Crohn’s disease from past to present: Research trends and global outcomes with scientometric analysis during 1980 to 2022

Abstract

Currently, there is no comprehensive bibliometric study in the literature on Crohn’s disease (CD). The aim of this study was to analyze articles published on CD using bibliometric and statistical methods. The aim was to identify current research trends, show global productivity, and determine important players such as countries, journals, institutions, and authors. A total of 16,216 articles published on CD between 1980 and 2022 were analyzed using various statistical and bibliometric methods. Bibliometric network visualization maps were used to perform trend topic analysis, citation analysis, and international collaboration analysis. Spearman’s correlation coefficient was used for correlation analysis. The top 3 contributing countries to the literature were the United States of America (USA) (n = 4344, 26.7%), the United Kingdom (UK) (n = 2036, 12.5%) and Germany (n = 1334, 8.2%). The most active institutions were Udice French Research Universities (n = 696), Assistance Publique Hopitaux Paris (n = 570), and Institut National de la Sante et de la Recherche Medicale Inserm (n = 479). The most productive journals were Inflammatory Bowel Diseases (n = 1100), Journal of Crohn’s & Colitis (n = 579), and Gut (n = 510). The most prolific author was Colombel JF. (n = 290). The most frequently researched topics from past to present included infliximab, ulcerative colitis, surgery, pediatrics, adalimumab, magnetic resonance imaging, inflammation, perianal CD/perianal fistula, azathioprine, magnetic resonance enterography, small bowel, stricture/strictureplasty, recurrence, therapy/treatment, ustekinumab, mucosal healing, biomarkers, fistula, quality of life, ultrasonography, epidemiology, capsule endoscopy, laparoscopic surgery/laparoscopy, endoscopy, disease activity, postoperative recurrence, and the Nucleotide Binding Oligomerization Domain Containing 2 gene. We have seen an exponential increase in worldwide publications on CD. In recent years, the major research topics related to CD have been ustekinumab, vedolizumab, fecal calprotectin, therapeutic drug monitoring, biologics, biomarkers, exclusive enteral nutrition, microbiome/microbiota, magnetic resonance enterography, anti-TNF, postoperative complications, and mucosal healing. We determined that countries with large economies, particularly the United States, United Kingdom, Germany, France, Canada, Italy, Japan and China, have taken the lead in research contributions to the development of CD literature.

1. Introduction

Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology that is thought to result from the interplay of environmental factors in genetically predisposed individuals.^[1,2] CD is a disease characterized by progressive intestinal damage and disability. It can affect individuals of all ages, from children to the elderly, leading to significant morbidity and diminished quality of life.^[3] Patients are often hospitalized with clinical symptoms such as abdominal pain, fever, signs of intestinal obstruction, and bloody or mucopurulent diarrhea, or a combination thereof.^[4] Chronic diarrhea is the most commonly observed symptom.^[5,6]

The underlying pathology of CD is thought to be due to a dysfunctional interaction between the human immune system and the symbiotic intestinal commensal microbiota.^[4] Genetic studies and in silico meta-analyses have identified and confirmed 71 susceptibility loci for CD on 17 chromosomes thus far.^[7] The identification of susceptibility loci has provided important insights into the dysfunctional pathways of the intestinal immune system, contributing to our understanding of the etiopathogenesis of the disease.^[4] Studies conducted in individuals with CD have demonstrated clustering and decreased biodiversity of Firmicutes and Bacteroidetes species, which are beneficial for intestinal health. A reduction in Faecalibacterium prausnitzii (a Firmicute) has been associated with an increased risk of postoperative recurrence in ileal CD.^[4,8]

There is no single gold standard method for diagnosing CD. The diagnosis is usually made by a combination of clinical assessment, endoscopy, computed tomography and magnetic resonance imaging (MRI) enterography or enteroclysis, ultrasound, and biomarkers such as C-reactive protein and the stool granulocyte proteins lactoferrin and calprotectin, or their combinations.^[4,6] In clinical studies, the Crohn’s Disease Activity Index (CDAI) is commonly used to select CD patients in clinical remission. CDAI index values of 150 and below are associated with disease remission, while values above indicate active disease. CDAI values above 450 are indicative of extremely severe disease. However, due to the limitations of the CDAI, objective data such as C-reactive protein < 10 mg/L, endoscopy, imaging, and even histology are increasingly needed to define disease remission.^[6,9]

In a recent systematic review that included 147 incidence and prevalence studies, the highest reported CD prevalence was found to be 322 per 100,000 in Germany in Europe and 319 per 100,000 in Canada. Overall, 16 out of 22 CD-related studies in North America and Europe reported a stable or declining incidence of IBD, although since 1990, the incidence has been increasing in newly industrialized countries in Africa, Asia, and South America, including Brazil and Taiwan.^[10] In a recent study in Sydney, the age-standardized rate for CD was reported as 166 cases per 100,000 populations (95% confidence interval [CI]: 141–192 cases).^[11]

