Alimentary tract and pancreas

                                     Alimentarni trakt i pankreas

                                     ARCH GASTROENTEROHEPATOL 2000: 19 ( No 2 – 3 ):

                                     PERSONAL VIEW

Mihailo Alic               A new look at Crohn ^, s disease

                                    Novi pogled na Crohn-ovu bolest

                                    (  accepted February 15th, 2000 )

Address correspondence to: Mihailo Alic, Independent IBD Researcher

                                                3720 Balboa St.

                                                E-mail: [email protected]

Introduction

A new millennium approaching is an opportune time to review what we know and have achieved, but also to pry open the door of the future and prognosticate where we could go from here. Crohn's disease is a serious chronic condition that belongs to the inflammatory bowel disease (IBD) group. It can affect any part of gastrointestinal tract from mouth to anus, has various extraintestinal manifestations, and results in high morbidity and need for repeated, non-curative surgery. Since it mainly affects young adults and has a chronic and progressive course, this disease presents a significant social and economic burden. Although cases consistent with Crohn's disease have been described much earlier, its recorded history starts with the paper presenting 14 cases of "terminal ileitis" published in 1932 (1). The disease was later named after Dr. Burrill Crohn who happened to be the first on the alphabetically arranged authorship of this seminal paper. Since then, its definition has been expanded to include transmural inflammation of both the small intestine and colon, but today we know that it can affect any other part of the digestive tract as well. First epidemiological studies started in the 1950s, but it was not until the mid- 1960s, when the rise in incidence in Western Europe and the U.S. was observed that it attracted a broader interest. Despite of more than a half a century of research, its etiology is still uncertain, diagnosis and treatment far from satisfactory.

After a decade of rapid increase in Crohn's disease incidence, it was thought that this has leveled off during the 1980s. However, the most recent studies (2-5) call for re-evaluation of our wishful thinking since they report continuing rise in incidence. A study from Croatia has shown a ten-fold increase in incidence in the period from 1973 to 1994, approaching the rates previously reported in Western Europe (2). Canadian study recorded the highest incidence ever of 14.6/100,000 and argued that the age distribution of prevalence indicated recent increase in incidence (3). Reports that the incidence of pediatric cases in Sweden more than doubled in less than a decade were consistent with observations from Wales, Scotland and Canada (4). Finally, a study from Israel has found that incidence almost doubled compared to a study from the 1980s (5). Although data for most European countries with long history of this disease have not shown increase in recent years, south European countries (Spain, Italy and Greece) have observed incidence rise, with rates becoming comparable to those of the more developed countries.

Many review papers have summarized our current knowledge and reader should refer to them as needed. This article, on the other hand, will discuss topics that were often skipped either because of their controversy or since they present a forward look into issues for which definitive answers are not available at present time. Although it has been postulated that Crohn's disease is influenced both by genetic and environmental factors, the global increase in incidence and ability to prevent discovered environmental risk factors has directed my focus.
 

Is it mildly communicable?

The observation that the number of Crohn's patient spouses developing the same disease during marriage is greater than expected by chance has been slowly gaining acceptance. Introduced cautiously in the 1980s by the U.K. researchers (6), supported by studies from the U.S. (7) and France (8) in the early 1990s, this has recently made the title prominence in follow-up study from France and Belgium (9). Initial study from 1994 reported 10 IBD cases in married couples of Northwestern France and Belgian county of Liege. The recent study has found 14 in NW France alone, and 13 in all of Belgium, concluding that this number is higher than expected by chance both for NW France (p < 0.00001) and Belgium (p < 0.05). Half of the IBD couples were concordant for Crohn's disease, while the other half was shared between mixed couples and couples concordant for ulcerative colitis. French IBD register used for these studies has been established in 1988 as a detailed database of all reported cases from NW France, and 1994 study reported participation of 95% of all local gastroenterologists.

Although statistical significance was not reached due to a small number of spouses and first degree relatives, a study of increased intestinal permeability, believed to be an early event in pathogenesis of Crohn's disease, has shown a trend where length of association and frequency of contacts with a patient correlated to abnormal permeability (10). Another large family study (11) has found the absence of a typical family pattern and high prevalence of increased permeability in spouses, pointing towards shared environmental factor(s).

