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Cancer and inflammatory bowel disease in the elderly
Digestive and Liver Disease - Available online 20 May 2016, In Press, Corrected Proof
Cancer may be a complication of inflammatory bowel disease (IBD) or its treatments. In older Crohn's disease and ulcerative colitis patients, the risk of malignancy is of particular concern. IBD diagnosis at an advanced age is associated with earlier development of colitis-associated colorectal cancer. Thiopurine use in older IBD patients is tied to an increased risk of non-Hodgkin's lymphoma, nonmelanoma skin cancer, and urinary tract cancers. Additionally, older age is accompanied by multimorbidity, an increased risk of malnutrition, and decreased life expectancy, factors that complicate the management of cancer in the elderly. The optimal approach to the increased risk of malignancy in older age IBD is appropriate cancer screening and medical treatment. This may include age-specific colorectal cancer screening and limiting UV radiation exposure. With a growing number of older IBD patients, further studies are necessary to delineate the risk of cancer in this population.
Keywords: Crohn's disease, Malignancy, Older, Ulcerative colitis.
The incidence and prevalence of older patients among those with inflammatory bowel disease (IBD) approaches 12% and 30%, respectively  and . When defining older-onset disease as IBD diagnosed after age 60, its incidence has recently been reported in a large Northern France population-based study at 2.6/105 inhabitants for Crohn's disease (CD) and 3.1/105 inhabitants for ulcerative colitis (UC) . With an increasing population of elderly, the number of IBD patients at an advanced age will grow. However due to a paucity of studies, the appropriate management of older IBD patients is unclear and often made more challenging due to concerns for disease and medication-related complications like serious infection and malignancy.
Overall, 50% of diagnosed malignancies and 70% of malignancy-related deaths occur in patients ≥65 years old . Additionally, in older age, cancer pathogenesis and behaviour differs. Older individuals have more progressive decreases in the DNA mismatch repair process in hematopoietic stem cells . Certain cell lines in older patients may be more susceptible to tumour spread . In colorectal cancer (CRC), advanced age is associated with smaller tumours, more frequent right-sided lesions, and decreased risk of metastasis . The degree to which IBD and its commencement in advanced age effects cancer onset and presentation is unknown.
Additionally, the impact of cancer on the patient at an advanced age differs. Often, chronological age does not predict a body's physiologic response, a measure more reflective of the number of comorbidities, cognition, physical impairment, nutrition status, and polypharmacy. These unique geriatric conditions may predispose patients to adverse effects of chemotherapy and lead to particular toxicities like peripheral neuropathy or cognitive impairment . Additionally, the pharmacodynamics and pharmacokinetics of new cancer therapies may directly impact many of treatments utilized in conditions associated with ageing . Therefore, the therapeutic approach to cancer therapy in the elderly can differ. However, since few studies in cancer evaluate the efficacy and tolerance of various chemotherapy and radiation therapies in older patients, providers base management decisions on studies in younger adults .
The goals of therapy in elderly IBD have yet to be elucidated potentially affecting appropriate treatment. Therapies like thiopurines disproportionately increase cancer risk among elderly, but at the same time the reluctance to start immune suppressive agents in advanced age increases the likelihood of undertreatment , , , and . In managing older IBD patients, the presence of an increased cancer risk and the degree to which that risk is elevated are important considerations. In this review, we describe and distinguish between disease and treatment-related malignancies in older IBD patients.
2.1. Colorectal cancer
CRC accounts for 10–15% of IBD-related deaths . Though there is variability between studies, after 20 years of disease, one meta-analysis found that 5.6% of UC patients will have been diagnosed with CRC . Using the ‘Surveillance, Epidemiology, and End Results’ (SEER) database, when comparing IBD to non-IBD patients >66 years old, the CRC incidence rate was 8.2 and 6.1 per 10,000 person years (p < 0.001), respectively . However, compared to younger-onset IBD, a French population-based cohort showed no increased risk of CRC in patients >60 years old at IBD diagnosis .
