- Email: [email protected]
Evidence for Life Before Inflammatory Bowel Disease
Accepted Manuscript Evidence for Life Before Inflammatory Bowel Disease Joana Torres, MD, Mark S. Riddle, MD, Jean-Frédéric Colombel, MD
PII: DOI: Reference:
S1542-3565(16)00244-5 10.1016/j.cgh.2016.03.006 YJCGH 54663
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 2 March 2016 Please cite this article as: Torres J, Riddle MS, Colombel J-F, Evidence for Life Before Inflammatory Bowel Disease, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.03.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Authors: Joana Torres, MD1; Mark S. Riddle, MD2; Jean-Frédéric Colombel, MD1
Title: Evidence for Life Before Inflammatory Bowel Disease
RI PT
Authors Affiliations 1- Icahn School of Medicine at Mount Sinai, New York, New York, USA 2- Naval Medical Research Center, Silver Spring, Maryland, USA
Jean-Frédéric Colombel, MD The Henry D. Janowitz Division of Gastroenterology
M AN U
Icahn School of Medicine at Mount Sinai,
SC
Corresponding author:
One Gustave Levy Place, New York, 10029 NY, USA. E-mail: [email protected]
Conflict of interest
Joana Torres has served as a consultant or speaker for AbbVie, Ferring, and Falk. Mark Riddle has no conflict of interest to declare. Professor Colombel has served as consultant, advisory
Celltrion,Danone,
TE D
board member or speaker for AbbVie, ABScience, Amgen, Bristol-Myers, Squibb, Celgene, Ferring,
Genentech,
Giuliani
SPA,
Given
Imaging,
Immune
Pharmaceuticals,Janssen, Kyowa Hakko Kirin Pharma, MedImmune, Merck & Co., Millennium Pharmaceuticals Inc., Navigant Consulting, Nestle, Nutrition Science Partners Ltd., Pfizer Inc.,
EP
Prometheus Laboratories, Protagonist, Receptos, Sano_,Schering Plough Corporation, Second Genome, Shire, Takeda, Teva Pharmaceuticals, TiGenix, UCB Pharma, Vertex and Dr. August
AC C
Wolff GmbH & Co.
Copyright Statement
One of the authors (M.S.R.) is an employee of the U.S. Government and is a military service member. This work was prepared as part of official duties. Title 17 U.S.C. §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties. The views expressed in this article do not necessarily reflect the official policy or position
ACCEPTED MANUSCRIPT
of the Department of the Navy, Department of Defense, nor the U.S. Government. This is a partial US Government work. There are no restrictions on its use. Authors contributions
RI PT
All authors have contributed to the study concept and design. JT drafted the manuscript. All authors critically revised the manuscript and all authors approved the final version of the manuscript.
SC
Editorial
Inflammatory bowel diseases (IBD) are chronic gastrointestinal inflammatory diseases that can result in irreversible tissue injury and disability. The acknowledgment of the progressive nature
M AN U
of IBD has resulted in a recent paradigm shift in the treatment and monitoring of these diseases. Efforts aimed at early diagnosis1, early intervention, and tight control of the inflammatory processes are underway, in the hope that complications and bowel damage can be prevented2,3. However, at the time of diagnosis, many patients already present with irreversible bowel damage, and over time, many others will loose response to therapies, and end-up developing complications that ultimately lead to surgery and organ loss4. All current therapeutic
TE D
interventions are directed towards well-established disease, and therefore, not able to reverse the primary events that lead to the chronic immune-inflammatory process. Changing this paradigm would require intervention at a stage when the primary immune dysregulation, dysbiosis, or other key pathogenic process, could still be reversed. Interventions directed at this early phase of disease could possibly be more effective at reversing or altering aberrant
EP
immune and inflammatory responses, before established disease pathways have been set5. However, for that to happen, we need to gain a better insight into the phase, where in the
AC C
absence of symptoms and organ injury, activation of the immune system has already occurred, and dysregulated inflammatory pathways have been primed for the potential of the fully overt stage of disease to manifest. While this so called “pre-clinical phase” of disease has been the subject of extensive research in other immune-mediated inflammatory diseases (IMIDs) such as Rheumatoid Arthritis (RA) or Type 1 Diabetes, it is still in its early steps in IBD. The work herein presented by Lochhead et al. in this issue of Clinical Gastroenterology and Hepatology provides further contribution into this field6.
