Indexed In : Science Citation Index Expanded(SCIE), MEDLINE,
Pubmed/Pubmed Central, Elsevier Bibliographic, Google Scholar,
Databases(Scopus & Embase), KCI, KoreaMed, DOAJ
Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.
The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.
Choong Wui Cho1 , Myung-Won You1
, Chi Hyuk Oh2
, Chang Kyun Lee2
, Sung Kyoung Moon1
Correspondence to: Myung-Won You
ORCID https://orcid.org/0000-0001-6262-5784
E-mail funfun2020@khu.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gut Liver 2022;16(2):157-170. https://doi.org/10.5009/gnl210118
Published online August 31, 2021, Published date March 15, 2022
Copyright © Gut and Liver.
Crohn’s disease (CD) is a chronic destructive inflammatory bowel disease that affects young people and is associated with significant morbidity. The clinical spectrum and disease course of CD are heterogeneous and often difficult to predict based on the initial presentation. In this article, changes in the disease location, behavior, clinical course during long-term follow-up, and predictive factors are reviewed. Generally, four different patterns of clinical course are discussed: remission, stable disease, chronic relapsing disease, and chronic refractory disease. Understanding the long-term disease course of CD is mandatory to reveal the underlying pathophysiology of the disease and to move toward a more optimistic disease course, such as remission or stability, and less adverse outcomes or devastating sequelae.
Keywords: Crohn disease, Inflammatory bowel disease, Disease course, Recurrence, Prognosis
Crohn’s disease (CD) is a chronic condition that can affect any site of the gastrointestinal tract, with a wide spectrum of severity and variable disease course.1 CD is traditionally known as a more prevalent disease in the Western world; however, the incidence of CD in Asia is increasing with the increase in the degree of urbanization from the 21st century onwards.2 Most patients with CD experience a waxing and waning clinical course of relapse and remission, and develop cumulative structural damage to the bowel over time.3 However, changes in the disease phenotype and severity are frequently heterogeneous and unpredictable for each patient. The evolution of anti-tumor necrosis factor (TNF) therapy improves the clinical outcomes of CD patients, such as clinical remission, steroid sparing, and mucosal healing.4 Anti-TNF therapy improved patients’ outcomes in terms of achievement of targets of treatment and modification of the natural history of the disease in a higher percentage of patients in conjunction with immunosuppressive medication. Nonetheless, primary nonresponse or loss of response (LOR) to anti-TNF therapy remains frequent, leading to significant morbidity.5 There are few data regarding the long-term course of CD during lifelong treatment and monitoring. In this article, we elaborate on the changes in disease patterns, long-term clinical course, and predictive factors.
Many reports have revealed that disease location remains relatively stable during the long-term disease course. Data on changes in disease location during the 10-year follow-up period are shown in Table 1. According to some Western studies, isolated colonic disease (L2) seems to have increased.6,7 Overall, the ileocolic area (L3) has been found to be the most frequently affected location in both Asian and Western studies.2,8-11 In a recent Asian-Pacific study conducted in eight countries across Asia and Australia, the distribution of disease location was almost the same.2 On the other hand, a Japanese study on pediatric CD patients demonstrated more frequent ileocolic (L3) and upper gastrointestinal (L4) involvement, and less colonic (L2) involvement compared with a European pediatric study based on a multicenter registry.15 Thia
Table 1 Changes in Disease Locations Over Time Based on the Montreal Classification: Long-term Follow-up Result (About 10-Year Period)
Author (year) | Country | Location | Baseline, % | 10 Years, % |
---|---|---|---|---|
Asian countries | ||||
Chow | Hong Kong | L1 | 11 | 0 |
L2 | 35 | 33 | ||
L3 | 54 | 67 | ||
L4 | 55.9 | 57.1 | ||
Ye | South Korea | L1 | 24.4 | 24.4 |
L2 | 8.3 | 8.3 | ||
L3 | 67.3 | 67.3 | ||
Makharia | India | L1 | 28.9 | |
L2 | 31.4 | |||
L3 | 39.6 | |||
L4 | 5.8 | |||
Ng | Asian-Pacific | L1 | 31/31* | |
L2 | 24/24* | |||
L3 | 45/45* | |||
L4 | 5/5* | |||
Kalaria | India | L1 | 28.9 | 36.8 |
L2 | 31.5 | 21 | ||
L3 | 39.4 | 42.2 | ||
L4 | 5.2 | 5.2 | ||
Western countries | ||||
Louis | Belgium | L1 | 44.8 | 43.3 |
L2 | 26.7 | 23.3 | ||
L3 | 24.2 | 30 | ||
Tarrant | New Zealand | L1 | 32 | 35 |
L2 | 49 | 41 | ||
L3 | 19 | 22 | ||
L4 | 0.6 | 2 | ||
Solberg | Norway | L1 | 27 | 25.9 |
L2 | 48.5 | 47.7 | ||
L3 | 22.7 | 24.3 | ||
L4 | 1.7 | 2 | ||
Lakatos | Hungary | L1 | 22 | 18.2 |
L2 | 29.1 | 36.8 | ||
L3 | 47.3 | 44.4 | ||
L4 | 6.4 | 0.5 | ||
Thia | USA | L1 | 45.1 | 42.5 |
L2 | 32 | 28.8 | ||
L3 | 18.6 | 23.2 | ||
L4 | 4.2 | 5.5 |
L1, ileal disease; L2, colonic disease; L3, ileocolic disease; L4, upper gastrointestinal involvement.
*Asian/Pacific.
