Anti-TNF-α monoclonal antibody therapy in pediatric inflammatory bowel disease

Introduction

Inflammatory bowel diseases (IBD) represent a group of chronic, relapsing disorders characterized by persistent inflammation of the gastrointestinal tract, with a complex etiology and multifactorial pathogenesis. The two major entities, ulcerative colitis (UC) and Crohn’s disease (CD), significantly affect the pediatric population, with a globally increasing incidence.

In developed countries such as the United States and the United Kingdom, the annual incidence of Crohn’s disease in children is estimated at 12-14 cases per 100,000 children, while the incidence of ulcerative colitis ranges between 10 and 15 cases per 100,000 children^(1,2). Additionally, the cumulative prevalence of inflammatory bowel disease in the pediatric population in the United States is estimated at approximately 122 cases per 100,000 children, with CD being more frequent than UC. In Eastern Europe, including the Republic of Moldova and Romania, the pediatric incidence is estimated at 3-4 cases per 100,000 children per year, with an upward trend^(3,4). Up to 25-30% of all cases of inflammatory bowel disease are diagnosed before the age of 18 years old⁽⁵⁾.

These data underscore that inflammatory bowel disease represents an emerging pediatric public health concern, and the increasing frequency of diagnosis necessitates a thorough understanding of the clinical characteristics, disease course and optimal therapeutic strategies for this population.

Over the past two decades, indications for anti-TNF therapy in pediatric inflammatory bowel disease have evolved significantly. According to international guidelines, anti-TNF agents are recommended for the induction and maintenance of remission in children with active Crohn’s disease, particularly in cases refractory to immunomodulators or corticosteroids (the “step-up” strategy)⁽⁶⁾. More recently, ESPGHAN guidelines recommend the use of anti-TNF therapy as a primary (“top-down”) strategy in children with Crohn’s disease and active fistulizing perianal disease⁽⁶⁾. This approach may also be considered in children with extensive intestinal involvement, significant growth delay, deep colonic ulcerations, severe osteoporosis, or stricturing/penetrating disease at diagnosis, to optimize therapeutic response and prevent long-term complications^(4,6). The introduction of anti-TNF-a monoclonal antibodies, such as infliximab and adalimumab, has represented a major shift in the management of moderate to severe inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, by improving clinical response rates and inducing remission^(2,7,8). Multiple studies and meta-analyses have demonstrated the efficacy of these agents in reducing inflammatory activity and maintaining short- to medium-term remission, with no significant differences in response induction rates between the two molecules in Crohn’s disease in most comparative analyses.

However, secondary loss of therapeutic response during anti-TNF therapy remains a significant clinical challenge. Defined as a recurrence of disease activity after an initial clinical response, this loss of efficacy is common. In ulcerative colitis, annualized rates of loss of response have been estimated at approximately 10% for infliximab and 13% for adalimumab, with dose-escalation rates of about 14% and 21%, respectively, undertaken in an attempt to recapture clinical benefit⁽⁹⁾.

Some patients develop anti-drug antibodies (ADAs), an immunogenic factor associated with a marked increase in drug clearance and a reduction in therapeutic serum concentrations, leading to diminished efficacy and loss of response. ADA detection occurs predominantly in patients treated with infliximab or adalimumab, and represents a well-established predictor of long-term loss of response⁽¹⁰⁾.

In the pediatric setting, available data suggest variable durability of anti-TNF therapy, with a substantial proportion of pediatric patients experiencing long-term treatment failure. In a population-based study, rates of anti-TNF therapy failure (predominantly due to loss of response) reached approximately 60-70% at five years, while treatment discontinuation due to adverse events occurred in about 13-14% of patients, without any associated mortality, malignancies, or tuberculosis during the observation period^(11,12).

Beyond loss of response, adverse events associated with anti-TNF therapy represent a significant cause of treatment discontinuation in clinical practice. Pharmacovigilance reports in the pediatric population have identified infusion-related reactions with infliximab and injection-site reactions with adalimumab, underscoring the need for ongoing, careful clinical and laboratory monitoring throughout therapy^(12-15).

In this context, golimumab, another anti-TNF monoclonal antibody, has recently been investigated in the pediatric population. Available studies indicate that the pharmacokinetic profile of golimumab in pediatric patients with moderate-to-severe ulcerative colitis or Crohn’s disease is comparable to that observed in adults, suggesting potential clinical benefit and a similar safety profile^(4,16-18).

