Safety Profile of Anti-TNF Agents in Polish Pediatric Patients with Crohn’s Disease

Special Article-Inflammatory Bowel Disease

Austin J Gastroenterol. 2014;1(4): 1016.

Safety Profile of Anti-TNF Agents in Polish Pediatric Patients with Crohn’s Disease

Edyta Szymanska1*, Maciej Dadalski2, Grzegorz Oracz2 and Jaroslaw Kierkus2

1Department of Pediatrics, the Children Memorial Health Institute, Poland

2Department of Gastroenterology, the Children Memorial Health Institute, Poland

*Corresponding author: : Edyta Szymanska, Department Pediatrics, Nutrition and Metabolic Disorders, The Children’s Memorial Heath Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland

Received: July 14, 2014; Accepted: August 20, 2014; Published: August 22, 2014


Back ground: In recent years, monoclonal antibodies against TNF-alpha, infliximab (IFX) and Adalimumab, have been gaining increasing popularity in Crohn’s disease (CD) management. Many clinical trials have shown that biologics are generally well-tolerated and safe. However, the follow-up time with regards to safety is too short and data on that issue are still limited. The aim of this study was to analyze the cumulative safety profile of biologic therapy with IFX and/or ADA, documented during up to 8-year follow-up of Polish children with moderately to severely active CD.

Patients and Methods: We have performed a retrospective analysis of 110 children, mean age 13.0 ±9.3 years, diagnosed with CD and treated with IFX and/or ADA within the period of 8 years, between 2005 and 2013. Safety data for all treated patients, collected throughout the entire treatment period, were included in the safety analyses.

Results: A total of 67 treatment related adverse events (TRAEs) were recorded, including 43 (64.17%) for IFX and 24 (35.83%) for ADA. The majority of TEAEs were mild-to-moderate in intensity. The most frequently reported TEAEs included anemia (n=17, 20.23% for IFX and n=9, 23.08% for ADA) and mild infections (n=9, 10.7% for IFX and n=5, 12.8% for ADA). No serious adverse events (sAEs) were documented.

Conclusion: Biologic therapy with infliximab and/or Adalimumab is generally well-tolerated and safe, and does carry the risk of sAEs.

Keywords: Biologic therapy; Safety; Crohn’s disease; Children


Crohn’s disease (CD) is an inflammatory condition of unknown etiology, which is classified in the inflammatory bowel disease (IBD) group, along with ulcerative colitis (UC) [1]. Since no effective CD treatment protocol has been developed [1]. The goals of both the pharmacotherapy and surgical management are limited to obtaining the longest possible remission and preventing relapse [1].

In recent years, however, the advent of biological drugs has had a significant impact on the management of IBD. Many clinical trials have demonstrated the efficacy and safety of monoclonal antibodies against tumor necrosis factor (TNF), Infliximab (IFX) and Adalimumab (ADA), in both induction [1] and maintenance [1] of clinical remission. Moreover, treatment with biologics was also revealed to result in endoscopic healing [1,2], which points to a possibility of longer clinical remission [3].

Nonetheless, the use of biologic agents is still limited, mostly due to high cost and uncertainty about long-term safety. The safety issue is especially important. Although biologics are generally considered a well-tolerated and safe therapy, the follow-up time with regards to safety is too short and the available data are still limited. The safety concerns associated with biologic therapies include increased risk of infections, autoimmune conditions, lymphomas, demyelinating diseases, and exacerbation of heart failure [4-6]. Reactivation of mycobacterium infections has also been reported in patients treated with anti-TNF agents [7].

The monoclonal antibodies used for anti-TNF therapy frequently induce formation of antibodies against infliximab (ATI) and Adalimumab (ATA). The presence of these antibodies was associated with a shorter duration of response to therapy and a higher incidence of infusion reactions [8].

The safety of IFX has been evaluated by the TREAT registry, which was established to study the long-term safety of this biologic agent and other therapies in prospectively followed patients with CD [9]. A total of 6,290 patients (3,179 IFX recipients and 3,111 recipients of other therapies) have been enrolled in this registry since August 2004. According to the available data, the general overall safety of IFX is similar to that of conventional immune modulator agents (IMMs) [9,10].

Nonetheless, the data from Central Europe concerning the safety of biologic therapy, especially ADA, are still limited. Therefore, the aim of this study was to analyze the cumulative safety profile of biologic treatment with IFX and/or ADA in Polish children with moderately to severely active CD.

Patients and Methods


A retrospective analysis of children with moderately to severely active CD, treated with biologic therapy with either IFX and/or ADA at the Department of Gastroenterology, Hepatology and Feeding Disorders, Children’s Memorial Health Institute in Warsaw (Poland), was conducted. The analysis included the 8-year period between 2005 and 2013.

Patients were qualified to biological therapy on the basis of a high disease activity index - Pediatric Crohn’s disease activity index (PCDAI) >30 and a lack of response to conventional therapy including steroids and immune modulators. The patients received IFX induction therapy (5 mg/kg) at weeks 0, 2, and 6. Additionally, all patients were receiving concomitant immune modulator therapy using azathioprine or methotrexate due to severe course of the disease. On week 10, the therapeutic responses were evaluated on the basis of PCDAI score and endoscopic examination. Patients with the clinical response were qualified on maintenance therapy. Clinical response was defined as a decrease in PCDAI score by ≥15 points and final PCDAI score lower than 30 points, and clinical remission defined as PCDAI ≤10 points. Five patients were primary non-responders.

Safety evaluation

Adverse events (AEs) were monitored throughout the entire treatment period. At each visit, AEs were documented, and blood samples were obtained for clinical laboratory evaluations. Safety data were reported for all patients, by prior biologic use, as well as by concomitant IMM and corticosteroid use at baseline of biologic therapy, and were included in the safety analyses. AEs that occurred on or after the first biologic agent dose and up to 70 days after the last dose thereof were considered treatment-emergent AEs (TEAEs). Clinical data analyzed during follow-up were gathered from both medical records and documentation, the database was created and statistical analysis was performed.

Serious AE (sAE) was defined as any adverse event occurring that results in any of the following outcomes: death, a life-threatening adverse event, requires inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/ incapacity, or a congenital anomaly/birth defect. Mild AE was defined as an experience that was transient and required no special treatment or intervention, and did not interfere with usual daily activities, including transient laboratory test alterations. Serious infection was defined as (invasive) infection requiring intra venous or oral antibiotics and/or any infection requiring hospitalization, if outpatient at onset. Mild infections included ssubtle infections of low intensity, which did not require antibiotics, such as viral upper respiratory tract infections.


A total of 67 TRAEs were recorded in all 110 patients, among them 43 (64.17%) events for IFX and 24 (35.83%) for ADA. Eight patients (7.3%) discontinued therapy, 5 of them were primary non-responders while 3 children had AEs (leucopenia) which disqualified them from therapy. The mean duration of follow-up was 5 years. Table 1 presents detailed characteristics of CD patients treated with biologic therapy.

Citation: Szymanska E, Dadalski M, Oracz G and Kierkus J. Safety Profile of Anti-TNF Agents in Polish Pediatric Patients with Crohn’s Disease. Austin J Gastroenterol. 2014;1(4): 1016. ISSN:2381-9219