Crohn disease (CD) is a chronic inflammatory disease, and its incidence in children is rising. Despite extensive reports and investigations, the pathogenesis of CD has not been clearly elucidated, particularly in regard to triggering factors. A genetic predisposition is considered important when investigating the mechanism leading to CD, and the discovery of new CD-associated genes has increased our understanding of its immunopathogenesis and improved the efficacy of its treatment of CD. Early detection and treatment (eg, as children) with gene-based precision therapy can effectively prevent complications related to CD. In this case, a Chinese Han boy with CD associated with a mutation of tumor necrosis factor α-induced protein 3 was treated with recombinant human tumor necrosis factor-a receptor II:IgG Fc fusion protein. We suspected the boy had CD because of chronic abdominal pain, aphthous stomatitis, moderate anemia, a high erythrocyte sedimentation rate (36–79 mm/h), multiple intestinal ulcers, knee joint swelling, and a tumor necrosis factor α-induced protein 3 mutation. After total enteral nutrition and hormone therapy for 5 months, his abdominal pain and joint symptoms did not improve, so we started gene-based precision therapy with recombinant human tumor necrosis factor-a receptor II: IgG Fc fusion protein, which may play an important role in restricting TNF-α-induced NF-κB signaling. After 3 weeks, inflammation indicators were within the normal range, and multiple ulcers and joint symptoms were relieved. The present case demonstrates a safe therapeutic schedule that leads to rapid improvements in the clinical and biochemical status of patients with CD.
Crohn disease (CD) is a kind of inflammatory bowel disease (IBD).1,2 The primary characteristic of CD is chronic relapsing transmural granulomatous inflammation.3 CD can be manifest with intestinal, parenteral, and systemic symptoms. Intestinal manifestations include abdominal pain, diarrhea, oral ulcers, and multiple ulcers in ileocecal areas; extraintestinal manifestations include arthritis, stomatitis, iritis, and nodular erythema; and systemic symptoms may include fever, malnutrition, weight loss, stagnant growth, and delayed development. Perianal fistulas and abscesses are common.3–5 Because of its chronic relapsing characteristics, many patients with CD experience a lifetime of debilitating physical symptoms.3,6 Therefore, early diagnosis and treatment are particularly important to avoid poor psychosocial well-being and complications.7
Although the complete mechanism leading to CD remains unclear,4–6 previous investigations suggest that genetics, environmental factors (eg, smoking, diet, microbiota), and immunologic factors are the main causes of CD.3,4 Among them, a genetic predisposition is considered to be important when investigating the mechanism of CD, and the identification of new CD-associated genes has increased our understanding of its immunopathogenesis. More than 37 alleles associated with CD have been confirmed by genome-wide association investigations.4,8,9 Moreover, some investigators have found that tumor necrosis factor α-induced protein 3 (TNFAIP3; also known as A20) mutations may cause systemic inflammatory disease.10 Authors of a molecular study further showed that TNFAIP3 (A20) was dysregulated in pediatric CD,11,12 indicating that TNFAIP3 (A20) is a key player in the inflammation associated with pediatric CD.11 Therefore, investigating the status of TNFAIP3 (A20) in children with CD could allow new insights into the mechanisms causing the symptoms of CD, which can help achieve an “immune-tailored” therapeutic approach.
In this article, we report the presentation and treatment of a Chinese Han boy aged 5 years and 4 months with pediatric CD and a TNFAIP3 mutation. Recombinant human tumor necrosis factor-a receptor II:IgG Fc fusion protein (rh TNFR:Fc) injection resulted in rapid normalization of his inflammation markers and MRI findings and led to clinical improvement. The administration of rh TNFR:Fc may trigger a better clinical response, leading to the general improvement of patients with CD.
In November 2018, a Chinese Han boy from Guangdong Province aged 5 years and 4 months presented to our gastrointestinal outpatient department with a 3-month history of chronic abdominal pain, aphthous stomatitis, loss of appetite, occasional vomiting, moderate malnutrition, perianal lesion, a 15-day history of bilateral knee joint swelling, and a 7-day history of bloody stool. His height and weight were 15.2 kg (z score: −2 SD) and 102 cm (z score: −3 SD), respectively, whereas his gestational age was 40 weeks, his birth weight was 3100 g, and his birth length was 48 cm.
His abdominal pain was mainly in the right lower abdomen. The pain was paroxysmal, which was spontaneously relieved after several minutes. On physical examination, his vital signs were stable, but he had pallor.
