- Email: [email protected]
Seasonality in IBD: Do we really know about it?
A. Aratari et al. / Digestive and Liver Disease 38 (2006) 319–323 [22] Kangro HO, Chong SKF, Hardiman B. A prospective study of viral and mycoplasma infections in chronic inflammatory bowel disease. Gastroenterology 1990;98:549–53. [23] Scott FD. Seasonal variations in host susceptibility and cycles of certain infectious diseases. Em Infect Dis 2001;7:369–74. [24] Velasco AC, Mateos ML, Mas G, Pedraza A, Diez M, Gutierrez A. Three-year prospective study of intestinal pathogens in Madrid. Spain J Clin Microbiol 1984;20:290–2. [25] Begue RE, Neill MA, Papa EF, Dennehy PH. A prospective study of Shiga-like toxin-associated diarrhoea in a pediatric population. J Pediatr Gastroenterol Nutr 1994;19:64–9. [26] Hugot JP, Alberti C, Berrebi D, Bingen E, Cezard JP. Crohn’s disease: the cold chain hypothesis. Lancet 2003;362:2012–5. [27] Naser SA, Ghobrial G, Ramero C, Valentie JF. Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn’s disease. Lancet 2004;364:1039–44. [28] Douglas AS, Strachan DP, Maxwell JD. Seasonality of tuberculosis: the reverse of the other respiratory diseases in the UK. Thorax 1996;51:944–6. [29] Rubin DT, Hanauer SB. Smoking and inflammatory bowel disease. Eur J Gastroenterol Hepatol 2004;12:855–62. [30] Chandra S, Chaloupka FJ. Seasonality in cigarette sales: patterns and implications for tobacco control. Tabacco Control 2003;12:105–7. [31] Di Franza JR, Savageau JA, Fletcher KE, Fletcher K, Ockene JK, McNeill AD, et al. The development of symptoms of tobacco dependence: 30 months follow-up data from the DANDY study. Tobacco Control 2002;11:228–35. [32] Felder JB, Korelits BI, Rajapakse R, Schwarz S, Horatagis AP, Gleim G. Effects of anti-inflammatory drugs on inflammatory bowel disease: a case control study. Am J Gastroenterol 2000;95:1859–61. [33] Fleming DM, Ross AM, Cross KW, Kendall H. The reducing incidence of respiratory tract infection and its relation to antibiotics prescribing. Br J Gen Pract 2003;53:778–83. [34] Aikman H. The association between arthritis and the weather. Int J Biometeorol 1997;40:192–9. [35] Godet PG, May GR, Sutherland LR. Meta-analysis of the role of oral contraceptive agents in inflammatory bowel disease. Gut 1995;37:668–73. [36] Rodgers JL, Udry JR. The season-of-birth paradox. Soc Biol 1988;35:171–85. [37] Nelson RJ. Seasonal immune function and sickness responses. Trends Immunol 2004;25:187–92.
