A Bibliometric Evaluation of the Top 100 Cited Dimethyl Fumarate Articles

Dimethyl fumarate is a cytoprotective and immunomodulatory drug used in the treatment of multiple sclerosis. We performed a bibliometric study examining the characteristics and trends of the top 100 cited articles that include dimethyl fumarate in the title. On 21 September 2020 we carried out an electronic search in the Web of Science (WOS), seeking articles that include the following terms within the title: dimethyl fumarate, BG-12, or Tecfidera. To focus our investigation on original research, we refined the search to include only articles, early access, others, case report, and clinical trials. We obtained a total of 1115 items, which were cited 7169 times, had a citation density of 6.43 citations/item, and an h-index of 40. Around 2010, there was a jump in the number of published articles per year, rising from 5 articles/year up to 12 articles/year. We sorted all the items by the number of citations and selected the top 100 most cited (T100). The T100 had 4164 citations, with a density of 37 citations/year and contained 16 classic research articles. They were published between 1961 and 2018; the years 2010–2018 amassed nearly 80% of the T100. We noted 17 research areas with articles in the T100. Of these, the number one ranking went to neurosciences/neurology with 39 articles, and chemistry ranked second on the T100 list with 14 items. We noticed that the percentage of articles belonging to different journals changed depending on the time period. Chemistry held the highest number of papers during 1961–2000, while pharmacology andneurosciences/neurology led the 2001–2018 interval. A total of 478 authors from 145 institutions and 25 countries were included in the T100 ranking. The paper by Gold R et al. was the most successful with 14 articles, 1.823 citations and a density of 140.23 citations/year. The biotechnological company Biogen led the T100 list with 20 articles. With 59 published articles, the USA was the leading country in publications. We concluded that this study analyzed the use of and research on dimethyl fumarate from a different perspective, which will allow the readership (expert or not) to understand the relevance of classic and recent literature on this topic.


Introduction
Among the many difficulties researchers encounter when facing a research topic, one is the huge number of journals and articles that are periodically published. It is often hard to understand or grasp the relevance of a particular article, especially when the article is not recent. In a totally subjective manner, the choice to read an article and interpret its relevance to the research topic may be left to a reader's intuition and biases. Bibliometric analysis is considered a very useful tool to overcome this problem, since it offers a cross-sectional view as well as the current state of research work on the topic of interest. Usually, a bibliometric analysis aims to identify the academic impact and features of a number of publications within a specific research field, all of which provide valuable information for researchers involved in the development of research strategies to address various problems. This analysis is based on a statistical and quantitative assessment that allows for an objective evaluation of a given article. It also performs a time-efficient, focused exploration within a larger field.
Bibliometric databases such as Science Citation Index (SCI), Scopus, and Google collect the citations received for each article, allowing a prescreened and targeted article selection based on the impact of the work [1]. This is important because the number of citations is a recognized measurement of the quality of an article [2]. Science Citation Index Expanded (SCI-EXPANDED) is a broad database of almost 10,000 journals with high-impact citations. It covers many fields, including social sciences, humanities, and the arts, and is the most recent journal citation system and database that has been made available by the Web of Science (WOS) [3]. We, and others, have performed numerous bibliometric analyses that address specific disciplines or terms [4][5][6][7][8][9].
Bibliometric analysis becomes especially powerful when applied to long-standing, classic drugs, such as dimethyl fumarate (BG-12, Tecfidera ® ). Dimethyl fumarate was synthesized in 1963. The main pharmacological effects are mediated by DMF itself, and its metabolite, monomethylfumarate. Wipke et al. showed how nuclear factor (erythroidderived 2)-like 2 (Nrf2)-mediated oxidative stress response pathways were exclusively regulated by DMF, whereas apoptotic pathways were activated by monomethylfumarate [10]. Therefore, Nfr2 activation promotes transcription of genes which have a marked antioxidant function, such as that of hemooxygenase-1, quinone oxidoreductase, glutathione S transferase, and glutathione peroxidase [11,12]. The efficacy and safety of this drug stands out, reducing the rate of relapses per year in patients with multiple sclerosis (MS). The clinical outcomes and safety profile led the Food & Drug Administration (FDA) to approve it for the treatment of MS in 2013. Dimethyl fumarate is metabolized by esterases, yielding monomethylfumarate before reaching systemic circulation. This enzymatic hydrolysis joins other additional metabolic reactions, such as the tricarboxylic acid cycle, but not the cytochrome P450 system [10].
