Immunomodulatory agents used in the treatment of children and adolescents with IBD include purine analogs that inhibit purine ribonucleotide synthesis and cell proliferation, 6-mercaptopurine (Purinethol) and azathioprine (Imuran). These agents are used in patients with UC who are steroid dependent or whose disease is refractory to steroid treatment. These medications generally require approximately 1–3 months to produce an effect and, therefore, are not used in acute exacerbations of the disease. Because of the delay in response, immunomodulators are frequently combined with corticosteroids initially.

The first controlled trial evaluating the efficacy of 6-MP in pediatric patients was published in 2000 [38]. Markowitz and colleagues hypothesized that 6-MP would reduce the need for corticosteroids in pediatric patients newly diagnosed with Crohn’s disease. At the time of diagnosis, pediatric patients with disease activity scores in the moderate to severe range were randomized to receive a corticosteroid plus 6-MP or a corticosteroid plus placebo. Patients were followed for 18 months. The results suggested that children in the 6-MP group required corticosteroids for a shorter period of time and were able to remain off of corticosteroids for longer. The adverse effects seen with 6-MP were similar to those seen in adults and included pancreatitis, hepatitis, and bone marrow suppression. There were limitations to this study, however, including small sample size.

Recently, a cohort of pediatric patients with ulcerative colitis treated with a thiopurine was prospectively observed [39]. At 1 year following initiation of thiopurine therapy, 50 % of patients had achieved corticosteroid-free inactive disease. The study further demonstrated that the likelihood of avoiding rescue therapy with a biologic, calcineurin inhibitor, or colectomy was 73 % at 1 year. Treatment with a thiopurine also seemed to improve the likelihood of avoiding rescue therapy at 2 years (59 %). When these patients were followed further than 1 year, however, the results were less favorable.

In clinical practice, for the treatment of patients with UC, 6-MP and azathioprine are used interchangeably. The standard initial dose in pediatric patients is 1.0–1.5 mg/kg/day of 6-MP or 2.0–2.5 mg/kg/day of azathioprine. Dosing is also based on the thiopurine methyltransferase (TPMT) enzyme activity level. The TPMT enzyme activity is typically assessed prior to initiation of therapy in order to prevent toxicity. Some individuals either lack the TPMT enzyme or have low levels, which increases their risk of toxicity. The active 6-thioguanine (6-TGN) metabolites can also be followed in order to ensure that therapeutic levels of the medication are achieved. There is recent data to suggest that in very young patients with IBD (age 6 and younger), the standard per kilogram dose may not be adequate [40]. When these patients are closely monitored, dosage escalations are acceptable and are generally effective and well tolerated.

Methotrexate is an analog of folic acid and of aminopterin, a folic acid antagonist. The mechanism of action is through dihydrofolate reductase, the enzyme involved in the de novo synthesis pathway for purines and pyrimidines. The exact anti-inflammatory effect of low-dose methotrexate is unclear [41]. The treatment of juvenile idiopathic arthritis (JIA) with low-dose oral methotrexate is well established and is the source of the majority of the literature regarding the safety of low-dose methotrexate in pediatric patients. Methotrexate has also been used to maintain remission in children with IBD who are steroid dependent and fail to respond to or are unable to tolerate thiopurines [42]. Parenteral (SQ) administration seems to be more effective than oral administration in IBD patients. A potential benefit of methotrexate is that the onset of action is slightly more rapid than 6-MP or azathioprine.

There is limited data available for the use of methotrexate in ulcerative colitis, although there is more significant evidence for its use in Crohn’s disease. There is only one double-blind, placebo-controlled study evaluating the efficacy of methotrexate in ulcerative colitis [43]. In this study, methotrexate was not found to be superior to placebo in the induction or maintenance of remission in UC patients. However, methotrexate was administered orally in this study. Additionally, lower dosing than what has been demonstrated to be effective in Crohn’s disease was used.

In the treatment of pediatric UC, methotrexate seems to be well tolerated [44]. However, further studies are required in order to establish efficacy. Common side effects include nausea and anorexia. More serious adverse events such as hepatotoxicity, bone marrow suppression, hypersensitivity pneumonitis, and opportunistic infections are rare. Finally, methotrexate is a known teratogen, and as such, many clinicians will avoid its use in adolescent females.

Infliximab is a monoclonal antibody against tumor necrosis factor (TNF)-alpha, and it is the most commonly used biologic medication in the treatment of ulcerative colitis. Clinical trials in adults with UC have demonstrated a role for infliximab in the treatment of moderate to severe disease or corticosteroid-resistant disease [41]. Infliximab has also become especially valuable as rescue therapy in the treatment of acute, severe exacerbations. There is adult literature to suggest that infliximab is effective in preventing or delaying colectomy in UC patients with steroid-refractory disease [42]. However, the long-term efficacy of infliximab in the treatment of UC remains largely unknown.

Available pediatric data supports the use of infliximab in the treatment of moderate to severe ulcerative colitis. In fact, in 2011, the FDA approved infliximab to treat moderately to severely active UC in children older than 6 years of age who have had inadequate response to conventional therapy. The infliximab dosage used in pediatric patients is 5 mg/kg. Similar to the adult population, intravenous infusions are given at 0, 2, and 6 weeks for induction. Hyams and colleagues recently performed a multicenter, prospective, observational cohort study of 332 pediatric patients with UC [45]. In this study, 61 % of patients who had failed intravenous corticosteroids and had been prescribed infliximab as a second-line therapy avoided colectomy at 24 months. In addition, at 12 months and 24 months, 28 % and 21 % of patients were in remission and off corticosteroids, respectively.