In the view of Crohn's disease rarity (roughly 1 in a 1000 population), its communicability has been suspected in clusters of unrelated affected individuals that have shared a close relationship or a household prior to the disease onset (12, 13). Four young adult females who have been close friends in their teens have developed Crohn's disease several years after parting to attend college (12). Geographical  clusters have also been reported (14-16). The most investigated cluster was in the parish of Blockley, U.K. (16), where the observed number of mostly unrelated patients (twelve) was much higher than expected (less than two) for parish population of about 2000, with no excess of patients in adjacent parishes. The parish has its own water supply, but extensive microbiological sampling have not identified a possible waterborne infectious agent. A study from Holland investigating water supply and disease incidence was also not able to establish the link between them (17). Blockley study was also negative for trace metal deficiencies in the soil and HLA genetic typing of patients. Most recently, a cluster was discovered in a small town in southeast Brazil (18, unpublished data), with 9 patients in a community of 15 000, in a country that has a much lower prevalence compared to the developed countries. Contacts between patients before the onset of their symptoms were not investigated in any of the above geographical clusters.

Looking for factors in postoperative recurrence of Crohn's disease a study examined intestinal mucosal inflammation induced by the contact with intestinal fluids in surgically excluded ileum (19). It was shown that recurrence may be triggered by agents in the fecal stream, pointing to fecal-oral route in suspected transmission.

Familial Crohn's disease has been always interpreted as a sign of genetic factors, but some reports have shown that temporal succession of occurrence may indicate infectious origin as well. A family where the father, the mother, and their 4 children all had Crohn's disease was described (20). The wife of one of the sons subsequently developed the disease as well. In another family, 7 of 11 children developed Crohn's disease, although neither parent was affected. There was no Crohn's disease in previous generations of either family, and no linkage to HLA haplotypes was found. The authors concluded, although they were unable to identify any common infectious agent, that data presents circumstantial evidence in favor of infectious etiology in these two clusters.

Identical twins are significantly more likely to be concordant for IBD than non-identical twins. Nevertheless, even in identical twins the study has shown concordance of only 17%, which suggests that non-genetic causes are more important in the development of Crohn's disease and ulcerative colitis (21).

In September 1996 issue of Gastroenterology where several articles on familial Crohn's disease have been published, the editorial by David Sachar (22) recognized that studies at hand were not able to confirm a genetic basis and do not rule out an infectious or other environmental cause for familiarity. Studies that made stronger claims for genetic influence were the ones that interpreted earlier onset in subsequent generations of familial cases as "genetic anticipation" by analogy with known autosomal-dominant inherited diseases. Unfortunately, later studies of this phenomenon found no evidence of genetic anticipation or genomic imprinting of age at diagnosis (23, 24). A letter from a physician commenting on this issue has explained earlier onset as a result of higher probability of acquiring an infectious agent due to increased frequency of contacts with a patient in familial setting (13).
 

Which are the known and less known risk factors?

The only well established risk factor so far is smoking. The use of oral contraceptives has been implicated, but studies differ in evaluating the risk associated with this factor. In looking for temporal trends I have collected studies reporting age and sex distribution of incidence over extended period of time, and established a correlation between oral contraceptive use and Crohn's disease female to male (F/M) incidence ratio (25). This was further supported with data from Japan where oral contraceptives were banned until very recently, and where F/M incidence ratio showed temporal constancy, contrasting the rest of the world where it followed trends in oral contraceptive use (26). The etiological hypothesis behind the studies of smoking and oral contraceptives as risk factors is that both may have similar effect on pathogenesis and disease exacerbation by enhancing procoagulant activity shown to exist in Crohn's disease.

A correlation of Crohn's disease with higher socioeconomic status is also fairly established (27). A less known factor that may be associated with socioeconomic status is workforce participation. Investigating sex and race trends in temporal and geographic workforce composition, I have established that they correlated with Crohn's disease F/M incidence ratios (28). It appeared that being employed or away from home increases one's chances of developing Crohn's disease. I have investigated protective effect of staying at home on a female 30-39 years old age group, since they are most likely to stay home due to childbearing and time spent bringing children up. Indeed, for the U.S. study covering the longest interval of time (1940-1993) although F/M incidence ratio was since the 1960s in majority of time periods and for other age groups greater than one, for this age group in all periods it was less than one (29, unpublished data). The same trend may be observed in many other studies.