At present, there is no bibliometric study with a global view which analyzes the relevance of publications on dimethyl fumarate. Therefore, the aim of our bibliometric study is to obtain a broad view of the literature on dimethyl fumarate, and to identify the most cited publications-as well as the most relevant features of these publications (authors, journals, and year of publication). The overall goal of this work is to allow the reader to efficiently and properly address the most important and influential articles in this field.

Results
On 21 September 2020, we conducted an electronic search in the Web of Science database for references that included the term methyl fumarate in the title. This yielded a total of 135 items. Because of the unexpectedly low number of entries for this term, we redefined the search to include the terms BG-12 and Tecfidera. Thus, the final search included dimethyl fumarate, BG-12, or Tecfidera. This second search resulted in a more than 10-fold increase of the number of retrieved citations, up to 1380 items. All of these references accumulated 11,587 citations, with an h-index value of 46, 8.39 average citations per item, and 192.95 average citations per year. Figure 1A shows the number of publications recorded per year, with the oldest paper dating back to 1950. It can be seen in this figure that, for almost 60 years , the number of published articles on this topic never exceeded ten per year. The year 2014 we arranged by the total number of citations. The 100 most cited (T100) were then selected.  appeared in the T100 ranking: #10, #50, and #92, with 123, 43, and 29 citations, respectively,  and a citation density of 41, 14.33, and 9.67 citations/year, respectively.  In order to address only original works, we refined our search by filtering for articles, case reports, letters, and clinical trials. This procedure retrieved 677 publications, which we arranged by the total number of citations. The 100 most cited (T100) were then selected. Table 1 depicts the T100, which totaled 11,272 entries from 5350 citing articles, with an h-index of 46 and an aggregate average citation density of 187.87 citations/year. The most cited article (#1) was from the year 2012 (933 citations and a citation density of 103.67 citations/year), while article #100 was published in the year 2017 (28 citations and a citation density of 7 citations/year). The oldest article (from the year 1961) is #19 in the T100 (79 citations; 1.32 citations/year). Papers published in 2018 included three articles which appeared in the T100 ranking: #10, #50, and #92, with 123, 43, and 29 citations, respectively, and a citation density of 41, 14.33, and 9.67 citations/year, respectively.  The T100 ranking list showed an average citation density of 10.01 citations/year. The highest citation density was that of articles #1 and #2 (103.67 and 81.33 citations/year, respectively). The lowest citation density (0.47 citations/year) was article #91.
Next, we focused on the authors of papers in the T100. This analysis was performed independent of the relevance or T100 position. We compiled a total of 478 authors, including affiliations with 145 institutions, across 25 different countries.  Figure 2A). The T100 ranking list showed an average citation density of 10.01 citations/year. The highest citation density was that of articles #1 and #2 (103.67 and 81.33 citations/year, respectively). The lowest citation density (0.47 citations/year) was article #91.
Next, we focused on the authors of papers in the T100. This analysis was performed independent of the relevance or T100 position. We compiled a total of 478 authors, including affiliations with 145 institutions, across 25 different countries. Table 2 summarizes these findings, showing the five authors with the highest number of publications within the T100. Gold R (Department of Neurology, University of Ruhr, Ruhr, Germany) leads this ranking with 14 articles, accumulating 1823 citations, and an average citation density of 140.23 citations/year (Table 2; Figure 2A). Figure 2B and Table 3 show the geographic distribution of the T100 list of papers. The highest ranking country was the USA, with 62 articles (5258 citations, 84.81 citations/article and 109.54 citations/year), including 8 of the top 10 (T10). Germany, with 2911 citations (50% lower than the USA), placed second.