Having access to clinical information and serum samples from the prospective cohorts Nurses’ Health Study I and II, the authors conducted a nested case-control study in patients with an
1
ACCEPTED MANUSCRIPT
incident diagnosis of IBD. From these nationwide cohorts, 83 new cases of CD and 90 new cases of UC, with available pre-diagnosis serum samples were identified and matched (1:2) to 344 healthy controls. For each individual, a single pre-diagnostic serum sample was tested for plasma concentrations of interleukin-6 (IL6) and high-sensitivity C-reactive protein (hsCRP) in
RI PT
order to assess their relation to the risk of incident IBD. Median age of CD and UC patients at the time of blood collection was 52.7 years and 50.4 years, and the median intervals between serum sample and diagnosis of CD and UC were 6.6 years and 6.8 years respectively. The main finding of this study was that both inflammatory markers were significantly higher in IBD as compared to controls. Median pre-diagnostic hsCRP levels (mg/L) were 2.3 in CD, 2.2 in UC,
SC
and 1.5 in controls. Comparably, median IL6 levels (pg/mL) were 1.7 in CD, 1.2 in UC and 1.0 in controls. Acknowledging the linear relationship between these inflammatory markers and risk of
M AN U
IBD, the authors showed that those patients with higher pre-diagnostic biomarker concentrations would bear the highest odds for developing disease, even after adjusting for smoking status, and other potentially confounding variables. To avoid the possibility that some of the findings may have been driven by undiagnosed cases at the time of blood collection, a sensitivity analysis excluding cases that were sampled within 2 years of diagnosis was performed and found similar directional, though attenuated, effect estimates. Additionally, adjustment for comorbidities with known inflammatory processes did not appreciably alter these
TE D
effects estimates. Finally, and somehow unexpected, no association between time to diagnosis and the magnitude of inflammatory response was found.
The authors are to be congratulated for expanding our knowledge on the the field of pre-clinical
EP
IBD. Using a well characterized cohort, with implemented quality control steps for case and phenotype ascertainment, a detailed matching procedure, and careful statistical analyses adjusting for multiple confounding variables, they were able to demonstrate for the first time,
AC C
that systemic inflammation is present in IBD many years before diagnosis. Furthermore, based on this work, it seems that the extent of the pre-clinical inflammatory response correlates with risk of subsequently developing overt disease. Although reproduction of these findings is needed, and generalizability may be limited by the study population (all female and advanced age at diagnosis), this work adds to the emerging literature demonstrating that overt, clinical IBD may be preceded several years by abnormal serological markers7–9 (table 1). The major limitation of this study resides in the paucity and lack of specificity of the markers that were assessed. For example, concomitant measurement of antimicrobial antibodies and other immunologic mediators could have been revealing about disease pathogenesis, as well as
2
ACCEPTED MANUSCRIPT
informing on the relationship and timing between appearance of these markers and development of systemic inflammation. IL6 and hsCRP, very likely, represent indirect evidence of an existent non-specific enhanced cytokine response. CRP has also been associated with an increased risk of colorectal cancer in IBD10. Being unspecific markers of inflammation, their up-
RI PT
regulation is not very informative in terms of the role of the immune system in the initiation or progression of disease. In this context, the lack of any temporal association between IL6 and hsCRP and time to diagnosis is surprising, as one would think that levels of these inflammatory biomarkers would increase as time to diagnosis decreases11. A larger study targeting a wider panel of cytokines, chemokines and immune responses to exogenous microbial and
SC
endogenous host epitopes, could provide information on the pathways that are dysregulated in pre-clinical period of disease. For example, in RA it has been demonstrated that cytokines best
M AN U
distinguishing pre-patients from controls were related to Th1, Th2, and Treg cells11, and that after disease onset, stromal cells and other angiogenic factors become important in distinguishing patients with established disease11. It has also been observed that some cytokines that are up-regulated before diagnosis, may normalize or decrease afterwards, suggesting that the mechanisms at play in the earliest phases of IMIDs may be different from those operating after fully-overt disease is established11. Multiple studies of IMIDs have shown that the preclinical period is characterized by the expansion of immune responses, with
