Background: Mucosal healing (MH) was proposed to be an ideal treatment goal for patients with inflammatory bowel disease (IBD). Instead of endoscopy to confirm MH, biomarkers are frequently used and have become an indispensable modality for the clinical examination of patients with IBD. Summary: Common biomarkers of IBD include C-reactive protein (CRP), erythrocyte sedimentation rate, antineutrophil cytoplasmic antibodies, anti-Saccharomyces cerevisiae antibodies, leucine-rich α2 glycoprotein, fecal calprotectin (FCP), and the fecal immunochemical test. Biomarkers play five major roles in the management of IBD: (1) diagnosing and distinguishing between IBD and non-IBD or ulcerative colitis and Crohn’s disease; (2) predicting treatment response, especially before administrating biologics; (3) monitoring and grasping endoscopic or histological disease activity; (4) replacing endoscopy for diagnosing MH, including endoscopic and histological remission; and (5) predicting recurrence before disease activity appears through symptoms. Many reports have demonstrated the usefulness of CRP and FCP for those five roles; however, they have limitations for diagnosing MH or predicting treatment response. In general, FCP has better ability in those positions than CRP; additionally, leucine-rich α2 glycoprotein can diagnose endoscopic disease activity better than CRP. The novel biomarker, prostaglandin E-major urinary metabolite, and anti-αvβ6 antibody are expected to be noninvasive and reliable biomarkers; however, more evidence is required for future studies. Oncostatin M and microRNA are also prospects, in addition to other familiar and novel biomarkers. Key Messages: Each biomarker has a useful feature; therefore, we should consider their features and use appropriate biomarkers for the five roles to enable noninvasive and smooth management of IBD.

Inflammatory bowel disease (IBD) – a disease with unknown pathogenesis – mainly occurs in the gut, sometimes with extraintestinal manifestations. Ulcerative colitis (UC) and Crohn’s disease (CD), representative IBDs, occur in young adolescents and require comprehensive management.

Recently, the number of affected patients has continuously increased [1]. The primary treatment strategy for IBD is introducing and maintaining remission. Mucosal healing (MH), defined as endoscopic or histological remission, was recently proposed to be an ideal treatment goal for patients with IBD due to its favorable prognosis, which presents a lower risk of recurrence or surgical treatment [2‒4]. Although endoscopy is the only tool for confirming MH [5], biomarkers are frequently used instead and have become an indispensable modality. C-reactive protein (CRP) and fecal calprotectin (FCP) are primarily used; however, many other biomarkers have useful features and roles. We herein review those biomarkers in IBD.

C-Reactive Protein

CRP was discovered as an acute-phase protein that reacted with the C-polysaccharide of Streptococcus pneumoniae [6]. Produced in the liver by interleukin (IL)-6 stimulation and increased with inflammation in vivo [7], it is commonly used in the evaluation of many inflammatory diseases. CRP is an effective monitoring marker to assess patients in the active phase of IBD and is appropriate for evaluating the efficacy of treatment through repeated measurement. By contrast, it is challenging to diagnose MH or inactivity if CRP is negative, due to its lower accuracy in patients with lower activity.

Erythrocyte Sedimentation Rate

Erythrocyte sedimentation rate (ESR) is one of the most classic inflammation markers and has been used since the 1920s. It indicates the amount of supernatant formed by sinking of blood cell components. High concentrations of globulin, fibrinogen, and complement increase the ESR [8, 9]. Therefore, it is helpful to evaluate chronic and subacute inflammation. In the recovery phase, the downregulation speed of ESR is much slower than that of CRP. Using both ESR and CRP may help make the inflammation course easier to follow; thus, ESR is used as an aid to CRP. Additionally, pregnancy [9] and anemia [10, 11] cause an increase in ESR.

P-Antineutrophil Cytoplasmic Antibody/Anti-Saccharomyces cerevisiae Antibody

Antibodies to gut microbiota and host antigens are involved in inflammation in patients with IBD [12, 13]. Among them, antineutrophil cytoplasmic antibodies (ANCAs) [14] and anti-Saccharomyces cerevisiae antibodies (ASCAs) [15] are believed to be related to IBD; additionally, their usefulness as biomarkers has been reported.

