-cell lymphoma on combination therapy, stopping the IS 6 months after ADA start seems a reasonable option. It is also not unreasonable to give ADA as monotherapy from the start as long as the slight increase in the absolute risk of treatment failure is recognised. A randomised trial is needed to confirm whether ADA+IS is more effective than ADA monotherapy, particularly to examine whether any benefit is limited to combination therapy in the first semester, and whether it simply decreases the need for ADA dose escalation, or whether it also decreases clinically relevant measures of patient outcome.