In accordance with other reports about successful switching from one TNF antagonist to another, the results of this study indicate that patients with RA who had previously discontinued treatment with IFX experienced clinically meaningful improvements in all effectiveness endpoints with adalimumab treatment [10
]. The patients who reported a loss of response under IFX treatment appeared to experience the greatest effectiveness with adalimumab by several disease-response measures, followed by the small patient subset that had been intolerant to IFX. The patients with no response to their previous IFX therapy had somewhat lower response rates to adalimumab. Similar results were recently published in another open-label study in a large patient cohort who switched from prior anti-TNF therapy to adalimumab [18
]. The documentation of reason for discontinuation of IFX is limited, as there was no other criterion but the investigator’s clinical assessment.
Interestingly, patients with a reported initial lack of response to IFX had the lowest mean DAS28 value and lowest joint counts at baseline among the subsets by reason of IFX discontinuation, whereas the mean HAQ DI at baseline was worst in these patients. However, most of the recent publications either from registers or from clinical studies on switching among TNF antagonists are based on the physician’s discretion when the reasons for discontinuation are reported [17
Results of subgroup analyses by patient’s baseline HACA status (available for 32 of the 41 patients) indicate that adalimumab is effective and well-tolerated in patients who may have developed HACA with prior IFX treatment. The low ACR50 and ACR70 and good EULAR response rates at Week 16 in patients with negative HACA appear to be more likely related to confounding baseline characteristics, such as a greater percentage of patients who had experienced no response to IFX and a longer RA duration compared with patients with positive HACA status. However, beyond Week 16, the response rates in the HACA-negative subset increased and even surpassed the rates achieved by HACA-positive patients.
Results of the pharmacokinetic analysis indicate that, for the majority of patients, the mean steady-state serum adalimumab trough concentrations achieved with the recommended regimen of 40 mg eow were near or above 4 to 8 µg/ml, which is consistent with what has been observed in other pharmacokinetic trials of adalimumab in patients with RA [26
]. These concentrations are three to seven times the average effective concentration in 50% of patients for TJC, SJC, and numeric ACR [27
]. Although mean serum adalimumab trough concentrations appeared to be lower in patients with measurable HACA at baseline, the potential for interference of HACA with the serum adalimumab assay has not been evaluated. In general, the mean and median serum adalimumab concentrations were greater in patients who concomitantly received methotrexate. In a recent study in 121 patients with RA treated with adalimumab, good responders had greater adalimumab serum concentrations than nonresponders, and the formation of AAA (present in 21/121) was reduced in patients who received concomitant methotrexate [28
]. AAAs were detected in two of the patients in this analysis, both were not receiving concomitant DMARDs and both had a positive HACA status at study entry. In previous clinical adalimumab trials, AAA had been documented in 12% of the patients and was not found to have an impact on the efficacy of adalimumab [29
Adalimumab was generally well-tolerated in this selected population, and safety results did not suggest any new signals with regard to the safety of the drug. In particular, no additional risks for allergic reactions under adalimumab were found in these 41 patients with a history of intolerance to IFX.
In the two patients diagnosed with lymphomas (cutaneous T cell lymphoma in one and a B cell lymphoma in the other), exposure to adalimumab was ≤1 year. The total exposure to anti-TNF therapy and the previous extensive immunosuppressive treatment for RA together in these patients represent a risk for the development of lymphoma.
Limitations of our study include the small number of patients in each subgroup and the nonrandomized study design.
The results of this pilot study indicate that adalimumab is generally effective and well-tolerated for the treatment of RA in patients who have failed IFX therapy, including those who have developed HACA for IFX.