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640 Systematic Review of Serious Infection and Lymphoma Risk With Anti-TNF Therapy for Pediatric IBD
640
AGA Abstracts
Systematic Review of Serious Infection and Lymphoma Risk With Anti-TNF Therapy for Pediatric IBD Parambir S. Dulai, Marla Dubinsky, Corey A. Siegel Background and Aim: The decision to initiate anti-TNF therapy in pediatric inflammatory bowel disease (IBD) is often met with hesitancy due to uncertainties regarding risk. We aimed to quantify the incidence of serious adverse events (SAEs) through a systematic review of the literature. Methods: A systematic review of the literature was conducted for studies evaluating infliximab (IFX) and adalimumab (ADA) in pediatric Crohn's Disease (CD) or Ulcerative Colitis (UC) using defined search terminology. Randomized controlled trials, cohort studies and single-center series of . 5 patients were included. 49 studies were identified with 11 being excluded. Risks were calculated based on number of events during total patient-years of exposure (PYE) or follow-up (PYF). Adverse events were classified as severe if they were categorized as severe by the original investigator(s) or resulted in discontinuation of therapy, hospitalization or death. SAEs of interest included serious infection, lymphoma and death. To understand the statistical significance of the occurrence of lymphoma, we calculated a standardized incidence ratio (SIR) compared to the expected incidence rate of lymphoma in pediatric patients. Due to the lack of a clear denominator at risk, the incidence of hepatosplenic T-cell lymphoma cannot be accurately calculated. Results: A total of 1,979 patients (1,550 IFX [1,321 CD, 229 UC], 429 ADA) received over 23,985 treatments. 1,436 patients (1,175 IFX, 261 ADA) were concomitantly taking thiopurines and 205 (134 IFX, 71 ADA) were receiving methotrexate concomitant with antiTNF therapy. During the 2,649 PYF and 1,559 PYE, 151 patients experienced SAEs requiring discontinuation of therapy in 132. The risk of serious infection was 3% in anti-TNF exposed patients. Four potential treatment related deaths occurred (2 IFX, 2 ADA): central line related sepsis (n=2), azathioprine induced leucopenia with sepsis, and an arrhythmia in a patient who had suffered a near cardiac death prior to IFX therapy. One patient developed Hodgkin's lymphoma resulting in an incidence rate of 3.8/10,000 PYF. This is numerically, but not statistically, different than the incidence rate of lymphoma previously reported with thiopurine monotherapy (4.4/10,000 PYF; SIR=0.84, p=0.93, 95% CI 0.016-16.1), the expected baseline rate for all lymphoid neoplasias (0.58/10,000 PYF; SIR=6.3, p=0.18, 95% CI 0.1451.9), and Hodgkin's lymphoma in pediatric patients (0.12/10,000 PYF; SIR=37.8, p=0.052, 95% CI 0.48-2693). Conclusion: In pediatric IBD patients treated with anti-TNF therapy, the risk of serious infection is similar to what has been seen in adult IBD patients receiving immunomodulator or anti-TNF mono- or combination therapy. The absolute rate of lymphoma is low, and not statistically different than when compared to thiopurine monotherapy or the baseline pediatric population.