323
[38] Shirai T, Magara KK, Motohashi S, Yamashita M, Kimura M, Suwazomo Y, et al. TH1-biased immunity induced by exposure to Antarctic winter. J Allergy Clin Immunol 2003;111:1353–60. [39] Termorshuizen F, Garssen J, Norval M, Koulu L, Laihia J, Leino L, et al. A review of study on effects of ultraviolet irradiation on the resistance to infections: evidence from rodent infection models and verification by experimental and observational human studies. Int Immunopharmacol 2002;2:263–75. [40] Termorshuizen F, Geskus RB, Roos MT, Coutinho RA, Van Loveren H. Seasonal influences on immunological parameters in HIV-infected homosexual men searching for immunomodulating effects of sunlight. Int J Hyg Environ Health 2002;205:379–84. [41] McCutcheon M. Studies on the locomotion of leukocytes. The effect of temperature on the rate of locomotion of human neutrophilic leukocytes in vitro. Am J Physiol 1923;66:185–90. [42] Mandeville RP, Wilkinson PC. Locomotion of human lymphoblasts towards glucose and other sugars. Effects of pH, temperature, and oxygen. Clin Exp Immunol 1982;36:733–42. [43] Kasper S, Rosenthal NE, Barberi S, Williams A, Tamarkin L, Rogers SL, et al. Psychiatry. Immunological correlates of seasonal fluctuations in mood and behaviour and their relationship to phototherapy. Psychiatry Res 1991;36:253–64. [44] MacMurray JP, Barker JP, Armstrong JD, Bozzetti LP, Kuhn IN. Circannual changes in immune function. Life Sci 1983;32:2360–70. [45] Linder M, Larson M, Prellner T, Brattsand R, Laitinen LA. Seasonal variation in the function of blood monocytes obtained from healthy non smokers, asymptomatic smokers, and smokers with chronic bronchitis. Chronobiol Int 1994;11:266–72. [46] Maes M, Stevens W, Scharpe S, Bosmans E, De Meyer F, D’Hondt P, et al. Seasonal variations in peripheral blood leukocyte subsets and in serum IL-6, and soluble IL-2 and IL-6 receptor concentrations in normal volunteers. Experientia 1994;50:821–9. [47] Paigen B, Ward E, Reilly A, Houten L, Gurtoo HL, Minowada J, et al. Seasonal variation of aryl hydrocarbon hydroxylase activity in human lymphocytes. Cancer Res 1981;41:2757–61. [48] Boctor F, Charmy R, Cooper E. Seasonal differences in the rythmicity of human male and female lymphocyte blastogenic responses. Immunol Invest 1989;18:775–84. [49] Maestroni GJ. The immunotherapeutic potential of melatonine. Expert Opin Investig Drugs 2001;10:467–76. [50] Nelson RJ, Drazen DL. Melatonine mediates seasonal adjustments in immune function. Reprod Nutr Dev 1999;39:383–98.
Commentary
Seasonality in IBD: Do we really know about it? R.W. Stockbrugger ∗ Department of Gastroenterology and Hepatology, University Hospital Maastricht, Debyelaan 25, 6202 Maastricht, The Netherlands Available online 23 March 2006
1. Introduction
∗
Tel.: +31 43 38 75021; fax: +31 43 38 75006. E-mail address: [email protected]
On pages 319 to 323 an interesting article by Aratari et al. [1] is published which deals with the seasonal variations in the onset of symptoms in Crohn’s disease, reporting results
324
R.W. Stockbrugger / Digestive and Liver Disease 38 (2006) 323–325
from three clinical centres in Italy. The article contains a good reference list covering the topic of seasonality for a number of other disorders, the literature concerning IBD under this aspect, and consequently a good number of studies and reviews on proven or putative risk factors of IBD. What then is the reason for the impetus to study seasonality in disorders – and here especially in IBD – from time to time? There are a number of reasons: first of all the lacking knowledge about the aetiology and/or pathogenesis of a certain disease; then, the search for factors that can elicit flares, recurrences, complications (or their opposite); all these in order to either prevent the disease or to improve the possibilities of management. IBD is a condition where the need for seasonality research is perfectly in place. The recent years have proven that neither genetic nor environmental factors alone are sufficient to explain the pathogenesis of the two main disorders UC and CD (which probably are different from each other in their respective aetio-pathogenetic pattern). Thus, the hunt is still open to catch one or several causative or modulating factors in the environmental field, some of which may be connected with characteristics of climate and/or biorhythms. What has been the result of studies into the seasonality of IBD so far? With a few words: not much and little consistent, as rightly described in the introduction of the Aratari paper; this paper also leaves behind, in my opinion, more open questions than answers. The reason for this frustrating result has to be sought in two areas: (1) the lack of a unitary aetio-pathogenetic concept and (2) deficiencies in epidemiological methods.