TE D
upregulation of a multitude of cytokines, cytokine-related factors, chemokines, and autoantibodies which accumulate in numbers and increase in magnitude towards the time of diagnosis11–14. The present study was not able to consider the longitudinal evolution of IL6 and hsCRP over time, as only one serum sample before diagnosis was tested. In contrast, a recent
EP
report from the PREDICTS study (Proteomic Evaluation and Discovery in an IBD Cohort of Triservice Subjects), a pre-clinical cohort utilizing medical encounter data and serial samples from the US Department of Defense serum repository, found that the magnitude of anti-microbial
AC C
serological responses increased as the time proximity approached diagnosis9. The ultimate utility of biomarkers in the pre-clinical disease phase depends on defining the time-frame and sequence associated with the stage transition from healthy, to pre-clinical to overt disease. Only through utilization of cohort study designs (retrospective or prospective) with multiple samples in the pre-clinical period, will we have the ability to draw the distinction between factors that trigger the initiation of the subclinical immuno-inflammatory process, and factors that lead to the expansion of this pre-clinical phase, culminating in overt disease (figure 1). Likely, a better definition of the pathways operating before disease develops, will also allow to differentiate subgroups of patients, leading to tailored and personalized interventions15,16. However, until we
3
ACCEPTED MANUSCRIPT
have an accurate understanding of the initiation, transition and disease stages, the development of prediction algorithms, and targeted interceptive strategies directed along each step of the pathway will remain a challenge.
RI PT
In conclusion, pre-clinical IBD is characterized by an increase in markers of systemic inflammation, as well in serological antimicrobial markers. The present study adds another piece of evidence into this field, and reinforces the need for further prospective studies of at-risk subjects, utilizing comprehensive panels of immunological, genetic and microbial biomarkers, which through integrative methods will allow the definitive elucidation of causal mechanisms
Author,
Setting
year
Type
Number of
of study
M AN U
possibilities, the ultimate one, being prevention of disease.
SC
preceding IBD. Gaining insight into this “pre-clinical” phase of disease could have endless
Time before
Tests
Main findings
individuals/sampl
diagnosis -
performed
es
sample
obtained (y)
2005
7
Israeli
Case-
32
Army
control
samples
serum
(1:3)
8
reposito
Schaik, 2013
8
EP Case-
77
control
samples
(1:2)
167
AC C
EPIC
study
UC,
38
CD:4.9 (mean)
ASCA
IgA
UC:5.6 (mean)
ASCA
IgG
10
CD,
UC,
samples
•
31.3%
of
CD
patients
ASCA+, vs 0% matched
pANCA
controls •
samples
ry
Van
CD,
TE D
Israeli,
Increase in proportion of ASCA+
patients
and
in
mean ASCA titters towards diagnosis •
25%
of
UC
patients
ANCA+, vs 0% of matched controls 77
167
CD:4.5 (mean)
ASCA
IgA
UC:4.4 (mean)
ASCA
IgG
•
patients tested positive at
pANCA AntiompC
39% CD and 35% UC
least for one Ab •
Anti-CBir1
combination markers predictive
of
multiple
had
better
accuracy
than
one marker alone •
The
risk
for
developing
disease in patients with a positive “serological score”
4
ACCEPTED MANUSCRIPT
was
higher
closer
to
diagnosis
2015
9
US DoD
Cohort
100
CD
Serum
men),
Reposit
samples
ory
(all 400
4 time points:
ASCA
IgA
median
6.0y,
ASCA
IgG
4.2y,
1.1y,
Anti-ompC
0.3y
before
Anti-CBir1
diagnosis
•
Increase in the proportion of positive markers towards
RI PT
Chong,
diagnosis
•
Patients w/ complications*
Anti-A4_Fla2
at
Anti-FlaX
higher
diagnosis
presented
titers of
SC
years before
Table 1- summary of prior studies conducted in pre-clinical phase of IBD. Y: years, vs: versus; Ab: antibodies, EPIC: European Prospective Investigation into Cancer and Nutrition (EPIC)
M AN U
study. DoD: Department of Defense; Ab: antibody, * complications: structuring, penetrating complications or surgery
Figure 1 – proposed phases in the evolution of IBD from health to disease. Intervening (dashed
TE D
arrow) in the pre-clinical period of disease could truly represent a window of opportunity to reverse or halt the auto-inflammatory process and immune dysregulated pathways from
Bibliography
2. 3.