638 5-Aminosalicylate (5-ASA) Induced Nephrotoxicity in Inflammatory Bowel Disease Kenji So, Claire M. Bewshea, Graham A. Heap, Andrew F. Muller, Michael P. Delaney, Tawfique K. Daneshmend, Ailsa L. Hart, Timothy R. Orchard, Peter M. Irving, Richard D'Souza, Chris Mulgrew, Jonathan Kwan, Mark S. Silverberg, Richard B. Gearry, Graham Radford-Smith, Gillian Watermeyer, Renata D'Incà, Vito Annese, Epameinondas V. Tsianos, International IBD Genetics Consortium (IIBDGC), Richard K. Russell, David C. Wilson, Miles Parkes, Jack Satsangi, Richard A. Oram, Rinse K. Weersma, Ian C. Lawrance, Arthur L. Holden, Charlie W. Lees, Tariq Ahmad Background: Nephrotoxicity is a rare idiosyncratic reaction to 5-ASA therapy. The precise pathogenic mechanisms are unknown but it is most commonly characterised by a progressive interstitial nephritis. This study aims to a) describe the clinical features of this rare complication b) explore the underlying mechanisms and c) identify clinically useful predictive genetic markers so that these drugs can be avoided, or monitoring intensified, in high-risk patients. Here we report the clinical features. Methods: Patients were recruited from 185 (130 UK) international sites and DNA extracted. Inclusion criteria comprise normal renal function prior to commencing 5-ASA + ≥50% rise in creatinine + medical opinion implicating 5ASA justifies drug withdrawal. An adjudication panel of expert gastroenterologists and nephrologists assessed causality from detailed case report forms. Patients were assigned as "definite" (requires positive rechallenge), "probable", "possible" or "unlikely" cases of 5-ASA nephrotoxicity using the validated Liverpool Adverse Drug Reaction Causality Assessment Tool. Results: 156 (44.5% Crohn's disease, 71.9% male) patients have been recruited to date. These include 4 definite, 105 probable, 20 possible, 3 unlikely cases and 14 to be adjudicated. One patient with microscopic colitis was excluded. The side effect was seen with all aminosalicylates (mesalazine, balsalazide, olsalazine and sulfasalazine). 5-ASA nephrotoxicity occurred at a median age of 38.2 years (range 7.7-87.7). 78.6% of patients were white British. Two patients had a confirmed family history of 5-ASA-induced renal impairment. 75% of cases were detected by routine blood monitoring. The interval between 5-ASA introduction and first abnormal blood test was 0.2-521.3 months with 22.4% occurring in the first 12 months. The mean peak creatinine recorded was 296.8 μmol/litre (range 112 -1726). A renal biopsy was performed in 46.9% cases. 81.1% had a ≥ 20% recovery in peak creatinine on drug withdrawal; of these the mean time to best-recovered renal function was 29.7 months (range 0.1-252.8 months). Seventeen patients required renal replacement therapy (15 transplantation). Conclusions: This is the largest most detailed study of 5-ASA induced nephrotoxicity. Whilst the incidence is low, the morbidity is high with 12% of patients requiring renal replacement therapy. Early recognition is important as drug withdrawal leads to renal recovery in only 81.1% of patients. Genome-wide association analysis (and subsequent sequencing) will be performed in February 2013.
641 Is There Any Residual Risk of Lymphoma After Stopping Thiopurines? A Nationwide Retrospective Cohort From the Veterans' Affairs Healthcare System Nabeel Khan, Yordanka N. Koleva, Ali Abbas Background: Thiopurine treatment is associated with increased risk of lymphoma. There is limited data regarding whether this effect persists after discontinuation of thiopurines. Our aim was to identify incidence of lymphoma after stopping thiopurines and to compare it with the incidence while taking the medication. Methods Ulcerative colitis (UC) patients who were followed-up in the Veterans Affairs (VA) healthcare system and used thiopurines between 2001 and 2011 were identified using ICD9 codes. We used retrospective cohort study design. Patients were followed-up from the index date of thiopurine filling from the VA pharmacy to the date of lymphoma diagnosis or October, 1st, 2011. Lymphoma cases were firstly identified by ICD9 codes and then by manual chart review to confirm the diagnoses and the dates. Person-year contribution was calculated for the included patients and the incidence rate of lymphoma was calculated while taking thiopurines and for the period after stopping them. Age, sex, race adjusted hazard ratio comparing the risk of lymphomas while taking thiopurines versus the risk after stopping them was calculated using time dependent Cox regression analysis. Results We included 4,734 patients in the analysis with mean thiopurine use duration of 1.6 year (median of one year) and mean of follow-up after thiopurines stopping of 3.9 years (median 3.6 years). Majority were Caucasian (78%), males (93%) with median age at inclusion of 55 years. Total person-year of followup analyzed was 7,777.3 while on and 17,949.7 after stopping thiopurines. Lymphoma cases identified were 18 while on and 5 after stopping thiopurines. Incidence rate of lymphoma was 2.3 per 1000 person-year while on thiopurines compared to only 0.3 per 1000 person-year after stopping thiopurines. Age, sex and race adjusted hazard ratio of lymphoma while on thiopurines was 8.2 (p ,0.001) compared to after stopping it (Table). Conclusion In this nationwide cohort, the risk of lymphoma after stopping thiopurines was comparable to the risk of lymphoma in Inflammatory Bowel Disease patients who never took thiopurines as reported in the literature. There was an eight-fold increase in the risk of lymphoma for the period while on therapy compared to the period after stopping therapy. Cox regression analysis, outcome lymphoma