When we examined the results of phenotypic changes in several reports, we found an obvious tendency of disease behavioral changes from simple inflammatory diseases to increased portions of complexity, either stricturing/penetrating or both diseases (Table 2). Many studies reported a complicated disease phenotype (B2/B3) of over 50% in a 10-year follow-up, compared to those in the baseline, which was approximately one-third. Cosnes
Table 2 Changes to Complicated Phenotypes (B2/B3) from Simple Inflammatory Phenotype (B1) Based on the Montreal Classification: Long-term Follow-up Result (≥10 Years)
Author (year) | Country | Phenotype | Baseline, % | ≥10 Years, % |
---|---|---|---|---|
Asian countries | ||||
Chow | Hong Kong | B1 | 67 | 43 |
B2/B3 | 33 | 57 | ||
Das | India | B1 | 51 | |
B2/B3 | 49 | |||
Ye | South Korea | B1 | 68.7 | 49.3 |
B2/B3 | 31.3 | 50.7 | ||
Makharia | India | B1 | 66.8 | |
B2/B3 | 33.2 | |||
Ng | Asian-Pacific | B1 | 66/88* | |
B2/B3 | 36/12* | |||
Kalaria | India | B1 | 74.7 | 50 |
B2/B3 | 25.2 | 49.9 | ||
Western countries | ||||
Cosnes | France | B1 | 40 | 12† |
B2/B3 | 60 | 88† | ||
Louis | Belgium | B1 | 73.7 | 30.6 |
B2/B3 | 26.3 | 69.4 | ||
Tarrant | New Zealand | B1 | 73 | 44 |
B2/B3 | 27 | 56 | ||
Solberg | Norway | B1 | 62 | 47 |
B2/B3 | 38 | 53 | ||
Lakatos | Hungary | B1 | 58.3 | 28.3 |
B2/B3 | 41.7 | 71.7 | ||
Thia | USA | B1 | 81.4 | 57.3 |
B2/B3 | 18.6 | 42.7 |
B2, stricturing; B3, penetrating.
*Asian/Pacific; †20 Years.
The clinical course of the disease can be classified into four different patterns in terms of the severity of bowel symptoms from diagnosis to the entire follow-up period. According to previous studies based on population-based prospective cohorts from Western countries (IBSEN study),6,23 the different patterns in the clinical course of CD were remission, aggravation, continuous refractory, and chronic relapsing. The percentages of each category were 43% (remission), 3% (aggravation), 19% (chronic refractory), and 32% (chronic relapsing). In this early 1990s cohort, the majority of the patients received oral 5-aminosalicylic acid and systemic steroids (73% to 88%) with 21% to 26% receiving AZA and only 4% receiving TNF blockers.6 Nowadays, the pattern of the clinical course should be modified according to the more prevalent and earlier use of TNF blockers as either monotherapy or combination therapy with immunosuppressants (IMS). Hence, salvaged cases from aggravation, refractory, or relapsing towards properly controlled disease course such as remission, improved, or stable disease will increase. In a recent prospective population-based cohort study, a significant portion of the patients was treated with biologics (23%) and IMS (69%), and the results showed a considerably more stable clinical course compared to previous reports.24 In this review, the clinical course of CD was defined partly based on the four disease activity patterns by Solberg
Remission is defined as a Crohn’s Disease Activity Index (CDAI) ≤150 (Fig. 2). A Danish cohort study conducted during 1960 to 1978 showed that 45% of patients with CD were in an inactive disease state at the end of the follow-up period.26 Solberg
Deep remission is defined as combined endoscopic and clinical remission.35 The therapeutic paradigm in CD has shifted from a mere symptom-oriented approach, aiming to heal the underlying inflammation and prevent long-term structural complications. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative has proposed this “treat-to-target” concept, that is, to achieve clinical/patient-reported outcome remission plus endoscopic/radiologic remission.35 The STRIDE guidelines recommend achieving both clinical and endoscopic remission (mucosal healing) to prevent adverse long-term outcomes and disability. Mucosal healing is best associated with favorable clinical symptomatic remission and disease-modifying outcomes such as hospitalization, surgical intervention, and quality of life.36,37 Recently, STRIDE-II has updated the 2015 STRIDE recommendations, and restoration of quality of life and absence of disability have been added to endoscopic remission as long-term targets.38 Moreover, transmural healing assessed using cross-sectional imaging has been recommended as an adjunctive goal, although it is not a formal treatment target. After the application of the treat-to-target concept, the remission rate was lowered; deep remission was achieved in about 16% of patients with moderate-to-severe CD in the EXTEND trial39 and in 39% of patients with early CD who were immunomodulatory and anti-TNF naïve in the SONIC trial.40
Surgical remission is another way to achieve remission. Surgery resulted in a longer duration of remission, suggesting that earlier surgery might be more beneficial from an economic perspective.29 Patients with CD who underwent surgery at diagnosis for acute abdomen showed a lower risk of reoperation and less use of steroids and IMS during follow-up than those who did not undergo surgery at diagnosis.41 On the other hand, surgery around the diagnosis (until 6 months) is clearly the result of complications already present at diagnosis and is more representative of the initial patient characteristics than a real outcome measure.42 Recent data suggest that surgery rates decreased prior to the advent of biologics,43-45 but the results were not confirmed in all studies, and the causative role is unproven. Surgery as an outcome parameter will be discussed later.
