In this prospective multicenter study, we evaluated the real-world clinical effectiveness of ADA treatment and factors associated with the clinical response in Korean patients with moderately to severely active UC. Our study showed similar or slightly higher rates of clinical response and remission than two previous pivotal studies conducted in Western countries: ULTRA-1 and ULTRA-2 (response rates, 50.4%–54.6%; remission rates, 16.5%–18.5% at week 8 and 30.2%–17.3% at week 52).14,15 Several studies investigating the real-world efficacy of ADA have been reported worldwide. Although it is difficult to directly compare these results, because each study defined clinical response and remission differently, they show similar trends in outcomes.16-18 A Japanese real-world study that applied the same definition for clinical response and remission as this study, reported similar outcomes.16 The mucosal healing rate in our study tended to be lower than that reported in previous Western studies,17,18 but similar to that reported in a Japanese study.16 Collectively, ADA was similarly effective for induction and maintenance treatments in Korean patients with active UC who were unresponsive to corticosteroids and/or azathioprine/6-mercaptopurine.
Previous experience with anti-TNF-α therapy was not found to impact the short- or long-term outcomes in our study. Prior anti-TNF-α therapy has been reported to have controversial effects on clinical outcomes of ADA in patients with UC. The ULTRA-2 and ULTRA-3 studies reported better outcomes in patients not treated with anti-TNF-α.14,19 A retrospective multicenter study in Spain investigated the influence of previous anti-TNF-α use on the outcomes of ADA maintenance treatment in patients with UC; patients not previously treated with anti-TNF-α had a numerically higher rate of clinical response at week 56 without statistical significance.20 They had significantly lower probabilities of avoiding colectomy and dose escalation. However, in a previous Hungarian prospective study, response to ADA and need for dose escalation were not associated with previous IFX therapy.18 A retrospective study performed in Ireland showed a pattern of improved outcomes in patients treated with anti-TNF-α compared with those who were not.21 Although a note of caution is due in our study because of the relatively small portion of patients treated with anti-TNF-α (n = 36, 24.7%), ADA can be suggested as a beneficial option for Korean patients with moderately to severely active UC treated previously with anti-TNF-α therapy. In addition, the combination therapy with azathioprine/6-mercaptopurine did not affect clinical response rate. This finding is consistent with that of previous studies showing no efficacy-related benefits following immunomodulator/ADA combination therapy.19,22,23
In this study, baseline BMI, endoscopic findings, and serum albumin level were associated with clinical response at week 8. At week 56, baseline BMI and clinical response, mucosal healing, CRP level, and Mayo score at week 8 were associated with clinical response. In the multivariate analysis, baseline non-severe endoscopic finding and clinical response at week 8 were independent factors for predicting response at weeks 8 and 52, respectively. Although it was a significant factor only in the univariate analysis, BMI was associated with both short- and long-term response. Previous studies have shown that obese patients tended to have higher risk of nonresponse to biologic agents because of their direct effect on inflammation and modification of pharmacokinetics.14,24 However, average BMI of both responder and non-responder groups were within the normal range in our study. Relatively higher BMI within the normal range might reflect less severe disease status. CRP level has been suggested as a predictor of poor outcome in UC patients25 and considered a biomarker of response to IFX induction therapy.26 Endoscopic finding is also one of the major factors determining the severity and prognosis of UC. In this study, the baseline CRP levels were lower in responders than in non-responders, though without statistical significance. The less severe endoscopic activity was associated with better response to induction therapy of ADA. The findings from this study suggest that ADA therapy may be more effective in moderately active UC than in severely active UC.
Parameters associated with early response such as mucosal healing, clinical response, and CRP level were associated with long-term response. Mucosal healing has been reported to be associated with long-term clinical outcomes17,27 and suggested as a predictive factor of long-term outcome in Korean UC patients treated with IFX.28 Early clinical response has also been demonstrated as a predictive factor of better long-term clinical outcomes in several real-world studies.16,29,30 In Korean patients with moderately to severely active UC, early response is also a positive predictor for long-term clinical response.
During the study period, 25 patients (17.1%) required dose escalation, and 40% and 20% of these regained clinical response and remission, respectively, at week 56. Compared to previous Western studies, the proportion of patients who experienced dose escalation in our study was relatively small; however, the clinical outcomes are similar to those of these studies.20,31,32
Consistent with previous studies on mucosal healing-associated FC levels,33-35 in this study, FC levels were well correlated with not only patients’ clinical outcomes, but also endoscopic activities. The predictive level was 274.8 mg/kg for mucosal healing and 98 mg/kg for endoscopic remission. These novel findings can be used to predict endoscopic activities in UC patients.
Serum ADA concentrations (trough level) at week 8 were associated significantly with clinical outcomes of induction therapy. The ADA concentrations in patients with clinical response or remission, including both UC and Crohn’s disease patients, have been reported at relatively lower rates than in previous studies.36-38 Few studies have been conducted to investigate ADA concentration in patients with UC only. A Belgian study including IFX responders and non-responders showed similar ADA concentrations as those in this study with respect to short-term mucosal healing.39 The researchers reported that the average ADA concentration of patients with mucosal healing at week 4 was 10.6 μg/mL, which was significantly higher than the concentration in those without mucosal healing (7.4 μg/mL, P = 0.014). The higher the drug concentration at week 8 after ADA induction therapy, the better was the expected clinical effect.
No new safety signals were observed in the present study, and the incidence rate was similar to that described in other studies.17 Any different tendency in safety from the approved label of ADA was not observed. Patients with severe adverse drug reactions including abdominal pain and pulmonary tuberculosis were treated properly, and no deaths were reported.
This was an observational study in routine clinical practice, having certain inherent limitations such as the lack of randomization, leading to potential bias. Moreover, the proportion of subjects who completed the evaluation without any major protocol deviation among the intent-to-treat set was relatively small. Furthermore, anti-ADA antibodies were not evaluated in this study, although it is used in clinical practice in Western countries. However, this study was the first multicenter prospective study to evaluate the efficacy and safety of ADA in Korean UC patients in the real-life clinical setting and explore clinical predictors of response to ADA, including FC and ADA drug levels.
In conclusion, this study showed that ADA is effective and safe for Korean patients with moderately to severely active UC regardless of prior anti-TNF-α therapy. ADA drug level is associated with the efficacy of induction therapy. A good response to induction therapy suggests positive long-term outcomes in Korean patients with moderately to severely active UC.