Two nationwide studies from Japan and Denmark have shown that UC-associated CRC has a worse prognosis than sporadic cancer  and . Traditionally, disease extent and duration are the most important factors related to the development of colitis-associated cancer  and . In older-onset IBD, disease duration may be less important as life expectancy is decreased. Several colorectal cancer screening guidelines in IBD suggest starting colonoscopy within 8–10 years following the diagnosis  and . The British Society of Gastroenterology suggests beginning CRC screening in IBD 10 years following symptom onset . However, CRC in older-onset IBD may be associated with a different pathophysiology and more rapid development. In comparison to younger-onset UC, older-onset patients have more rapid shortening of telomeres, a process associated with an increased risk of CRC . There is increasing evidence that older-onset IBD patients may be at increased risk for developing flat dysplasia and CRC before suggested screening guidelines , , , and . In a European study examining IBD-associated CRC in tertiary centres, 22% of patients developed CRC within 10 years of their CD or UC diagnosis. Despite undergoing more colonoscopies, when compared to younger patients, older-onset IBD was associated with a decreased interval to CRC and more advanced cancer at diagnosis . In a Dutch population-based study, 35% of patients developed CRC within 8 years of their IBD diagnosis, with ongoing intestinal inflammation and older age associated with earlier onset of CRC . The median time to CRC diagnosis decreased with each subsequent decade at diagnosis . Though disease duration may have played a factor in these findings, a multicenter study from Hong Kong revealed that 5.8% of older-onset patients developed flat dysplasia with similar rates between those with <8 and ≥8 years of disease . This suggests that the older age of IBD onset, rather than disease duration, may be responsible for this trend.
The additional sporadic colon cancer risk with ageing in IBD has led to particular concern regarding the timing of initiation and interval CRC screening in older IBD patients. Using the SEER-Medicare shared database, Wang et al. found that surveillance colonoscopy may be lower than expected in older IBD patients prior to development of CRC . Colonoscopy may confer greater risk of complications including bleeding, perforation, and cardiorespiratory events in the elderly making appropriate patient selection imperative . No specific CRC screening guidelines exist in the elderly. However, since 10–15% dysplasia and CRC may develop within one year of IBD diagnosis in older adults  and , initiating dysplasia/CRC screening with colonoscopy one year following the diagnosis of Crohn's colitis and extensive or left-sided UC may be appropriate. The decision to perform ongoing CRC surveillance with colonoscopy should be based on the patient's life expectancy, whether findings on colonoscopy change management, the ability of the patient to undergo surgery, and patient desires  (Fig. 1). Among patients with colitis and in the absence of a history of colonic dysplasia, US guidelines recommend colonoscopy every 1–2 years for CRC screening while European guidelines base interval screening on various CRC risk factors  and . Since the overall risk of CRC in older-onset IBD appears similar to those with IBD at a younger age, guidelines for ongoing CRC surveillance in adults may be applicable to older-onset CD and UC. Further studies will identify the necessity of age-specific recommendations for CRC screening (Table 1).
|Type of malignancy||Type of study||Number of patients||Study period||Follow-up||Main resultsa||Risk in elderly vs. adultsb||Ref.|
|Colon||Retrospective cohort using Netherlands inpatient database||3739||1990–2006||Median 12 years||Median age 58.8 vs. 28.4 in patients who develop CRC <8 and ≥8 years, respectively||–||, , , , and |
|Retrospective cohort in 3 Norway hospitals||67||<2005||Median 17 years||For every increase in 1 year in age of onset of IBD, colitis-CRCc interval decreased by a factor of 0.154||(Cancer develops earlier but no overall increased risk)|
|Retrospective cohort of Hong Kong patient registry||1225||1981–2013||Median 11 years||CRC rate 3.2 vs. 0.9% when comparing IBD age of onset ≥60 and <60, respectively|
|Retrospective cohort of 5 Alberta hospitals||31||1991–2002||Median 16 years||ORd 11.5 of CRC when comparing age of dx >40 to <40 y/o|
|Retrospective population-based French cohort (EPIMAD)||844||1988–2006||Median 6 years||SIRe 1.03 of developing CRC when comparing age of dx >60 and <60 y/o|
|Small intestinal||Retrospective cohort of >66 y/o using SEER-Medicare database||143,193 (923 with CD)||1993–1999||>2 years||1.6% prevalence||?|||
|Retrospective population-based French cohort (EPIMAD)||844||1988–2006||Median 6 years||Similar risk of developing SIAf when comparing age of dx >60 and <60 y/o|||
|Urinary tract||Prospective national French cohort (CESAME)||20,775||May 2004–December 2007||Median 35 months||HRg 13.26 (3.52–50.03) in ≥65 y/o when compared to <50 y/o||↑|||
|Cholangio-carcinoma||Population- based study using Denmark national patient registry||454,076||1979–2003||Not reported||0.12% vs. 0.03% absolute risk comparing age at diagnosis ≥40 and <40, respectively||↑|||
a All results are statistically significant.
b Overall risk accounting for all studies in table.
c Colorectal cancer.
d Odds ratio.
e Standardized incident ratio.
f Small intestinal adenocarcinoma.
g Hazard ratio.
