Introduction
The central role of medical treatment for Crohn’s disease (CD) is the early prevention of disease progression through immunosuppressive therapy. In recent decades, the development of biologic agents, such as antibodies against tumor necrosis factor (TNF) alpha, has led to significant change in the medical treatment of CD [
1]. After the initial approval of the anti-TNF antagonist infliximab, medical therapy for CD has advanced rapidly. Recently, there has been a paradigm shift in the way medical treatment is approached: early use of biologics is increasingly performed as a “top-down-therapy” or at least “rapid step-up therapy” compared to the more traditional “step-up” approaches [
2]. The search for additional treatment strategies has led to the development of a plethora of novel therapeutics in the field. It is speculated that with the steady increase in medical options, the number of operations in CD patients will diminish. However, treatment failure with TNF antagonists is observed in up to 30–50% of patients [
2]. For the new drug targets, the reported efficacy of all drugs vs. placebo is still fairly limited [
3]. Therefore, despite all medical advances, the introduction of biologics does not appear to have a major impact on the likelihood that a patient will or will not undergo surgery. Surgery is still required in a significant proportion of patients and constitutes an important part of the treatment algorithm in the management of CD [
4].
The aim of this study was to analyze the development of CD with special reference to surgical treatment within the last decade. A population-based systematic analysis was performed to assess all inpatient CD cases from 2010 to 2017 in Germany. The number of hospitalizations and surgical procedures for CD were summarized, and surgical complications as well as in-hospital mortality are presented.
Discussion
More than 20 years after the introduction of biological therapy, an increasing variety of biological therapeutics are now available to treat patients with CD [
8]. Nevertheless, surgery continues to play a significant role and a percentage of patients still require surgery for refractory disease or disease-related complications.
This analysis of more than 200,000 cases provides an overview of the absolute number of inpatient Crohn’s disease cases and surgical procedures in a Western world country from 2010 to 2017, revealing an increase in inpatient cases of almost 10%. Interestingly, CD-related complications such as intestinal stenosis or malnutrition were increasingly diagnosed. The relative rate of surgical interventions did not change during the analyzed time period. Hence, on average, about 6.8% of all Crohn’s disease inpatient cases received either an ileocecal resection or right-sided hemicolectomy. While the number of laparoscopic procedures increased, postoperative morbidity remained comparably low. Mortality was consistently low at 0.3%. Compared with open procedures, patients undergoing laparoscopic procedures had lower postoperative morbidity and shorter length of stay.
Previous studies suggest that recent advances in biological therapy for CD have led to a reduction in the number of surgeries for CD. For instance, Mao et al. recently reported a reduction in hospitalization and surgery due to the use of TNF antagonists [
9]. In their systematic review and meta-analysis, they concluded that anti-TNF biologics reduced the odds of hospitalization by half and surgery by 33–77%. As their study focused on the use of biologicals within the setting of clinical trials, the situation in the real world is more heterogeneous, making it difficult to draw a conclusion about the specific effect of introducing TNF antagonists [
10]. Another meta-analysis of population-based studies from 2013 showed a decline of surgeries for CD [
11]. Nonetheless, subsequent studies have shown that this decline is not necessarily related to immunomodulators or biologicals, and progression to complicated disease was still common [
12]. In a prospective population-based cohort study from 2000 to 2012, Golovics et al. showed that hospitalization and re-hospitalization rates at 1, 3, and 5 years of follow-up were still 32.3%, 45.5%, 53.7% and 13.6%, 23.9%, 29.8%, respectively. Hospitalizations in the first year were related to diagnostic procedures (37%), surgery (27%), or disease activity (21%) [
13]. A Polish study based on National Health Insurance Fund data with 1393 patients from 2012 to 2014 reported a reduction in hospitalization and the need for surgery depending on previous treatments [
14]. The latter is an important point to elaborate on. A population-based analysis from Manitoba, Canada, including 3400 patients, reported that only a small percentage of patients were being treated with infliximab in the first decade of the century [
15], while a report from France from 2000 to 2008 demonstrated an overall use of 65% [
16]. In this cohort, of all patients who required surgery, about 60% were treated with at least one biological. Altogether, the rate of biologic therapy varies in different populations, which might also be a confounding factor in our analysis.
