Crohn's disease genotypes of patients in remission vs relapses after infliximab discontinuation

AIM： To investigate genetic differences between Crohn＇s disease （CD） patients with a sustained remission vs relapsers after discontinuing infliximab while in cortico- steroid-free remission. METHODS： Forty-eight CD patients received infliximab and were in full corticosteroid-free clinical remission but then discontinued infliximab for reasons other than a loss of response, were identified by review of an electronic database and charts. Infliximab-associated remis- sion was defined as corticosteroid-free plus normaliza- tion of clinical disease activity [CD activity index （CDAI） 〈 150] during follow-up visits based on physician global assessments. A CD relapse （loss of infliximab-induced remission） was clinically defined as a physician visit for symptoms of disease activity （CDAI 〉 220） and a thera- peutic intervention with CD medication（s）, or a hospital- ization with complications related to active CD. Genetic analyses were performed on samples from 14 patients （n = 6 who had a sustained long term remission after stopping infliximab, n -- 8 who rapidly relapsed after stopping infliximab）. Nucleotide-binding oligomerization domain 2 （NOD2）/caspase activation recruitment do- main 15 （CARD15） polymorphisms （R702W, G908R and L1007fs） and the inflammatory bowel disease 5 （IBDS） polymorphisms （IGR2060a1 and IGR3081a1） were ana- lyzed in each group. RESULTS： Five single nucleotide polymorphisms of IBD5 and NOD2/CARD15 genes were successfully analyzed for all 14 subjects. There was no signifcant increase in frequency of the NOD2/CARD15 polymor- phisms （R702W, G908R and L1007fs） and the IBD5 polymorphisms （IGR2060al and IGR3081a1） in either group of patients; those whose disease relapsed rap- idly or those who remained in sustained long term remission following the discontinuation of infliximab. Nearly a third of patients in full clinical remission who stopped infliximab for reasons other than loss of re- sponse remained in sustained clinical remission, while two-thirds relapsed rapidly. There was a marked dif- ference in the duration of clinical remission following discontinuance of infliximab between the two groups. The patients who lost remission did so after 1.0 years 4- 0.6 years, while those still in remission were at the time of this study, 8.1 years 4- 2.6 years post-discon- tinuation of infliximab, P 〈 0.001. The 8 patients who had lost remission after discontinuing infiiximab had a mean number of 5 infusions （range 3-7）, with a mean treatment time of 7.2 mo （range 1.5 mo-15 mo）. The mean duration of time from the last infusion of inflix- imab to the time of loss of remission was 382 d （range 20 d-701 d）. The 6 patients who remained in remission after discontinuing infliximab had a mean number of 6 infusions （range 3-12）, with a mean treatment dura- tion of 12 mo （range 3.6 mo-32 too） （P = 0.45 relative to those who lost remission）. CONCLUSION： There are no IBD5 or NOD2/CARD15 mutations that predict which patients might have sus- tained remission and which will relapse rapidly after stopping infliximab.

AIM:To investigate genetic differences between Crohn's disease(CD) patients with a sustained remission vs relapsers after discontinuing infliximab while in corticosteroid-free remission.METHODS:Forty-eight CD patients received infliximab and were in full corticosteroid-free clinical remission but then discontinued infliximab for reasons other than a loss of response,were identified by review of an electronic database and charts.Infliximab-associated remission was defined as corticosteroid-free plus normalization of clinical disease activity [CD activity index(CDAI) < 150] during follow-up visits based on physician global assessments.A CD relapse(loss of infliximab-induced remission) was clinically defined as a physician visit for symptoms of disease activity(CDAI > 220) and a therapeutic intervention with CD medication(s),or a hospitalization with complications related to active CD.Genetic analyses were performed on samples from 14 patients(n = 6 who had a sustained long term remission after stopping infliximab,n = 8 who rapidly relapsed after stopping infliximab).Nucleotide-binding oligomerization domain 2(NOD2)/caspase activation recruitment domain 15(CARD15) polymorphisms(R702W,G908R and L1007fs) and the inflammatory bowel disease 5(IBD5) polymorphisms(IGR2060a1 and IGR3081a1) were analyzed in each group.RESULTS:Five single nucleotide polymorphisms of IBD5 and NOD2/CARD15 genes were successfully analyzed for all 14 subjects.There was no significant increase in frequency of the NOD2/CARD15 polymorphisms(R702W,G908R and L1007fs) and the IBD5 polymorphisms(IGR2060a1 and IGR3081a1) in either group of patients;those whose disease relapsed rapidly or those who remained in sustained long term remission following the discontinuation of infliximab.Nearly a third of patients in full clinical remission who stopped infliximab for reasons other than loss of response remained in sustained clinical remission,while two-thirds relapsed rapidly.There was a marked difference in the duration of clinical remission following discontinuance of infliximab between the two groups.The patients who lost remission did so after 1.0 years ± 0.6 years,while those still in remission were at the time of this study,8.1 years ± 2.6 years post-discontinuation of infliximab,P < 0.001.The 8 patients who had lost remission after discontinuing infliximab had a mean number of 5 infusions(range 3-7),with a mean treatment time of 7.2 mo(range 1.5 mo-15 mo).The mean duration of time from the last infusion of infliximab to the time of loss of remission was 382 d(range 20 d-701 d).The 6 patients who remained in remission after discontinuing infliximab had a mean number of 6 infusions(range 3-12),with a mean treatment duration of 12 mo(range 3.6 mo-32 mo)(P = 0.45 relative to those who lost remission).CONCLUSION:There are no IBD5 or NOD2/CARD15 mutations that predict which patients might have sustained remission and which will relapse rapidly after stopping infliximab.