mild clinical behaviour of Crohn disease in elderly patients in a latin american country : a case-control study

1Inflammatory Bowel Disease Clinic, Department of Gastroenterology. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; 2Pan American Crohns and Colitis Organisation (PANCCO) Correspondence: Dr Jesús K Yamamoto-Furusho, Head of the Inflammatory Bowel Disease Clinic, Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. President of PANCCO: Vasco de Quiroga 15, Colonia Sección XVI, Tlalpan, CP 14000, Mexico City, Mexico. Telephone 52-55-55733418, fax 52-55-56550942, e-mail kazuofurusho@hotmail.com Received for publication April 6, 2015. Accepted April 7, 2015 Inflammatory bowel disease (IBD) includes Crohn disease (CD) and ulcerative colitis (UC). Little is known regarding its multifactorial and etiopathogenic mechanisms, of which three main factors – genetics, immunity and the environment – are involved (1). The course of CD is characterized by fluctuating clinical behaviour, which is influenced by various factors including hospitalization rates, treatment response, postsurgical recurrence, relapses, exacerbations and older age at diagnosis. In 2014, the world’s population was estimated to be 7.2 billion and, from this number, 8% appeared to be older adults (2); however, by 2050, the number of older persons worldwide is projected to more than double to two billion (3). Population aging is occurring in every country, although each country is at a different stage of this transition (4). For example, by 2050, Mexico’s aged are projected to represent 27.7% of the population (5), while the same demographic in the United States is expected to represent 20.3% (6). This fast-growing elderly population represents part of an age group in which important physiological changes occur, including immune deficiency (peculiar to old age), increased frequency of comorbidities and polypharmacy. These characteristics place this age group at higher risk, which undoubtedly affects the clinical course of CD. Despite the fact that fewer than onethird of epidemiological studies have documented a bimodal distribution of IBD incidence with a second peak between 60 and 70 years of age (7), elderly patients with CD should not be treated with aggressive JK Yamamoto-Furusho, A Sarmiento-Aguilar. Mild clinical behaviour of Crohn disease in elderly patients in a Latin American country: A case-control study. Can J Gastroenterol Hepatol 2015;29(8):435-439.

Several studies have proposed that elderly patients diagnosed with CD have a less aggressive clinical course compared with those diagnosed at a younger age.This suggests that gastrointestinal tract changes occur with aging and produce dietary shifts among older individuals, alterations in gastrointestinal motility and gastric pH due to mucosal atrophy, increased intestinal permeability and changes in the gut microbiota associated with aging that may influence host-inflammatory responses (27)(28)(29)(30).For example, the risk for surgery decreases with older age at diagnosis, disease distribution and history of cigarette smoking (31).In CD, the prevalence of diarrhea, abdominal pain, extraintestinal manifestations, weight loss and fever decreases in older or elderly patients (18,32).A large population-based cohort study involving a French population that included 841 IBD patients concluded that the clinical course is mild in elderly onset IBD patients due to disease behaviour, and was reported to remain stable in 91% of patients with elderly onset CD after a median follow-up period of six years (33).Other studies have concluded that the clinical manifestations of the first flare of CD are similar in the >60 years of age and younger age groups (18), characterized by the predominance of inflammatory behaviour (18,21,34,35).To date, no data from genetic studies have been published regarding elderly onset IBD variants to further define the contribution of specific gene associations with elderly onset IBD; however, the role of genetic factors is believed to be greater in pediatric-onset than in late-onset IBD (18).It has also been found that older patients with IBD may have an increased susceptibility to gastrointestinal infection because the response to stress in the setting of acute inflammation may be altered or blunted (28,30,36).
There are some key features considered for elderly onset CD: inflammatory disease behaviour, colonic or ileocolonic disease location, uncommon family history of IBD, and reduced progression to penetrating or stricturing disease phenotypes (37).Prompted by the lack of data from Latin America evaluating the clinical behaviour of CD in the elderly, the aim of the present study was to evaluate the clinical course of elderly compared with younger-onset CD in the Mexican population.

METHODS
The present analysis was a retrospective case-control study that included 132 patients with histopathological diagnosis of CD between 1983 and 2013 in the IBD clinic of a tertiary care centre (National Institute of Medical Sciences and Nutrition "Salvador Zubirán", Mexico).Clinical records were reviewed and a database including the following variables was constructed: sex, age, place of birth, place of residence, weight, height and body mass index; family history of IBD and family or personal history of other immune-mediated diseases; pack-years of smoking (number of cigarettes smoked daily multiplied by the years of smoking divided by 20); history of appendectomy or tonsillectomy; intake of nonsteroidal anti-inflammatory drugs; thrombosis and its location (upper limbs, lower limbs, pulmonary thromboembolism, acute coronary syndrome or vascular brain disease); age at diagnosis; disease phenotype (inflammatory, stricturing or fistulizing); location (terminal ileum, ileocolonic, colonic, upper digestive tract); clinical course (initially active followed by long-term remission, intermittent activity (less or one relapse a year) or continuous activity (≥2 relapses per year); extraintestinal manifestations such as arthritis, arthralgia, ankylosing spondylitis, sacroiliitis, sclerosing cholangitis, pyoderma gangrenosum, erythema nodosum or uveitis; number of hospitalizations; treatment response and reasons for lack of response response and surgical treatment.Other variables included were: postsurgical recurrence; current CD treatment; and clinical activity or remission of the disease at the time of evaluation.The present research was approved by the local ethics committee.