2. Concepts and hypotheses Looking at the onset and course of whatever disorder, one has to accept that exogenous pathogenetic factors can act in differential ways: factors co-responsible for the initiation of a disorder may have a smaller/greater influence (or none at all) on recurrences and complications during disease course. Theoretically, disorders may also be initiated by genetic factors, but in the later course mainly come under the influence of exogenous events. To be honest, a large number of theoretical models could be constructed in this way. Planning studies such as those about seasonality of IBD, one or several clear hypotheses have to be formulated, preferably on the basis of theoretical premises (inductive) or previous findings (deductive). Studies started without such hypotheses can be called “exploratory”, “pilot” or similar. They will rarely give convincing evidence but may trigger the wish for more systematic approaches. Regarding the study of Aratari et al., the two main results are, that in 353 patients with IBD the onset of symptoms occurred more frequently in spring and summer than in the remaining seasons (after a sub-division into UC and CD, a statistical significance only remains for CD), and there were
more smokers in the CD patients than in UC at onset of the disease. In a recent study by Auslander et al. [2], a huge NorthAmerican database of endoscopic procedures was questioned in a sophisticated way for the proportion of colonoscopies and sigmoidoscopies employed for patients with IBD (but not including those performed for cancer surveillance). Again, taking both IBD sub-diseases together, no seasonality could be discovered; however, taking CD alone, there were four more or less distinct peaks with higher frequency of colonoscopies (September 2000, May 2001, February 2002 and November 2002). In the discussion, the authors shortly speculate whether GI- or other infections could be responsible for the temporary increase of flares. In a third study by Van Ranst et al. [3] from a 1025 patients strong Belgian database with 5125 non-IBD patient hospital controls, it was observed that the month of birth was associated with the later development of Crohn’s disease: birth in April and August was a risk factor and birth in June appeared to be protective. Following the above discussion, the three mentioned studies belong to the category “exploratory”, as they have no formulated questions or hypotheses at the onset of data collection and analysis. Like in many such cases there was a hope for some more or less spectacular finding, that would have led to follow-up investigations. In addition, the few more or less significant evidences (four irregularly distributed seasonal peaks in the Auslander study; increased frequency of CD onset during spring and summer in the Aratari study) do not carry such biological potential, that the authors remain with them too long in their relatively non-specific discussions. However, they do not seem to be convinced that there is no seasonality at all. After the reader is left with this mainly negative result, the question arises whether the quasi non-seasonality of IBD should finally be accepted, or whether the study methods hitherto applied were not really appropriate to answer a still unanswered question. I would go for the latter option and will explain why.
3. Methodological comments The Aratari study is a retrospective study on a prospectively collected patients cohort. The authors state that the diagnosis of these patients has been made according to “standard criteria”; however, we do not learn in what way the topic of the present evaluation “onset of symptoms” has been ascertained at the first diagnosis. The authors present a very large time range for the period between first symptoms and diagnosis (up to 385 months) and the reader has really to doubt whether the patient memory was good enough to indicate month or even season of first symptoms after such time delays. An important argument about the adequacy of the patient population investigated arises from the size of the patient material: three university hospital pop-
R.W. Stockbrugger / Digestive and Liver Disease 38 (2006) 323–325
ulations were included over 10 years. The resulting 425 patients (about 140 patients per centre or 14 patients per centre and year) cannot be representative for the surrounding catchment areas and probably not even for the totality of newly diagnosed patients in each of the centres! The suspicion must be that these patients are selected to severity, social status, living area or whatever other factor that could interfere with representiveness. Certainly this approach is not population-based, and therefore conclusions cannot be generally accepted for the two disorders investigated for the purpose of aetio-pathogenesis and natural history. In the Auslander study, the epidemiological methods are even more doubtful in this respect: the analysis was performed without any access to patient data apart from the