4. 5. 6.
Danese S, Fiorino G, Mary JY, et al. Development of Red Flags Index for Early Referral of Adults with Symptoms and Signs Suggestive of Crohn’s Disease: An IOIBD Initiative. J Crohns Colitis 2015;9:601–606. Ordás I, Feagan BG, Sandborn WJ. Early use of immunosuppressives or TNF antagonists for the treatment of Crohn’s disease: time for a change. Gut 2011;60:1754–1763. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-toTarget. Am J Gastroenterol 2015;110:1324–1338. Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn’s disease. Inflamm Bowel Dis 2002;8:244–250. Finckh A, Deane KD. Prevention of rheumatic diseases: strategies, caveats, and future directions. Rheum Dis Clin North Am 2014;40:771–785. Lochhead P, Khalili H, Ananthakrishnan AN, et al. Association Between Circulating Levels of C-Reactive Protein and Interleukin-6 and Risk of Inflammatory Bowel Disease. Clin
AC C
1.
EP
progressing into overt disease.
5
markers
ACCEPTED MANUSCRIPT
12.
13.
14.
15. 16.
RI PT
SC
11.
M AN U
10.
TE D
9.
EP
8.
AC C
7.
Gastroenterol Hepatol 2016. Israeli E, Grotto I, Gilburd B, et al. Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease. Gut 2005;54:1232– 1236. Schaik FD van, Oldenburg B, Hart AR, et al. Serological markers predict inflammatory bowel disease years before the diagnosis. Gut 2013;62:683–688. Choung RS, Stockfisch TP, Princen F, et al. 78 Longitudinal Status of Serological Markers Predict Crohn’s Disease Phenotype Before Diagnosis: A “PREDICTS” Study. Gastroenterology 2015;148:S–22. Ananthakrishnan AN, Cheng SC, Cai T, et al. Serum inflammatory markers and risk of colorectal cancer in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2014;12:1342–8.e1. Kokkonen H, Söderström I, Rocklöv J, et al. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum 2010;62:383–391. Deane KD, O’Donnell CI, Hueber W, et al. The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner. Arthritis Rheum 2010;62:3161–3172. Hughes-Austin JM, Deane KD, Derber LA, et al. Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimmunity in first-degree relatives without rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA). Ann Rheum Dis 2013;72:901–907. Nielen MM, Schaardenburg D van, Reesink HW, et al. Increased levels of C-reactive protein in serum from blood donors before the onset of rheumatoid arthritis. Arthritis Rheum 2004;50:2423–2427. Fiocchi C. Tailoring Treatment to the Individual Patient - Will Inflammatory Bowel Disease Medicine Be Personalized? Dig Dis 2015;33 Suppl 1:82–89. Shapiro JM, Cho JH, Sands BE, et al. Bridging the gap between host immune response and intestinal dysbiosis in inflammatory bowel disease: does immunoglobulin A mark the spot? Clin Gastroenterol Hepatol 2015;13:842–846.