Clinical parameters reflecting mild inflammation, such as a lower CDAI and non-stricturing and non-penetrating behaviors, were associated with mid- to long-term responsiveness to steroids.46 A prospective observational study from Italy reported that postinduction fecal calprotectin combined with weighted pediatric CDAI are predictors of 1-year clinical and endoscopic remission to IFX in pediatric CD.47 Although previous studies have reported comparable effectiveness of elemental diet to steroid use48 and the role of diet control in prolonging remission,49 nutritional therapy is regarded as only appropriate for adjunctive treatment to support nutrition, unlike the management of pediatric/adolescent CD.50
Stable disease refers to a case with decreased severity of bowel symptoms during the follow-up period, but with mild residual activity or sequelae, as shown in the radiological or endoscopic assessment, not disturbing everyday life (Fig. 3). This is our potential explanation of cases showing discrepancies according to comprehensive assessments of biochemical, radiologic, and endoscopic parameters. Therefore, improved and stable disease includes cases in clinical remission but not in endoscopic and/or radiologic remission. According to a recently published report by Wintjens
Data regarding benign courses are scarce compared to those regarding unfavorable courses. Factors associated with non-severe 15-year clinical course, defined as clinically inactive disease for greater than 12 years, less than one intestinal resection without permanent stoma and no death, were non-smoking status, rectal sparing, high educational level, older age, and longer disease duration.58
Maintenance of remission in CD should last at least 12 months according to the recommendations of the European Crohn’s and Colitis Organisation.59 Relapse is defined as a flare of symptoms in an established CD patient in clinical remission. Studies usually define relapse as CDAI >150 or reappearance of symptoms requiring treatment modification, hospitalization, or surgery (Fig. 4).60 In clinical practice, relapse is confirmed by laboratory parameters, imaging, or endoscopy. Early relapse is defined as relapse within an arbitrary period of <3 months after achieving remission in a particular therapy.50 Based on the pattern of relapse, they can be categorized as infrequent (<1/year) or frequent (>2/year).27
Relapse rates in several previous studies ranged from 11% to 58%,60 while studies in the 2000s exhibited higher relapse rates (31% to 58%).61,62 Recent studies in the 2010s exhibited lower relapse rates (11% to 27%).63,64 These changes in relapse rates over time may have been caused by changes in medical treatments. A larger proportion of IMS and biologics were prescribed for CD patients in recent studies, whereas mainly aminosalicylic acids were prescribed for patients in the earlier 2000s. Although Laharie
At the time of the initial diagnosis of CD, induction therapy is necessary for patients exhibiting signs and symptoms of active disease.27 Once remission is achieved, patients are placed on maintenance therapy to ensure that remission is maintained for the longest possible period.27 Failure of maintenance therapy results in disease relapse. The majority of patients who were treated with corticosteroids to induce remission usually relapsed within 1 year without specific effective maintenance therapy.28 Although sulfasalazine and mesalamine are not effective agents in the maintenance of remission, IMS such as thiopurines, methotrexate, and TNF blockers are effective in the maintenance of CD remission.66 Despite the increasing use of IMS and TNF blockers, the remission rate has remained unchanged during the last decades (approximately 43% to 45%) and the improvement of the natural course of CD is still questionable. However, treatment options have been stratified according to comprehensive risk assessments, including initial disease activity, extent, and poor prognostic factors. The initial treatment of relapse should be based on previously successful therapies.50 However, several factors should be reassessed while deciding the treatment strategy for relapsing disease. These include time to relapse, initial therapy resulting in optimal response, adverse effects of current therapy, adherence to the prescribed therapy, and concurrent therapy. In case of early relapse, opinions remain divided on whether to use the same treatment to induce remission and taper more slowly or to use more potent induction therapy, and usually it necessitates the initiation of IMS to prevent future relapse.50 Moderate-to-severe relapsing disease warrants initiation of TNF blockers, and concurrent therapy with IFX and AZA is also noted to be more effective than either therapy alone.50,67
Relapse during TNF blocker treatment can be caused by a LOR. Patients who initially respond to anti-TNF induction regimen subsequently lose response and experience flare of symptoms necessitating dose escalation, switching of anti-TNF agents, or surgical intervention.5 LOR usually occurs within the first 12 months, and the rate of LOR after 12 months of anti-TNF therapy in CD patients ranges from 23% to 46% for both IFX and adalimumab.68,69 The annual risk of LOR is between 13% and 24% as judged by the need for dose intensification70 and 7% per year experience LOR despite dose intensification.69 The most investigated mechanism for LOR is the formation of antibodies against anti-TNF agents. Antibodies-to-IFX is associated with lower serum levels of the drug due to increased drug clearance.71 Management options for LOR include dose optimization such as dose increase or interval shortening, switching to another TNF blocker, and addition of another IMS to restore effective TNF blockade.5 A recent randomized controlled trial reported that the addition of AZA to the switch of anti-TNF yielded higher survival rates without clinical failure and the occurrence of unfavorable pharmacokinetics in patients with immune-mediated LOR to the first anti-TNF.68 Furthermore, treatment with a third anti-TNF agent or even retreatment with a previously failed anti-TNF can confer sustained clinical response in one-third of patients.72 However, switching from anti-TNF to another biologic with a different mode of action may prove more beneficial.73 In this respect, agents targeting leukocyte trafficking, such as anti-integrin vedolizumab or agents targeting IL-12/23 (anti-p40 antibody) such as ustekinumab, can be used as the next step in therapy for moderate-to-severe disease relapse in patients who have an inadequate response to TNF blockers and/or IMS.27
Several clinical and environmental predictors of relapse have been reported, including younger age at diagnosis (<25 years), perianal disease, terminal ileal location,6,22 disease location in the proximal small bowel/upper gastrointestinal tract,23 short period of remission before relapse (<6 months),74 oral contraceptive use75 and stress.76 According to the European Crohn’s and Colitis Organisation, common factors associated with higher relapse risk following withdrawal of IMS or anti-TNF are smoking, elevated C-reactive protein level, elevated fecal calprotectin, fistularizing perianal disease, and short duration of remission. Patients with deep remission (clinical, biological, and endoscopic) have a lower risk of relapse after anti-TNF withdrawal, and maintenance of IMS treatment seems to reduce the risk of relapse.77 In pediatric CD patients, baseline anti-