An assessments of serum high-sensitivity C-reactive protein levels, erythrocyte sedimentation rate, hemoglobin, and blood laboratory analysis were conducted on a blood sample from the patient. The relevant laboratory data indicated that he was anemic (hemoglobin: 76–89 mg/L) and had hypoalbuminemia (30 g/L), high levels of high-sensitivity C-reactive protein (19.9–131 mg/L), high erythrocyte sedimentation rate (36–79 mm/h), and high tumor necrosis factor alpha (TNF)-α levels (3.51 pg/mL) measured with enzyme-linked immunosorbent assay in the serum (his TNF-α before the onset of symptoms was 0.8 pg/mL).
Multiple ulcers in his colon were observed by ileocolonoscopy. The lesions were more obvious in the ileocecum, ascending colon, transverse colon, and sigmoid colon, and the lesions showed a dramatic change from normal tissues. Their endoscopic features and histologic features are illustrated in Fig 1. The longitudinal and lateral ulcers had fused with each other (Fig 1D), and the residual mucosa of the island between the ulcers was highly edematous, forming longitudinal ulcers (Fig 1A) and a cobblestone-like appearance (Fig 1B). Inflammatory cells, such as lymphocytes, plasma cells, and eosinophils, existed in the crypt architecture of the gastric mucosa (Fig 1C). Cryptitis (Fig 1F) and crypt abscesses (Fig 1G) were observed in the colonic mucosa. Furthermore, a negative T-SPOT.TB blood test and a negative tuberculin skin test13 eliminated the possibility of intestinal tuberculosis. He was diagnosed with CD. His high TNF-α level confirmed the diagnosis of CD because TNF-α is increased in the serum of patients with CD.14–17
MRI revealed a large amount of effusion in the left iliac sac and knee joint, and the synovial membrane around the joint was obviously hyperplastic and thickened, and the left popliteal lymph node was enlarged (Fig 2), which may be the cause of the observed bilateral knee joint swelling. A previous investigation revealed that cases of pediatric CD could initially present for rheumatology evaluation.18 Therefore, the bilateral knee joint swelling in the patient may be caused by the CD.
The treatment of CD involves induction and maintenance regimens. The therapeutic approaches to CD include corticosteroids, nutritional therapy, immunosuppressants, anti-TNF therapy, surgery, and new biological drugs.4,19 Nutritional support is a key component in the treatment of patients with CD with malnutrition.4 Hence, the treatments of our patient with moderate malnutrition started with total enteral nutrition, which was helpful in the remission of malnutrition and some improvement of autoimmunity symptoms. At the same time, we advised whole exon gene detection for this patient. However, his parents did not agree. After 5 months, his abdominal pain symptoms were relieved, and his bloody stool disappeared, whereas his knee joint swelling was not relieved.
Steroids can be used to treat mild to moderately active disease according to the guidelines.19 We also added hormone therapy (prednisone acetate tablets; starting with 1 mg/kg per day and gradually reducing the dose during outpatient follow-up to maintenance treatment with 0.2 mg/kg per day, for 8 weeks). After the hormone therapy, his joint pain did not improve, and small ulcers were still seen on ileocolonoscopy. His inflammatory indicators were still high. The immunopathogenesis of CD in this patient remained unclear. We therefore performed whole exon gene detection for this patient with permission from his parents.
5-Aminosalicylic acid is an anti-inflammatory drug widely used in the treatment of CD.20 The patient was also treated with mesalazine (27 mg/kg per day). His abdominal pain remained recurrent. Then, he was treated with methotrexate (0.5 mg/kg per day, once per week). However, his joint symptoms did not improve.
The results of genetic analysis showed that a novel mutation genotype, c.909_913del (p.L303fs), in the TNFAIP3 gene was found in the affected patient (Fig 3). His father and mother had no mutation in TNFAIP3, indicating that the TNFAIP3 mutation in this patient is a de novo heterozygous truncating mutation. Previous investigations have revealed that this TNFAIP3 mutation leads to truncated A20 proteins that encode NF-κB.21 The truncated A20 proteins might cause haploinsufficiency, as seen in previous reports of TNFAIP3 mutations.22–25 Therefore, we speculated that the CD in this patient was associated with haploinsufficiency of A20.