6
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
PII: DOI: Reference:
S1542-3565(16)00244-5 10.1016/j.cgh.2016.03.006 YJCGH 54663
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 2 March 2016 Please cite this article as: Torres J, Riddle MS, Colombel J-F, Evidence for Life Before Inflammatory Bowel Disease, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.03.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Authors: Joana Torres, MD1; Mark S. Riddle, MD2; Jean-Frédéric Colombel, MD1
Title: Evidence for Life Before Inflammatory Bowel Disease
RI PT
Authors Affiliations 1- Icahn School of Medicine at Mount Sinai, New York, New York, USA 2- Naval Medical Research Center, Silver Spring, Maryland, USA
Jean-Frédéric Colombel, MD The Henry D. Janowitz Division of Gastroenterology
M AN U
Icahn School of Medicine at Mount Sinai,
SC
Corresponding author:
One Gustave Levy Place, New York, 10029 NY, USA. E-mail: [email protected]
Conflict of interest
Joana Torres has served as a consultant or speaker for AbbVie, Ferring, and Falk. Mark Riddle has no conflict of interest to declare. Professor Colombel has served as consultant, advisory
Celltrion,Danone,
TE D
board member or speaker for AbbVie, ABScience, Amgen, Bristol-Myers, Squibb, Celgene, Ferring,
Genentech,
Giuliani
SPA,
Given
Imaging,
Immune
Pharmaceuticals,Janssen, Kyowa Hakko Kirin Pharma, MedImmune, Merck & Co., Millennium Pharmaceuticals Inc., Navigant Consulting, Nestle, Nutrition Science Partners Ltd., Pfizer Inc.,
EP
Prometheus Laboratories, Protagonist, Receptos, Sano_,Schering Plough Corporation, Second Genome, Shire, Takeda, Teva Pharmaceuticals, TiGenix, UCB Pharma, Vertex and Dr. August
AC C
Wolff GmbH & Co.
Copyright Statement
One of the authors (M.S.R.) is an employee of the U.S. Government and is a military service member. This work was prepared as part of official duties. Title 17 U.S.C. §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties. The views expressed in this article do not necessarily reflect the official policy or position
ACCEPTED MANUSCRIPT
of the Department of the Navy, Department of Defense, nor the U.S. Government. This is a partial US Government work. There are no restrictions on its use. Authors contributions
RI PT
All authors have contributed to the study concept and design. JT drafted the manuscript. All authors critically revised the manuscript and all authors approved the final version of the manuscript.
SC
Editorial
Inflammatory bowel diseases (IBD) are chronic gastrointestinal inflammatory diseases that can result in irreversible tissue injury and disability. The acknowledgment of the progressive nature
M AN U
of IBD has resulted in a recent paradigm shift in the treatment and monitoring of these diseases. Efforts aimed at early diagnosis1, early intervention, and tight control of the inflammatory processes are underway, in the hope that complications and bowel damage can be prevented2,3. However, at the time of diagnosis, many patients already present with irreversible bowel damage, and over time, many others will loose response to therapies, and end-up developing complications that ultimately lead to surgery and organ loss4. All current therapeutic
TE D
interventions are directed towards well-established disease, and therefore, not able to reverse the primary events that lead to the chronic immune-inflammatory process. Changing this paradigm would require intervention at a stage when the primary immune dysregulation, dysbiosis, or other key pathogenic process, could still be reversed. Interventions directed at this early phase of disease could possibly be more effective at reversing or altering aberrant
EP
immune and inflammatory responses, before established disease pathways have been set5. However, for that to happen, we need to gain a better insight into the phase, where in the
AC C
absence of symptoms and organ injury, activation of the immune system has already occurred, and dysregulated inflammatory pathways have been primed for the potential of the fully overt stage of disease to manifest. While this so called “pre-clinical phase” of disease has been the subject of extensive research in other immune-mediated inflammatory diseases (IMIDs) such as Rheumatoid Arthritis (RA) or Type 1 Diabetes, it is still in its early steps in IBD. The work herein presented by Lochhead et al. in this issue of Clinical Gastroenterology and Hepatology provides further contribution into this field6.