endoscopies extracted from a huge national database. The authors must have supposed that sigmo- or colonoscopy are the given investigations at the onset of disease or at eventual flare-ups, a very doubtful assumption from the clinical point of view. The diagnosis may alternatively be obtained during an acute surgical intervention via a barium enema and/or a small bowel follow-through. Also, taking an endoscopic database as information source for either onset of disease and/or flare-up of a condition, information has to be available about the national, regional and social representation of the population in that database, hereby, considering factors as accessibility and waiting times. Furthermore, the selection of patients with IBD to the Auslander analysis may be biased by the fact that an endoscopic diagnosis of UC and CD not necessarily must be matched or confirmed by the subsequent histological diagnosis. Thus, unfortunately, the advantage of the big numbers of the Auslander study is counter-acted by the relative non-specificity of the endoscopic IBD diagnosis and the lack of cases not diagnosed by way of endoscopy. What then are the conclusions after these two recent publications? Regarding the Van Ranst study, it is very difficult to draw a conclusion from the fact, that birth early in the summer should be protective and late in the summer riskful for Crohn’s disease. Would astrology help? Seasonality of first presentation, first diagnosis, flareups and complications of IBD remain very interesting in the aetio-pathogenetic search regarding this disorder with its putative multi-factorial genetic-environmental origin. Approaching this topic scientifically, a preference would be given to hypothesis-driven approaches, especially as there are sufficient potential exogenous players identified (e.g. infections; nutritional components; smoking or smoking abstinence). Nothing would forbid to include into such specific questioning factors that are less specific or even unexplored in previous studies. When performing these studies, the temporal sequence of implicated events has to be critically considered: “onset of disease” may be prepared by facts and interactions occurring during many years; “first symptoms” are very difficult to define, as they are heavily influenced by patients’ personality and expression; “first diagnosis” is again determined by
325
Table 1 Conditions useful and/or necessary for the study of seasonality in IBD 1. Trigger for research by previous observations or publications 2. Formulation of one or several biologically plausible hypotheses 3. Study based on patient population(s) representative of the entire disease spectrum and a larger geographic (regional, national) context 4. Prospective design of patient inclusion and data sampling 5. Acceptable definitions of “onset of first symptoms”, “time of diagnosis”, “recurrence” or “complication” 6. Inclusion of the largest possible number of factors describing the environment; although the amount of data wanted may not be prohibitive for the study feasibility 7. Permission from participating patients for subsequent collection of additional data in the case of inconclusive results or at the occasion of new hypotheses
patient personality but also by health care organization; and finally, “flare-ups” are co-determined by past and present treatment, patient tolerance, and again the reactivity of the health care system. In a retrospective scientific registration, each of these factors can easily move the moment of observation and reporting from one month or season to the next. If we are really aiming at biologically acceptable conclusions for a single disorder or a group of them, there seems to be no easy way around the choice of a population that is representative. Such populations have to be populationbased, ideally including every patient available in a chosen and well-defined population. The population has further to be representative for the general pattern of the surrounding macro-population, be it a region, nation or continent. Finally, retrospective data – even if they are collected in a prospectively constructed cohort – tend to be incomplete without a prospective formulation of hypotheses, especially as numerical data tend to get weaker with the time elapsed since the disease event(s), and this probably in an exponential way. The perfect study about seasonality in IBD will never be published. In Table 1 a number of conditions are listed, that can contribute to the quality of studies exploring the seasonality or any other exogenous/environmental factor in this particular disease, . . . or any other. Conflict of interest statement None declared.
References [1] Aratari A, Papi C, Galletti B, Angelucci A, Viscido A, D’Ovidio V, et al. Seasonal variations in onset of symptoms in Crohn’s disease. Dig Liver Dis 2006;38:319–23. [2] Auslander J, Lieberman D, Sonnenberg A. Lack of seasonal variation in the endoscopic diagnoses of Crohn’s disease and ulcerative colitis. Am J Gastroenterol 2005;100:2233–8. [3] Van Ranst M, Joossens M, Joossens S, Van Steen K, Pierik M, Vermeire S, et al. Crohn’s disease and month of birth. Inflamm Bowel Dis 2005;11:597–9. doi: 10.1016/j.dld.2006.01.006