Since the exact etiology of CD is unknown, there is currently no curative treatment.^[3,6] Existing treatments do not address the genetic basis of this chronic disease, leaving patients in need of long-term management.^[4,12] Classifying patients based on prognostic risk factors and personalizing treatment are important steps to optimize patient care. Several factors, such as disease location, disease activity and severity, response to previous treatments, and presence of complications, influence the choice of medical treatment.^[3] CD is classified based on disease phenotype (Montreal classification), disease activity (often based on CDAI), and response to treatment (steroid-resistant or steroid-dependent).^[6]

Various agents are used for the medical treatment of CD, including mesalazine, locally acting steroids (such as budesonide), systemic steroids, thiopurines (such as azathioprine and mercaptopurine), methotrexate, and biologic therapies (anti-tumor necrosis factor [anti-TNF] and anti-interleukin agents).^[3] Effective drugs for maintaining remission in CD are known, including azathioprine, infliximab, adalimumab, and vedolizumab. There is also sufficient evidence to support the use of ustekinumab, methotrexate, certolizumab, and natalizumab.^[6]

The specific indications for surgical intervention at CD include abscesses, complex perianal or internal fistulas that are unresponsive or poorly responsive to medical treatment, fibrostenotic strictures with symptoms of partial or complete intestinal obstruction, high-grade dysplasia, and cancer.^[4,12]

In recent years, the scientific literature has grown rapidly with the development of online publishing and advances in technology. Also, the increasing number of articles, bibliometric studies have been conducted in various medical fields and have become a widely used quantitative research method for evaluating the literature.^[13,14] Bibliometrics provides comprehensive analysis and structured information about a specific topic, research area, institution, or country, assisting in the identification of important insights for future research.^[15,16] Currently, there is no comprehensive bibliometric study available in the literature focusing on CD. This study aims to analyze articles published between 1980 and 2022 using bibliometric and statistical methods in the field of CD. The aim is to uncover current research trends, determine global productivity, and identify key players such as countries, journals, institutions, and authors.

2. Methods

2.1. Search strategy

Web of Science (WoS) (Clarivate Analytics, Philadelphia, PA, USA) was used to search for publications indexed in CD between 1980 and 2022,. The search strategy used in this study was as follows: [(Title = (crohn disease*) OR Title = (crohns disease*) OR Title = (crohn’s disease*)] AND [Document Type = (Article) AND Publication period: 1980–2022)]. This search strategy was used to access all studies that contained any of the phrases “Crohn disease,” “Crohns disease,” or “Crohn’s disease” in their title (Articles were accesses on March 1, 2023). Only original articles were included in the bibliometric analysis, whereas other publication types were excluded.

2.2. Statistical analysis

Statistical analyses were performed with the SPSS package programme (Version: 22.0; SPSS Inc., Chicago, IL). Bibliometric analyses were performed using the VOSviewer package programme (Version 1.6.19; Leiden University).^[17] VOSviewer is a software package used for visualizing and constructing bibliometric networks. These bibliometric networks can include researchers, journals, or specific publications, and they can be constructed based on citation, co-citation, or co-authorship relationships. VOSviewer also provides text mining capabilities to create and visualize co-occurrence networks of important terms from the scientific literature. Analysis of the co-occurrence of keywords is a bibliometric method used to map the research landscape. In bibliometrics, co-occurrence analysis is used to examine the potential relationship between 2 terms that appear in the same publication. It examines the presence of item pairs (keywords) that appears together in a document to determine the relationships between the terms presented in the text. There is a relationship between co-word analysis and co-citation analysis. While co-word analysis focuses on the keywords in the documents, co-citation analysis focuses on the citations. Co-citation analysis provides a method for mapping the structure of a research field through jointly cited pairs of documents.^[13–17]

To predict article trends in CD for the next 5 years, the Smoothing Forecast function in Microsoft Office Excel was used. Seasonal adjustment was applied in the prediction model. The world map of countries’ contributions to the literature in the field of CD, presented as a color intensity graph, was obtained from the website https://app.datawrapper.de. The normality of the data was tested using the Kolmogorov–Smirnov test. The Spearman correlation coefficient was used to analyze the correlation between the number of articles from WoS and economic indicators obtained from the World Bank.^[18] A significance level of P < .05 was considered statistically significant.

3. Results

As a result of the literature search, we obtained 39,022 publications on CD. Out of these publications, 16,216 (41.6%) were articles, 15,478 (39.7%) were meeting abstracts, 2605 (6.7%) were letters, 1890 (4.8%) were review articles, 895 (2.3%) were proceeding papers, and the remaining were categorized as other publication types such as editorial material, notes, biographical articles, book chapters, etc. Only the 16,216 articles were included in the bibliometric analyses. Almost all articles, 92% (n = 14,925), were indexed in SCI-expanded, and 7.1% (n = 1152) were indexed in ESCI. The articles were predominantly published in English, 93% (n = 15,087), while the remaining articles appeared in other languages, including German (494), French (329), Spanish (157), Russian (55), Polish (28), Korean (22), Italian (13), Hungarian (8), Portuguese (7), Turkish (5), Japanese (4), Czech (3), Dutch (1), Estonian (1), Flemish (1), and Norwegian (1).

