544 3. 4.
Correspondence Millonig G, et al. Hepatology 2008;48:1718–1723. Harata M, et al. Hepatol Res 2011;41:423–429.
Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.06.033
Gastroenterology Vol. 147, No. 2
References 1. 2. 3.
Panaccione R, et al. Gastroenterology 2014;146:392–400. Reich K, et al. Br J Dermatol 2013;168:1325–1334. Menter A, et al. J Am Acad Dermatol 2007;56:31. e1–31.e15.
Conflicts of interest The authors disclose no conflicts.
Are We Ready for Combination Ther- http://dx.doi.org/10.1053/j.gastro.2014.03.053 apy in Moderate-to-Severe Ulcerative Infliximab for Moderate to Severe Colitis? Ulcerative Colitis: The Jury Isn’t in Yet Dear Editor: The results of UC SUCCESS trial,1 which assessed the effect of combination therapy with infliximab (IFX) and azathioprine (AZA) in ulcerative colitis (UC), were recently published in Gastroenterology. Although this study provided insight into the effects of combination therapy, it raised various concerns, especially regarding the conclusions drawn from the results. We understand the reasons behind the low power and appreciate the decision to halt the trial owing to serious infusion reactions observed in another trial that evaluated the effects of IFX in patients with psoriasis (RESTORE2).2 We cannot comprehend that, despite using similar AZA dose, there were more adverse events in AZA arm than in IFXþAZA arm. Likewise, the lower incidence of infusion reactions observed in IFX and IFXþAZA arms does not align with previous reports,2,3 especially when such reactions from the RESTORE2 trial were cited as the reason to stop the UC SUCCESS trial prematurely. Based on these concerns, we are skeptical of our readiness for combination therapy in moderate-to-severe UC. Moreover, it may be misleading for the authors to suggest that combination therapy is superior to monotherapy with “either” agent, when the study did not actually demonstrate a clear superiority. Until we have a more robust study, the decision to pursue combination therapy should be individualized and weighed against the risk–benefit ratio as well as cost. YEONG YEH LEE Department of Medicine Section of Gastroenterology & Hepatology Georgia Regents University Augusta, Georgia and School of Medical Sciences Universiti Sains Malaysia Kubang Kerian Kelantan, Malaysia VENUGOPALAREDDY GANGIREDDY SANDEEP KHURANA SATISH S. C. RAO Department of Medicine Section of Gastroenterology & Hepatology Georgia Regents University Augusta, Georgia
Dear Editor: The study by Panaccione et al1 concluding that a combination of infliximab (IFX) and azathioprine (AZA) is superior to either drug as monotherapy in moderate to severe ulcerative colitis (UC) made for interesting reading, but also raised a number of questions. Despite an appropriate primary endpoint, defined as corticosteroid (CS)-free remission at 16 weeks, 3 aspects of the study design seem to have ensured that the true proportion of patients responding to AZA would be underestimated. First, patients not responding to AZA by week 8 were denoted as failure of therapy and given additional rescue IFX, even though the efficacy of AZA may not be fully evident for 17 weeks.2 Such a move ensured that a whopping 26 of 79 patients (32.9%) on AZA were prematurely classified as treatment failures. Second, CS needed to be tapered and stopped only by week 14, a clear 6 weeks after the time point for determining failure of AZA therapy. This meant that the remission achieved in some patients on IFX at 16 weeks, who were still on CS until 2 weeks earlier might have actually been owing to the latter drug, the AZA group not having such an advantage. Third, not estimating thiopurine methyltransferase activity before starting full-dose AZA as against current recommendations to do so3,4 contributed in part to a high number discontinuing therapy early in the AZA group owing to adverse events. This number 11 (13.7%), although not significantly different from the other groups, was nonetheless numerically higher and contributed to about 40% of the overall discontinuations in the AZA group. The latter event, we calculated using the chi square test, was significantly higher in the AZA group as against the other 2 groups (27 [33%] vs 14 [17%] and 17 [21%]; P ¼ .046], but the authors are silent about this, or its effect on the overall results of the study. Because of the limited duration under observation, the large numbers discontinuing therapy and variable periods of steroid-free remission complicated by a premature termination of the study, Kaplan–Meier estimates for the period of remission would have provided additional information, but the authors do not do so. The premature termination of the trial, that too because of an extraneous reason, is disappointing, because the consequent underpowering of the study weakened the authors’
Correspondence Millonig G, et al. Hepatology 2008;48:1718–1723. Harata M, et al. Hepatol Res 2011;41:423–429.
Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.06.033
Gastroenterology Vol. 147, No. 2
References 1. 2. 3.
Panaccione R, et al. Gastroenterology 2014;146:392–400. Reich K, et al. Br J Dermatol 2013;168:1325–1334. Menter A, et al. J Am Acad Dermatol 2007;56:31. e1–31.e15.
Conflicts of interest The authors disclose no conflicts.
Are We Ready for Combination Ther- http://dx.doi.org/10.1053/j.gastro.2014.03.053 apy in Moderate-to-Severe Ulcerative Infliximab for Moderate to Severe Colitis? Ulcerative Colitis: The Jury Isn’t in Yet Dear Editor: The results of UC SUCCESS trial,1 which assessed the effect of combination therapy with infliximab (IFX) and azathioprine (AZA) in ulcerative colitis (UC), were recently published in Gastroenterology. Although this study provided insight into the effects of combination therapy, it raised various concerns, especially regarding the conclusions drawn from the results. We understand the reasons behind the low power and appreciate the decision to halt the trial owing to serious infusion reactions observed in another trial that evaluated the effects of IFX in patients with psoriasis (RESTORE2).2 We cannot comprehend that, despite using similar AZA dose, there were more adverse events in AZA arm than in IFXþAZA arm. Likewise, the lower incidence of infusion reactions observed in IFX and IFXþAZA arms does not align with previous reports,2,3 especially when such reactions from the RESTORE2 trial were cited as the reason to stop the UC SUCCESS trial prematurely. Based on these concerns, we are skeptical of our readiness for combination therapy in moderate-to-severe UC. Moreover, it may be misleading for the authors to suggest that combination therapy is superior to monotherapy with “either” agent, when the study did not actually demonstrate a clear superiority. Until we have a more robust study, the decision to pursue combination therapy should be individualized and weighed against the risk–benefit ratio as well as cost. YEONG YEH LEE Department of Medicine Section of Gastroenterology & Hepatology Georgia Regents University Augusta, Georgia and School of Medical Sciences Universiti Sains Malaysia Kubang Kerian Kelantan, Malaysia VENUGOPALAREDDY GANGIREDDY SANDEEP KHURANA SATISH S. C. RAO Department of Medicine Section of Gastroenterology & Hepatology Georgia Regents University Augusta, Georgia
Dear Editor: The study by Panaccione et al1 concluding that a combination of infliximab (IFX) and azathioprine (AZA) is superior to either drug as monotherapy in moderate to severe ulcerative colitis (UC) made for interesting reading, but also raised a number of questions. Despite an appropriate primary endpoint, defined as corticosteroid (CS)-free remission at 16 weeks, 3 aspects of the study design seem to have ensured that the true proportion of patients responding to AZA would be underestimated. First, patients not responding to AZA by week 8 were denoted as failure of therapy and given additional rescue IFX, even though the efficacy of AZA may not be fully evident for 17 weeks.2 Such a move ensured that a whopping 26 of 79 patients (32.9%) on AZA were prematurely classified as treatment failures. Second, CS needed to be tapered and stopped only by week 14, a clear 6 weeks after the time point for determining failure of AZA therapy. This meant that the remission achieved in some patients on IFX at 16 weeks, who were still on CS until 2 weeks earlier might have actually been owing to the latter drug, the AZA group not having such an advantage. Third, not estimating thiopurine methyltransferase activity before starting full-dose AZA as against current recommendations to do so3,4 contributed in part to a high number discontinuing therapy early in the AZA group owing to adverse events. This number 11 (13.7%), although not significantly different from the other groups, was nonetheless numerically higher and contributed to about 40% of the overall discontinuations in the AZA group. The latter event, we calculated using the chi square test, was significantly higher in the AZA group as against the other 2 groups (27 [33%] vs 14 [17%] and 17 [21%]; P ¼ .046], but the authors are silent about this, or its effect on the overall results of the study. Because of the limited duration under observation, the large numbers discontinuing therapy and variable periods of steroid-free remission complicated by a premature termination of the study, Kaplan–Meier estimates for the period of remission would have provided additional information, but the authors do not do so. The premature termination of the trial, that too because of an extraneous reason, is disappointing, because the consequent underpowering of the study weakened the authors’
