According to current treatment algorithms, in case of acute colitis, unless toxic megacolon, perforation or severe bleeding-which are absolute indication for surgery-occur, patients are started on high-dose iv steroids[44]. Response to treatment is assessed by objective measures (e.g., Oxford index or Sweden index) on day 3-4. Two different strategies have been developed in the attempt of avoiding surgery when a first course of steroids fails to control an acute flare. The standard approach in the ‘80s was to prolong the administration of steroids for other 7-10 d, which did not show any reduction in colectomy rates[45-47]. Ten years later, cyclosporine was found to be effective in patients with acute severe UC non responsive to steroids, and has been used as rescue therapy[44,48-51]. In a randomized controlled trial (RCT) 82% of patients on cyclosporine improved, while no patient improved in the placebo group[52]. However, as many as 50% of patients that responded to cyclosporine, required colectomy in subsequent studies with longer follow-up[35,53]. Moreover, the management of patients under cyclosporine can represent a real challenge, given the risk of severe and potentially fatal toxicities, which greatly limit the use of this medication.

Infliximab, an anti-tumor necrosis factor (TNF) antibody, has been approved recently by the United States FDA for the treatment of UC to reduce signs and symptoms, to induce clinical remission and healing of the intestinal mucosa, and to eliminate the use of corticosteroids in patients presenting with moderately-to-severely active UC without adequate response or who are intolerant or have medical contraindications to therapy with corticosteroids or immune modulators[54].

Response to infliximab has been assessed in RCTs with various endpoints such as clinical response, remission and colectomy rates. In patients with severe, steroid-refractory UC, the initial small trials demonstrated modest efficacy after single infusions when early clinical response was determined. The first published trial by Sands et al[55] in 2001 randomized 11 patients with steroid refractory UC to a single infliximab infusion or placebo, and noted a 50% (4/8) clinical response rate with infliximab at a week 2 evaluation. Subsequent studies by Probert et al[56] and Järnerot et al[51] also enrolled patients with steroid-refractory disease. The first study failed to show any significant difference between placebo and 2 infusions of infliximab 5 mg/kg in inducing remission as measured by endoscopy or clinical score. However, Järnerot et al[51] demonstrated in patients with moderate and severe steroid-refractory UC that only 7/24 (29%) patients who received a single infliximab infusion underwent colectomy within 90 d, compared with 14/21 (67%) who received placebo. The superiority of infliximab was only statistically significant in patients with moderate to severe disease, but not in those with more severe disease on the fulminant colitis score, although the study was not powered to detect differences between these two last groups. Even though a later report showed that at 2 years follow-up, the colectomy rate in patients who received infliximab had increased to 46%[57], these studies positioned infliximab as a therapeutic option for patients with steroid-refractory disease. The first controlled trial[58] involving patients who had moderate to severe disease that were neither steroid-dependent nor steroid-refractory, reported superior clinical response rates compared to those seen in steroid-refractory populations. These trials reported high response rates (100% and 83%, respectively), but follow-up was short (9.7 and 3 mo, respectively). The active ulcerative colitis trial (ACT) 1 and ACT 2 trials[59] each randomized 364 patients with moderate to severe UC who were failing conventional therapy (but did not require hospitalization) to either placebo or induction/maintenance infliximab 5 mg/kg or 10 mg/kg. Both in ACT 1 and ACT 2, eligible patients had moderate to severe UC despite concurrent treatment with corticosteroids, alone or in combination with azathioprine or mercaptopurine, but ACT 2 also required that the patient had failed 5-aminosalicylic acid (5-ASA) therapy. In ACT 1, both doses of infliximab (5 mg/kg and 10 mg/kg) resulted in a statistically significant clinical response at week 8 (68.4% and 61.5% respectively, P < 0.01, compared to a placebo response of 37.2%). This was similar in ACT 2, with clinical response at week 8 in 64.5% of patients in the infliximab 5 mg/kg group and 69.2% in the infliximab 10 mg/kg group, compared to a 29.3% response rate in the placebo group (P < 0.001). Clinical remission rates in the infliximab arms at week 8 ranged from 27.5% to 38.8% across both studies compared to placebo-induced remission rates of 14.9% (ACT 1) and 5.7% (ACT 2). Mucosal healing and steroid-free remission rates were also superior in the infliximab arms of these studies. Sandborn et al[60] reported colectomy rates in ACT 1 and ACT 2 patients in a follow-up study. The cumulative colectomy rate at 54 wk was 10% in patients treated with infliximab, compared with 17% in those treated with placebo. These colectomy rates were not unexpected since the enrolled patients had moderate to severe disease, however in 13% of the enrolled patients the colectomy follow-up data was unavailable. The ACT 1 and ACT 2 studies were well-designed, large studies, with comprehensive assessment of clinical and secondary endpoints. They provided important data to support the use of infliximab in patients with moderate to severe UC who have failed other therapies such as steroids, immunomodulators and mesalamine. However, infliximab is not a panacea for all; the proportion of patients who started the study on steroids and were able to come off and remain in remission, was low (20%)[59].