3.1. Prominent research areas on CD

The research areas with the highest number of published articles on CD (areas where at least 60 articles were flagged) are presented in Table 1. The top research areas on CD are as follows, based on the number of articles and corresponding research fields where CD-related articles were extensively tagged: Gastroenterology Hepatology (number of articles = 9110), Surgery (1926), Medicine General Internal (1394), Pharmacology Pharmacy (795), Paediatrics (793), Radiology Nuclear Medicine Medical Imaging (726), Nutrition Dietetics (617), Immunology (563), Medicine Research Experimental (417), Multidisciplinary Sciences (320), Pathology (281), Genetics Heredity (235), Microbiology (229), Cell Biology (211), and Biochemistry Molecular Biology (210).

Table 1.

The research areas with 60 or more articles on Crohn’s disease.

Research areas	N	C	Research areas	N	C
Gastroenterology Hepatology	9110	56.2	Dermatology	190	1.2
Surgery	1926	11.9	Oncology	137	0.8
Medicine General Internal	1394	8.6	Medical Laboratory Technology	97	0.6
Pharmacology Pharmacy	795	4.9	Public Environmental Occupational Health	94	0.6
Pediatrics	793	4.9	Clinical Neurology	81	0.5
Radiology Nuclear Medicine Medical Imaging	726	4.5	Endocrinology Metabolism	81	0.5
Nutrition Dietetics	617	3.8	Biotechnology Applied Microbiology	79	0.5
Immunology	563	3.5	Urology Nephrology	79	0.5
Medicine Research Experimental	417	2.6	Rheumatology	78	0.5
Multidisciplinary Sciences	320	2	Infectious Diseases	76	0.5
Pathology	281	1.7	Obstetrics Gynecology	75	0.5
Genetics Heredity	235	1.4	Neurosciences	74	0.5
Microbiology	229	1.4	Health Care Sciences Services	69	0.4
Cell Biology	211	1.3	Ophthalmology	62	0.4
Biochemistry Molecular Biology	210	1.3

C = number of citations, N = number of articles.

These research areas highlight the multidisciplinary nature of CD research, encompassing various medical specialties and scientific fields, including gastroenterology, surgery, internal medicine, pharmacology, pediatrics, radiology, nutrition, immunology, pathology, genetics, microbiology, cell biology, and biochemistry.

3.2. Publication trend of Crohn’s disease from past to future

Figure 1 shows a line graph depicting the historical and predicted publication trends of articles related to CD taking into account seasonal adjustments using the smoothing estimator. The model-generated results show that an estimated 972 articles (95% CI: 895–1050) related to CD will be published in 2023. Furthermore, it is predicted that the number of publications will increase to 1191 articles (95% CI: 871–1511) in 2027 (Fig. 1).

Figure 1.

Line graph showing the change in the number of articles published on Crohn’s disease over the years and the trend in the number of articles to be published in the next 5 years.

3.3. Active countries in Crohn’s disease

Figure 2 shows a bar graph of the top 20 countries that have made the highest contributions to the literature on CD, as well as a world map is showing the countries’ contributions to the literature by color intensity. Among the 101 countries that have published articles on CD, the top 25 countries with more than 200 contributions are as follows: USA: 4344 articles (26.7%), UK: 2036 articles (12.5%), Germany: 1334 articles (8.2%), France: 1303 articles (8%), Canada: 1225 articles (7.5%), Italy: 1225 articles (7.5%), Japan: 970 articles (5.9%), China: 924 articles (5.6%), Spain: 761 articles (4.6%), Netherlands: 742 articles (4.5%), Belgium: 680 articles (4.1%), Israel: 493 articles (3%), Sweden: 454 articles (2.8%), Australia: 420 articles (2.5%), Denmark: 405 articles (2.4%), South Korea: 372 articles (2.2%), Switzerland: 299 articles (1.8%), Austria: 270 articles (1.6%), Poland: 252 articles (1.5%), and Greece: 209 articles (1.2%).

Figure 2.

Bar graph showing the top 25 contributors to the Crohn’s disease literature and a world color density map showing global article productivity.

Among the 101 countries that published articles on CD, analysis of international collaboration was conducted and cooperation scores were calculated to determine the collaboration strength. The 10 countries with the highest collaboration scores are as follows: USA (Total collaboration score = 2810), England in UK (1911), Canada (1741), Germany (1674), Belgium (1602), France (1549), Netherlands (14,759), Italy (1411), Spain (1111), and Israel (953). Significant correlations were found between the number of articles published by countries on CD and their economic indicators, especially Gross Domestic Product (GDP) and GDP per capita (R = 0.705, P < .001; R = 0.691, P < .001) respectively.

3.4. Prominent journals in CD research

All articles on CD were published by 1918 different scientific journals. The top 43 journals (publishing 50 or more articles), their total number of citations (NC) and the average NC per article are shown in Table 2.

Table 2.

The leading 43 scientific journals with 50 or more articles on Crohn’s disease.