CD is generally distinguished by a sequence of flare-up episodes and remissions of varying durations, whereas 10% to 15% of patients undergo a chronic refractory disease course (Fig. 5).79 Refractory disease refers to individuals showing persistent clinical symptoms without a period of remission. This might have been caused by the failure of induction treatment. A short course of steroids is effectively used for the induction treatment of active disease, and anti-TNF induction is recommended to treat steroid-resistant CD or moderate-to-severe disease with poor prognostic factors.28,80 However, 20% of patients receiving corticosteroid therapy remained refractory to steroids at 1 year. Moreover, 36% of patients develop steroid dependence within the first year of therapy, and in these patients, steroids could not be tapered or discontinued without precipitation of a symptomatic relapse.81 Polymorphism in multi-drug resistant 1, TNF, and migration inhibitory factor genes has been associated with steroid refractoriness.82,83 In steroid-refractory cases, other treatment options, including IMS, anti-TNF agents, ustekinumab, or vedolizumab, are available depending on the extent of the disease, prior disease response, and patient preference.27 A combination of steroids with an anti-TNF agent and an IMS is also possible and may improve outcomes.50 Anti-TNF refractory diseases can be caused by primary nonresponse. Primary nonresponse occurs in 20% to 40% of patients in clinical trials with both IFX and adalimumab, whereas lower rates of 10% to 20% primary nonresponse are generally reported in clinical real-life series.84 Several factors such as genetics, environmental insults, and the phenotype of the disease have been associated with an increased risk of primary nonresponse.85 Longer disease duration (>2 years), small bowel extent of disease, smoking, and normal C-reactive protein have been reported to confer an increased risk of primary nonresponse.85 Certain genetic mutations and/or polymorphisms in the apoptosis-related genes of FAS-L, caspase-9 and IBD5 loci can also be risk factors.84 Cases of familial CD, that is, having a first-degree relative with the disease, are usually diagnosed at a younger age and have an increased risk of extraintestinal manifestations and refractory disease to medical therapy.60 However, the effect of family history is controversial because some studies have reported no significant influence of family history on the disease course.86,87 Primary nonresponse to anti-TNF treatment is probably not a class-effect phenomenon. Switching to another IMS or another anti-TNF agent can still be effective, referring to previous articles showing a 50% to 65% response rate after primary nonresponse to a first and/or second anti-TNF agent.72 Other options include treatment with ustekinumab or vedolizumab, or surgical intervention. Both ustekinumab and vedolizumab are effective as induction and maintenance treatments in patients with CD, either naïve or exposed to anti-TNF.88 A recent French study compared the effectiveness and safety of ustekinumab and vedolizumab in CD patients refractory to anti-TNF, and they suggested that ustekinumab is associated with a higher rate of clinical remission and treatment persistence.89
In a previous prospective observational study from the United Kingdom, low drug concentration at week 14 after starting anti-TNF treatment (IFX and adalimumab) was the only factor associated with primary nonresponse.90 The authors explained that refractoriness to anti-TNF is mediated in part by the generation of anti-drug antibodies. Predictors of nonresponse to ustekinumab in treatment-refractory CD are male sex, the presence of extraintestinal manifestations, the use of steroids at baseline, perianal disease, Harvey-Bradshaw index, and current opioid use.91,92
Surgery and colectomy are among the most objective and extensively studied outcomes of CD. Major surgery and colectomy are needed in approximately 40% to 50% of CD cases within 10 years of diagnosis.93 The most common indications for surgical resection include medically refractory disease, bowel perforation, and persistent or recurrent obstruction.27 Recent data suggest that surgery rates decreased prior to the advent of biologics, parallel with the increased use of IMS and biological therapy.43,45 However, controversial results showing an association between the duration of AZA and anti-TNF and the risk for surgery, similar risk of hospitalization, surgery, and phenotype progression have also been reported.30,94 Therefore, improvement in natural history and disease outcome with the advent of biologics needs to be further investigated. Clinical predictors for surgery include age at onset, disease location, disease behavior, disease behavioral change, early use of AZA/biologics, perianal disease, smoking, and specialist care.42 While young age at diagnosis (<40 years), terminal ileal or ileocolonic location, complicated disease behavior (stricturing and penetrating), and smoking were identified as risk factors,6,21,95 age over 40 years, isolated colonic localization, and gastroenterology specialist care were protective factors for surgery.6,96 The presence of NOD2 polymorphism has been associated with an earlier need for first surgery and a reduced postoperative disease-free interval.97
Data on changes in the natural history of CD indicate that surgery rates have declined in the last decade, partly associated with a greater proportion of patients with uncomplicated disease behavior, changes in patient monitoring, and different therapeutic strategies.98 However, further investigations are needed to assess whether objective patient monitoring or early administration of biologics leads to superior outcomes.
Disease location remains stable with initial manifestation over time and is mostly determined by genetic/familial factors. Disease behavior evolves from simple inflammatory to complicated phenotypes, such as stricturing and/or penetrating disease, in over 50% of CD patients after a long-term follow-up period. A comprehensive assessment of disease activity is mandatory during long-term treatment and monitoring. The long-term disease course can be categorized into four groups: remission, stable, chronic relapsing, and refractory diseases. With the introduction of biologics, the natural history of disease course and outcome seem to be enhanced with increased remission rates, decreased relapse rates, and decreased surgery rates. However, there are controversial results in several studies regarding this topic; therefore, more concrete research is required. Understanding changes in disease patterns, disease course, outcome, and predictive factors is necessary for the development of treatment strategies and better patient care in patients with CD.
This article is based on a scientific exhibition presented at the 76th Korean Congress of Radiology (KCR) on September 17-19, 2020, in Seoul, Korea.
No potential conflict of interest relevant to this article was reported.
Study concept and design: M.W.Y., C.K.L., C.H.O. Drafting of the manuscript: C.W.C., C.H.O. Supervision: M.W.Y., C.K.L., S.K.M. Writing-review & editing: S.K.M., M.W.Y., C.H.O., C.K.L.
Gut and Liver 2022; 16(2): 157-170
Published online March 15, 2022 https://doi.org/10.5009/gnl210118
Copyright © Gut and Liver.
Choong Wui Cho1 , Myung-Won You1
, Chi Hyuk Oh2
, Chang Kyun Lee2
, Sung Kyoung Moon1
Departments of 1Radiology and 2Internal Medicine, Kyung Hee University Hospital, Seoul, Korea
Correspondence to:Myung-Won You
ORCID https://orcid.org/0000-0001-6262-5784
E-mail funfun2020@khu.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Crohn’s disease (CD) is a chronic destructive inflammatory bowel disease that affects young people and is associated with significant morbidity. The clinical spectrum and disease course of CD are heterogeneous and often difficult to predict based on the initial presentation. In this article, changes in the disease location, behavior, clinical course during long-term follow-up, and predictive factors are reviewed. Generally, four different patterns of clinical course are discussed: remission, stable disease, chronic relapsing disease, and chronic refractory disease. Understanding the long-term disease course of CD is mandatory to reveal the underlying pathophysiology of the disease and to move toward a more optimistic disease course, such as remission or stability, and less adverse outcomes or devastating sequelae.
Keywords: Crohn disease, Inflammatory bowel disease, Disease course, Recurrence, Prognosis
Crohn’s disease (CD) is a chronic condition that can affect any site of the gastrointestinal tract, with a wide spectrum of severity and variable disease course.1 CD is traditionally known as a more prevalent disease in the Western world; however, the incidence of CD in Asia is increasing with the increase in the degree of urbanization from the 21st century onwards.2 Most patients with CD experience a waxing and waning clinical course of relapse and remission, and develop cumulative structural damage to the bowel over time.3 However, changes in the disease phenotype and severity are frequently heterogeneous and unpredictable for each patient. The evolution of anti-tumor necrosis factor (TNF) therapy improves the clinical outcomes of CD patients, such as clinical remission, steroid sparing, and mucosal healing.4 Anti-TNF therapy improved patients’ outcomes in terms of achievement of targets of treatment and modification of the natural history of the disease in a higher percentage of patients in conjunction with immunosuppressive medication. Nonetheless, primary nonresponse or loss of response (LOR) to anti-TNF therapy remains frequent, leading to significant morbidity.5 There are few data regarding the long-term course of CD during lifelong treatment and monitoring. In this article, we elaborate on the changes in disease patterns, long-term clinical course, and predictive factors.