639 Anti-TNF Antibody-Induced Psoriasiform Skin Lesions in Patients With Inflammatory Bowel Disease Are Characterized by Interferon-γ-Expressing TH1 Cells and IL-17A/IL-22-Expressing TH17 Cells and Respond to Anti-IL12/IL-23 Antibody Treatment Cornelia Tillack, Laura M. Ehmann, Matthias Friedrich, Julia Diegelmann, Jürgen Schauber, Andreas Wollenberg, Stephan Brand Background: We analyzed incidence, predictors, histological features and specific treatment options of anti-tumor necrosis factor (TNF)- α antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD). Design: IBD patients were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-IL-12/IL-23 p40 antibody ustekinumab. Results: Among 434 anti-TNF treated IBD patients, 21 patients (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, CI 1.55-13.60) and an increased body mass index (p=0.029; OR 1.12, CI 1.01-1.24) as main predictors for these lesions. A common feature found in 85.7% of patients with these skin lesions, were elevated titers of antinuclear antibodies (ANA). Nine CD patients with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterized by infiltrates of IL-17A/IL-22-secreting Th17 cells and IFN- γsecreting Th1 cells. Strong IL-17A expression was significantly more often found in very severe psoriasiform skin lesions requiring ustekinumab therapy than in less severe lesions responding to topical therapy (p=0.0047). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab. There was a trend towards a higher number of C/T heterozygotes of the IL23R SNP rs7530511 (p.Leu310Pro) in the patients with severe skin lesions requiring ustekinumab therapy compared to anti-TNF-treated IBD patients without skin lesions (42.9% vs. 21.6%; p=0.05). Conclusions: New onset psoriasiform skin lesions develop in nearly 5% of antiTNF-treated IBD patients. We identified smoking as the main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterized by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL-23 antibody therapy is a highly effective therapy for these lesions.
AGA Abstracts
S-112
AGA Abstracts
Systematic Review of Serious Infection and Lymphoma Risk With Anti-TNF Therapy for Pediatric IBD Parambir S. Dulai, Marla Dubinsky, Corey A. Siegel Background and Aim: The decision to initiate anti-TNF therapy in pediatric inflammatory bowel disease (IBD) is often met with hesitancy due to uncertainties regarding risk. We aimed to quantify the incidence of serious adverse events (SAEs) through a systematic review of the literature. Methods: A systematic review of the literature was conducted for studies evaluating infliximab (IFX) and adalimumab (ADA) in pediatric Crohn's Disease (CD) or Ulcerative Colitis (UC) using defined search terminology. Randomized controlled trials, cohort studies and single-center series of . 5 patients were included. 49 studies were identified with 11 being excluded. Risks were calculated based on number of events during total patient-years of exposure (PYE) or follow-up (PYF). Adverse events were classified as severe if they were categorized as severe by the original investigator(s) or resulted in discontinuation of therapy, hospitalization or death. SAEs of interest included serious infection, lymphoma and death. To understand the statistical significance of the occurrence of lymphoma, we calculated a standardized incidence ratio (SIR) compared to the expected incidence rate of lymphoma in pediatric patients. Due to the lack of a clear denominator at risk, the incidence of hepatosplenic T-cell lymphoma cannot be accurately calculated. Results: A total of 1,979 patients (1,550 IFX [1,321 CD, 229 UC], 429 ADA) received over 23,985 treatments. 1,436 patients (1,175 IFX, 261 ADA) were concomitantly taking thiopurines and 205 (134 IFX, 71 ADA) were receiving methotrexate concomitant with antiTNF therapy. During the 2,649 PYF and 1,559 PYE, 151 patients experienced SAEs requiring discontinuation of therapy in 132. The risk of serious infection was 3% in anti-TNF exposed patients. Four potential treatment related deaths occurred (2 IFX, 2 ADA): central line related sepsis (n=2), azathioprine induced leucopenia with sepsis, and an arrhythmia in a patient who had suffered a near cardiac death prior to IFX therapy. One patient developed Hodgkin's lymphoma resulting in an incidence rate of 3.8/10,000 PYF. This is numerically, but not statistically, different than the incidence rate of lymphoma previously reported with thiopurine monotherapy (4.4/10,000 PYF; SIR=0.84, p=0.93, 95% CI 0.016-16.1), the expected baseline rate for all lymphoid neoplasias (0.58/10,000 PYF; SIR=6.3, p=0.18, 95% CI 0.1451.9), and Hodgkin's lymphoma in pediatric patients (0.12/10,000 PYF; SIR=37.8, p=0.052, 95% CI 0.48-2693). Conclusion: In pediatric IBD patients treated with anti-TNF therapy, the risk of serious infection is similar to what has been seen in adult IBD patients receiving immunomodulator or anti-TNF mono- or combination therapy. The absolute rate of lymphoma is low, and not statistically different than when compared to thiopurine monotherapy or the baseline pediatric population.