In a recent study by Colombel et al[61], the association between early mucosal healing (defined as Mayo endoscopy subscore at week 8 endoscopy) and clinical outcomes in ACT-1 and ACT-2 patients was investigated. The authors observed that a low week 8 endoscopy subscore was significantly associated with a lower rate of colectomy at 54 wk follow-up (P = 0.0004; placebo P = 0.47) and better outcomes in terms of symptoms and need for steroids at weeks 30 and 54 (P < 0.0001, infliximab; P < 0.01, placebo), especially for those patients who did not achieve clinical remission at week 8[61].

A Cochrane meta-analysis of RCTs concluded that, when compared to placebo, treatment with infliximab is three-fold as effective in inducing clinical remission [relative risk (RR) 3.22; 95% CI: 2.18-4.76] and nearly twice as effective in inducing clinical response (RR: 1.99; 95% CI: 1.65-2.41) or endoscopic remission (RR: 1.88; 95% CI: 1.54-2.28) at week 8 in patients presenting with moderate-to-severe UC refractory to conventional treatment with corticosteroids and/or immune modulators[10].

Another specific pattern of UC disease is represented by steroid-dependent patients, in whom a response can be obtained with systemic steroids, but the relapse will occur as the dose is tapered or a few weeks or months after discontinuation, making it necessary to increase the dosage again or resume treatment to achieve control of symptoms[36]. As UC patients become dependent-upon or refractory to corticosteroids, the range of action from a medical standpoint become limited and a colectomy becomes a treatment option as the disease is deemed as refractory to medical treatment, or because of the occurrence of complications either related to the disease or associated with side effects of medications[1].

Often, immunomodulator therapies, such as azathioprine or mercaptopurine (6-mercaptopurine) are considered in these patients before surgery as a steroid-sparing treatment. However, the efficacy of azathioprine or mercaptopurine in UC is still debated[62]. Thiopurines are an effective maintenance therapy for patients who require repeated courses of steroids, however the quality of available data is quite poor, as stated in a recent Cochrane review[63]. Currently, the recommendation for using thiopurines in UC is based on the evidence shown by only one RCT of Ardizzone et al[64] which found steroid-free, clinical and endoscopic remission in 53% patients on azathioprine compared with 21% given only 5-ASA [odd ratio (OR) on intention to treat analysis 4.78, 95% CI: 1.57-14.5]. Azathioprine maintenance treatment of UC is beneficial for at least 2 years if patients have achieved remission while taking the drug, but not in those with chronic activity despite the drug[65].

When a steroid-dependent patient fails to benefit from thiopurines or shows intolerance to them, there are very few alternatives to conventional drugs, which lack of current definitive evidence of efficacy. Methotrexate has been tested and, although some uncontrolled studies suggested some benefit with its use[66-68], the only double-blind, placebo-controlled trial, showed no therapeutic benefit[69]. Therefore, current guidelines do not consider methotrexate as an evidence-based therapy in steroid-dependent UC.

After the demonstration of clinical efficacy of infliximab in the treatment of moderate-severe resistant UC, few small series have included steroid dependent patients. Only one study from Italy[70] specifically evaluated steroid dependent UC in an open-label study on 20 patients randomized to infliximab or methylprednisolone. This was the first RCT to implement a regimen of a triple infliximab infusion for induction followed by infusions to maintain remission. Even if this study was statistically underpowered, it demonstrated the benefit of infliximab therapy for responders, who were able to taper and then discontinue steroids during the maintenance phase (9 of 10 patients), as compared with the methylprednisolone group (8 of 10 patients), where responders required continued steroid therapy.

The concept of pushing conservative treatment until surgery is strictly required may be risky, as it has been shown that mortality three years after elective colectomy for UC (3.7%) is significantly lower than that after admission without surgery (13.6%) or when an emergency operation is performed (13.2%)[80]. Moreover, a British study recently reported a significantly higher risk to develop major complications at a 5 year follow up for patients who received a longer course of medical therapy for acute severe UC before surgery, suggesting that the threshold for elective surgery may be too high in current practice[81].

While it’s well known that high-dose systemic corticosteroid therapy (> 40 mg/d prednisolone-equivalent) is a widely recognized risk factor for pouch-related septic complications after restorative surgery[82], whether or not the preoperative administration of infliximab may increase the rates of septic complications is still controversial (Table 1)[9,12,13,83-86]. Nevertheless, the group from the Cleveland Clinic has found a covariate-adjusted risk of early complication for patients treated with infliximab 3.54 times higher, with the rate of sepsis increased by 13.8 folds, despite a significantly higher rate of three-stage procedures in the infliximab group[85]. Similar results have been shown in a paper by Mayo Clinic, where patients treated with infliximab prior to pouch surgery had a significantly higher incidence of anastomotic leaks, pouch specific and infectious complications, with the administration of anti-TNF-alpha as the only factor independently associated with septic complications (OR 3.5)[13]. In another study, a synergic interaction in increasing surgical morbidity was found between infliximab and cyclosporine A when administered together in the preoperative time[12]. These concerns are supported by a recent meta-analysis conducted including 5 studies and 706 patients, which revealed an increased risk of short-term post-operative complications (OR 1.80, 95% CI: 1.12-2.87) associated with preoperative infliximab use, along with a trend towards increased post-operative infection[87].