Leucine-Rich α2 Glycoprotein

Leucine-rich α2 glycoprotein (LRG) is a protein of approximately 50 kDa, produced in cells such as hepatocytes, neutrophils, and macrophages. It contains eight domains called leucine-rich repeats [16] and is induced by multiple inflammatory cytokines, such as tumor necrosis factor (TNF)-α, IL-22, IL-1β, and IL-6 [17, 18]; however, it is a biomarker that does not depend on IL-6. LRG is also derived from cytokine-stimulated neutrophils and epithelium in the intestinal epithelial cells of patients with IBD and is released in serum [19]. In other words, LRG is more likely to reflect intestinal inflammation than CRP. Gastric cancer [20] and colorectal cancer [21] also result in elevated LRG level. Although clinical data are insufficient, LRG is a biomarker with a different mechanism from that of CRP, and further accumulation of evidence is expected in the future.

Fecal Calprotectin

Calprotectin is a calcium-binding S100 protein family A8/A9 complex, most abundant in the cytoplasm, granulocytes, and monocytes of intestinal epithelial cells [22]. FCP is a stool test to measure calprotectin derived from inflammatory cells that infiltrate the intestinal mucosa, injure the intestinal epithelial cells, and mix with feces [23] during inflammation. Since it measures fecal substances, FCP can selectively evaluate inflammation of the intestinal tract, rather than that of the whole body. It is highly stable and not affected by fecal collection methods due to its uniformity in feces. The reference instead of the normal value is used as the FCP value, and the cutoff value varies among several measurement kits. This is due to the variations and differences in cutoff values among the many reports of FCP. Instead, it is easy to grasp the change in activity by observing the transition of this value.

Fecal Immunochemical Test

The fecal immunochemical test (FIT) is a test for detecting blood contained in feces using anti-human hemoglobin antibodies and is performed as a screening tool for colorectal cancer worldwide.

Treat-to-target was proposed as a therapeutic strategy for IBD, and the normalization of biomarkers was manifested as the second step to finally achieve MH in Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) [24] and STRIDE2 [25]. There are five positions of biomarkers in IBD treatment (as shown in Fig. 1). The first is diagnosing and distinguishing between IBD and non-IBD, or UC and CD. The second is predicting the treatment response and prognosis after the start of treatment; it is particularly beneficial to predict the effects of biologics early or before the treatment.

Fig. 1.

Five positions of biomarkers in inflammatory bowel disease. There are five roles of biomarkers in the management of inflammatory bowel disease. A. Diagnosis. B. Prediction of treatment response. C. Monitoring disease activity. D. Diagnosing MH. E. Prediction of recurrence. MH, mucosal healing.

Fig. 1.

Five positions of biomarkers in inflammatory bowel disease. There are five roles of biomarkers in the management of inflammatory bowel disease. A. Diagnosis. B. Prediction of treatment response. C. Monitoring disease activity. D. Diagnosing MH. E. Prediction of recurrence. MH, mucosal healing.

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The third position is to monitor and evaluate the disease activity. Diagnosing endoscopic disease activity in daily practice is helpful in cases where clinical symptoms cannot be determined. Particularly, biomarkers are needed to diagnose disease activity in the clinical remission phase, wherein fewer symptoms are expressed. The fourth position is to diagnose MH, which is crucial for biomarkers. Half of the patients with UC in clinical remission did not reach a Mayo endoscopy subscore (MES) of 0 [26], which indicates endoscopic remission; therefore, it is difficult to determine the achievement of MH only by the disappearance of symptoms. Similarly, clinical remission is not equal to the accomplishment of MH in patients with CD [27, 28]. Thus, the ability to diagnose MH without using endoscopy is highly beneficial to patients with IBD. The fifth position is to predict recurrence before it appears through symptoms; early prediction of recurrence can lead to appropriate treatment and improve the prognosis of patients with IBD, including those with postsurgical CD.

What is needed and expected for an ideal biomarker is accuracy, promptness, noninvasiveness, easy access, and cost-effectiveness [29, 30]. In patients with IBD, it is particularly desirable to meet these conditions for each of these five roles.

First Position: Diagnosing IBD

FCP helps distinguish IBD from irritable bowel syndrome (IBS) [31] or colorectal cancer [32], which have similar symptoms to IBD. Its usefulness was demonstrated for diagnosing pediatric IBD [33]. CRP is superior for distinguishing functional gastrointestinal diseases, such as IBS [34]. In a meta-analysis, the likelihood of diagnosing IBD was <1% if the FCP value was <40 μg/g or <0.5 mg/dL [35]. Since CRP is elevated in many diseases with acute inflammation, a diagnosis of IBD should be made using full clinical information, including biomarkers, symptoms, and endoscopy.