Journals	N	C	AC	Journals	N	C	AC
Inflammatory Bowel Diseases	1100	46,063	41.9	Hepato-Gastroenterology	98	1660	16.9
Journal of Crohns & Colitis	579	19,318	33.4	BMC Gastroenterology	97	1444	14.9
Gut	510	61,102	119.8	Gastroenterologie Clinique Et Biologique	95	998	10.5
American Journal of Gastroenterology	450	30,914	68.7	Revista Espanola De Enfermedades Digestivas	86	574	6.7
Digestive Diseases and Sciences	438	12,503	28.5	British Journal of Surgery	85	3846	45.2
Gastroenterology	428	75,427	176.2	Intestinal Research	84	587	7.0
Alimentary Pharmacology & Therapeutics	417	22,464	53.9	Scientific Reports	74	1216	16.4
Scandinavian Journal of Gastroenterology	388	13,182	34.0	Acta Gastro-Enterologica Belgica	73	418	5.7
Journal of Pediatric Gastroenterology and Nutrition	345	9049	26.2	Medicine	69	606	8.8
Diseases of the Colon & Rectum	284	12,960	45.6	Journal of Gastrointestinal Surgery	66	1468	22.2
European Journal of Gastroenterology & Hepatology	262	5804	22.2	Abdominal Imaging	64	2248	35.1
World Journal of Gastroenterology	261	5792	22.2	Digestive Diseases	64	934	14.6
Journal of Clinical Gastroenterology	209	6368	30.5	Clinical and Experimental Immunology	62	3253	52.5
Clinical Gastroenterology and Hepatology	187	14,761	78.9	Canadian Journal of Gastroenterology	58	783	13.5
Digestive and Liver Disease	166	3882	23.4	American Journal of Roentgenology	55	3113	56.6
International Journal of Colorectal Disease	165	3710	22.5	Gastrointestinal Endoscopy	55	3358	61.1
Plos One	160	5030	31.4	Gastroenterology Research and Practice	54	490	9.1
Digestion	135	3304	24.5	Lancet	54	16,980	314.4
Journal of Gastroenterology and Hepatology	132	2949	22.3	European Radiology	53	2362	44.6
Zeitschrift Fur Gastroenterologie	121	1189	9.8	Annals of Surgery	50	3966	79.3
Journal of Gastroenterology	105	3130	29.8	Deutsche Medizinische Wochenschrift	50	474	9.5
Colorectal Disease	102	1872	18.4

AC = average citation per document, C = number of citations, N = number of articles.

3.5. Prominent institutions in CD research

The following institutions have made significant contributions to the literature on CD with 300 or more articles: Udice French Research Universities: 696 articles, Assistance Publique Hopitaux Paris: 570 articles, Institut National De La Sante Et De La Recherche Medicale Inserm: 479 articles, Harvard University: 468 articles, Universite Paris Cite: 460 articles, University of California System: 418 articles, Katholieke Universiteit Leuven: 402 articles, University of London: 401 articles, Icahn School of Medicine at Mount Sinai: 385 articles, Mayo Clinic: 370 articles, University of Toronto: 357 articles, Cleveland Clinic Foundation: 350 articles, Universite De Lille: 336 articles, University of Amsterdam: 317 articles.

3.6. Active authors on CD

The active authors who have made significant contributions to research of CD by publishing 100 or more articles are listed below: Colombel JF. (290 articles), Sandborn WJ. (246 articles), Rutgeerts P. (233 articles), Vermeire S. (187 articles), Peyrin-biroulet L. (141 articles), Feagan BG. (136 articles), Schreiber S. (125 articles), Reinisch W. (111 articles), D’haens G. (108 articles), Li Y. (108 articles), Loftus EV. (106 articles), Louis E. (106 articles), Panaccione R. (102 articles).

3.7. Co-word analysis: past and current research trends on CD

To perform the co-word (or co-occurrence) analysis, a threshold of 40 (minimum number of occurrences of a keyword) was chosen in the VOSviewer package. This means that 77 different keywords were identified that were used together in at least 40 different articles. In a total 13,305 different keywords were used in all 16,216 articles published on CD. Table 3 shows 77 different keywords that were used in 40 or more articles. The results of the clustering analysis showing the association clustering of the keywords are shown in Figure 3. The results of the clustering analysis show that the research on CD has 7 main foci. These foci, in order of cluster size, were as follows: the red cluster focused on diagnostic imaging techniques such as endoscopy, computed tomography, MRI enterography, ultrasound; the green cluster focused on mucosal healing, nutrition, and biomarkers; the blue cluster on therapeutic drug treatments; the yellow cluster on surgical treatments and complications; the purple cluster on genetic studies; the turquoise cluster on cellular aspects (apoptosis, autophagy, cytokines); and the orange cluster on perianal fistula. Additionally, through the analysis of co-occurrence of keywords, the development of research hotspots was identified. The visualization map of the trend network depicting the presence of keywords in past and current research is shown in Figure 4. Using to the network map, we were able to identify 7 clusters of keywords representing important areas of interest at CD. The citation network visualization map showing the keywords in the most frequently cited articles is also presented in Figure 5.

Table 3.

The 77 most frequently used keywords in published articles on Crohn’s disease.