Many reports have revealed that disease location remains relatively stable during the long-term disease course. Data on changes in disease location during the 10-year follow-up period are shown in Table 1. According to some Western studies, isolated colonic disease (L2) seems to have increased.6,7 Overall, the ileocolic area (L3) has been found to be the most frequently affected location in both Asian and Western studies.2,8-11 In a recent Asian-Pacific study conducted in eight countries across Asia and Australia, the distribution of disease location was almost the same.2 On the other hand, a Japanese study on pediatric CD patients demonstrated more frequent ileocolic (L3) and upper gastrointestinal (L4) involvement, and less colonic (L2) involvement compared with a European pediatric study based on a multicenter registry.15 Thia
Table 1 . Changes in Disease Locations Over Time Based on the Montreal Classification: Long-term Follow-up Result (About 10-Year Period).
Author (year) | Country | Location | Baseline, % | 10 Years, % |
---|---|---|---|---|
Asian countries | ||||
Chow | Hong Kong | L1 | 11 | 0 |
L2 | 35 | 33 | ||
L3 | 54 | 67 | ||
L4 | 55.9 | 57.1 | ||
Ye | South Korea | L1 | 24.4 | 24.4 |
L2 | 8.3 | 8.3 | ||
L3 | 67.3 | 67.3 | ||
Makharia | India | L1 | 28.9 | |
L2 | 31.4 | |||
L3 | 39.6 | |||
L4 | 5.8 | |||
Ng | Asian-Pacific | L1 | 31/31* | |
L2 | 24/24* | |||
L3 | 45/45* | |||
L4 | 5/5* | |||
Kalaria | India | L1 | 28.9 | 36.8 |
L2 | 31.5 | 21 | ||
L3 | 39.4 | 42.2 | ||
L4 | 5.2 | 5.2 | ||
Western countries | ||||
Louis | Belgium | L1 | 44.8 | 43.3 |
L2 | 26.7 | 23.3 | ||
L3 | 24.2 | 30 | ||
Tarrant | New Zealand | L1 | 32 | 35 |
L2 | 49 | 41 | ||
L3 | 19 | 22 | ||
L4 | 0.6 | 2 | ||
Solberg | Norway | L1 | 27 | 25.9 |
L2 | 48.5 | 47.7 | ||
L3 | 22.7 | 24.3 | ||
L4 | 1.7 | 2 | ||
Lakatos | Hungary | L1 | 22 | 18.2 |
L2 | 29.1 | 36.8 | ||
L3 | 47.3 | 44.4 | ||
L4 | 6.4 | 0.5 | ||
Thia | USA | L1 | 45.1 | 42.5 |
L2 | 32 | 28.8 | ||
L3 | 18.6 | 23.2 | ||
L4 | 4.2 | 5.5 |
L1, ileal disease; L2, colonic disease; L3, ileocolic disease; L4, upper gastrointestinal involvement..
*Asian/Pacific..
When we examined the results of phenotypic changes in several reports, we found an obvious tendency of disease behavioral changes from simple inflammatory diseases to increased portions of complexity, either stricturing/penetrating or both diseases (Table 2). Many studies reported a complicated disease phenotype (B2/B3) of over 50% in a 10-year follow-up, compared to those in the baseline, which was approximately one-third. Cosnes
Table 2 . Changes to Complicated Phenotypes (B2/B3) from Simple Inflammatory Phenotype (B1) Based on the Montreal Classification: Long-term Follow-up Result (≥10 Years).
Author (year) | Country | Phenotype | Baseline, % | ≥10 Years, % |
---|---|---|---|---|
Asian countries | ||||
Chow | Hong Kong | B1 | 67 | 43 |
B2/B3 | 33 | 57 | ||
Das | India | B1 | 51 | |
B2/B3 | 49 | |||
Ye | South Korea | B1 | 68.7 | 49.3 |
B2/B3 | 31.3 | 50.7 | ||
Makharia | India | B1 | 66.8 | |
B2/B3 | 33.2 | |||
Ng | Asian-Pacific | B1 | 66/88* | |
B2/B3 | 36/12* | |||
Kalaria | India | B1 | 74.7 | 50 |
B2/B3 | 25.2 | 49.9 | ||
Western countries | ||||
Cosnes | France | B1 | 40 | 12† |
B2/B3 | 60 | 88† | ||
Louis | Belgium | B1 | 73.7 | 30.6 |
B2/B3 | 26.3 | 69.4 | ||
Tarrant | New Zealand | B1 | 73 | 44 |
B2/B3 | 27 | 56 | ||
Solberg | Norway | B1 | 62 | 47 |
B2/B3 | 38 | 53 | ||
Lakatos | Hungary | B1 | 58.3 | 28.3 |
B2/B3 | 41.7 | 71.7 | ||
Thia | USA | B1 | 81.4 | 57.3 |
B2/B3 | 18.6 | 42.7 |
B2, stricturing; B3, penetrating..
*Asian/Pacific; †20 Years..