The diagnostic ability of ESR for diagnosing IBD in adults was 0.78 (both sensitivity and specificity) [36]; however, this was reported decades ago and included smaller samples. Conversely, its usefulness has been demonstrated for the diagnosis of pediatric IBD; the sensitivity and specificity of combined ESR with anemia were 0.48 and 0.96, respectively [37].

p-ANCAs/ASCAs were also reported to be useful diagnostic biomarkers in distinguishing CD from UC. ASCA-positive status was typically observed in patients with CD with a sensitivity of 100%; however, the specificity was 50% for the diagnosis of CD [13]. p-ANCA was significantly higher in patients with UC and colonic CD [38]. According to a meta-analysis, the sensitivity and specificity of ASCA+/p-ANCA− were 0.55 and 0.93 for the diagnosis of CD, and 0.63 and 0.93 for the diagnosis of IBD, respectively [38]. Therefore, it may aid in distinguishing CD from UC or non-IBD. However, it should be remembered that its sensitivity is relatively low, except for the diagnosis of the pediatric CD where the sensitivity and specificity of ASCA+/p-ANCA− were 0.70 and 0.93 [39], respectively.

Second Position: Predicting Treatment Response or Effectiveness

FCP and CRP are established biomarkers with sufficient evidence. Decreasing CRP was associated with a better response and short- or middle-term prognosis in several randomized controlled tests including anti-TNF-alfa antibody or vedolizumab [40‒45]. It is strongly suggested that a reduced or low CRP value after the treatment is associated with a better prognosis in IBD; nevertheless, whether the CRP at the baseline can predict treatment response remains controversial.

Reinisch et al. [40] reported that patients with CD with a baseline CRP value >0.7 mg/dL before receiving infliximab were significantly induced to remission when compared with patients with CD with a baseline CRP value <0.7 mg/dL. By contrast, Magro et al. [41] reported that patients with CD with a higher CRP value tended to be nonresponders to IFX treatment. In patients with UC, a high CRP value before treatment predicts resistance against treatment [46‒48].

Additionally, a decreasing FCP value observed early after the treatment predicts a better prognosis. It was reported that decreased FCP levels, 6 weeks after administering ustekinumab, predicted endoscopic remission after 52 weeks in a study on CD [49], while decreased FCP levels observed 2 [50] and 8 [51] weeks after administering biologics indicated remission in patients with UC. Furthermore, some studies reported low response rate of infliximab in patients with p-ANCA-positive CD [52, 53] and UC [54].

Third Position: Monitoring and Understanding the Activity of IBD

CRP is a known, valuable biomarker for assessing inflammation. Many reports demonstrate that CRP is associated with endoscopic activity in patients with IBD. Particularly, higher sensitivity was revealed in patients with CD than in those with UC [34]; however, this was not significant. In the active phase, physicians can understand the activity of IBD from symptoms and CRP levels [55]; still, FCP is superior to CRP for diagnosing endoscopic disease activity [56‒60]. It was reported that 92.9% of patients with CD without CRP elevation, but with any other symptom, exhibited endoscopic activity [61]. In a meta-analysis by Mosli et al. [62], the sensitivity and specificity of CRP for the diagnosis of endoscopic inflammation in patients with UC were reported to be 0.49 and 0.92, respectively. In daily practice, the CRP of patients with mild or limited inflammation is in the normal range.

FCP best correlates with the severity of endoscopic inflammation in patients with UC [63] and is already an established method for evaluating the activity of UC as an alternative to colonoscopy [62, 64]. Conversely, the evidence assessing the activity of CD was inferior to that of UC. While it was previously reported [65] that FCP did not correlate with endoscopic activity, Schoepfer et al. [27] reported that among multiple biomarkers, FCP was most closely associated with the simple endoscopic score for CD; FCP also correlated with the simple endoscopic score for CD in patients with pediatric CD [33]. Iwamoto et al. [66] evaluated the findings of balloon-assisted endoscopy in patients with CD in the small intestine only; they found that FCP is also correlated with inflammation. It was demonstrated that FCP could assess endoscopic disease activity in patients with CD; still, inflammation of the small intestine tends to be less strongly correlated than in the colon [67].

