Adalimumab for treatment of very early onset inflammatory bowel disease.

To the Editor: The incidence of inflammatory bowel disease (IBD) has been increasing in recent years; nevertheless, neonatal IBD with IL10-RA gene mutations are rare with great therapeutic challenges. Herein, we reported a case of very early onset inflammatory bowel disease (VEO-IBD) with an IL-10RA gene mutation which was effectively treated by adalimumab.

The boy was born at 36+3 weeks of gestational age with a birth weight of 2360 g. He was the fourth child of non-consanguineous healthy parents. His mother has been pregnant for five times and delivered four babies. All of the previous three babies got fever, oral ulcer, and abdominal distention 1 week after birth, and died within 2 months. The fourth fetus succumbed to the arrested fetal development.

Fourteen days after birth, the boy developed purulent bloody stool and diarrhea. Then anal fissure and perianal abscess occurred. The main extra-intestinal symptoms were recurrent rash and oral ulcer, the systemic symptoms included fever, anemia, hypoalbuminemia, and malnutrition.

On admission, laboratory examinations revealed the C-reactive protein level (CRP), erythrocyte sedimentation rate (ESR) and complete blood count were all normal. As the disease progressed, he got many times recurrences, and the CRP and ESR increased synchronously. Repeated endoscopic examinations were performed when the boy was 25 days old, 19 months old, and 45 months old, respectively. The first colonoscopy revealed erosion, bleeding, edema, and small ulcers along the whole ascending colon. Then, the disease progressed gradually. The third colonoscopy revealed multiple segmental ulceration and cobblestone-like appearance in the whole colon [Figure 1]. Pathology showed inflammation and edema in the small intestine and colorectal mucosa with focal infiltration of lymphocytes, occasional plasma cells, and neutrophils. Genetic examination revealed the c.537G>A homozygous mutation in the IL-10RA gene. A diagnosis of Crohn disease (CD) was made.

Figure 1

The third colonoscopy reveals multiple segmental ulceration and cobblestone-like appearance in the colon.

The patient was treated with the extensively-hydrolyzed formula (EHF) and mesalazine. The symptoms were alleviated for 3 months but recurred. Subsequently, a five-course (1–2 months for each course) treatment with corticosteroids was added. During the treatment, oral ulcers reoccurred intermittently, while the patient's temperature was normal and the stool character and frequency were significantly improved. However, after the withdrawal of corticosteroids, the symptoms recurred. Eighteen months later, the growth and development of the boy were retarded (10 kg; 79 cm) due to recurrent symptoms. Then, he was given five doses of infliximab. After the first two doses, he defecated 1 to 3 times per day, and the bloody mucopurulent stool was significantly improved; the body temperature was normal. After the third dose, the disease relapsed. At the age of 27 months, the pediatric Crohn disease activity index (PCDAI) was 36, and thalidomide was added. The symptoms were improved and the condition remained stable for about 1 year. His weight increased to 11.5 kg when 36 months old. Then, his parents stopped the medicine on their own.

After stopped treatment for 9 months, the boy developed weight loss (3y9m; 10 kg; 90 cm), frequent fever, mucous or water-like stools (more than 10 times per day). The PCDAI was 52.5 and antibiotics did not provide remarkable benefits. Intravenous methylprednisolone was attempted, which could temporarily control the disease. Considering the steroid-dependence and infliximab-resistance, hematopoietic stem cell transplantation (HSCT) was recommended; nevertheless, the parents refused the treatment for economic reasons. Therefore, subcutaneous injection of adalimuma was performed for five courses (40 mg for the initial dose and 20 mg per week for the subsequent treatment). After the treatment, the patient's temperature returned to normal and the frequency of defecation decreased to 3 to 10 times per day, and stools had normal appearance. CRP and ESR were normal as well. The body weight increased to 12.5 kg. There is no serious infection, pancytopenia, allergy, metabolic disorders, elevated aminotransferase, nausea, or vomiting.

The boy was eventually diagnosed as VEO-IBD with the c.537G>A homozygous mutation in the IL-10RA gene. HSCT was performed finally. Unfortunately, the first transplantation failed. The second transplantation 8 months later succeeded, and the patient remained stable during the following 5 months. He can eat freely without stool changes or fever.

CD is an autoimmune disease that can involve any part of the digestive tract. Approximately 0.2% of all patients with CD showed symptoms during the neonatal period. Mutations in IL-10, IL-10-RA, IL-10-RB, TTC7A, PLCG2, ADAM17, and MEFV genes have been reported to be associated with neonatal IBD.[ The mutation in the IL-10RA gene is relatively rare. We identified a mutation (c.G537A) in the exon 4 of IL-10RA, which has been reported previously. Additionally, the symptoms of this mutation carrier in the literature is consistent with our findings.

The therapeutic regimens for CD included 5-aminosalicylic acid, steroids, and immunosuppressive agents such as 6-mercaptopurine and anti-tumor necrosis factor (anti-TNF) antibodies. However, considering the potential adverse effects, medications for children, especially those with VEO-IBD, are usually limited. In our case, EHF, aminosalicylic acid, steroids, and infliximab were attempted but provided no remarkable benefits.

Among the anti-TNF antibodies, infliximab is the first approved drug. Infliximab is an antibody harvested from mouse, and adalimumab is a human anti-TNF antibody[ with confirmed safety and efficacy in CD.[ Noteworthy, adalimumab is also effective in children unresponsive to infliximab.[ However, adalimumab used in the treatment of children under 6-year-old has not yet been reported. In our case, the dose was chosen after weighing the efficiency and side effects and combined with the application experience in the literature for older children and the patient's age and weight.

In summary, we reported a case with VEO-IBD that was treated with adalimumab. Our findings indicate that adalimumab is safe and effective for young children. However, we still recommend HSCT as the optimal treatment for this disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the work, the patient's legal guardians gave their consent for the images, and other clinical information to be reported in the article. They understand that neither the patient's name nor initials will be published, and due effort will be made to conceal her identity, although total anonymity cannot be guaranteed.

Conflicts of interest

None.