The clinical course of the disease can be classified into four different patterns in terms of the severity of bowel symptoms from diagnosis to the entire follow-up period. According to previous studies based on population-based prospective cohorts from Western countries (IBSEN study),6,23 the different patterns in the clinical course of CD were remission, aggravation, continuous refractory, and chronic relapsing. The percentages of each category were 43% (remission), 3% (aggravation), 19% (chronic refractory), and 32% (chronic relapsing). In this early 1990s cohort, the majority of the patients received oral 5-aminosalicylic acid and systemic steroids (73% to 88%) with 21% to 26% receiving AZA and only 4% receiving TNF blockers.6 Nowadays, the pattern of the clinical course should be modified according to the more prevalent and earlier use of TNF blockers as either monotherapy or combination therapy with immunosuppressants (IMS). Hence, salvaged cases from aggravation, refractory, or relapsing towards properly controlled disease course such as remission, improved, or stable disease will increase. In a recent prospective population-based cohort study, a significant portion of the patients was treated with biologics (23%) and IMS (69%), and the results showed a considerably more stable clinical course compared to previous reports.24 In this review, the clinical course of CD was defined partly based on the four disease activity patterns by Solberg
Remission is defined as a Crohn’s Disease Activity Index (CDAI) ≤150 (Fig. 2). A Danish cohort study conducted during 1960 to 1978 showed that 45% of patients with CD were in an inactive disease state at the end of the follow-up period.26 Solberg
Deep remission is defined as combined endoscopic and clinical remission.35 The therapeutic paradigm in CD has shifted from a mere symptom-oriented approach, aiming to heal the underlying inflammation and prevent long-term structural complications. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative has proposed this “treat-to-target” concept, that is, to achieve clinical/patient-reported outcome remission plus endoscopic/radiologic remission.35 The STRIDE guidelines recommend achieving both clinical and endoscopic remission (mucosal healing) to prevent adverse long-term outcomes and disability. Mucosal healing is best associated with favorable clinical symptomatic remission and disease-modifying outcomes such as hospitalization, surgical intervention, and quality of life.36,37 Recently, STRIDE-II has updated the 2015 STRIDE recommendations, and restoration of quality of life and absence of disability have been added to endoscopic remission as long-term targets.38 Moreover, transmural healing assessed using cross-sectional imaging has been recommended as an adjunctive goal, although it is not a formal treatment target. After the application of the treat-to-target concept, the remission rate was lowered; deep remission was achieved in about 16% of patients with moderate-to-severe CD in the EXTEND trial39 and in 39% of patients with early CD who were immunomodulatory and anti-TNF naïve in the SONIC trial.40
Surgical remission is another way to achieve remission. Surgery resulted in a longer duration of remission, suggesting that earlier surgery might be more beneficial from an economic perspective.29 Patients with CD who underwent surgery at diagnosis for acute abdomen showed a lower risk of reoperation and less use of steroids and IMS during follow-up than those who did not undergo surgery at diagnosis.41 On the other hand, surgery around the diagnosis (until 6 months) is clearly the result of complications already present at diagnosis and is more representative of the initial patient characteristics than a real outcome measure.42 Recent data suggest that surgery rates decreased prior to the advent of biologics,43-45 but the results were not confirmed in all studies, and the causative role is unproven. Surgery as an outcome parameter will be discussed later.
Clinical parameters reflecting mild inflammation, such as a lower CDAI and non-stricturing and non-penetrating behaviors, were associated with mid- to long-term responsiveness to steroids.46 A prospective observational study from Italy reported that postinduction fecal calprotectin combined with weighted pediatric CDAI are predictors of 1-year clinical and endoscopic remission to IFX in pediatric CD.47 Although previous studies have reported comparable effectiveness of elemental diet to steroid use48 and the role of diet control in prolonging remission,49 nutritional therapy is regarded as only appropriate for adjunctive treatment to support nutrition, unlike the management of pediatric/adolescent CD.50
Stable disease refers to a case with decreased severity of bowel symptoms during the follow-up period, but with mild residual activity or sequelae, as shown in the radiological or endoscopic assessment, not disturbing everyday life (Fig. 3). This is our potential explanation of cases showing discrepancies according to comprehensive assessments of biochemical, radiologic, and endoscopic parameters. Therefore, improved and stable disease includes cases in clinical remission but not in endoscopic and/or radiologic remission. According to a recently published report by Wintjens
Data regarding benign courses are scarce compared to those regarding unfavorable courses. Factors associated with non-severe 15-year clinical course, defined as clinically inactive disease for greater than 12 years, less than one intestinal resection without permanent stoma and no death, were non-smoking status, rectal sparing, high educational level, older age, and longer disease duration.58
Maintenance of remission in CD should last at least 12 months according to the recommendations of the European Crohn’s and Colitis Organisation.59 Relapse is defined as a flare of symptoms in an established CD patient in clinical remission. Studies usually define relapse as CDAI >150 or reappearance of symptoms requiring treatment modification, hospitalization, or surgery (Fig. 4).60 In clinical practice, relapse is confirmed by laboratory parameters, imaging, or endoscopy. Early relapse is defined as relapse within an arbitrary period of <3 months after achieving remission in a particular therapy.50 Based on the pattern of relapse, they can be categorized as infrequent (<1/year) or frequent (>2/year).27
Relapse rates in several previous studies ranged from 11% to 58%,60 while studies in the 2000s exhibited higher relapse rates (31% to 58%).61,62 Recent studies in the 2010s exhibited lower relapse rates (11% to 27%).63,64 These changes in relapse rates over time may have been caused by changes in medical treatments. A larger proportion of IMS and biologics were prescribed for CD patients in recent studies, whereas mainly aminosalicylic acids were prescribed for patients in the earlier 2000s. Although Laharie
At the time of the initial diagnosis of CD, induction therapy is necessary for patients exhibiting signs and symptoms of active disease.27 Once remission is achieved, patients are placed on maintenance therapy to ensure that remission is maintained for the longest possible period.27 Failure of maintenance therapy results in disease relapse. The majority of patients who were treated with corticosteroids to induce remission usually relapsed within 1 year without specific effective maintenance therapy.28 Although sulfasalazine and mesalamine are not effective agents in the maintenance of remission, IMS such as thiopurines, methotrexate, and TNF blockers are effective in the maintenance of CD remission.66 Despite the increasing use of IMS and TNF blockers, the remission rate has remained unchanged during the last decades (approximately 43% to 45%) and the improvement of the natural course of CD is still questionable. However, treatment options have been stratified according to comprehensive risk assessments, including initial disease activity, extent, and poor prognostic factors. The initial treatment of relapse should be based on previously successful therapies.50 However, several factors should be reassessed while deciding the treatment strategy for relapsing disease. These include time to relapse, initial therapy resulting in optimal response, adverse effects of current therapy, adherence to the prescribed therapy, and concurrent therapy. In case of early relapse, opinions remain divided on whether to use the same treatment to induce remission and taper more slowly or to use more potent induction therapy, and usually it necessitates the initiation of IMS to prevent future relapse.50 Moderate-to-severe relapsing disease warrants initiation of TNF blockers, and concurrent therapy with IFX and AZA is also noted to be more effective than either therapy alone.50,67