According to our study, the most productive institution was Biogen (Cambridge, MA, USA), with 24 items, a total of 3196 citations, and an average citation density of 243.77 citations/year ( Table 4). The first T100 item from this institution was published in 2010. Of note, four of the papers from this institution placed in the T10, including the top 3 rankings. Ruhr University Bochum (Germany) had the second-highest number of T100 articles with 15. Figure 2C illustrates the collaborations and interactions between the top 5 institutions, analyzed by detecting coauthorship.  Figure 2B and Table 3 show the geographic distribution of the T100 list of papers. The highest ranking country was the USA, with 62 articles (5258 citations, 84.81 citations/article and 109.54 citations/year), including 8 of the top 10 (T10). Germany, with 2911 citations (50% lower than the USA), placed second. According to our study, the most productive institution was Biogen (Cambridge, MA, USA), with 24 items, a total of 3196 citations, and an average citation density of 243.77 citations/year ( Table 4). The first T100 item from this institution was published in 2010. Of note, four of the papers from this institution placed in the T10, including the top 3 rankings. Ruhr University Bochum (Germany) had the second-highest number of T100 articles with 15. Figure 2C illustrates the collaborations and interactions between the top 5 institutions, analyzed by detecting coauthorship. We found 17 research areas publishing articles in the T100, including neurosciences/ neurology with 39 articles in the first position, and chemistry with 14 articles (36% of the previous) in the second position. Next, we analyzed whether the percentage of articles in the distribution of research areas changed over time. To do this, we divided the T100 list into two groups of publication, either before or after the year 2000. The 1961-2000 interval included 15 articles, of which 11 (69%) belonged to the chemistry research area and 2 (15%) were found either in the electrochemistry or materials science research areas. No article in this earlier period of time was found within the neurosciences/neurology area. The 2001-2018 interval accounted for the remaining 85 articles, which were included in two main research areas: pharmacology/pharmacy (70 articles, 80%) and neurosciences/neurology (63, articles; 72%). Only 6 papers (6.9%) were within the chemistry area.
The papers ranked in the T100 list were published in 59 journals (Table 5). Multiple Sclerosis Journal published 6 articles belonging to this list with 275 citations and an average citation density of 30.56 citations/year. Their first article appearing in T100 was published in 2014. The New England Journal of Medicine, with 5 articles in the T100 ranking, is the journal with the highest number of citations (2048, and an average citation density of 277.56 citations/year).

Discussion
To our knowledge, this is the first bibliometric study of dimethyl fumarate. We believe that this study will help readers to identify the highest-quality papers with the most relevant discoveries and trends regarding this drug's history and evolution. This study offers three main relevant conclusions. The first is that any electronic search for dimethyl fumarate should also include the terms BG-12 and Tecfidera. The second is that, when we consider the total number of articles published per year, our results show a sharp point of inflection in the year 2013. One of the strengths of this study is that it has been performed without a date limit, elucidating the fluctuations in interest in this drug. This led us to the third major point: the clear change after 2013 in the areas of research covering this topic. Before 2013, the leading research area was chemistry and after 2013 it was neurosciences/neurology.
When we studied the T10 publications, we found three groups of papers: (i) clinical trials, (ii) papers reporting side effects, and (iii) papers focused on the mechanism of action of the drug. The three most cited articles were clinical trials. Of these, both #1 and #2 compared the effects of 240 mg of dimethyl fumarate administered twice or three times a day versus a placebo. A particular point of interest for citations of paper #1 is that the authors included data on the effects of dimethyl fumarate on incapacity progression. While paper #2 additionally reported on the effects of glatiramer acetate, the number of citations was lower. This is possibly due to the fact that this clinical trial was not designed to investigate the differences between the two drugs. Despite being older than papers #1 and 2, publication #3 was cited less, probably because it was a phase IIb trial with a small number of patients. Articles #5 and #6 reported cases of side effects of dimethyl fumarate in which patients developed progressive multifocal leukoencephalopathy. Articles #4 and #10 studied the anti-inflammatory mechanism of action. It is worth mentioning that they were carried out after clinical trials were published demonstrating the efficacy of dimethyl fumarate in MS. Both articles highlight that the mechanism of action is not mediated, as was previously thought, through the action of dimethyl fumarate on the activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) antioxidative pathway. Most interesting is that these articles suggested possible pharmacological targets in the development of anti-MS drugs such as hydroxycarboxylic acid receptor 2 or the downregulation of aerobic glycolysis.