While the stage of CRC can predict the overall prognosis, the likelihood of benefit from chemotherapy in elderly is difficult to measure due to their underrepresentation in clinical trials. Despite the paucity of data from randomized controlled trials, large population studies have shown that the elderly may respond differently to colorectal cancer treatment given in the adjuvant setting than their younger counterparts  and . Population studies from the SEER database and pooled analysis from elderly patients enrolled in clinical studies have shown that they also derive benefit from some adjuvant chemotherapy regimens but not others, despite similar toxicity profiles between older and younger patients  and . In metastatic disease, the use of polychemotherapy in the elderly appears to show benefit that is similar to younger patients. However, the use of systemic polychemotherapy in the elderly is typically solely based on functional status and medical comorbidities. The dosing and sequencing of these agents in the elderly remains poorly defined and typically is given at the discretion of the treating provider. Further studies are needed in the elderly to examine if predisposing factors (i.e., environmental and biological) affect outcome and treatment responses.
2.2. Small intestinal adenocarcinoma
After 25 years of ileal CD, the risk of small intestinal adenocarcinoma (SIA) is 2.2%, accounting for 45% of the gastrointestinal carcinomas . A prospective study of the Cancers et Surrisque Associe aux Maladies Inflammatoires Intestinales in France (CESAME) cohort revealed the standard incident rate of SIA was 0.5 per 1000 patient-years among patients with >8 years of small bowel CD . Over a median follow-up of 6 years in a French population-based study, when compared to younger-onset IBD, there was no increased risk of small intestinal carcinoma in patients with an IBD diagnosis after age 60 . Using the SEER database, Shaukat et al. found a strong association between SIA and patients >66 years old (OR = 12.1). Among CD and non-CD patients, the rate of SIA was 8.6% and 0.63%, respectively. However, the duration of CD and follow-up in the two groups was unclear. Since only 1.6% of the cancers were from patients with CD however, the absolute risk was low . Small intestinal carcinoma associated with CD tends to involve the distal small bowel, occur more often in younger-onset IBD, and the age of cancer diagnosis is younger than sporadic cases . On average, the duration between CD diagnosis and SIA, 20–25 years in most studies , suggests that older-onset IBD patients may not have CD long enough to develop cancer. Rather, SIA may be more common in CD patients transitioning to old age with their disease.
Due to the low absolute risk for SIA and the absence of primary prevention data in CD, there are no current screening guidelines. Some have advocated for endoscopic evaluation in patients with long-standing small bowel CD without previous resection , but the cost-effectiveness of this and various potential screening small bowel imaging modalities is questionable  and . There are recommendations that prolonged duration of small bowel stricturing CD, symptomatic strictures after a prolonged period of remission, and small bowel strictures refractory to medical therapy require further evaluation for small bowel malignancy . Since age is an independent factor for endoscopic complications , further studies will need to weigh the possibility of SIA against the risk of endoscopic evaluation in potentially frail geriatric patients with a small absolute risk of developing SIA.
Cholangiocarcinoma is a rare gastrointestinal cancer with standard incident rates of 7.6 per 100,000 person years . IBD itself is a risk factor for cholangiocarcinoma, independent of primary sclerosing cholangitis (PSC), with a 4-fold increased incidence compared to non-IBD patients . In patients with IBD and PSC the lifetime risk of cholangiocarcinoma is 10–15% . Using a nationwide population-based Danish registry from 1978–2003, when comparing IBD and non-IBD patients in their 60s, the incidence rate of cholangiocarcinoma was 15.3 and 3.6 cases per 100,000 person years, respectively. Though the difference was less robust at age 70 and beyond, this trend continued . After 10 years, when compared to younger patients, patients with an IBD diagnosis ≥40 years old have a 4-fold increased risk of developing cholangiocarcinoma . Prognosis is poor regardless of IBD status. There are no current screening guidelines for cholangiocarcinoma in IBD with or without PSC. The low absolute risk of cholangiocarcinoma, even in older-onset IBD, makes screening in asymptomatic adults unlikely to be cost-effective.