Keywords	NU	Keywords	NU	Keywords	NU
Crohn’s disease	8305	endoscopy	106	calprotectin	57
inflammatory bowel disease(s) (or IBD)	2273	disease activity	105	corticosteroids	57
infliximab	707	postoperative recurrence	105	tumor necrosis factor-alpha	57
ulcerative colitis	621	NOD2	103	colonoscopy	56
surgery	393	biologics	98	microbiome	55
child/ children	302	anti-TNF	96	polymorphism	54
adalimumab	293	fibrosis	96	therapeutic drug monitoring	54
pediatric (s)	245	genetics	93	vitamin D	52
magnetic resonance imaging (or MRI)	237	cytokines	85	CT enterography	51
inflammation	230	complications	82	pregnancy	51
perianal crohn’s disease/ perianal fistula	190	enteral nutrition	80	remission	51
azathioprine	171	risk factors	78	computed tomography	50
magnetic resonance enterography (or mr enterography)	168	prognosis	72	CARD15	48
small bowel/ small intestine	165	smoking	70	methotrexate	48
stricture/ strictureplasty	162	c-reactive protein	69	biological therapy	47
recurrence	156	diagnosis	69	autophagy	46
therapy/ treatment	156	vedolizumab	69	anal fistula	44
ustekinumab	153	exclusive enteral nutrition	67	extraintestinal manifestations	44
mucosal healing	143	granuloma	67	loss of response	44
biomarker(s)	140	nutrition	66	postoperative complications	44
fistula	139	fecal calprotectin	63	phenotype	43
quality of life	129	microbiota	60	thiopurines	43
ultrasonography/ultrasound	123	abscess	59	apoptosis	42
epidemiology	109	osteoporosis	59	budesonide	42
capsule endoscopy	108	colitis	58
laparoscopic surgery/ laparoscopy	108	meta-analysis	58

NU = number of uses.

Figure 3.

Network visualization map showing clustering trends of Crohn’s disease topics. In general, the closer 2 terms are to each other, the stronger their relationship. The size and color of a term, respectively, represent the number of publications in which the term appears and its clustering. Each cluster is shown with a different color. Keywords with the same colors are in the same clusters. The size of the circle increases as the number of keywords used in the articles increases.

Figure 4.

A network visualization map showing past and current trends in Crohn’s disease The indicator in the lower right corner of the figure changes from blue to red (blue-green-yellow-red) as the topicality of the topics increases over the years. The blue term indicates that the publications in which the term appears were published in earlier years, while the red term indicates that the publications in which the term appears were published in later years. The size of the circle increases as the number of keywords used in the articles increases.

Figure 5.

A network visualization map showing the most cited influential topics on Crohn’s disease. The indicator in the lower right-hand corner of the figure changes from blue to red (blue-green-yellow-red) as the keyword becomes more cited. The blue term indicates that the publications in which the term appears have a lower average citation impact, while the red term indicates that the publications have a higher average citation impact. The size of the circle increases as the number of keywords used in the articles increases.

3.8. Citation analysis in CD

To perform the citation analysis, the “Documents” option was selected in the VOSviewer software package and a threshold of 1000 (minimum NC of a document) was chosen. Table 4 presents the publication information, total NC, and average NC per year for 28 influential articles with over 1000 citations selected from the 16,216 articles published on CD. The citation networks of the articles presented in Table 4 were shown in Figure 6A. Articles that did not have citation links with other studies were not shown in the map. Normalized citation values were used for weighting when determining the size of the circles in the network map. The normalized citation count of a document is obtained by dividing its citation count by the average citation count of all documents published in the same year. Normalization corrects for the fact that older documents have more time to receive citations compared to newer ones.^[17]

Table 4.

The first 29 high-impact articles with more than 1000 citations based on the total number of citations on Crohn’s disease.