Our results are consistent with Bradford's Law, which establishes that most articles of interest in an area are published in a small number of high-impact journals [13]. All T10 articles have been published in top quartile (Q1) journals of their respective areas of knowledge, including four in the New England Journal of Medicine. Furthermore, we found that the highest correlations obtained were between the number of citations and the journal impact factor or with the article influence score. Interestingly, both correlated more than with the Eigenfactor, probably because of the way this factor is calculated (the Eigenfactor rates the citations obtained from higher ranked journals more highly) which highlights different citation patterns within each discipline and eliminates self-care [14].
With regard to institutions published within the T100, Biogen stood out with a total of 24 articles. Furthermore, Biogen supported at least three articles within the T10 (#1, #2, and #9), all of which provided helpful data on the efficacy of dimethyl fumarate. Not surprisingly, it is this institution that launched the drug in 2013 [15]. Biogen was also the institution with the highest number of articles within the T100 in a previous bibliometric study conducted by our research group and centered on natalizumab, a humanized antialpha-4 integrin antibody used in the management of MS [4].
If we focus on the countries where the research publication took place, the USA was #1, with 62 articles and 5258 citations. This was followed by Germany, with 31 articles and 2911 citations.
It cannot be ignored that the present work, like other bibliometric studies, has limitations. We would like to address two of them. The first is that this bibliometric study could be labeled as a mere snapshot taken on a certain date. While this is true, it can be counterweighted by taking into account the density of citations per year for each particular publication. Using this parameter, we should be able to determine whether or not a specific article maintains the interest of the scientific community. It is also possible to anticipate if a specific article's position within the T100 will change. For instance, we can predict that article #10 of the T100, which has an average citation density of 41.0 citations/year should rise in its ranking within the T100, reaching the top 4. Interestingly, article #10 addresses a possible mechanism of action of dimethyl fumarate at an immunomodulatory level, where it would inhibit aerobic glycolysis in myeloid and lymphoid cells, causing an anti-inflammatory effect which might be useful in immune diseases such as MS and psoriasis.
Another study limitation is that this search was performed using a single bibliometric database. However, it is important to stress that we chose this database because we aimed to study the drug's history and evolution over time. Other bibliometric databases, including Scopus, reference only recent citations.
In conclusion, we have tried to shed light on the use of dimethyl fumarate over the years by searching for information on which publications are the most cited, as well as the associated investigators, countries, and institutions participating in the studies. We highlighted changes in the leading research areas that have taken place since this drug was first synthesized. This will provide readers with a strong tool to efficiently select the most relevant articles on dimethyl fumarate for their own interest, research and clinical applications.

Material and Methods
On 21 September 2020 we carried out the last literature search on the Web of Science (WOS, Clarivate Analytics, Philadelphia, PA, USA) of all articles containing the terms dimethyl fumarate, BG-12 or Tecfidera. The databases used were: SCI-EXPANDED, Social Science Citation Index (SSCI), Arts & Humanities Citation Index (A & HCI), Conference Proceedings Citation Index-Science (CPCI-S), Conference Proceedings Citation Index-Social Science & Humanities (CPCI-SSH), Emerging Sources Citation Index (ESCI), Current Chemical Reactions-Expanded (CCR-EXPANDED), and Index Chemicus (IC). No filters were applied to the period of publication, language of publication, authors, participating institutions, topics, or grant funding of the articles. We would like to remark that this project required several searches and studies before the present analysis was achieved. As a result of these searches, we grew to understand the bibliometric behavior of this drug. For instance, we realized that the search should include the terms BG-12 and Tecfidera in addition to dimethyl fumarate. After performing preliminary searches, we also came to the decision that the final analysis should be limited to entries which include the name of the drug as part of the title of the article, excluding those where it appears only in the abstract. Then, in order to obtain only original works, we refined the search to article, early access, other, case report, and clinical trial.