Given the concern of increased rate of complications in patients on aggressive medical management, several different surgical approaches have been proposed. First described by Parks and Nichols in 1978, restorative proctocolectomy with IPAA has progressively gained acceptance to become the gold standard in the surgical treatment of UC for the last 25 years[88,89]. The introduction of this technique-most often fashioned as a J pouch created with the terminal ileum and anastomosed to the anal canal-was a real breakthrough, offering a curative treatment to these patients without the need for a permanent stoma, thus preserving their body image, achieving a quality of life comparable to that of the general population[38,90]. However, the procedure is technically demanding and is associated with a significant morbidity rate (around 30%), and an incidence of postoperative pelvic sepsis ranging between 5%-24%[91]. Since it has been shown that the occurrence of a pelvic infection can dramatically affect the functional outcome of the pouch, and considering that long-term steroid use and malnutrition are recognized risk factors for pelvic sepsis, surgical strategies have been developed in order to minimize the occurrence of infectious complications, especially in this subset of patients[92,93]. A total abdominal colectomy with end ileostomy is the operation of choice as first step of a restorative procedure, as it can be performed safely and quickly in the hands of an experienced colorectal surgeon, allowing the patient to overcome the colitis, wean off the medications, and return to an optimal health and nutritional status[94,95]. Moreover, as it is well known that a postoperative diagnosis of indeterminate colitis or Crohn’s disease is not rare after colectomy in these patients[96], a multistep surgical procedure allows for selecting the most appropriate reconstructive surgery on the basis of the pathological findings of the colectomy specimen[19,94,97].

The removal of the rectum and the restoration of the bowel continuity with IPAA are performed as a second step when the patient has fully recovered, and the creation of a temporary ileostomy, although adding the need for one more operation, can further reduce the risk of local sepsis secondary to anastomotic leaks[98,99]. Albeit restorative surgery is not free from long term complications, such as incontinence and soiling (10%-60% of patients, depending on series and entity), pouchitis (about 50% of patients), and sexual dysfunction (20%-25% of cases), with a rate of pouch failure requiring excision ranging between 5%-15%, the majority of these conditions are manageable with medical and physical therapy, which explains the overall satisfaction in patients after IPAA, which exceeds the 90% in most series[40,98,100-105].

Indeed, most recent researches have shown that social and sexual function as well as overall quality of life is significantly improved after restorative surgery, when compared to the period with active UC or diverting ileostomy[106-109].

The application of minimally invasive techniques to the surgical treatment of UC at the beginning of the 1990s contributed in significantly improving the acceptance and tolerability of the procedure[110]. Numerous case series and, finally, two meta-analyses have been published since then, demonstrating the feasibility and safety of the laparoscopic approach, at the cost of longer operative times[110-117]. A subsequent RCT showed that operative time could be significantly reduced with the adoption of a hand-assisted technique, which at the same time allows for preserving the advantages of a minimal invasive approach[118]. Scant data is available so far regarding long-term outcomes, however the few series with adequate follow-up report laparoscopy pouch function results as good as the ones achieved with open surgery[21,119]. Laparoscopy has also been adopted with good results in the emergency setting[120,121], and similarly as for open surgery, a staged approach to a minimally invasive restorative procedure should be preferred which is as effective in significantly reducing the rate of postoperative pelvic sepsis[121-123]. Furthermore, when a staged procedure is planned, laparoscopy has been shown to decrease postoperative adhesion formation with less intraoperative adhesiolysis required during subsequent completion proctectomy and IPAA[124]. Similarly, a study by Indar and colleagues on 34 patients who underwent laparoscopic IPAA, where a laparoscopic exploration of the abdominal cavity was performed during the ileostomy closure, found that no patient had dense adhesion and only a minority of patients had filmy avascular adhesion to the abdominal wall (32%) and to the adnexa (29%), which represents a significant improvement compare to the rates reported for open surgery (as high as 90%)[125].

Despite the lack of strong evidence about the benefits attainable with laparoscopy in terms of short-term outcomes[21,126], it has been proven that patients treated laparoscopically are more satisfied with the cosmetic results and perceive a better body image-aspect anything but negligible in this usually young and socially active patient population-especially in the women’s subset, as confirmed by the results of a RCT with a median follow-up of 2.7 years[21,119]. More recently, the quest for further minimizing surgical trauma and extent of incisions, has led to the development of single incision laparoscopy (SIL), which has already been applied in the field of colorectal diseases with proven benefits in terms of short-term outcomes over standard laparoscopy[127-131]. To date only few cases of SIL for UC has been reported, but preliminary results show that particularly for the total abdominal colectomy, this “no scar” approach have the potential for improving not only the cosmesis, but also the postoperative course, with less pain and reduced need for narcotics, which may translate in shorter hospital stay and faster return to normal activities[132-135]. Considering the excellent outcome of restorative surgery, heightened by the potentials of minimal invasive techniques, surgery should not be considered the last resort when everything has failed, but rather a valid alternative to an expensive and risky medical therapy[136].