No	Article	Author	Journal	PY	TC	AC
1	Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease	Hugot JP. et al	Nature	2001	4254	184.96
2	A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease	Ogura Y. et al	Nature	2001	3788	164.7
3	Maintenance infliximab for Crohn’s disease: the ACCENT I randomized trial	Hanauer SB. et al	Lancet	2002	3167	143.95
4	Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients	Sokol H. et al	Proceedings of the National Academy of Sciences of the United States of America	2008	2758	172.38
5	A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease	Targan SR. et al	New England Journal of Medicine	1997	2642	97.85
6	Infliximab, azathioprine, or combination therapy for Crohn’s disease.	Colombel JF. et al	New England Journal of Medicine	2010	2189	156.36
7	Infliximab for the treatment of fistulas in patients with Crohn’s disease	Present DH. et al	New England Journal of Medicine	1999	2033	81.32
8	Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease	Barrett JC. et al	Nature Genetics	2008	2016	126
9	Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci	Franke A. et al	Nature Genetics	2010	1896	135.43
10	The treatment-naive microbiome in new-onset Crohn’s disease	Gevers D. et al	Cell Host & Microbe	2014	1865	186.5
11	Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: The CHARM trial	Colombel JF. et al	Gastroenterology	2007	1611	94.76
12	Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease	Baert F. et al	New England Journal of Medicine	2003	1592	75.81
13	Reduced diversity of fecal microbiota in Crohn’s disease revealed by a metagenomic approach	Manichanh C. et al	Gut	2006	1575	87.5
14	Infliximab maintenance therapy for fistulizing Crohn’s disease	Sands BE. et al	New England Journal of Medicine	2004	1548	77.4
15	A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1	Hampe J. et al	Nature Genetics	2007	1449	85.24
16	Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis	Rioux JD. et al	Nature Genetics	2007	1396	82.12
17	Vedolizumab as induction and maintenance therapy for Crohn’s disease	Sandborn WJ. et al	New England Journal of Medicine	2013	1312	119.27
18	Crohn’s disease	Baumgart DC.; Sandborn WJ.	Lancet	2012	1305	108.75
19	Predictability of the postoperative course of Crohns-disease	Rutgeerts P. et al	Gastroenterology	1990	1239	36.44
20	Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial	Hanauer SB. et al	Gastroenterology	2006	1220	67.78
21	3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 1: diagnosis and medical management	Gomollon F. et al	Journal of Crohns & Colitis	2017	1172	167.43
22	High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease	Darfeuille-Michaud A. et al	Gastroenterology	2004	1104	55.2
23	The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: current management	Dignass A. et al	Journal of Crohns & Colitis	2010	1094	78.14
24	Disparate CD4(+) lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease - Crohn’s disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5	Fuss IJ. et al	Journal of Immunology	1996	1048	37.43
25	Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo	Atreya R. et al	Nature Medicine	2000	1043	43.46
26	Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomized, double-blind placebo-controlled trial	Hueber W. et al	Gut	2012	1043	86.92
27	Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD	Daperno M. et al	Gastrointestinal Endoscopy	2004	1011	50.55
28	A simple classification of Crohn’s disease: report of the working party for the world congresses of gastroenterology, Vienna 1998	Gasche C. et al	Inflammatory Bowel Diseases	2000	1006	41.92

AC = average citations per year, PY = publication year, TC = total citation

Figure 6.

(A) Network visualization map for citation analysis. (B) Network visualization map for co-citation analysis. Each circle is labeled with the first author of the article and the publication year. The size of the circle represents the normalized citation count received by the articles, and the thickness of the lines represents the strength of co-citation links. The connection and proximity between 2 articles define their citation relationship. The color of the circle indicates the cluster to which the article is associated.

3.9. Co-citation analysis in CD

For the analysis of co-citations, the “cited-references” option in the VOSviewer package was used, with a threshold of at least 200 citations for a cited reference. In this way, 86 studies were identified that were cited together in at least 200 different articles. The co-citation networks of the articles in CD research were presented in Figure 6B. Additionally, the 7 most influential studies, which were cited together in at least 700 different articles, were identified. In the reference section of all 16,216 articles published on CD, a total of 163,675 publications were cited. Among these publications, the 7 most influential studies with 700 or more co-citations were, in order: Best et al^[9] (number of co-citations: 1463), Hanauer et al^[19] (NC: 965), Harvey and Bradshaw^[20] (NC: 778), Silverberg et al^[21] (NC: 777), Satsangi et al^[22] (NC: 718), Present et al^[23] (NC: 708), and Targan et al (NC: 705).^[24]

4. Discussion

When examining the article distribution in the field of CD between the years 1980 to 2022, 4 different publication trends were found: 1980–1995, 1996–2006, 2007–2019, and 2020–2022. During the period of 1980 to 1995, an average of 176 articles (minimum-maximum: 146–199) were published. Starting in 1996, the number of articles increased, and during the period of 1996 to 2006, an average of 308 articles (min–max: 244–407) were published. With the year 2007, a second increase in the number of articles began, and during the period of 2007 to 2019, an average of 570 articles (min–max: 417–709) were published. The increasing trend continued with the year 2020, and during the period of 2020 to 2022, an average of 867 articles (min–max: 830–900) were published. The results of the forecasts for the next 5 years, it is assumed that research on CD will continue to follow an exponential growth trend.

The top 25 countries in terms of global productivity from CD are mostly developed countries or countries with large economies such as India, China and Turkey. There is a high significant correlation between the number of articles related to CD, GDP, and GDP per capita of the countries, indicating that the economic indicators of the countries are also an influencing factor for the productivity of CD research. This effect has also been observed in the findings of correlation analyses conducted in various other research areas.^[13–16] However, it is known that there are various factors beyond the economic development of countries that can influence the article productivity, such as prevalence rate, national medical burden, research infrastructure, investment and funding, scientific collaboration and networks, education and talent, scientific publishing and communication, and incentive and reward systems. One of the most important factors affecting the productivity of scientific articles in a country is having a strong research infrastructure. This infrastructure includes universities, research centers, laboratories, and other scientific institutions. Well-equipped laboratories, technological facilities, and financial resources that support researchers are important for article productivity.^[25] Countries should provide adequate funding for research and development activities, support researchers, and invest in scientific projects. Well-funded projects can contribute to higher article productivity.^[26] International scientific collaboration can increase article productivity. Collaboration and knowledge sharing among researchers across countries should be encouraged. Scientific networks promote collaborative research projects, conferences, and workshops, fostering scientific cooperation.^[27] Well-educated and talented researchers are critical for scientific article productivity. Countries should focus on cultivating qualified human resources for scientific research and promoting scientific education.^[28] It is important for a country to have accessible scientific journals for researchers to publish and share their work. The ease of access to scientific publications and the speed of publication processes can influence article productivity. Countries should develop a suitable system to promote scientific research and article productivity. Awards can provide incentives for researchers and recognize their scientific achievements.^[29]