LRG correlated with disease activity and was superior to CRP regarding the CD activity index [68]. The correlation between LRG and the clinical activity of patients with UC exceeds that of CRP; additionally, LRG demonstrated a significant association with endoscopic and histological activity and remission [69‒71]. Shinzaki et al. [72] demonstrated the usefulness of LRG as a monitoring marker, reporting decreasing values with endoscopic and clinical improvement after administering adalimumab in the PLANET study analysis. ESR was reportedly more likely to elevate in the active phase of CD than in UC [73‒75]; however, it should be noted that the value change was slower than the change in disease activity [73].

Few studies reported a correlation between FIT and endoscopic activity. The sensitivity and specificity of FIT for the diagnosis of an MES ≥2 in patients with UC were 0.87 and 0.60, respectively [76]. There are no reports regarding the association between FIT and adolescent CD.

Fourth Position: Diagnosing MH

There is an apparent limitation regarding the diagnosis of MH using CRP. An overview report on the accuracy of CRP within the normal range for diagnosing MH reported average sensitivities and specificities of 66% and 82% in UC, and 79.5% and 61% in CD, respectively [77]. Conversely, the sensitivity and specificity of FCP reported in a systematic review were 89.7% and 93.3% for a cutoff level of 58 μg/g, and 100% and 62% for a cutoff level of 490 μg/g, respectively [78]. Another systematic review, including 1,168 patients from 12 studies, demonstrated that FCP correlated with histological disease activity; however, the authors insisted that the cutoff value for diagnosing MH was not determined [79].

FCP can determine histological remission among patients with endoscopic remission for both UC and CD [80]; however, better accuracy was observed for UC [78]. It was reported that FCP could predict MH diagnosed using double-balloon endoscopy with better accuracy than CRP in patients with CD (sensitivity, 0.91; specificity, 0.82) [81]. The combined use of FCP and FIT helps diagnose MH in patients with pediatric CD [27]. Thus, FCP can generally diagnose MH in both patients with UC and CD; however, the accuracy is higher in patients with UC.

In a Japanese study, the diagnostic ability of LRG for MH was good, as the area under the receiver operating characteristics curve (AUROC) was demonstrated to be 0.75–0.85 in patients with UC [82] and 0.85 in patients with CD [70]. The cutoff value for LRG was 16 μg/mL, while the probability of MH was higher when the value was <13 μg/mL [70, 71, 83]; however, it was highlighted that there is a limitation to the diagnostic ability in clinical remission. It was reported that the diagnostic ability of LRG for the diagnosis of endoscopic remission did not differ from that of CRP [69], and that LRG was not superior to other biomarkers for diagnosing MH [84]. However, the sample size was limited in these reports, and further evidence is needed to diagnose MH in remission and its cutoff level.

FIT can predict MH with a high probability. In UC, the sensitivity and specificity of FIT in the normal range for diagnosing an MES of 0 were 0.92 and 0.71, respectively [74]. If MH was determined as an MES of <1, the sensitivity and specificity were 0.6 and 0.87, respectively. Takashima et al. [85] reported that FCP and FIT were equivalent for diagnosing an MES of <1; FIT was only more sensitive for diagnosing an MES of 0. Conversely, the sensitivity of FIT for diagnosing MH in CD was 0.96, and the specificity was 0.48 [85]; the sensitivity reduced to 0.40, which was considerably low for MH diagnosed only in the small intestine.

Fifth Position: Predicting Disease Recurrence

FCP helps predict disease recurrence. In a systematic review, increased FCP level in patients with IBD in the clinical remission phase was associated with recurrence within 3 months. If the FCP value remains within the reference value, it predicts the maintenance of remission after 3 months with a high probability [86]. In a meta-analysis by Mao et al. [87], the sensitivity, specificity, and AUROC of FCP for recurrence prediction were 78%, 73%, and 0.83, respectively. While comparable results were obtained in both patients with UC and CD, the impact on the recurrence prediction of CD was insufficient due to the small sample size of patients with small intestinal CD. Costa et al. [88] reported that the positive predictive value and negative predictive value of increasing FCP for disease recurrence were 81% and 90% in patients with UC, and 87% and 43% in patients with CD, respectively. When the FCP value collected during the remission phase was ≥150 mg/g, the risk ratio of disease recurrence was 14 times higher in UC, and two times higher in CD [88] when compared with <150 mg/g.