As discussed previously, pediatric patients with ulcerative colitis often present with acute, severe disease, and in these situations, the treatment options are limited. Corticosteroids are considered to be first-line therapy in acute, severe exacerbations. However, as is the case in adults, approximately 1/3 of pediatric patients with severe UC will not have a complete response to corticosteroids. A recent multicenter, prospective, observational study was designed in order to evaluate outcomes in severe pediatric UC [7], in which pediatric patients hospitalized for severe UC were enrolled. The PUCAI, calculated on day 3 and 5 of IV corticosteroid treatment, was able to predict patients who would require rescue therapy. Of the patients who required rescue treatment with infliximab, 76 % responded and 52 % remained well 1 year following initiation of therapy.

Adalimumab, a fully humanized monoclonal anti-TNF, can be used in the treatment of ulcerative colitis. Generally, adalimumab is reserved for patients who either lose response or become intolerant to infliximab. The onset of action of adalimumab may be slower to demonstrate efficacy as compared to infliximab which would make it somewhat less suitable for the treatment of acute, severe exacerbations [46]. Recently, adalimumab was found to be effective in the induction of remission in adult patients with moderate to severe UC who had failed corticosteroids and/or other immunosuppressive medications [47]. There are currently no studies which examine the efficacy of adalimumab in the treatment of pediatric UC patients.

Golimumab is the most recently approved fully humanized monoclonal anti-TNF for the treatment of patients with ulcerative colitis. Golimumab is a human anti-TNF monoclonal antibody-binding soluble and transmembrane TNF-α (therefore, the binding of TNF to its receptors, with consequent activation of inflammation, is inhibited). It is administered subcutaneously. Since 2009, the therapy of golimumab has been approved for the treatment of autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, in Europe. In 2013 this agent gained regulatory approval in the USA for the treatment of refractory ulcerative colitis.

There are no currently published trials that have evaluated golimumab in pediatric patients with ulcerative colitis; however, a recent trial was published that assessed the efficacy and safety of golimumab in polyarticular pediatric juvenile idiopathic arthritis patients (aged 2 to <18 years) with active arthritis despite methotrexate for ≥3 months. The results of this study demonstrated that JIA patients with active polyarticular disease demonstrated rapid response to golimumab [48].

Cyclosporine is a potent inhibitor of the inflammatory cascade, and it has occasionally been used as salvage therapy in pediatric patients with UC who do not respond to corticosteroids. There have been several retrospective pediatric studies evaluating the efficacy of cyclosporine in severe UC. However, the cohorts have been small. No prospective studies have been performed in children. The available literature suggests that in the short term, cyclosporine can effectively induce remission and obviate the need for immediate surgical intervention [5]. However, multiple studies have shown that the use of cyclosporine as monotherapy in steroid-refractory UC patients is associated with high failure rates [49]. Currently, in pediatric patients, cyclosporine is rarely used. When cyclosporine is prescribed, it is prescribed in combination with an immunomodulator such as 6-MP or azathioprine. As a rule, cyclosporine is used exclusively as a bridging therapy to allow 6-MP or azathioprine to become therapeutic. Because cyclosporine is a potent immunosuppressive agent, infections which can mimic IBD exacerbations, such as CMV, must be ruled out prior to initiating therapy. Also, patients must be monitored closely for the side effects and adverse events associated with cyclosporine treatment. For example, cyclosporine is nephrotoxic and may cause irreversible renal insufficiency.

In some centers, tacrolimus has been utilized in pediatric patients with steroid-refractory colitis. A retrospective analysis of a single center’s experience with tacrolimus in the treatment of steroid-refractory pediatric UC was recently published [50]. During the study period, 46 hospitalized patients were treated with tacrolimus. All but five patients responded to tacrolimus therapy, and response was defined as an improvement in the PUCAI score of more than 20 points. Most patients were able to be discharged from the hospital without undergoing colectomy. However, many patients experienced exacerbation of disease when transitioned to maintenance therapy, and 60 % still ultimately required colectomy. Tacrolimus may be valuable as a bridge to maintenance therapy in pediatric patients with steroid-refractory UC. There may also be a role for tacrolimus in the stabilization of acutely ill steroid-refractory UC patients prior to surgery [50]. However, further studies are necessary before routine use can be recommended.

At some point during the course of the illness, surgical removal of the colon may become a necessity for patients with ulcerative colitis. Because in UC the disease is limited to the colon, colectomy is considered a curative procedure. The most commonly performed procedure in children with UC is the ileal pouch-anal anastomosis (IPAA), which is performed in 2–3 stages. The rate of surgery in pediatric patients is higher than in the adult population. In pediatrics, 40 % of patients require colectomy 10 years after diagnosis [51]. This is compared to 5–20 % of adult patients who require colectomy 10 years after diagnosis [52]. In children, elective colectomy is considered when severe, medically refractory disease significantly interferes with growth and nutrition, when symptoms prevent the patient from maintaining a normal lifestyle, or when dysplasia or malignancy is detected. Because of the potential toxicities of therapy, colectomy should be considered in patients who will require prolonged escalation of therapy in order to maintain remission. Apart from elective colectomy, a smaller percentage of pediatric patients will require acute surgical intervention because of fulminant colitis refractory to medical therapy.