Relapse during TNF blocker treatment can be caused by a LOR. Patients who initially respond to anti-TNF induction regimen subsequently lose response and experience flare of symptoms necessitating dose escalation, switching of anti-TNF agents, or surgical intervention.5 LOR usually occurs within the first 12 months, and the rate of LOR after 12 months of anti-TNF therapy in CD patients ranges from 23% to 46% for both IFX and adalimumab.68,69 The annual risk of LOR is between 13% and 24% as judged by the need for dose intensification70 and 7% per year experience LOR despite dose intensification.69 The most investigated mechanism for LOR is the formation of antibodies against anti-TNF agents. Antibodies-to-IFX is associated with lower serum levels of the drug due to increased drug clearance.71 Management options for LOR include dose optimization such as dose increase or interval shortening, switching to another TNF blocker, and addition of another IMS to restore effective TNF blockade.5 A recent randomized controlled trial reported that the addition of AZA to the switch of anti-TNF yielded higher survival rates without clinical failure and the occurrence of unfavorable pharmacokinetics in patients with immune-mediated LOR to the first anti-TNF.68 Furthermore, treatment with a third anti-TNF agent or even retreatment with a previously failed anti-TNF can confer sustained clinical response in one-third of patients.72 However, switching from anti-TNF to another biologic with a different mode of action may prove more beneficial.73 In this respect, agents targeting leukocyte trafficking, such as anti-integrin vedolizumab or agents targeting IL-12/23 (anti-p40 antibody) such as ustekinumab, can be used as the next step in therapy for moderate-to-severe disease relapse in patients who have an inadequate response to TNF blockers and/or IMS.27
Several clinical and environmental predictors of relapse have been reported, including younger age at diagnosis (<25 years), perianal disease, terminal ileal location,6,22 disease location in the proximal small bowel/upper gastrointestinal tract,23 short period of remission before relapse (<6 months),74 oral contraceptive use75 and stress.76 According to the European Crohn’s and Colitis Organisation, common factors associated with higher relapse risk following withdrawal of IMS or anti-TNF are smoking, elevated C-reactive protein level, elevated fecal calprotectin, fistularizing perianal disease, and short duration of remission. Patients with deep remission (clinical, biological, and endoscopic) have a lower risk of relapse after anti-TNF withdrawal, and maintenance of IMS treatment seems to reduce the risk of relapse.77 In pediatric CD patients, baseline anti-
CD is generally distinguished by a sequence of flare-up episodes and remissions of varying durations, whereas 10% to 15% of patients undergo a chronic refractory disease course (Fig. 5).79 Refractory disease refers to individuals showing persistent clinical symptoms without a period of remission. This might have been caused by the failure of induction treatment. A short course of steroids is effectively used for the induction treatment of active disease, and anti-TNF induction is recommended to treat steroid-resistant CD or moderate-to-severe disease with poor prognostic factors.28,80 However, 20% of patients receiving corticosteroid therapy remained refractory to steroids at 1 year. Moreover, 36% of patients develop steroid dependence within the first year of therapy, and in these patients, steroids could not be tapered or discontinued without precipitation of a symptomatic relapse.81 Polymorphism in multi-drug resistant 1, TNF, and migration inhibitory factor genes has been associated with steroid refractoriness.82,83 In steroid-refractory cases, other treatment options, including IMS, anti-TNF agents, ustekinumab, or vedolizumab, are available depending on the extent of the disease, prior disease response, and patient preference.27 A combination of steroids with an anti-TNF agent and an IMS is also possible and may improve outcomes.50 Anti-TNF refractory diseases can be caused by primary nonresponse. Primary nonresponse occurs in 20% to 40% of patients in clinical trials with both IFX and adalimumab, whereas lower rates of 10% to 20% primary nonresponse are generally reported in clinical real-life series.84 Several factors such as genetics, environmental insults, and the phenotype of the disease have been associated with an increased risk of primary nonresponse.85 Longer disease duration (>2 years), small bowel extent of disease, smoking, and normal C-reactive protein have been reported to confer an increased risk of primary nonresponse.85 Certain genetic mutations and/or polymorphisms in the apoptosis-related genes of FAS-L, caspase-9 and IBD5 loci can also be risk factors.84 Cases of familial CD, that is, having a first-degree relative with the disease, are usually diagnosed at a younger age and have an increased risk of extraintestinal manifestations and refractory disease to medical therapy.60 However, the effect of family history is controversial because some studies have reported no significant influence of family history on the disease course.86,87 Primary nonresponse to anti-TNF treatment is probably not a class-effect phenomenon. Switching to another IMS or another anti-TNF agent can still be effective, referring to previous articles showing a 50% to 65% response rate after primary nonresponse to a first and/or second anti-TNF agent.72 Other options include treatment with ustekinumab or vedolizumab, or surgical intervention. Both ustekinumab and vedolizumab are effective as induction and maintenance treatments in patients with CD, either naïve or exposed to anti-TNF.88 A recent French study compared the effectiveness and safety of ustekinumab and vedolizumab in CD patients refractory to anti-TNF, and they suggested that ustekinumab is associated with a higher rate of clinical remission and treatment persistence.89
In a previous prospective observational study from the United Kingdom, low drug concentration at week 14 after starting anti-TNF treatment (IFX and adalimumab) was the only factor associated with primary nonresponse.90 The authors explained that refractoriness to anti-TNF is mediated in part by the generation of anti-drug antibodies. Predictors of nonresponse to ustekinumab in treatment-refractory CD are male sex, the presence of extraintestinal manifestations, the use of steroids at baseline, perianal disease, Harvey-Bradshaw index, and current opioid use.91,92
Surgery and colectomy are among the most objective and extensively studied outcomes of CD. Major surgery and colectomy are needed in approximately 40% to 50% of CD cases within 10 years of diagnosis.93 The most common indications for surgical resection include medically refractory disease, bowel perforation, and persistent or recurrent obstruction.27 Recent data suggest that surgery rates decreased prior to the advent of biologics, parallel with the increased use of IMS and biological therapy.43,45 However, controversial results showing an association between the duration of AZA and anti-TNF and the risk for surgery, similar risk of hospitalization, surgery, and phenotype progression have also been reported.30,94 Therefore, improvement in natural history and disease outcome with the advent of biologics needs to be further investigated. Clinical predictors for surgery include age at onset, disease location, disease behavior, disease behavioral change, early use of AZA/biologics, perianal disease, smoking, and specialist care.42 While young age at diagnosis (<40 years), terminal ileal or ileocolonic location, complicated disease behavior (stricturing and penetrating), and smoking were identified as risk factors,6,21,95 age over 40 years, isolated colonic localization, and gastroenterology specialist care were protective factors for surgery.6,96 The presence of NOD2 polymorphism has been associated with an earlier need for first surgery and a reduced postoperative disease-free interval.97
Data on changes in the natural history of CD indicate that surgery rates have declined in the last decade, partly associated with a greater proportion of patients with uncomplicated disease behavior, changes in patient monitoring, and different therapeutic strategies.98 However, further investigations are needed to assess whether objective patient monitoring or early administration of biologics leads to superior outcomes.