323
[38] Shirai T, Magara KK, Motohashi S, Yamashita M, Kimura M, Suwazomo Y, et al. TH1-biased immunity induced by exposure to Antarctic winter. J Allergy Clin Immunol 2003;111:1353–60. [39] Termorshuizen F, Garssen J, Norval M, Koulu L, Laihia J, Leino L, et al. A review of study on effects of ultraviolet irradiation on the resistance to infections: evidence from rodent infection models and verification by experimental and observational human studies. Int Immunopharmacol 2002;2:263–75. [40] Termorshuizen F, Geskus RB, Roos MT, Coutinho RA, Van Loveren H. Seasonal influences on immunological parameters in HIV-infected homosexual men searching for immunomodulating effects of sunlight. Int J Hyg Environ Health 2002;205:379–84. [41] McCutcheon M. Studies on the locomotion of leukocytes. The effect of temperature on the rate of locomotion of human neutrophilic leukocytes in vitro. Am J Physiol 1923;66:185–90. [42] Mandeville RP, Wilkinson PC. Locomotion of human lymphoblasts towards glucose and other sugars. Effects of pH, temperature, and oxygen. Clin Exp Immunol 1982;36:733–42. [43] Kasper S, Rosenthal NE, Barberi S, Williams A, Tamarkin L, Rogers SL, et al. Psychiatry. Immunological correlates of seasonal fluctuations in mood and behaviour and their relationship to phototherapy. Psychiatry Res 1991;36:253–64. [44] MacMurray JP, Barker JP, Armstrong JD, Bozzetti LP, Kuhn IN. Circannual changes in immune function. Life Sci 1983;32:2360–70. [45] Linder M, Larson M, Prellner T, Brattsand R, Laitinen LA. Seasonal variation in the function of blood monocytes obtained from healthy non smokers, asymptomatic smokers, and smokers with chronic bronchitis. Chronobiol Int 1994;11:266–72. [46] Maes M, Stevens W, Scharpe S, Bosmans E, De Meyer F, D’Hondt P, et al. Seasonal variations in peripheral blood leukocyte subsets and in serum IL-6, and soluble IL-2 and IL-6 receptor concentrations in normal volunteers. Experientia 1994;50:821–9. [47] Paigen B, Ward E, Reilly A, Houten L, Gurtoo HL, Minowada J, et al. Seasonal variation of aryl hydrocarbon hydroxylase activity in human lymphocytes. Cancer Res 1981;41:2757–61. [48] Boctor F, Charmy R, Cooper E. Seasonal differences in the rythmicity of human male and female lymphocyte blastogenic responses. Immunol Invest 1989;18:775–84. [49] Maestroni GJ. The immunotherapeutic potential of melatonine. Expert Opin Investig Drugs 2001;10:467–76. [50] Nelson RJ, Drazen DL. Melatonine mediates seasonal adjustments in immune function. Reprod Nutr Dev 1999;39:383–98.
Commentary
Seasonality in IBD: Do we really know about it? R.W. Stockbrugger ∗ Department of Gastroenterology and Hepatology, University Hospital Maastricht, Debyelaan 25, 6202 Maastricht, The Netherlands Available online 23 March 2006
1. Introduction
∗
Tel.: +31 43 38 75021; fax: +31 43 38 75006. E-mail address: [email protected]
On pages 319 to 323 an interesting article by Aratari et al. [1] is published which deals with the seasonal variations in the onset of symptoms in Crohn’s disease, reporting results
324
R.W. Stockbrugger / Digestive and Liver Disease 38 (2006) 323–325
from three clinical centres in Italy. The article contains a good reference list covering the topic of seasonality for a number of other disorders, the literature concerning IBD under this aspect, and consequently a good number of studies and reviews on proven or putative risk factors of IBD. What then is the reason for the impetus to study seasonality in disorders – and here especially in IBD – from time to time? There are a number of reasons: first of all the lacking knowledge about the aetiology and/or pathogenesis of a certain disease; then, the search for factors that can elicit flares, recurrences, complications (or their opposite); all these in order to either prevent the disease or to improve the possibilities of management. IBD is a condition where the need for seasonality research is perfectly in place. The recent years have proven that neither genetic nor environmental factors alone are sufficient to explain the pathogenesis of the two main disorders UC and CD (which probably are different from each other in their respective aetio-pathogenetic pattern). Thus, the hunt is still open to catch one or several causative or modulating factors in the environmental field, some of which may be connected with characteristics of climate and/or biorhythms. What has been the result of studies into the seasonality of IBD so far? With a few words: not much and little consistent, as rightly described in the introduction of the Aratari paper; this paper also leaves behind, in my opinion, more open questions than answers. The reason for this frustrating result has to be sought in two areas: (1) the lack of a unitary aetio-pathogenetic concept and (2) deficiencies in epidemiological methods.