Although FCP helps predict disease recurrence, its accuracy is relatively low for small intestinal lesions in patients with CD. There are many reports regarding the association of FCP value with disease recurrence after intestinal resection in patients with CD, and endoscopy is recommended if the FCP value is ≥200 μg/g [89]; an FCP value ≥100 μg/g can predict disease recurrence more sensitively than high-sensitivity CRP [90]. The POCER study demonstrated that monitoring with CRP or FCP and performing endoscopy with appropriate timing leads to a favorable prognosis [91].

Several studies reported that elevated CRP and ESR can predict the recurrence of CD [92‒96]; however, its usefulness was not established due to the lack of high accuracy data. A previous study that examined patients with UC reported that plasma cell infiltration is associated with disease recurrence, but not CRP and ESR [96].

There are very few reports regarding the association between FIT and disease recurrence prediction. According to Hiraoka et al. [97], among 83 patients with UC who achieved MH, 43 who were negative for FIT had no recurrence, while 25 of the 40 who were positive exhibited disease recurrence.

Prostaglandin E-Major Urinary Metabolite

In the arachidonic acid cascade – a series of inflammation-causing reactions – prostaglandin E2 (PGE2) is generated by acting cyclooxygenase and PGE2 synthase after arachidonic acid is released from cell membrane phospholipids by the action of phospholipase A2 due to tissue inflammation. PGE2 is a major chemical mediator for promoting and suppressing inflammation, and has been shown to increase in the blood, especially due to the effects of deep mucosal inflammation [98‒100]. PGE2 metabolites are excreted in the urine through enzymatic reactions in the lungs and oxidation in the liver and kidneys [101]; its main component is tetranor-PGEM (9,15-dioxo-11a-hydroxy-13,14-dihydro-2,3,4,5-tetranor-prostan-1,20-dioic acid), also known as prostaglandin E-major urinary metabolite (PGE-MUM).

PGE-MUM is highly stable and has no chronotype. Smokers tend to have a higher value than nonsmokers, particularly when the Brinkman index is 400 or higher. While this is thought to be due to lung damage caused by smoking [102], users of senna-based laxatives also exhibit fluctuations in the values [103]. Oral nonsteroidal anti-inflammatory drugs decrease the value, while PGE drugs increase the value. Studies on PGE-MUM as an inflammatory marker have also reported that the levels are elevated in UC [104], and extremely high levels of PGE-MUM indicated chronic enteropathy associated with SLCO2AI, caused by a genetic abnormality in the PGE transporter [105, 106]. In addition to intestinal diseases, it has also been reported that PGE-MUM increases in patients with interstitial pneumonia [105].

Arai et al. [104] reported that PGE-MUM correlated strongly with MES and histological activity (Matts classification). The diagnostic ability was better than that of CRP, as the AUROC of CRP and PGE-MUM were 0.96 and 0.98 for the diagnosis of an MES of <1 (endoscopic MH), and 0.77 and 0.90 for the diagnosis of an MES of 0, respectively. PGE-MUM can also diagnose the achievement of endoscopic remission, histological remission, and complete MH (as the achievement of both an MES of 0 and Matts grade ≤2), even in patients in clinical remission [107].

The diagnostic ability of PGE-MUM for the diagnosis of endoscopic remission, histological remission, and complete MH was equivalent to that of both FCP and FIT. Furthermore, the PGE-MUM value did not differ among UC disease phenotypes. It was also reported that the PGE-MUM value paralleled the change in endoscopic disease activity in the same patient [108]; thus, as with FCP and LRG, it is expected to be used as a monitoring marker instead of colonoscopy and tissue biopsy. Less invasiveness can be a great advantage of PGE-MUM for the management of pediatric UC [109]. Regarding the prediction of relapse, it was only reported that if patients in remission showed high PGE-MUM at a certain point, the subsequent likelihood of recurrence is significantly higher [110].

Microribonucleic Acid

Microribonucleic acid (miRNA) is a single-stranded, noncoding RNA, and one of the 17–25 nucleotide small RNAs [111]. It is common in various organs and is abnormally expressed in various diseases, including UC. It controls the immune response of UC and participates in the progression from UC to colorectal neoplasms [112].