Disease location remains stable with initial manifestation over time and is mostly determined by genetic/familial factors. Disease behavior evolves from simple inflammatory to complicated phenotypes, such as stricturing and/or penetrating disease, in over 50% of CD patients after a long-term follow-up period. A comprehensive assessment of disease activity is mandatory during long-term treatment and monitoring. The long-term disease course can be categorized into four groups: remission, stable, chronic relapsing, and refractory diseases. With the introduction of biologics, the natural history of disease course and outcome seem to be enhanced with increased remission rates, decreased relapse rates, and decreased surgery rates. However, there are controversial results in several studies regarding this topic; therefore, more concrete research is required. Understanding changes in disease patterns, disease course, outcome, and predictive factors is necessary for the development of treatment strategies and better patient care in patients with CD.
This article is based on a scientific exhibition presented at the 76th Korean Congress of Radiology (KCR) on September 17-19, 2020, in Seoul, Korea.
No potential conflict of interest relevant to this article was reported.
Study concept and design: M.W.Y., C.K.L., C.H.O. Drafting of the manuscript: C.W.C., C.H.O. Supervision: M.W.Y., C.K.L., S.K.M. Writing-review & editing: S.K.M., M.W.Y., C.H.O., C.K.L.
Table 1 Changes in Disease Locations Over Time Based on the Montreal Classification: Long-term Follow-up Result (About 10-Year Period)
Author (year) | Country | Location | Baseline, % | 10 Years, % |
---|---|---|---|---|
Asian countries | ||||
Chow | Hong Kong | L1 | 11 | 0 |
L2 | 35 | 33 | ||
L3 | 54 | 67 | ||
L4 | 55.9 | 57.1 | ||
Ye | South Korea | L1 | 24.4 | 24.4 |
L2 | 8.3 | 8.3 | ||
L3 | 67.3 | 67.3 | ||
Makharia | India | L1 | 28.9 | |
L2 | 31.4 | |||
L3 | 39.6 | |||
L4 | 5.8 | |||
Ng | Asian-Pacific | L1 | 31/31* | |
L2 | 24/24* | |||
L3 | 45/45* | |||
L4 | 5/5* | |||
Kalaria | India | L1 | 28.9 | 36.8 |
L2 | 31.5 | 21 | ||
L3 | 39.4 | 42.2 | ||
L4 | 5.2 | 5.2 | ||
Western countries | ||||
Louis | Belgium | L1 | 44.8 | 43.3 |
L2 | 26.7 | 23.3 | ||
L3 | 24.2 | 30 | ||
Tarrant | New Zealand | L1 | 32 | 35 |
L2 | 49 | 41 | ||
L3 | 19 | 22 | ||
L4 | 0.6 | 2 | ||
Solberg | Norway | L1 | 27 | 25.9 |
L2 | 48.5 | 47.7 | ||
L3 | 22.7 | 24.3 | ||
L4 | 1.7 | 2 | ||
Lakatos | Hungary | L1 | 22 | 18.2 |
L2 | 29.1 | 36.8 | ||
L3 | 47.3 | 44.4 | ||
L4 | 6.4 | 0.5 | ||
Thia | USA | L1 | 45.1 | 42.5 |
L2 | 32 | 28.8 | ||
L3 | 18.6 | 23.2 | ||
L4 | 4.2 | 5.5 |
L1, ileal disease; L2, colonic disease; L3, ileocolic disease; L4, upper gastrointestinal involvement.
*Asian/Pacific.
Table 2 Changes to Complicated Phenotypes (B2/B3) from Simple Inflammatory Phenotype (B1) Based on the Montreal Classification: Long-term Follow-up Result (≥10 Years)
Author (year) | Country | Phenotype | Baseline, % | ≥10 Years, % |
---|---|---|---|---|
Asian countries | ||||
Chow | Hong Kong | B1 | 67 | 43 |
B2/B3 | 33 | 57 | ||
Das | India | B1 | 51 | |
B2/B3 | 49 | |||
Ye | South Korea | B1 | 68.7 | 49.3 |
B2/B3 | 31.3 | 50.7 | ||
Makharia | India | B1 | 66.8 | |
B2/B3 | 33.2 | |||
Ng | Asian-Pacific | B1 | 66/88* | |
B2/B3 | 36/12* | |||
Kalaria | India | B1 | 74.7 | 50 |
B2/B3 | 25.2 | 49.9 | ||
Western countries | ||||
Cosnes | France | B1 | 40 | 12† |
B2/B3 | 60 | 88† | ||
Louis | Belgium | B1 | 73.7 | 30.6 |
B2/B3 | 26.3 | 69.4 | ||
Tarrant | New Zealand | B1 | 73 | 44 |
B2/B3 | 27 | 56 | ||
Solberg | Norway | B1 | 62 | 47 |
B2/B3 | 38 | 53 | ||
Lakatos | Hungary | B1 | 58.3 | 28.3 |
B2/B3 | 41.7 | 71.7 | ||
Thia | USA | B1 | 81.4 | 57.3 |
B2/B3 | 18.6 | 42.7 |
B2, stricturing; B3, penetrating.
*Asian/Pacific; †20 Years.