Study of disease phenotype and its association with prognosis of paediatric inflammatory bowel disease in China

Inflammatory bowel disease (IBD) includes Crohn’s disease (CD) and ulcerative colitis (UC); IBD-unclassified (IBD-U) is a group of chronic gastrointestinal inflammatory diseases. Approximately 25% of patients manifest with the disease in childhood or adolescence [1]. Our previous studies have indicated that the morbidity of paediatric IBD has been rapidly increasing in China over the past three decades [2]. Studies have also shown that paediatric IBD manifests as an extensive and aggressive disease [3, 4]. However, further study suggested that the clinical manifestations and prognosis varied greatly in patients with various onset ages [5]. In our study, the paediatric Paris classification released in 2013 was used, as it is valuable for paediatric IBD studies [6]. Using the Paris classification, we further sub-classified IBD patients into two groups, A1a (0–10 y) and A1b (10–17 y). We also focused on the children with very early onset IBD (VEO-IBD), including infantile and toddler onset IBD, as infantile IBD might be partially linked to monogenic diseases such as defects in IL-10 or its receptors, Wiskott-Aldrich Syndrome, XIAP deficiency, leukocyte adhesion deficiencies, CD40L deficiency, IPEX syndrome and several others [7‐9]. The clinical manifestations and phenotypes in this group of patients were different from those of patients in other age groups. However, it remains controversial as to whether these patients with monogenic diseases phenotype should be classified as having IBD [9, 10].

Because the clinical manifestations and phenotypes vary in IBD children, the prognosis of IBD is remarkably different in patients of different ages, and there is a lack of long-term follow-up studies on the natural course of the disease. In the current study, the natural course of disease was recorded with long-term follow-up to define the features and progression of paediatric IBD in China.

Medical records were retrospectively selected from the Department of Paediatrics, Ruijin hospital and North Ruijin Hospital; patients were diagnosed as having UC, CD, or IBD-U from January 2002 to September 2016. As a paediatric IBD centre, patients suspected of having IBD were recorded and followed up. The diagnosis was confirmed by at least three gastrointestinal (GI) paediatricians after complete physical examination, endoscopy, pathological examination, and radiological imaging determinations. The diagnosis was made according to the Porto criteria and Paris classification [6, 11, 12]. Complex patients with unclear diagnosis were re-evaluated by a multi-disciplinary team (MDT) of IBD professionals, consisting of GI paediatricians, radiologists, nutritionists, surgeons, nurses and adult gastroenterologists. Once the diagnosis was confirmed, the patients were followed up at the outpatient department regularly, and some patients were admitted to hospital for further treatment if necessary. A well-trained administrative staff was assigned to collect, document and store all the data.

There were 200 patients primarily reviewed. Fourteen diagnosed as having IBD-U could not be precisely classified until final follow-up and were therefore excluded from this study. Thirty-two patients with a follow-up period of less than 6 months were also excluded; however, the 11 patients who died within 6 months after diagnosis were included. Another 11 patients with incomplete medical records or without reports of endoscopy or imaging examination were excluded as well. Finally, there were 143 patients included in this study. All were less than 17 years old at the time of diagnosis. The patients were classified into three groups according to their age at diagnosis: 0–2, 3–9 and 10–16 years old groups. Clinical information and laboratory tests were collected at diagnosis and at each follow-up.

In this study, we analysed the relationship between disease phenotype and prognosis of paediatric inflammatory bowel disease in China. Younger patients may have extensive and aggressive disease. In the present study, 56% of paediatric IBD patients were younger than 10 years and 23.8% patients were younger than 3 years old. By contrast, the rate was quite low in a study carried out in Italy in which the VEO-IBD (0–3 y) was only 4%; however, the fundamental difference was that patients with genetic defects were excluded [22]. In addition, the proportion of patients younger than 10 years old were also higher than in other studies (23.2–50%) [22‐25]. The explanation may be that, as a hospital specializing in refractory IBD, we observed more refractory patients who were recruited for this study and the patients recruited were much younger.