638 5-Aminosalicylate (5-ASA) Induced Nephrotoxicity in Inflammatory Bowel Disease Kenji So, Claire M. Bewshea, Graham A. Heap, Andrew F. Muller, Michael P. Delaney, Tawfique K. Daneshmend, Ailsa L. Hart, Timothy R. Orchard, Peter M. Irving, Richard D'Souza, Chris Mulgrew, Jonathan Kwan, Mark S. Silverberg, Richard B. Gearry, Graham Radford-Smith, Gillian Watermeyer, Renata D'Incà, Vito Annese, Epameinondas V. Tsianos, International IBD Genetics Consortium (IIBDGC), Richard K. Russell, David C. Wilson, Miles Parkes, Jack Satsangi, Richard A. Oram, Rinse K. Weersma, Ian C. Lawrance, Arthur L. Holden, Charlie W. Lees, Tariq Ahmad Background: Nephrotoxicity is a rare idiosyncratic reaction to 5-ASA therapy. The precise pathogenic mechanisms are unknown but it is most commonly characterised by a progressive interstitial nephritis. This study aims to a) describe the clinical features of this rare complication b) explore the underlying mechanisms and c) identify clinically useful predictive genetic markers so that these drugs can be avoided, or monitoring intensified, in high-risk patients. Here we report the clinical features. Methods: Patients were recruited from 185 (130 UK) international sites and DNA extracted. Inclusion criteria comprise normal renal function prior to commencing 5-ASA + ≥50% rise in creatinine + medical opinion implicating 5ASA justifies drug withdrawal. An adjudication panel of expert gastroenterologists and nephrologists assessed causality from detailed case report forms. Patients were assigned as "definite" (requires positive rechallenge), "probable", "possible" or "unlikely" cases of 5-ASA nephrotoxicity using the validated Liverpool Adverse Drug Reaction Causality Assessment Tool. Results: 156 (44.5% Crohn's disease, 71.9% male) patients have been recruited to date. These include 4 definite, 105 probable, 20 possible, 3 unlikely cases and 14 to be adjudicated. One patient with microscopic colitis was excluded. The side effect was seen with all aminosalicylates (mesalazine, balsalazide, olsalazine and sulfasalazine). 5-ASA nephrotoxicity occurred at a median age of 38.2 years (range 7.7-87.7). 78.6% of patients were white British. Two patients had a confirmed family history of 5-ASA-induced renal impairment. 75% of cases were detected by routine blood monitoring. The interval between 5-ASA introduction and first abnormal blood test was 0.2-521.3 months with 22.4% occurring in the first 12 months. The mean peak creatinine recorded was 296.8 μmol/litre (range 112 -1726). A renal biopsy was performed in 46.9% cases. 81.1% had a ≥ 20% recovery in peak creatinine on drug withdrawal; of these the mean time to best-recovered renal function was 29.7 months (range 0.1-252.8 months). Seventeen patients required renal replacement therapy (15 transplantation). Conclusions: This is the largest most detailed study of 5-ASA induced nephrotoxicity. Whilst the incidence is low, the morbidity is high with 12% of patients requiring renal replacement therapy. Early recognition is important as drug withdrawal leads to renal recovery in only 81.1% of patients. Genome-wide association analysis (and subsequent sequencing) will be performed in February 2013.