In regard to CD-related comorbidities, a considerable increase in the frequency of stenosis formation was observed, which may indicate a tendency toward chronicity of disease rather than improvement in disease progression in the era of biological therapy. Immunosuppression might reduce intestinal inflammation but ultimately leads to fibrosis and obstructive courses of disease due to stenosis formation. In our analysis, this is accompanied by an increase in malnutrition, which could also point to a trend toward more chronic forms of disease.
Not only has medical therapy evolved, but surgical techniques have also advanced significantly over the past few years. With the advent of minimally invasive techniques and improvements in surgical equipment, surgical management of patients with CD can now be performed with less morbidity. With respect to surgical techniques, it is noticeable that laparoscopic procedures increased in 2017 compared with 2010 and accounted for nearly 50% of procedures in the later phase of our analysis. This applies to both ileocecal resection and right hemicolectomy.
As for postoperative complications in general, we did not observe a profound increase. Relative rates were consistently low, underlining the safety and efficacy of surgery in CD. Similar findings were recently presented by Mege et al. who demonstrated that despite a higher incidence of comorbidities, postoperative morbidity remained widely unchanged [
17]. In addition, the authors reported an increase in laparoscopic procedures, which is comparable to our results. Here, our analysis revealed that overall postoperative complications remained at a low level. Further, coding of postoperative complications did occur less frequently following minimally invasive procedures. The latter might lead to the assumption that more complicated cases are still performed as open procedures. Nonetheless, our data show that surgery in CD patients is feasible to perform and safe even in the age of biological therapy.
The present study has several limitations that need to be addressed. First, cases with outpatient treatment and application of immunotherapeutics were not analyzed. Therefore, the overall development of CD cases in Germany is underestimated in our analysis. In addition, approximately 40% of all cases were admitted to the hospital as an emergency, which might have influenced the data on complications and ileocolonic procedures. As patients were not identified personally, multiple admissions per year cannot be excluded. Furthermore, large hospital discharge data-based cohort studies are potentially biased by possible mislabeling and inaccurate coding behavior, which cannot be excluded nor controlled for. Additionally, for some years, exact numbers cannot be presented due to confidentiality reasons. The latter occurs when too little overall case numbers might allow tracing of individual patients. In particular, regarding postoperative complications, only 2010, 2012, 2015, and 2016 were available for our analysis. Further, the postoperative complication “anastomotic leakage” has been introduced in 2013 so data extraction was based on 2015 and 2016. Hence, for some of the complications, data has been pooled to allow for overall estimation of current developments. However, given these limitations, the predominant advantage of this study is the large data set. While other studies represent only a fraction of all cases, our study included all inpatient cases of Crohn’s disease admitted to the hospital in Germany. This corresponds to 201,165 patients over the entire study period.
The results indicate that despite an increase in conservative therapeutic options, the rate of surgical treatment of Crohn’s disease in German hospitals remained stable in recent years. In addition, both the mortality rate and the rate of complications were low. All in all, it can therefore be concluded that surgery as a therapeutic option for Crohn’s disease has its own significance. Recent studies have shown that both drug therapy and surgical options should be considered as equal therapeutic strategies, which is why current guidelines mandate interdisciplinary consultation prior to intensifying treatment options [
18‐
21]. While in some cases, the use of biologicals leads to remission of the disease, in selected subgroups of patients, early surgery may be associated with good surgical outcomes [
8,
22]. In particular, laparoscopic ileocolonic resection might be an attractive alternative to several years of drug therapy and can lead to long-lasting remission [
23]. For these reasons, it is critical that surgical management of CD patients be individualized in the biological era, and case-based, multidisciplinary decision-making is crucial to achieve favorable outcomes.
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