Lymphoma, particularly non-Hodgkin's lymphoma (NHL), is associated with thiopurine use and more prevalent with advanced age. Studies examining the link between thiopurines and lymphoma differ according to duration of follow-up, concomitant biologic exposure, and the age of IBD onset in patients, making it difficult to define the actual risk particularly in older-onset IBD . Over a median follow-up of 3 years, the CESAME group determined that when compared to those without previous thiopurine exposure, IBD patients 50–65 years old actively taking thiopurines had a 6-fold higher incidence of lymphoproliferative disorders (LDs). The absolute risk of LDs was highest in patients on thiopurines >65 years old . However, 10% of patients were exposed to anti-TNFs and concomitant anti-TNF and thiopurine users had the highest standardized incidence ratio (SIR) of LDs at 10.2 . Another study using the nationwide Veteran's Affairs database found that after a median follow-up of 7 years, when compared to unexposed patients, UC patients >65 years old actively using thiopurines had a 6-fold higher risk of all types of lymphoma . Less than 1% of patients were exposed to anti-TNF agents, and when these patients were excluded from the analysis the rate of lymphoma was unchanged . A recent meta-analysis found that compared to the general population, there was nearly a 6-fold higher incidence of NHL and HL with at least 1 year of thiopurine therapy and that the risk went away upon cessation of use . That risk was elevated in patients >50 years old with a SIR of 1.81 (95% confidence interval [CI] = 1.07–2.87) but was not sustained in patients >60 years old. Excluding one outlier study, comparing IBD and non-IBD patients >50 years old, the lymphoma risk was 1 in 350 and 1 in 1694 per patient year, respectively . These data suggest that older patients actively using thiopurines appear to be particularly susceptible to lymphoma with possible further increased risk with concomitant anti-TNF use (Table 2).
|Medicationa and b||Type of malignancy||Type of study||Number of patients||Study period||Follow-up||Main resultsc||Risk in elderly vs. adultsd||Ref.|
|Thiopurines||Lymphoma||Prospective national French cohort (CESAME)||20,775||May 2004–December 2007||Median 35 months||HRe 6.45 in 50–65 y/o and HR 3.22 in >65 y/o comparing users vs. nonusers||↑||, , and |
|Retrospective nationwide VA UC cohort||36,891||2001–2011||Median 6.7 years||HR 5.57 in >65 y/o comparing users vs. nonusers|
|Retrospective population-based French cohort (EPIMAD)||844||1988–2006||Median 6 years||SIRf 2.55 of developing malignant haematological diseases when comparing age of dx >60 and ≤60 y/o|
|Urinary Tract||Prospective national French cohort (CESAME)||20,775||May 2004–December 2007||Median 35 months||HR 6.30 in males >65||↑(Males only)|||
|Non-Melanoma||Prospective national French cohort (CESAME)||20,775||May 2004–December 2007||Median 35 months||HR 4.81 in >65 and 4.32 in 50–65 y/o comparing users vs. nonusers (HR 6.79 in >65 in former vs. never users)||↑|| and |
|Retrospective nationwide VA cohort||14,527 UC patients||2001–2011||Median 8.1 years||HR 2.54 in >65 and 2.53 in 40–65 y/o comparing users vs. nonusers|
|Anti-TNFs||Lymphoma||Meta-analysis compared to SEER database||21,178 patient years||–||Median ≥48 weeks||SIR 16.8 for 55–64 y/o men (95% CI 2–64.4)g||?|||
|Melanoma||Database of rheumatological drug trials||4322||Variable||≥1 dose||No difference between ≥65 and <65 y/o||?|| h|
a No data on the risk of malignancy with methotrexate and combination therapy with anti-TNF agent and immune modulator agent in elderly.
b No data on the risk of melanoma with thiopurines in advanced age; no data on the risk of urinary tract cancers and NMSCs with Anti-TNFs in the elderly.
c Unless otherwise noted, all results are statistically significant.
d Overall risk based on all studies in table.
e Hazard ratio.
f Standard incidence ratio.
g Not statistically significant.
h Study done in rheumatological diseases using etanercept.
The role of methotrexate in the development of lymphoma in IBD is less clear. In the rheumatology literature, a large prospective study revealed an increased risk of HL but not NHL in rheumatoid arthritis (RA), while a population-based study showed no increased rate of Hodgkin's lymphoma  and . Wolfe et al. showed higher rates of HL with increasing age in RA regardless of methotrexate use when compared with the SEER database . Since RA itself has been associated with lymphoma, the additional risk of IBD and ageing with concomitant anti-TNF and methotrexate therapy is not yet clear.