In terms of international collaboration, it was determined that the USA, Canada, and European countries (England, Germany, Belgium, France, Netherlands, Italy, Spain, Sweden, Denmark, Switzerland, Austria) are pioneers, along with Israel and Australia. Epidemiological studies related to IBD in the early 21st century indicate an increasing incidence in newly industrialized countries with westernization.^[10] Although the disease incidence has stabilized in western countries, the prevalence has exceeded 0.3%, indicating the continued importance of CD. New research is needed to manage this complex and costly disease.^[10] Epidemiological studies on IBD in many developing countries indicate an increase in both the incidence and prevalence of CD in different regions of the world.^[30] When evaluating the findings of our study on the global productivity of CD, we believe that it is necessary to support research on CD in underdeveloped or developing countries as well.

In terms of contributing to the literature in the field of CD, the prominent journals were ranked as follows: Inflammatory Bowel Diseases, Journal of Crohn’s & Colitis, Gut, American Journal of Gastroenterology, Digestive Diseases and Sciences, Gastroenterology, Alimentary Pharmacology & Therapeutics, Scandinavian Journal of Gastroenterology, Journal of Paediatric Gastroenterology and Nutrition, Diseases of the Colon & Rectum, European Journal of Gastroenterology & Hepatology, World Journal of Gastroenterology, and Journal of Clinical Gastroenterology. These journals can be recommended as a priority for authors who want to publish their research in this field. When comparing the average NC per article published by these journals, the most influential journals were found to be Nature (1827), Nature Genetics (741), New England Journal of Medicine (688), Nature Medicine (494), Nucleic Acids Research (438), Cell Host & Microbe (426), Science (356), Proceedings of the National Academy of Sciences of the United States of America (343), Clinical Microbiology Reviews (324), Cell (315), Lancet (314), and Current Biology (305). We can suggest researchers who want their articles to have a greater impact to consider these journals.

Among all the articles, the most influential article in terms of total citations was determined to be the study titled “Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease” by Hugot et al,^[2] published in Nature. The second most impactful study was “A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease” by Ogura et al,^[1] also published in Nature. The third most effective study was the article “Maintenance infliximab for Crohn’s disease: the ACCENT I randomized trial” by Hanauer et al^[19] published in The Lancet. The fourth and fifth most influential studies were the articles published by Sokol et al^[8] in the Proceedings of the National Academy of Sciences of the United States of America and by Targan et al^[24] in the New England Journal of Medicine.

The main findings of the articles by Hugot et al and Ogura et al are that the NOD2 gene predisposes to CD and there is a link between innate immune response to bacterial components and disease development.^[1,2] These articles have contributed to our understanding of one of the pathophysiological mechanisms of CD. The main finding of the study by Hanauer et al is that Crohn’s patients who respond to an initial dose of infliximab have a higher likelihood of being in remission and discontinuing corticosteroids.^[19] This article has contributed to our understanding that maintenance infliximab is a safe and well-tolerated treatment option in CD. The main finding of the study by Sokol et al is that Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified through intestinal microbiota analysis in CD patients.^[8] This article has contributed to our understanding that the commensal bacterium Faecalibacterium prausnitzii can be used as a probiotic agent in CD treatment and holds promise for future CD therapies. The main finding of the study by Targan et al is that a single chimeric monoclonal antibody infusion, cA2, is an effective treatment for patients with treatment-resistant moderate to severe CD.^[24] This study has provided information that chimeric monoclonal antibody therapy, which remains one of the most effective treatment methods today, was used as early as 1997.

The study that had the highest impact in terms of the average NC per year among all the articles was “The Treatment-Naive Microbiome in New-Onset Crohn’s Disease” by Gevers et al.^[31] The second most efficient one was the one by Hugot et al.^[2] The third most influential study was the one by Sokol et al.^[8] The fourth most influential study was the consensus on the “Diagnosis and Management of Crohn’s Disease” published by Gomollon et al.^[6] The fifth most influential study was the one by Ogura et al.^[1] Noteworthy studies in recent years, based on the average NC per year, were “Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease” by Feagan et al^[32] published in the New England Journal of Medicine and “ECCO Guidelines on Therapeutics in Crohn’s Disease” by Torres et al^[3] published in the Journal of Crohn’s & Colitis.

According to the co-citation analysis conducted on all the analyzed articles, the notable high-impact studies based on the shared co-citation counts were Best et al,^[9] Hanauer et al,^[19] Harvey and Bradshaw,^[20] Silverberg et al,^[21] Satsangi et al,^[22] Present et al,^[23] and Targan et al.^[24] We can recommend researchers interested in this subject to read these studies as a priority.