Recently, the U.S. Food and Drug Administration (FDA) approved golimumab (October 2025) for the treatment of children with moderate-to-severe ulcerative colitis weighing at least 15 kg^(18,19). This approval extends the indication of golimumab, which was initially authorized for adults with moderate-to-severe ulcerative colitis. This development represents a significant advance in the pediatric management of ulcerative colitis, providing a new therapeutic option for children who require biologic therapy.

Furthermore, the integration of golimumab into pediatric anti-TNF treatment strategies may offer additional options for patients who are refractory to or intolerant of infliximab and adalimumab^(1,9), thereby expanding the available therapeutic armamentarium for the management of pediatric inflammatory bowel disease.

Study aim

The present study aimed to evaluate the long-term efficacy and safety of golimumab therapy in pediatric inflammatory bowel disease (ulcerative colitis and Crohn’s disease) and to assess its use in pediatric patients followed for a period of 98 weeks.

Materials and method

The study was conducted at the Institute of Mother and Child, Chișinău, Republic of Moldova, within the Department of Gastroenterology and Hepatology, from 2021 to 2024. A total of 45 pediatric patients with inflammatory bowel disease were included: 41 children with ulcerative colitis and four children with Crohn’s disease. The patients were divided into three groups (Figure 2), according to their prior treatment history and the initial therapeutic response.

Age distribution analysis showed that the majority of included patients were between 7 and 18 years old (Figure 1). This distribution reflects the predominance of inflammatory bowel disease in older children and adolescents.

Group I comprised 12 children previously recei­ving combination therapy, of whom nine were cor­ti­co­ste­roid-dependent and three azathioprine-depen­dent. Prior therapy was discontinued, and golimumab mo­no­ther­apy was initiated.

Group II included 29 patients who received golimumab as first-line therapy.

Group III consisted of four children with Crohn’s disease in whom golimumab monotherapy was insufficient. These patients exhibited persistent abdominal pain, frequent loose stools (2-5/day), rectal bleeding, anemia and a marked impairment in quality of life. Beginning at week 12, combination therapy was initiated (golimumab in association with corticosteroids or azathioprine).

The pediatric patients were treated with golimumab according to pediatric clinical practice protocols. Dosing was adjusted based on body weight: 21 children (15-40 kg) received 45 mg, while 24 children (>40 kg) received 50 mg. Therapeutic response and safety monitoring were performed throughout the study period in accordance with clinical standards, including documentation of adverse events and assessment of relevant clinical parameters.

Demographic, clinical and therapeutic data were systematically collected and analyzed to determine the efficacy and safety of treatment according to the administered dose.

Results and discussion

The study included 45 children aged 7 to 18 years old, diagnosed with inflammatory bowel disease (IBD). The analysis of clinical symptoms revealed a distinct distribution between patients with ulcerative colitis and those with Crohn’s disease.

In children with ulcerative colitis, the primary clinical manifestations included chronic diarrhea with blood and mucus, colicky abdominal pain and tenesmus. Additionally, anemia and fatigue were frequently observed, and a significant proportion of patients exhibited extraintestinal manifestations, such as arthritis, erythema nodosum and uveitis.

Among children with Crohn’s disease, the predominant symptoms were recurrent abdominal pain, mainly localized in the right lower quadrant, and chronic diarrhea, typically without blood. These patients often exhibited weight loss and impaired growth (stunted height and reduced weight gain), as well as recurrent febrile episodes.

A comparative analysis of clinical manifestations across the three study groups highlighted significant differences in rectal bleeding, abdominal pain and growth retardation (Figure 3). Specifically, rectal bleeding was reported in 38 patients (92.6%) with ulcerative colitis (UC) and in one patient (25%) with Crohn’s disease (CD), with the difference reaching statistical significance (p<0.05). Abdominal pain was noted in 28 children (68.3%) with UC and in three children (75%) with CD. Similarly, growth retardation was predominantly observed in children with CD. Diarrhea was present in both disease entities, without statistically significant differences (p>0.05).

The observed differences in clinical manifestations between the two groups suggest a distinct symptomatic pattern, consistent with the existing literature on the clinical presentation of pediatric inflammatory bowel disease.

The pediatric patients included in the study were evaluated using a comprehensive protocol, including biological, endoscopic, histological and imaging investigations.