On the basis of the genetic test results, personalized therapy was adopted, and he was treated with an rh TNFR:Fc injection (0.8 mg/kg, subcutaneous, once a week) and subcutaneous rh TNFR:Fc 12.5 mg once a week for a total of 12 weeks. After 3 cycles of treatment, his inflammation indicators fell within the normal range, his TNF-α levels measured with enzyme-linked immunosorbent assay were reduced to 1.1 pg/mL, and he had relief from his multiple ulcers and joint symptoms (Fig 2 C and D). The ulcers and diseased intestinal mucosal tissues gradually improved after the treatment with rh TNFR:Fc, as observed on colonoscopy and histopathology images (Fig 4). These results indicate that this CD case presenting with knee joint swelling and chronic abdominal pain is probably associated with the TNFAIP3 mutation. No adverse reactions were observed during the administration of the rh TNFR:Fc or during continued maintenance medication.
This is a report of a case of pediatric CD. The observations of ileocolonoscopy were consistent with previous ileocolonoscopy observations in patients with CD.26 Some investigators have reported that chronic inflammation and altered immunity may be associated with TNFAIP3 mutations.12 The results of whole exon gene detection revealed a TNFAIP3 mutation in this patient. Hence, we suspect that the CD of our patient is associated with this mutation of TNFAIP3. In addition, rapid resolution of his multiple ulcers and knee joint symptoms and achievement of normal inflammation indicators after rh TNFR:Fc injection confirmed that his pathogenesis was associated with dysregulation of the TNFAIP3 gene.
Investigators have revealed that chronic inflammatory diseases can be induced by overproduction of TNF-α.27 Our patient with extensive inflammation of the intestine and a TNFAIP3 mutation may have been experiencing overproduction of TNF-α. Inhibiting TNF-α signaling through TNFR1 or TNFR2 can effectively cease NF-κB signaling and improve various inflammatory diseases. Many reports and investigations have suggested that an obvious remission of CD can be achieved by anti-TNFα therapies, such as infliximab, adalimumab, and certolizumab.3,4,27,28 Tong et al29 (2015) revealed that infliximab can cause more adverse events than rh TNFR:Fc after the follow-up of 402 Chinese Han patients treated with anti-TNFα therapy. Therefore, rh TNFR:Fc was chosen to treat our patient and may play an important role in restricting TNF-α-induced NF-κB signaling.
The administration of rh TNFR:Fc triggered a better clinical response and led to his general improvement. Other factors may have also contributed to his improvement, such as total parenteral nutrition, hormone therapy, anti-inflammatory drugs, and inherent child maturation. We must also take into account that monoclonal antibodies have the potential for immunogenicity.30 In clinical practice, anti-TNF therapy is found to be generally well tolerated. However, it is also associated with an increased risk of infections and an increased risk of melanoma.31,32 Therefore, total enteral nutrition is the optimal therapy, and anti-TNF therapy should be the last choice for treating pediatric CD.
Previous investigators have shown that etanercept can be used in the treatment of patients with arthritis associated with CD.33 However, some investigators have reported that etanercept does not significantly improve symptoms of CD, although the use of lower doses or less frequent dosing may be responsible for its general lack of effect.21 In addition, etanercept may also induce new-onset IBD.34 In the current study, rh TNFR:Fc was found to improve the knee joint swelling, intestinal symptoms, mucosal lesions, and mucosal pathology. This indicates that rh TNFR:Fc may have a good effect for treating both CD and any associated arthritis.
We report the case of a Chinese Han boy with CD. He was heterozygous for a novel mutation genotype, c.909_913del (p. L303fs), of the TNFAIP3 gene. Anti-TNF therapy with rh TNFR:Fc can effectively improve the clinical symptoms of CD associated with TNFAIP3 mutations through restricting TNF-α–induced NF-κB signaling. The rh TNFR:Fc triggered a better clinical response and led to his general improvement. This case may contribute to the development of a new therapeutic approach to pediatric CD based on the variability of clinical phenotypes associated with TNFAI3P mutations.
This research was supported by the Shenzhen Science and Technology Commission Foundation (JCYJ20160429090648512).
Drs Zou and Zhou conceptualized and designed the study, collected the data, and drafted, reviewed, and revised the manuscript; Prof Wang contributed to the analysis and interpretation of the data and revised it critically for important intellectual content; Drs Gou and Wang made substantial contributions to the conception and design of this manuscript and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.
FUNDING: All phases of this study were supported by the Shenzhen Science and Technology Commission [JCYJ20160429090648512].
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.