Having access to clinical information and serum samples from the prospective cohorts Nurses’ Health Study I and II, the authors conducted a nested case-control study in patients with an
1
ACCEPTED MANUSCRIPT
incident diagnosis of IBD. From these nationwide cohorts, 83 new cases of CD and 90 new cases of UC, with available pre-diagnosis serum samples were identified and matched (1:2) to 344 healthy controls. For each individual, a single pre-diagnostic serum sample was tested for plasma concentrations of interleukin-6 (IL6) and high-sensitivity C-reactive protein (hsCRP) in
RI PT
order to assess their relation to the risk of incident IBD. Median age of CD and UC patients at the time of blood collection was 52.7 years and 50.4 years, and the median intervals between serum sample and diagnosis of CD and UC were 6.6 years and 6.8 years respectively. The main finding of this study was that both inflammatory markers were significantly higher in IBD as compared to controls. Median pre-diagnostic hsCRP levels (mg/L) were 2.3 in CD, 2.2 in UC,
SC
and 1.5 in controls. Comparably, median IL6 levels (pg/mL) were 1.7 in CD, 1.2 in UC and 1.0 in controls. Acknowledging the linear relationship between these inflammatory markers and risk of
M AN U
IBD, the authors showed that those patients with higher pre-diagnostic biomarker concentrations would bear the highest odds for developing disease, even after adjusting for smoking status, and other potentially confounding variables. To avoid the possibility that some of the findings may have been driven by undiagnosed cases at the time of blood collection, a sensitivity analysis excluding cases that were sampled within 2 years of diagnosis was performed and found similar directional, though attenuated, effect estimates. Additionally, adjustment for comorbidities with known inflammatory processes did not appreciably alter these
TE D
effects estimates. Finally, and somehow unexpected, no association between time to diagnosis and the magnitude of inflammatory response was found.
The authors are to be congratulated for expanding our knowledge on the the field of pre-clinical
EP
IBD. Using a well characterized cohort, with implemented quality control steps for case and phenotype ascertainment, a detailed matching procedure, and careful statistical analyses adjusting for multiple confounding variables, they were able to demonstrate for the first time,
AC C
that systemic inflammation is present in IBD many years before diagnosis. Furthermore, based on this work, it seems that the extent of the pre-clinical inflammatory response correlates with risk of subsequently developing overt disease. Although reproduction of these findings is needed, and generalizability may be limited by the study population (all female and advanced age at diagnosis), this work adds to the emerging literature demonstrating that overt, clinical IBD may be preceded several years by abnormal serological markers7–9 (table 1). The major limitation of this study resides in the paucity and lack of specificity of the markers that were assessed. For example, concomitant measurement of antimicrobial antibodies and other immunologic mediators could have been revealing about disease pathogenesis, as well as
2
ACCEPTED MANUSCRIPT
informing on the relationship and timing between appearance of these markers and development of systemic inflammation. IL6 and hsCRP, very likely, represent indirect evidence of an existent non-specific enhanced cytokine response. CRP has also been associated with an increased risk of colorectal cancer in IBD10. Being unspecific markers of inflammation, their up-
RI PT
regulation is not very informative in terms of the role of the immune system in the initiation or progression of disease. In this context, the lack of any temporal association between IL6 and hsCRP and time to diagnosis is surprising, as one would think that levels of these inflammatory biomarkers would increase as time to diagnosis decreases11. A larger study targeting a wider panel of cytokines, chemokines and immune responses to exogenous microbial and
SC
endogenous host epitopes, could provide information on the pathways that are dysregulated in pre-clinical period of disease. For example, in RA it has been demonstrated that cytokines best
M AN U
distinguishing pre-patients from controls were related to Th1, Th2, and Treg cells11, and that after disease onset, stromal cells and other angiogenic factors become important in distinguishing patients with established disease11. It has also been observed that some cytokines that are up-regulated before diagnosis, may normalize or decrease afterwards, suggesting that the mechanisms at play in the earliest phases of IMIDs may be different from those operating after fully-overt disease is established11. Multiple studies of IMIDs have shown that the preclinical period is characterized by the expansion of immune responses, with
TE D
upregulation of a multitude of cytokines, cytokine-related factors, chemokines, and autoantibodies which accumulate in numbers and increase in magnitude towards the time of diagnosis11–14. The present study was not able to consider the longitudinal evolution of IL6 and hsCRP over time, as only one serum sample before diagnosis was tested. In contrast, a recent
EP
report from the PREDICTS study (Proteomic Evaluation and Discovery in an IBD Cohort of Triservice Subjects), a pre-clinical cohort utilizing medical encounter data and serial samples from the US Department of Defense serum repository, found that the magnitude of anti-microbial
AC C
serological responses increased as the time proximity approached diagnosis9. The ultimate utility of biomarkers in the pre-clinical disease phase depends on defining the time-frame and sequence associated with the stage transition from healthy, to pre-clinical to overt disease. Only through utilization of cohort study designs (retrospective or prospective) with multiple samples in the pre-clinical period, will we have the ability to draw the distinction between factors that trigger the initiation of the subclinical immuno-inflammatory process, and factors that lead to the expansion of this pre-clinical phase, culminating in overt disease (figure 1). Likely, a better definition of the pathways operating before disease develops, will also allow to differentiate subgroups of patients, leading to tailored and personalized interventions15,16. However, until we
3
ACCEPTED MANUSCRIPT
have an accurate understanding of the initiation, transition and disease stages, the development of prediction algorithms, and targeted interceptive strategies directed along each step of the pathway will remain a challenge.