Statistical analysis
Demographic, clinical, and laboratory characteristics are presented as mean ±SD, median and range.The Fisher's exact probability test was used to compare categorical variables when the number of expected subjects was <5 and by the χ 2 test otherwise.The unpaired t test was used to compare differences in the means of continuous variables.Nonparametric variables in independent samples were compared using the Mann-Whitney U test.ORs and 95% CIs were calculated using univariate and multivariate analyses adjusted for age, sex, extent of disease, Mayo Score, C-reactive protein level and current medical treatment.P≤0.05 was considered to be statistically significant and Bonferroni correction for P value was applied for multiple comparison calculated as α/n.All statistical analyses were performed using SPSS version 17.0 (IBM Corporation, USA).

RESULTS
A total of 132 patients were evaluated 73 (55.3%) men and 59 (44.7%) women divided in two groups: 27 (20.5%)who were diagnosed at >60 years of age (cases) and 105 (79.5%) who were diagnosed at ≤60 years of age (controls).Detailed demographic and clinical characteristics are summarized in Table 1 and 2, respectively.

Factors influencing the clinical course of CD in elderly patients
The univariate analysis found that the following factors influenced the clinical course of CD in elderly patients: female sex (OR 2.55 [CI 95% 1.06 to 6.10]; P=0.02); a less frequent colonic location (OR=0.22

DISCUSSION
The present study clearly showed a milder clinical course of CD in elderly patients, and was the first performed in the Latin American population.We found that women were predominantly affected, similar to a previous study (the EPIMAD registry [19]) and one study from the United States Military Health Care Population (38).Smoking was associated with increased risk for CD and worse outcomes over the disease course (18,39,40) and, interestingly, our study found a higher proportion of smoking patients in the young group than in the elderly group, which could have also influenced the different outcomes.In the present study, CD patients had a less frequent colonic location and had a more common inflammatory pattern, compared with the French registry, which found that pure colonic disease and inflammatory behaviour were the most frequent phenotypes (14).A study from Hungary (41) found pure colonic disease and a more common stenosing pattern.A retrospective study concluded that older and younger patients underwent surgery in similar percentages (83% versus 77%) (42), a finding similar to that reported in our population (66.6% versus 74.28%).
The elderly patients in the present study exhibited mild clinical disease behaviour, characterized by initially active disease followed by longterm clinical remission, better response to medical treatment and more use of sulfasalazine and less use of azathioprine.These findings were also reported in other studies.For example, the Hungarian study (41) found that their elderly population required less systemic steroids compared with their younger groups.A French study (43) concluded that immunosuppressants were more frequently required in the childhoodonset group than in the elderly onset patients.In this study, it was also found that older adults were less likely to require immunosuppressants or readmission for CD flares compared with younger patients (44).It has even been concluded that corticosteroid response is similar in older and younger patients hospitalized for IBD, but older corticosteroidresponsive patients are less likely to be treated with an anti-tumour necrosis factor agent than younger patients (45).Furthermore, care providers should be aware of polypharmacy and its potential for drug interactions because it has been shown that the prevalence of medication use is higher among patients with IBD than matched members of the general population, particularly the use of analgesic and psychiatric drugs (46).Regarding the extraintestinal manifestations of IBD, thromboembolic events represent a major cause of morbidity and mortality (47,48), and it is known that IBD is an independent risk factor for thromboembolic phenomena (49).One study also found a more frequent prevalence of venous thromboembolism (TE) in elderly patients with IBD (6.15%) compared with the control group (1.62%) (50).This correlates with the fact that our elderly patients tended to present with pulmonary TE more frequently.Other studies have concluded that the most frequent thromboembolic complications are deep vein thromboses and pulmonary emboli, and that this event can occur as a postsurgical complication or spontaneous event (48).
This less agressive clinical behaviour is gradually occupying an important place among the diverse factors that influence the decisionmaking process regarding the therapeutic approach to an elderly patient   diagnosed with CD.Nevertheless, it should not be considered without taking into account all other aspects that play a role in each specific case.For example, one current approach to drug therapy in the elderly is to 'start low; go slow' and then reassess their candidacy for more aggressive therapy (biologics, apheresis, surgery), and not treat or exclude patients on the basis of age alone (51).In conclusion, elderly patients with CD had a mild disease course characterized by long-term remission, less use of aggressive therapy, such as thiopurines and anti-tumour necrosis factor agents, and better response to medical treatment.

DISCLOSURES:
The authors have no financial disclosures or conflicts of interest to declare.

CONCLUSIONS
Elderly patients had a less aggressive clinical course compared with younger patients, and commonly achieved remission without the need of escalating the treatment beyond aminosalycilates.There are no data from Latin America that evaluate the clinical behaviour of CD in elderly patients.The present study showed that elderly patients with CD had a mild clinical course characterized by the lack of escalation to immunosuppressive and anti-tumour necrosis factor therapy, as well as long-term remission.