2. Concepts and hypotheses Looking at the onset and course of whatever disorder, one has to accept that exogenous pathogenetic factors can act in differential ways: factors co-responsible for the initiation of a disorder may have a smaller/greater influence (or none at all) on recurrences and complications during disease course. Theoretically, disorders may also be initiated by genetic factors, but in the later course mainly come under the influence of exogenous events. To be honest, a large number of theoretical models could be constructed in this way. Planning studies such as those about seasonality of IBD, one or several clear hypotheses have to be formulated, preferably on the basis of theoretical premises (inductive) or previous findings (deductive). Studies started without such hypotheses can be called “exploratory”, “pilot” or similar. They will rarely give convincing evidence but may trigger the wish for more systematic approaches. Regarding the study of Aratari et al., the two main results are, that in 353 patients with IBD the onset of symptoms occurred more frequently in spring and summer than in the remaining seasons (after a sub-division into UC and CD, a statistical significance only remains for CD), and there were
more smokers in the CD patients than in UC at onset of the disease. In a recent study by Auslander et al. [2], a huge NorthAmerican database of endoscopic procedures was questioned in a sophisticated way for the proportion of colonoscopies and sigmoidoscopies employed for patients with IBD (but not including those performed for cancer surveillance). Again, taking both IBD sub-diseases together, no seasonality could be discovered; however, taking CD alone, there were four more or less distinct peaks with higher frequency of colonoscopies (September 2000, May 2001, February 2002 and November 2002). In the discussion, the authors shortly speculate whether GI- or other infections could be responsible for the temporary increase of flares. In a third study by Van Ranst et al. [3] from a 1025 patients strong Belgian database with 5125 non-IBD patient hospital controls, it was observed that the month of birth was associated with the later development of Crohn’s disease: birth in April and August was a risk factor and birth in June appeared to be protective. Following the above discussion, the three mentioned studies belong to the category “exploratory”, as they have no formulated questions or hypotheses at the onset of data collection and analysis. Like in many such cases there was a hope for some more or less spectacular finding, that would have led to follow-up investigations. In addition, the few more or less significant evidences (four irregularly distributed seasonal peaks in the Auslander study; increased frequency of CD onset during spring and summer in the Aratari study) do not carry such biological potential, that the authors remain with them too long in their relatively non-specific discussions. However, they do not seem to be convinced that there is no seasonality at all. After the reader is left with this mainly negative result, the question arises whether the quasi non-seasonality of IBD should finally be accepted, or whether the study methods hitherto applied were not really appropriate to answer a still unanswered question. I would go for the latter option and will explain why.
3. Methodological comments The Aratari study is a retrospective study on a prospectively collected patients cohort. The authors state that the diagnosis of these patients has been made according to “standard criteria”; however, we do not learn in what way the topic of the present evaluation “onset of symptoms” has been ascertained at the first diagnosis. The authors present a very large time range for the period between first symptoms and diagnosis (up to 385 months) and the reader has really to doubt whether the patient memory was good enough to indicate month or even season of first symptoms after such time delays. An important argument about the adequacy of the patient population investigated arises from the size of the patient material: three university hospital pop-
R.W. Stockbrugger / Digestive and Liver Disease 38 (2006) 323–325
ulations were included over 10 years. The resulting 425 patients (about 140 patients per centre or 14 patients per centre and year) cannot be representative for the surrounding catchment areas and probably not even for the totality of newly diagnosed patients in each of the centres! The suspicion must be that these patients are selected to severity, social status, living area or whatever other factor that could interfere with representiveness. Certainly this approach is not population-based, and therefore conclusions cannot be generally accepted for the two disorders investigated for the purpose of aetio-pathogenesis and natural history. In the Auslander study, the epidemiological methods are even more doubtful in this respect: the analysis was performed without any access to patient data apart from the endoscopies extracted from a huge national database. The authors must have supposed that sigmo- or