Biological assessment revealed elevated inflammatory markers, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), as well as anemia and increased fecal calprotectin levels, indicating intestinal inflammatory activity. Endoscopic evaluation showed continuous lesions in patients with ulcerative colitis and discontinuous (“skip”) lesions in those with Crohn’s disease. Histological examination demonstrated superficial inflammation confined to the mucosa and submucosa in ulcerative colitis, whereas Crohn’s disease was characterized by granulomatous and transmural inflammation. Imaging studies, including abdominal MRI and ultrasound, helped assess the extent and severity of lesions and identify potential associated complications.

In this study, ulcerative colitis activity in pediatric patients was assessed using standardized clinical indices, such as the Pediatric Ulcerative Colitis Activity Index (PUCAI). These indices allow for quantification of disease severity, monitoring of treatment response and objective comparison between patients. The results showed that the majority of included children had moderate-to-severe disease activity (PUCAI ≥65), supporting the need to initiate or adjust biologic therapy (Table 1).

In this study, the Mayo score was also used to assess the disease severity and monitor the therapeutic response in pediatric patients. This scoring system allows for objective quantification of clinical symptoms, endoscopic findings and inflammatory markers, providing standardized criteria to compare patient status before and after treatment.

The pediatric patients received golimumab treatment according to recommended clinical protocols, with dosing adjusted based on body weight.

Patients ≥40 kg

Induction: 200 mg at week 0, followed by 100 mg at week 2.

Maintenance: 50 mg at week 6 and then every four weeks.

Patients ≥15 kg to

Induction: 90 mg at week 0, followed by 45 mg at week 2.

Maintenance: 45 mg at week 6 and then every four weeks.

Of the 45 patients included in the study, 21 children received 45 mg, and 24 children received 50 mg. Golimumab is indicated for pediatric patients with active ulcerative colitis (and off-label use in Crohn’s disease) weighing at least 15 kg, and it is administered via subcutaneous injection using a prefilled syringe⁽⁷⁾.

Group I, which included 12 children previously receiving combination therapy (corticosteroids and azathioprine), discontinued the prior treatment and initiated the golimumab monotherapy. Initial clinical improvements were observed between weeks 6 and 12, with complete remission achieved by week 48. Long-term maintenance of remission was achieved through regular administration of golimumab doses.

In Group II (29 patients receiving golimumab as first-line therapy), symptom improvement occurred between weeks 6 and 12, and complete remission was reached by week 48, maintained long-term without the need for adjunctive therapy.

Group III comprised four children with Crohn’s disease who experienced persistent abdominal pain, frequent loose stools (2-5/day), rectal bleeding, anemia and significant impairment of quality of life on golimumab monotherapy. Beginning at week 12, combination therapy was initiated (golimumab with corticosteroids or azathioprine). One patient achieved a clinical response, and three entered remission after 74 weeks of treatment, highlighting the efficacy of combination therapy in cases refractory to monotherapy.

During the observation period, no patients experienced serious adverse events necessitating treatment discontinuation. Additionally, no severe infections, systemic infusion reactions, malignancies or injection-site reactions were reported, confirming a favorable safety profile of golimumab, both as monotherapy and in combination therapy.

For efficacy assessment, clinical remission was defined as a PUCAI score below 10, while a reduction in PUCAI score of at least 20 points was considered a clinical response. Primary non-response was defined as a PUCAI ≥10 with no improvement of ≥20 points within 12 weeks.

The results indicate that golimumab administration led to a significant reduction in both PUCAI and Mayo scores, reflecting clinical, endoscopic and biological improvement of the disease. The majority of patients transitioned from moderate-to-severe disease to partial or complete remission, demonstrating the efficacy of anti-TNF therapy in the pediatric population (Figure 4).

These results support the efficacy of golimumab in inducing and maintaining long-term clinical remission in children with inflammatory bowel disease, including moderate and severe forms refractory to conventional therapies.

Conclusions

1. The study demonstrates that golimumab represents an effective and safe therapeutic option for pediatric patients with moderate-to-severe ulcerative colitis and Crohn’s disease, including cases refractory to conventional therapies.

2. Most patients in the active disease phase achieved both clinical and endoscopic remission, with responses maintained on the long term, highlighting the durability of the therapeutic effect.

3. The results emphasize the importance of strict monitoring in specialized centers, with ongoing assessment of both treatment response and safety.

4. Considering that pediatric inflammatory bowel diseases are characterized by early onset, aggressive course and a significant impact on growth and development, these findings support the use of golimumab as an effective strategy for the optimal management of severe disease forms.

Autor corespondent:  Ina Pogonea E-mail: ina.pogonea@usmf.md

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.