When evaluating the findings of the citation analysis network visualization map, it can be observed that articles with the highest NC form 5 distinct clusters based on total citation count (Figure 6A). These clusters are related to microbiota (blue cluster), biological drug treatments for CD (red cluster), CD and its treatment (yellow cluster), pathophysiological mechanisms (purple cluster), and genetics (green cluster).

In the co-citation analysis of the CD topic, it is seen that it forms 4 distinct clusters (Figure 6B). These clusters are related to the effects of biological drugs on treatment (yellow cluster), general IBD (blue cluster), CD diagnosis, monitoring, and classification (red cluster), and CD surgery (green cluster).

When considering the citation and co-citation analyses, it is evident that research on CD has focused on surgical and drug treatments, activity indices, diagnosis, monitoring and classification, microbiota, pathophysiological mechanisms, and the genetic dimension from the past to the present.

According to the keyword analysis, the most extensively studied topics in the field of CD from the past to the present (with at least 100 different articles) were infliximab, ulcerative colitis, surgery, pediatrics/children, adalimumab, MRI, inflammation, perianal CD/perianal fistula, azathioprine, magnetic resonance enterography, small bowel/small intestine, stricture/strictureplasty, recurrence, therapy/treatment, ustekinumab, mucosal healing, biomarkers, fistula, quality of life, ultrasonography/ultrasound, epidemiology, capsule endoscopy, laparoscopic surgery/laparoscopy, endoscopy, disease activity, postoperative recurrence, and NOD2.

According to the cluster analysis findings, it was determined that CD research has 7 main focal points. The main focal points, where the literature studies clustered, were imaging techniques, surgery and complications, genetic studies, perianal fistula, treatments with a particular emphasis on therapeutic drugs, mucosal healing/nutrition/biomarkers and cells.

The most cited keywords from the past to the present were abscess, genetics, caspase recruitment domain-containing protein 15, treatment, cytokines, perianal CD, budesonide, microbiota, ulcerative colitis, inflammation, and strictureplasty.

According to the findings of the keyword analysis, 12 keywords were identified as the emerging trends. The trending topics studied in recent years were ustekinumab, vedolizumab, fecal calprotectin, therapeutic drug monitoring, biologics, biomarkers, exclusive enteral nutrition, microbiome/microbiota, magnetic resonance enterography, anti-TNF, postoperative complications, and mucosal healing. This indicates the latest developments in CD treatments. The trend keyword analysis shows us the focus areas of CD treatment in the past and present. Before 2014, the main areas of focus were CD complications, surgery, and postoperative complications. However, after 2016, topics related to CD diagnostic methods and medical treatment regimens became the primary research points. We anticipate that in future research, medical treatments will replace surgery and complication studies as the main focus in CD treatment.

There is no specific bibliometrics study published so far for the overall topic of CD in the literature. Only the studies by Kostoff^[33] and Schöffel et al^[34] related to CD were found. Kostoff attempted to identify text-based common factors for Parkinson’s disease and CD.^[33] Schöffel et al^[34] did not include recent publications after 2013. One of the strengths of this research is that it is the first comprehensive and up-to-date bibliometrics study conducted on the subject of CD. In our study, we preferred to search only the WoS database because citation analyses cannot be performed in the PubMed database. The Scopus database also indexes articles published in lower impact journals that are not included in the SCI-expanded or ESCI indexes.^[13–16,35] A second limitation of our study is that descriptive statistics were provided only for the number of articles published by journals, institutions, and authors, without qualitative evaluation. However, since the primary aim of this study was trend keyword, co-word, and co-citation analysis, qualitative evaluation of journals, institutions, and authors was not conducted. Therefore, a higher number of articles does not necessarily imply better quality for authors and institutions in this study, as the focus was primarily on quantitative analysis.

5. Conclusions

This study demonstrates the general trends in scientific research on CD. We identified an exponential increase in global publications. In recent years, the trending research topics related to CD are ustekinumab, vedolizumab, fecal calprotectin, therapeutic drug monitoring, biologics, biomarkers, exclusive enteral nutrition, microbiome/microbiota, magnetic resonance enterography, anti-TNF, postoperative complications, and mucosal healing. We determined that countries with significant economies, especially the USA, UK, Germany, France, Canada, Italy, Japan, and China, have research leadership in the development of CD literature. This study can provide researchers with new ideas for future studies on CD.

Author contributions

Conceptualization: Alpaslan Karabulut.

Data curation: Alpaslan Karabulut, Muhammed Kaya.

Formal analysis: Alpaslan Karabulut, Muhammed Kaya.

Investigation: Alpaslan Karabulut, Muhammed Kaya.

Methodology: Alpaslan Karabulut, Muhammed Kaya.

Resources: Alpaslan Karabulut, Muhammed Kaya.

Software: Alpaslan Karabulut, Muhammed Kaya.

Supervision: Alpaslan Karabulut, Muhammed Kaya.

Visualization: Alpaslan Karabulut.

Writing – original draft: Alpaslan Karabulut, Muhammed Kaya.

Writing – review & editing: Alpaslan Karabulut, Muhammed Kaya.