Unlike thiopurines, studies evaluating anti-TNF agent use in IBD have not shown a clear association with lymphoma. In a meta-analysis evaluating anti-TNF use among randomized controlled trials, cohort studies, and cases series, the SIR of developing lymphoma was 3.23 (CI, 1.5–6.9) . And though the SIR increased with age, the age-specific SIR was not increased in ≥55 years old . Additionally, many patients also had been exposed to thiopurines so the lymphoma risk associated with anti-TNF monotherapy is difficult to interpret. A more recent meta-analysis of 22 RCTs in IBD did not show an increased risk of lymphoma with anti-TNF agents . However, none of these studies extended beyond one year and there were few enrolled older IBD patients.
There are no current screening guidelines for lymphoma. However, in older IBD patients, particularly those taking thiopurines or possibly methotrexate, providers should suspect lymphoma in patients with unexplained weight loss, fever, night sweats, and lymphadenopathy.
3.2. Melanoma and non-melanoma skin cancer
Melanoma incidence has been increasing in recent decades with the highest rise in incidence occurring in patients >65 years old . In patients between the age of 60–79, the incident rate of melanoma in the US is nearly 100/100,000 person years and peaks in ≥80 years old . Twenty percent of melanomas are fatal and the elderly having higher mortality than younger counterparts . A recent meta-analysis in CD and UC revealed a 52% increased risk of melanoma before the approval of anti-TNF agents . However, the included studies did not control for other well-known melanoma risk factors or frequency of exposure to the health care system. Recent IBD studies evaluating melanoma and anti-TNF agents have produced mixed results with some showing an association , and others showing no association  and . In the rheumatology literature, an integrated database of multiple clinical trials revealed that the incidence of melanoma in ≥65 and <65 year old patients was similar among patients on etanercept . Due to the infrequency of melanoma and paucity of data, it is difficult to delineate the risk of melanoma in elderly IBD patients independent of and with anti-TNF therapy.
Non-melanoma skin cancers are the most common cancers worldwide, with increasing incidence in the US . Advanced age is a known risk factor in all patients, with individuals between the ages of 80–84 having the highest incidence . In patients >65 years old, the number of outpatient visits for NMSCs was 60–160 per 1000 persons . Though IBD itself may serve as a risk factor  and , in patients ≥50 years old there appears to be no increased risk in IBD vs. a non-IBD cohort . The highest and most consistent risk factor in IBD is linked to thiopurine use. The association of azathioprine and 6-MP with NMSC was first described in post-transplant patients , and is highest in older patients regardless of duration of use .
Traditional risk factors for NMSC development include UV radiation exposure and immune surveillance. With ageing, a diminished immune response and a decrease in enzymatically active melanocytes responsible for absorbing UV radiation enhance the risk of persistent epidermal and dermal damage .
In a prospective observational IBD cohort, the CESAME group examined 49,719 patient-years of follow-up and found 32 incident NMSC cases. The incidence of squamous and basal cell skin cancers associated with thiopurines increased with age and the highest rate of development was in current and former thiopurine users >65 years old (hazard ratios of 4.04 and 5.70, respectively) . The results of the thiopurine association with NMSC were unchanged when adjusting for use of other immunosuppression. Abbas et al. retrospectively analyzed the Veteran Affairs nationwide database over an 11-year span and identified 14,527 UC patients, 3346 of them who used thiopurines. They found that although the incidence rate of NMSC is highest in patients >65 years old on current thiopurines (12.2 in exposed vs. 4.8 in unexposed cohort), it returned close to baseline once the drug was stopped . At the same time, the risk of NMSC appears to increase with both dose and duration of thiopurine therapy  and . A study using an administrative database examining all IBD patients showed an increase of NMSC with combination anti-TNF and thiopurine therapy but no association with methotrexate . In the rheumatology literature, when compared to other biologics including anti-TNF agents and disease-modifying anti-rheumatic drugs, methotrexate was associated with higher risks of NMSC and this increased with age . However, study patients often were exposed to multiple other agents so it is unclear if methotrexate, another medication alone, or a combination of medications drove this risk.
Preventive strategies for melanoma and NMSC are similar for all IBD adults. Efforts to limit UV radiation exposure and the use of broad-spectrum sunscreen are reasonable starting points. The risks and benefits of ongoing thiopurine use need to be weighed. Expert opinions suggest routine skin cancer screening but no formal guidelines exist . However implementation of guidelines for all IBD patients, though possibly cost-effective , will be difficult to develop due to the heterogeneity of patient risk factors. With increased skin cancer rates in elderly IBD patients on thiopurines, it may be reasonable to suggest yearly screening skin examinations particularly when other skin cancer risk factors are present.