Earlier studies have noticed a greater proportion of single persons among patients than found in general population. I have correlated Olmsted study (29) incidence data for 4 age groups (20-59) and 4 decades (1954-93) for males and females to the percentage of that group in U.S. population being married in the same time period and results have shown negative correlation as expected (unpublished data). From a common experience we know that for social reasons single people prefer to live in the cities rather than in suburbs or rural communities. A study from Holland reported lower incidence and much lower F/M incidence ratio for suburban (3.0 per 100,000 and 0.54 respectively) and agrarian (3.6 and 0.59) communities compared to the urban (5.1 and 2.2) population of the same region (17). Another important finding of this study was that incidence did not correlate with population density or different water supplies in these communities as some may speculate. Assuming a higher percentage of married people in suburbs than in the city and that married women are more likely than single ones to stay at home and not be in the workforce (while this is opposite for men), recorded lower F/M incidence ratio in suburbs further supports influence of the risk factors we examined.

Childhood events is another area of investigation for risk factors. Several studies were able to correlate Crohn's disease incidence with bottle feeding in infants and availability of residential hot water in childhood. The etiological hypothesis behind these studies is that early childhood events modulate immunological response to enteric pathogens later in life, predisposing some individuals to Crohn's disease. This predisposition is assumed to be inherited in familial cases, or acquired in sporadic cases.

Most recently I have hypothesized that a major risk factor may be contact with a patient in familial and communal cases and eating out in sporadic cases, based on the possibility of fecal-oral transmission of a still unknown infectious agent and matching of eating out and incidence trends (27, 30). As many authors have suggested, an infectious agent may induce a persistent low-grade inflammation or just be a triggering event for the predisposed host immune system which perpetuates the inflammation.
 

Could we diagnose some patients earlier?

A delay from the onset of symptoms to diagnosis has been well recognized in Crohn's disease. Current diagnostic methods are such that an average patient suffers symptoms for a couple of years before the right diagnosis is made, while also withstanding "it's all in your head" attitude from doctors, family and friends. Actual numbers in different studies range between 20 and 50 percent of the patients diagnosed later than 1 year after the onset of symptoms (31, 2, 32). Diagnosis of definitive Crohn's disease has relied for decades on endoscopy of parts of the digestive tract that can be reached or radiographic findings of disturbed bowel morphology, which may be a later stage in transmural inflammation. A recent study tried to explain the delay to diagnosis to be due to delays in consulting the general practitioner and of the referral to gastroenterologist (33). However, the group from Cedars-Sinai Medical Center, known for the highest number of IBD patients seen in the U.S., has recently published findings that the delay is a prolonged prodromal period with negative investigations (34). This indicates that even with appropriate workup Crohn's disease in the portion of patients may not be diagnosed for extended periods of time due to its insidious onset and  insufficient sensitivity of our current diagnostic tools. The last two decades of the 20th century has brought us several promising new diagnostic methods: leukocyte scintigraphy, doppler ultrasound, fecal calprotectin (35), Anti-Saccharomyces cerevisiae mannan antibodies (ASCA) and platelet activating factor (36). Most of them are still in the research phase, although clinicians have occasional access to them.

Another important finding of the Cedars-Sinai's study was that a quarter of patients in prodromal period were given a wrong diagnosis of Irritable bowel syndrome (IBS). With the development of the Roma Criteria, IBS is being more defined than previously, yet potential overlap with undiagnosed Crohn's disease still exists. IBS is an example of a disease for which there are no laboratory tests, and diagnosis is based on criteria that relies on clinical picture. Considering diagnostic delay in the portion of Crohn's disease patients, similar criteria should be developed to establish the probable diagnosis. Indeed, clinical picture of the early Crohn's disease should be easily distinguishable from IBS since its presentation may be augmented with known extraintestinal manifestations (oral and skin lesions, arthritis, unexplained malaise, occasional fever, anemia, psoriasis), less studied symptoms (excessive flatulence (34), muscle tenderness and fatigue (37)), or rarely reported and subtle signs (loss of hair (38) and subcutaneous fat (39)) to name a few. Not all of these symptoms may present before the definitive diagnosis, but they may be "red flags" indicating more than just IBS.