DNA sequencing tests for VEO-IBD patients were performed in the current study since 2012, and we found that 58.3% of the tested patients had monogenetic disorders with the gene mutation on IL-10 receptor A (IL-10RA). Glocker et al. first reported in 2009 that the mutation of IL-10 receptor caused IBD [26]; since then, IL-10 receptor defects have drawn much attention by paediatric IBD researchers worldwide [27, 28]. It is interesting that most studies in East Asia including our results pointed out the dominance of IL-10RA mutations in IBD patients. By contrast, based on the European data, the numbers of patients with IL-10RA and IL-10 receptor B (IL-10RB) mutation were somewhat equivalent. In addition, our data demonstrated that none of our patients suffered from lymphoma and no parents were consanguineous; these observations are also different from those of the European survey [28]. Because of the high percentage of positive findings, one would speculate that there should be more patients with gene mutations related to IBD in those diagnosed before 2012 who were not examined by the NGS test. Furthermore, some studies demonstrated that many monogenetic disorders may cause IBD [29]. We had a patient who developed IBD secondary to GSD Ib, something that has not been reported in China before. It is noteworthy that 77% of GSD Ib patients may have IBD, and for these patients, recommended treatment is with G-CSF and mesalazine rather than with steroids [30, 31]. We also diagnosed two younger patients with diarrhoea as having chronic granulomatous disease (CYBB mutation) and hyper-IgM syndrome (CD40LG mutation). Both of which have been reported as monogenetic disorders causing IBD. Since they did not have typical IBD endoscopic and pathological manifestations, these two patients were not included in the study. Another study also reported mutations in EPCAM, TNFAIP3 and LRBA in China. However, based on all the data, it has been confirmed that IL-10 RA may be the main mutation in China [32, 33].

The clinical manifestations and phenotypes of diseases were analysed for patients diagnosed in the current study. Patients in the 0–2 y group commonly manifested systemic symptoms such as fever, weight loss and limitation of activity, colonic lesions, strictures and perianal disease; this was similar to what was reported in other studies [34]. It was reported that patients usually had accompanying extra-intestinal symptoms of joints, skin, liver, and eyes with percentages as high as 10–20% [23, 35]; however, few patients in the current study developed these extra-intestinal symptoms. It is worth noting that there were two patients with histories of juvenile rheumatoid arthritis (JIA) in the study; further investigation is needed to elucidate whether JIA and IBD are associated with the same pathogenesis.

Our centre has a standardized protocol of treatments for IBD patients. Of the total, 76.2% went into remission or improved after induction therapy. However, patients younger than 3 years old may relapse or suffer from various complications, possibly leading to a poor prognosis. Our findings indicated that infantile patients, penetrating lesions and steroid dependency were risk factors for poor prognosis, a finding that accorded with the consensus guidelines of ECCO/ESPGHAN [20].

Death reports were relatively high in this study, and all the deaths were in patients < 6 years old with CD. Most of these were very sick when they were recruited at the centre and half of them died within the first 3 months after diagnosis. Some patients responded to the treatment of IBD but developed infections and died unexpectedly. Some deaths were confirmed as being associated with IL-10RA defects. It was reported that IL-10RA mutations affected immune function, and patients with IL-10RA mutations may have a poorer prognosis [13]. Fortunately, IL-10RA and IL-10RB mutations can now be cured through haematopoietic stem cell transplantation [9, 36].

Based on our follow-up data, patients with a poor response to medicine would improve after colectomy, especially combined with colostomy. It was reported that all patients with IL-10RA and IL-10RB mutations need surgical interventions, including partial or subtotal colectomy. This may prolong survival time, but cannot help patients achieve remission [37]. Our experience showed that colostomy might be an effective therapy that can maintain clinical remission but cannot lead to mucosal healing. As some patients refused to have colostomy when advised, the reported percentage of surgery may be lower than medically necessary. Because a limited number of patients had long follow-up of colostomy, more clinical observation is required.

Our results have some limitations. As a hospital specializing in refractory IBD, the clinical features of patients presenting with refractory IBD differ from those of the general population. This may cause referral bias. A national IBD network should be set up to recruit more patients within the Chinese population. Another limitation was that, as a retrospective study, non-standardized documentation may have resulted in the inability to determine disease prognosis with various treatments. Furthermore, antibiotics and supportive treatment including parenteral or enteral nutrition were not recorded in detail. The potential variability in treatment practices could impact outcomes. It is worthwhile to set up a randomized controlled trial to analyse the long-term efficacy and safety of these medicines in different age groups. It is worth noting that the development of diagnostic methods during our study period may have affected the evaluation and treatments in the study. For example, genetic testing may have impacted the rate of detection of monogenic disease and changes in investigations (MRE and capsule endoscopy) over the study period, possibly impacting determination of the extent of small bowel Crohn’s disease.

We determined that age was the major factor determining the various clinical manifestations and prognoses for IBD patients. Infantile IBD may be caused by monogenic defects, particularly IL-10 RA mutations. Colostomy can improve clinical symptoms, but haematopoietic stem cell transplantation might cure these patients. NGS should be performed for each VEO-IBD, especially for infants. It is necessary to incorporate genetic testing into medical insurance plans and to regard it as a routine examination. This will improve the diagnosis and treatment of VEO-IBD in China.