RI PT
In conclusion, pre-clinical IBD is characterized by an increase in markers of systemic inflammation, as well in serological antimicrobial markers. The present study adds another piece of evidence into this field, and reinforces the need for further prospective studies of at-risk subjects, utilizing comprehensive panels of immunological, genetic and microbial biomarkers, which through integrative methods will allow the definitive elucidation of causal mechanisms
Author,
Setting
year
Type
Number of
of study
M AN U
possibilities, the ultimate one, being prevention of disease.
SC
preceding IBD. Gaining insight into this “pre-clinical” phase of disease could have endless
Time before
Tests
Main findings
individuals/sampl
diagnosis -
performed
es
sample
obtained (y)
2005
7
Israeli
Case-
32
Army
control
samples
serum
(1:3)
8
reposito
Schaik, 2013
8
EP Case-
77
control
samples
(1:2)
167
AC C
EPIC
study
UC,
38
CD:4.9 (mean)
ASCA
IgA
UC:5.6 (mean)
ASCA
IgG
10
CD,
UC,
samples
•
31.3%
of
CD
patients
ASCA+, vs 0% matched
pANCA
controls •
samples
ry
Van
CD,
TE D
Israeli,
Increase in proportion of ASCA+
patients
and
in
mean ASCA titters towards diagnosis •
25%
of
UC
patients
ANCA+, vs 0% of matched controls 77
167
CD:4.5 (mean)
ASCA
IgA
UC:4.4 (mean)
ASCA
IgG
•
patients tested positive at
pANCA AntiompC
39% CD and 35% UC
least for one Ab •
Anti-CBir1
combination markers predictive
of
multiple
had
better
accuracy
than
one marker alone •
The
risk
for
developing
disease in patients with a positive “serological score”
4
ACCEPTED MANUSCRIPT
was
higher
closer
to
diagnosis
2015
9
US DoD
Cohort
100
CD
Serum
men),
Reposit
samples
ory
(all 400
4 time points:
ASCA
IgA
median
6.0y,
ASCA
IgG
4.2y,
1.1y,
Anti-ompC
0.3y
before
Anti-CBir1
diagnosis
•
Increase in the proportion of positive markers towards
RI PT
Chong,
diagnosis
•
Patients w/ complications*
Anti-A4_Fla2
at
Anti-FlaX
higher
diagnosis
presented
titers of
SC
years before
Table 1- summary of prior studies conducted in pre-clinical phase of IBD. Y: years, vs: versus; Ab: antibodies, EPIC: European Prospective Investigation into Cancer and Nutrition (EPIC)
M AN U
study. DoD: Department of Defense; Ab: antibody, * complications: structuring, penetrating complications or surgery
Figure 1 – proposed phases in the evolution of IBD from health to disease. Intervening (dashed
TE D
arrow) in the pre-clinical period of disease could truly represent a window of opportunity to reverse or halt the auto-inflammatory process and immune dysregulated pathways from
Bibliography
2. 3.
4. 5. 6.
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