In the absence of early markers, epidemiology should be used to investigate symptoms prior to definitive diagnosis, establishing criteria for probable diagnosis, as Cedars-Sinai's study may be considered. Another study in this direction has established that after 8 years of follow-up, 80 percent of patients initially diagnosed with indeterminate colitis were re-classified as Crohn's disease or ulcerative colitis (40). Symptoms indicative of Crohn's disease were fever at onset and extra-intestinal complications.

For a serious disease with an insidious onset as Crohn's, options should be examined for an early treatment based on the probable diagnosis. In many other diseases, initial period has been shown to be the time when the course and natural history can be influenced the most, and this window of opportunity should not be wasted because of the lack of early diagnostic tools.
 

Should we include newly diagnosed patients in clinical trials?

The standard treatment for Crohn's disease includes 5-aminosalicylic acid (5-ASA) products, oral steroids, immunomodulators and, when all this fails to control the symptoms, surgery. This regiment, starting from less effective ("step-up approach") has been used for several decades in mostly unchanged form. To minimize side effects, evolution of these agents led to changing their delivery from systemic to topical with pH modified preparations that deliver its effect to a targeted part of the intestine. Topical 5-ASA products have been in use for some time, oral steroids are awaiting FDA approval, while such immunomodulators are still in the early research phase. However, current approach has never been satisfactory, and as many as 40 percent of patients required surgery only three years after diagnosis. Because of this, and based on accumulated experience and safety record of immunomodulators used, the clinical symposium "Immunomodulators for new onset Crohn's disease: first line therapy or fall back position" at Digestive Disease Week (Orlando, Florida, 1999) discussed changing the approach to include immunomodulators early on in the treatment. The expectation was that this approach would minimize steroid use and reduce their side effects, prolong remission and delay need for surgery, changing the natural history of the disease and improving patients' quality of life while reducing treatment cost (41). Initial results reported were quite encouraging: the relapse rate at 18 months was only 9% in the group treated with immunomodulators plus steroids, compared with a 47% relapse rate in steroid alone group, while cumulative steroid dose and time off steroids were significantly better in the former group. The most recent study by Korelitz et. al. has reported almost 30 years of experience with immunomodulators in Crohn's disease, further testifying to their safety (42).

Emphasizing the importance of newly diagnosed patients, Crohn's and Colitis Foundation of Canada has established The IBD Network, to enable researchers' access to these patients, since early-stage disease may holds etiological and pathogenesis clues harder discernible in well established and complicated later stages.

A seasoned researcher, in his editorial discussing antibiotics use in different chronic intestinal diseases of animals and humans and their potential in Crohn's disease also makes the point that patients need to be stratified in clinical trials to make results more meaningful, and that there are patients whose disease has progressed beyond medical resolution (43). Historically, new and investigational treatments were first tried in refractory patients, but as Van Kruiningen states, failure of a therapy in end-stage "irreversible disease" may not be a fair assessment of the treatment's potential. Recent animal models have shown that novel anti-cytokine treatments can resolve an early-stage disease but are ineffective in the late stage (44).
 

Conclusions

Crohn's disease has, in spite of its long history, remained a disease of enigmatic etiology, less then perfect diagnostic and mostly palliative treatment resulting in need for repeated surgery in considerable number of patients. Its toll on patients and health system is considerable because of the highest incidence among young adults, reduced work capacity in their most productive years, and life long need for therapy. Because of all these reasons, we need bold new breakthroughs to move from this point at the turn of the century.

Majority of epidemiological studies so far were descriptive, reporting data on incidence, prevalence and its age and sex distribution. As important as collecting data is, analyzing it for trends should be the next step in our quest for better understanding of risk factors and in formulating etiological hypotheses.

Patients are reluctant to consider the evidence of its possible communicability, feeling that they are already isolated enough and don't need additional reasons to be avoided by friends and family. Clinicians and patient's organizations are also slow to recognize this research. Although the putative infectious agent has yet not been identified, the message of a potential communicability should not be confined to the research community but cautiously introduced into clinical practice in order to possibly prevent or reduce occurrence of familial and communal Crohn's disease (13).

Novel diagnostic tests need to be explored in their ability to differentiate Crohn's disease from other intestinal disorders and reveal the disease prior to standard later-stage tests currently in use. Emphasis on earlier treatment holds a promise of stopping or reversing the disease course and changing the natural history, while further insights into its etiology should lead towards finding the cure in the new millennium.
 

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