It is reported that miRNAs can be helpful biomarkers for diagnosing and monitoring UC; for example, miR-21 and miR-29a have significantly higher expression in patients with active UC than in those with and without IBS, with specificities of 92% and 100%, respectively [113]. Furthermore, circulating miR-375 is highly expressed in patients with UC than in those with CD and non-IBD [114], demonstrating its usefulness as a diagnostic marker. Several studies suggested the possibility of predicting treatment response and the necessity of treatment enhancement [115‒117].

Oncostatin M

Oncostatin M (OSM) is a family of cytokines and a growth regulator that suppresses the growth of several tumor cell lines. It adjusts the production of cytokines, including endothelial cell-derived IL-6, G-CSF, and granulocyte-macrophage CSF [118‒121].

Patients with IBD express higher levels of OSM cytokines and their receptors (OSMR) in inflamed intestinal tissue than healthy controls, correlating with histological severity [122]. OSM was reported to predict the effects of anti-TNFα antibodies; patients with low plasma OSM before initiating treatment had a significantly higher rate of clinical remission 1 year after TNF therapy [123], while patients with high plasma OSM were significantly associated with the discontinuation of anti-TNFα antibodies. Low effectiveness of anti-TNFα antibodies was shown even when limited to patients with CD [124‒126]. It was shown that patients with high OSM levels in the colonic mucosa were less likely to respond to anti-TNF-α antibodies and vedolizumab [127]. By contrast, low serum OSM levels before treatment predicted the efficacy of anti-TNF-α antibody treatment without vedolizumab [128]. Although results may differ between colonic mucosa and serum, OSM was associated with patients with refractory anti-TNFα antibodies and is expected to be a potential biomarker and therapeutic target for IBD.

Anti-Integrin αvβ6 Antibody

Integrins are dimeric cell surface proteins known as cell adhesion molecules [129]; they include an α chain and β chain, and 24 combinations of chains have been identified [129]. The αvβ6 protein is a receptor that constitutes the extracellular matrix network responsible for tissue structure maintenance, is only expressed in epithelial cells, and is deeply involved in maintaining the function of the epithelial barrier [130‒132]. Anti-integrin αvβ6 antibody was identified as an autoantibody against epithelial adhesion molecules in the pathology of UC. The rate of positivity for this antibody was extremely high at 92.0% in patients with UC, compared with 5.2% in healthy subjects. The sensitivity and specificity were 92.0% and 94.8%, respectively, for the diagnosis of UC [133]. Additionally, there was a positive correlation between the antibody titer of the αvβ6 antibody and the Mayo score. It was thus confirmed to be helpful as a diagnostic, as well as a monitoring marker [133]. Although this was a once-off report, it is a marker with great prospects.

There are five positions demonstrating the usefulness of various biomarkers, shown in Table 1. The strategy of using biomarkers has been established for the direction of treatment, diagnosing MH, and predicting disease recurrence. CRP can be sufficiently evaluated during the active phase, while FCP and LRG are advantageous in the clinical remission phase; FIT in the normal range strongly diagnoses MH. While it is possible to predict recurrence by primarily using FCP, PGE-MUM and LRG may be more promising markers than FCP; however, more evidence is needed to evaluate these markers. However, there are specific limitations of each marker; proper use of these biomarkers thus involves understanding the features of each marker and selecting the appropriate marker for each role.

Table 1.

Biomarkers and five positions for the management of patients with IBD

 Biomarkers and five positions for the management of patients with IBD
 Biomarkers and five positions for the management of patients with IBD

Many biomarkers are used in IBD treatment. While complete biomarkers have not yet emerged, we can proceed with our management of IBD noninvasively and smoothly by understanding the characteristics of each marker and the five positions, and selecting appropriate markers to determine the condition of the intestinal mucosa.

Toshiyuki Sakurai had no conflicts of interest to declare. Masayuki Saruta received scholarship/research grants from EA Pharma Co., Ltd.; Zeria Pharmaceutical Co., Ltd.; Kissei Pharmaceutical Co., Ltd.; and Mochida Pharmaceutical Co., Ltd., and honoraria (lecture fee) from AbbVie GK, Mitsubishi Tanabe Pharma, Janssen Pharma K.K., and Takeda Pharmaceutical Co., Ltd.

No funding was received for the manuscript.

Toshiyuki Sakurai and Masayuki Saruta, drafting the manuscript.

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