3.3. Urinary tract cancer
The urinary tract cancers, comprised of mainly bladder and kidney cancer, tend to occur at an advanced age. It is estimated that in 2016 the overall incidence of kidney and renal pelvis cancers in US patients aged 60–69 and ≥70 will be 1/158 and 1/76, respectively . A systematic review and meta-analysis evaluating the risk of urinary cancers in all adult IBD patients found a SIR of 2.03 in Crohn's disease . The incident rate of urinary tract cancers in elderly IBD patients has not been studied. Using the national Danish patient registry data, Pasternak et al. revealed that when compared to nonusers, azathioprine use was associated with increased urinary tract cancer rates (rate ratio of 2.84) . The CESAME group found when comparing users to nonusers, the incidence rate of urinary tract cancers with thiopurines in males >65 years old was 6-fold higher . Smoking status, a risk factor for urinary tract cancers, was not followed prospectively in most of this cohort. However, in a subcohort of patients, smoking rates were similar regardless of thiopurine exposure . Anti-TNF monotherapy does not appear to increase bladder and kidney cancer risk in adults , but this has not been studied in the elderly. Therefore, older men with IBD taking thiopurines are at risk for urinary tract cancers but the effect of anti-TNFs alone or in combination with thiopurines are unclear.
Since elderly IBD males on thiopurines appear to be most susceptible to urinary tract cancers, other risk factors for urinary tract cancer should be considered before initiating therapy. In addition to smoking, these can include previous occupation exposures to aromatic amines and chlorinated hydrocarbons, certain herbal medications, hypertension, and obesity , , and . If these other risk factors are present, it may be reasonable to consider options beyond thiopurines.
There are currently no screening guidelines for urinary tract cancers in any population. However, elderly IBD patients, particularly men on thiopurine therapy, should be further evaluated for urinary tract cancers if symptoms like hematuria or obstructive uropathy develop.
Both IBD and its medical therapies predispose older patients to malignancy. Studies to date have mixed IBD patients diagnosed at advanced age with those transitioning to older age though it is unclear the risk of malignancy in these two populations is similar. Although a degree of cancer risk in this population may be attributed to older age and duration of disease, when these factors have been considered, several cancers still are associated with premature onset and increased frequency. Older-onset IBD patients are susceptible to earlier-onset CRC. Additionally, thiopurine use in the elderly is associated with higher than expected risk of NHL, NMSC, and urinary tract cancer. The challenge in advanced age is to mitigate the increased susceptibility to malignancy with appropriate treatment strategies. The paucity of cancer therapy trials in elderly makes cancer prevention strategies imperative. As more studies examine populations of elderly IBD and the development of malignancy, age-specific cancer screening guidelines may be necessary.
Conflict of interest
LPB has received consulting fees from Merck, AbbVie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, Pfizer, HAC-Pharma, Index Pharmaceuticals, Amgen, Sandoz, and Forward Pharma GmbH. LPB has received lecture fees from Merck, AbbVie, Takeda, Janssen, Takeda, Ferring, Norgine, Tillots, Vifor, Therakos, Mitsubishi, and HAC-pharma.
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a Division of Gastroenterology, University of Arizona College of Medicine, Tucson, AZ, United States
b University of Arizona Center of Aging, Department of Medicine, Tucson, AZ, United States
c Hematology/Oncology, University of Arizona College of Medicine, Tucson, AZ, United States
d Public Health, Epidemiology and Health Economics, EPIMAD Registery, Regional House of Clinical Research, Regional University Hospital, Lille Cedex, France
e Lille Inflammation Research International Center, LIRIC-UMR 995 Inserm, Lille University 2, Lille University Hospital, Lille University, France
f Inserm U954 and Department of Gastroenterology, Nancy University Hospital, Lorraine University, Vandœuvre-lès-Nancy, France
⁎ Corresponding author at: Banner University Medical Center, Section of Gastroenterology, 1501 N. Campbell Avenue, Tucson, AZ 85724, United States. Tel.: +1 520 626 6119; fax: +1 520 874 7133.
☆ This work was completed at the University of Arizona in Tucson, AZ.
© 2016 Editrice Gastroenterologica Italiana S.r.l., Published by Elsevier B.V.