641 Is There Any Residual Risk of Lymphoma After Stopping Thiopurines? A Nationwide Retrospective Cohort From the Veterans' Affairs Healthcare System Nabeel Khan, Yordanka N. Koleva, Ali Abbas Background: Thiopurine treatment is associated with increased risk of lymphoma. There is limited data regarding whether this effect persists after discontinuation of thiopurines. Our aim was to identify incidence of lymphoma after stopping thiopurines and to compare it with the incidence while taking the medication. Methods Ulcerative colitis (UC) patients who were followed-up in the Veterans Affairs (VA) healthcare system and used thiopurines between 2001 and 2011 were identified using ICD9 codes. We used retrospective cohort study design. Patients were followed-up from the index date of thiopurine filling from the VA pharmacy to the date of lymphoma diagnosis or October, 1st, 2011. Lymphoma cases were firstly identified by ICD9 codes and then by manual chart review to confirm the diagnoses and the dates. Person-year contribution was calculated for the included patients and the incidence rate of lymphoma was calculated while taking thiopurines and for the period after stopping them. Age, sex, race adjusted hazard ratio comparing the risk of lymphomas while taking thiopurines versus the risk after stopping them was calculated using time dependent Cox regression analysis. Results We included 4,734 patients in the analysis with mean thiopurine use duration of 1.6 year (median of one year) and mean of follow-up after thiopurines stopping of 3.9 years (median 3.6 years). Majority were Caucasian (78%), males (93%) with median age at inclusion of 55 years. Total person-year of followup analyzed was 7,777.3 while on and 17,949.7 after stopping thiopurines. Lymphoma cases identified were 18 while on and 5 after stopping thiopurines. Incidence rate of lymphoma was 2.3 per 1000 person-year while on thiopurines compared to only 0.3 per 1000 person-year after stopping thiopurines. Age, sex and race adjusted hazard ratio of lymphoma while on thiopurines was 8.2 (p ,0.001) compared to after stopping it (Table). Conclusion In this nationwide cohort, the risk of lymphoma after stopping thiopurines was comparable to the risk of lymphoma in Inflammatory Bowel Disease patients who never took thiopurines as reported in the literature. There was an eight-fold increase in the risk of lymphoma for the period while on therapy compared to the period after stopping therapy. Cox regression analysis, outcome lymphoma
639 Anti-TNF Antibody-Induced Psoriasiform Skin Lesions in Patients With Inflammatory Bowel Disease Are Characterized by Interferon-γ-Expressing TH1 Cells and IL-17A/IL-22-Expressing TH17 Cells and Respond to Anti-IL12/IL-23 Antibody Treatment Cornelia Tillack, Laura M. Ehmann, Matthias Friedrich, Julia Diegelmann, Jürgen Schauber, Andreas Wollenberg, Stephan Brand Background: We analyzed incidence, predictors, histological features and specific treatment options of anti-tumor necrosis factor (TNF)- α antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD). Design: IBD patients were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-IL-12/IL-23 p40 antibody ustekinumab. Results: Among 434 anti-TNF treated IBD patients, 21 patients (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, CI 1.55-13.60) and an increased body mass index (p=0.029; OR 1.12, CI 1.01-1.24) as main predictors for these lesions. A common feature found in 85.7% of patients with these skin lesions, were elevated titers of antinuclear antibodies (ANA). Nine CD patients with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterized by infiltrates of IL-17A/IL-22-secreting Th17 cells and IFN- γsecreting Th1 cells. Strong IL-17A expression was significantly more often found in very severe psoriasiform skin lesions requiring ustekinumab therapy than in less severe lesions responding to topical therapy (p=0.0047). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab. There was a trend towards a higher number of C/T heterozygotes of the IL23R SNP rs7530511 (p.Leu310Pro) in the patients with severe skin lesions requiring ustekinumab therapy compared to anti-TNF-treated IBD patients without skin lesions (42.9% vs. 21.6%; p=0.05). Conclusions: New onset psoriasiform skin lesions develop in nearly 5% of antiTNF-treated IBD patients. We identified smoking as the main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterized by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL-23 antibody therapy is a highly effective therapy for these lesions.
AGA Abstracts
S-112