colonoscopy are the given investigations at the onset of disease or at eventual flare-ups, a very doubtful assumption from the clinical point of view. The diagnosis may alternatively be obtained during an acute surgical intervention via a barium enema and/or a small bowel follow-through. Also, taking an endoscopic database as information source for either onset of disease and/or flare-up of a condition, information has to be available about the national, regional and social representation of the population in that database, hereby, considering factors as accessibility and waiting times. Furthermore, the selection of patients with IBD to the Auslander analysis may be biased by the fact that an endoscopic diagnosis of UC and CD not necessarily must be matched or confirmed by the subsequent histological diagnosis. Thus, unfortunately, the advantage of the big numbers of the Auslander study is counter-acted by the relative non-specificity of the endoscopic IBD diagnosis and the lack of cases not diagnosed by way of endoscopy. What then are the conclusions after these two recent publications? Regarding the Van Ranst study, it is very difficult to draw a conclusion from the fact, that birth early in the summer should be protective and late in the summer riskful for Crohn’s disease. Would astrology help? Seasonality of first presentation, first diagnosis, flareups and complications of IBD remain very interesting in the aetio-pathogenetic search regarding this disorder with its putative multi-factorial genetic-environmental origin. Approaching this topic scientifically, a preference would be given to hypothesis-driven approaches, especially as there are sufficient potential exogenous players identified (e.g. infections; nutritional components; smoking or smoking abstinence). Nothing would forbid to include into such specific questioning factors that are less specific or even unexplored in previous studies. When performing these studies, the temporal sequence of implicated events has to be critically considered: “onset of disease” may be prepared by facts and interactions occurring during many years; “first symptoms” are very difficult to define, as they are heavily influenced by patients’ personality and expression; “first diagnosis” is again determined by
325
Table 1 Conditions useful and/or necessary for the study of seasonality in IBD 1. Trigger for research by previous observations or publications 2. Formulation of one or several biologically plausible hypotheses 3. Study based on patient population(s) representative of the entire disease spectrum and a larger geographic (regional, national) context 4. Prospective design of patient inclusion and data sampling 5. Acceptable definitions of “onset of first symptoms”, “time of diagnosis”, “recurrence” or “complication” 6. Inclusion of the largest possible number of factors describing the environment; although the amount of data wanted may not be prohibitive for the study feasibility 7. Permission from participating patients for subsequent collection of additional data in the case of inconclusive results or at the occasion of new hypotheses
patient personality but also by health care organization; and finally, “flare-ups” are co-determined by past and present treatment, patient tolerance, and again the reactivity of the health care system. In a retrospective scientific registration, each of these factors can easily move the moment of observation and reporting from one month or season to the next. If we are really aiming at biologically acceptable conclusions for a single disorder or a group of them, there seems to be no easy way around the choice of a population that is representative. Such populations have to be populationbased, ideally including every patient available in a chosen and well-defined population. The population has further to be representative for the general pattern of the surrounding macro-population, be it a region, nation or continent. Finally, retrospective data – even if they are collected in a prospectively constructed cohort – tend to be incomplete without a prospective formulation of hypotheses, especially as numerical data tend to get weaker with the time elapsed since the disease event(s), and this probably in an exponential way. The perfect study about seasonality in IBD will never be published. In Table 1 a number of conditions are listed, that can contribute to the quality of studies exploring the seasonality or any other exogenous/environmental factor in this particular disease, . . . or any other. Conflict of interest statement None declared.
References [1] Aratari A, Papi C, Galletti B, Angelucci A, Viscido A, D’Ovidio V, et al. Seasonal variations in onset of symptoms in Crohn’s disease. Dig Liver Dis 2006;38:319–23. [2] Auslander J, Lieberman D, Sonnenberg A. Lack of seasonal variation in the endoscopic diagnoses of Crohn’s disease and ulcerative colitis. Am J Gastroenterol 2005;100:2233–8. [3] Van Ranst M, Joossens M, Joossens S, Van Steen K, Pierik M, Vermeire S, et al. Crohn’s disease and month of birth. Inflamm Bowel Dis 2005;11:597–9. doi: 10.1016/j.dld.2006.01.006