The aminosalicylates, sulfasalazine (SASP), and mesalamine (or 5-aminosalicylic acid or 5-ASA) constitute first-line treatment for both the induction of remission and the maintenance of remission in patients with mild to moderate UC. The mechanism of action involves several pathways, including inhibition of activation of transcription factor NF-κB [40], inhibition of prostaglandin synthesis [41], and scavenging of free radicals [42]. SASP (4–6 g/day), the prototype aminosalicylate formulation, contains a sulfapyridine moiety linked by an azo bond to the 5-ASA moiety. Sulfapyridine accounts for most of the adverse effects, whereas 5-ASA accounts for most of the therapeutic benefits. SASP is minimally absorbed by the small intestine and remains intact until reaching the colon, where bacteria cleave the azo bond to release free sulfapyridine and 5-ASA. 5-ASA is poorly absorbed by the colon (and therefore has minimal systemic effects) and has topical (mucosal) anti-inflammatory activity. In effect, sulfapyridine functions as a carrier, delivering the active 5-ASA moiety to the colon. Dose-dependent efficacy and toxicity are observed, mediated by the mesalamine and sulfapyridine moieties, respectively. Up to 40 % of patients may experience dose-related side effects, such as nausea, dyspepsia, headaches, and sperm abnormalities. Idiosyncratic side effects are also observed, including bone marrow suppression and hepatotoxicity. SASP inhibits absorption of folate. Advantages of SASP include lower cost than mesalamine and effectiveness against peripheral arthritis. The starting dose is typically 500 mg 2–3 times daily with meals. The dose is gradually increased as tolerated to a maximal dose of 4–6 g/day, taken three times daily with meals. As SASP inhibits folate absorption, folate supplementation is advised.

Oral, sulfa-free aminosalicylates were developed in order to circumvent the side effects of sulfapyridine and now constitute the most commonly prescribed oral therapies. These formulations target 5-ASA release to the site of inflammation along the gastrointestinal tract, differing in the mode of release and site of 5-ASA delivery. Preparations that are available in the USA, the sites of targeted 5-ASA release, and the usual dosages for the treatment of UC are listed below:

A recent systematic review included 11 RCTs with 2,086 patients comparing 5-ASA or SASP versus placebo as inductive therapy in active UC [43]. The majority of studies enrolled patients with mild to moderately active UC. There was a strong effect in favor of 5-ASA therapy, with a number needed to treat (NNT) of 6 (95 % confidence interval (CI) 5–8). 40 % of patients achieved remission in the active treatment group, compared with 20 % in the placebo group. The quality of evidence was graded as moderate. There was no difference in efficacy among the different 5-ASA preparations. The systematic review found similar remission rates at low (2.0–2.5 mg/day) versus high doses (>2.5 mg/day). Nonetheless, RCTs and clinical experience are consistent with a dose-response curve with specific oral 5-ASA agents (Asacol^®, Pentasa^®, Lialda^®), with a maximal effect at 4.0–4.8 g/day [44]. In clinical practice, the choice of preparation is usually based on cost and convenience, rather than on claims of superiority of a particular formulation.

The same systematic review also assessed 11 RCTs with 1,502 participants that compared 5-ASA versus placebo in patients with quiescent UC. There was a strong effect in favor of 5-ASA, with a NNT of 4 (95 % CI 3–7). 40 % of patients on 5-ASA relapsed compared with 63 % of patients taking placebo over 6–12 months. The quality of evidence was graded as high. As with active UC, there was no evidence that efficacy varied between different preparations. The optimal maintenance 5-ASA dose appeared to be 2.0–2.4 g/day. Among the seven trials that compared a daily dose of <2 g of 5-ASA with a dose of ≥2 g/day, there was a statistically significant effect in favor of the higher dose (NNT = 10; 95 % CI 5–33). The single trial comparing high versus standard dose (>2.5 g/day vs. 2.0–2.5 g/day; n = 113) found no difference between the two doses. The authors stated that current evidence supports using 2.4 g/day, but conceded that further research is needed to address a possible dose response of 5-ASA in preventing relapse. Again, clinical experience suggests that higher doses (3.6–4.8 g/day) are more effective than lower doses (2.4 g/day) in maintaining remission. In clinical practice, the maintenance dose is frequently the same as the inductive dose.

Only 40 % of patients are compliant with oral 5-ASA therapy [45] and noncompliance is associated with a higher risk of relapse [46]. A study of once daily dosing found lower relapse rates [47]. 5-ASA nephrotoxicity is seen rarely so that renal function should be monitored periodically [48].

Topical forms, either as monotherapy or in conjunction with oral therapies, should be used in patients with distal UC, as well as patients with more extensive disease but prominent distal symptoms. Topical mesalamine formulations that are available in the USA include:

Response is usually seen within 3–4 weeks. Remission rates in distal UC using topical formulations are 50–75 %, superior to those observed with oral 5-ASA monotherapy and with topical steroids [49]. However, the combination of topical and oral 5-ASA is more effective than either agent alone [50, 51]. In addition, the combination of oral 5-ASA and enemas twice a week has been shown to be superior to oral 5-ASA alone in maintaining remission in patients with disease extent greater than proctitis and a history of multiple relapses [52]. Patients on topical therapies may complain of leakage, problems with retention, anal irritation, cramps, and bloating but these symptoms improve over time. Common treatment errors included not maximizing topical therapies in the induction of remission and not utilizing them for maintenance.

Corticosteroids are used for the induction of remission in patients with moderate disease (oral steroids) or severe disease (intravenous steroids). The patient is then transitioned to appropriate maintenance therapy, such 5-ASA (oral and/or topical), thiopurines, or infliximab, depending on the clinical assessment. A subset of patients develops steroid-dependent disease, defined as inability to taper off steroids without experiencing a flare. In these patients, the multitude of steroid toxicities mandates the initiation of steroid-sparing, maintenance therapies. In one population study, approximately one-third of 185 patients with newly diagnosed UC required corticosteroid treatment [53]. Half of these patients went into remission with prolonged response at 1 year. However, 14 (22 %) patients became steroid-dependent and 18 (29 %) required surgery.

Corticosteroids were first shown to be effective in UC in 1955 [54]. Patients with chronic, active UC severe enough to require at least 6 weeks of hospital stay were randomized to cortisone (100 mg orally once daily, n = 109) versus placebo (n = 101). In the cortisone group, 58.7 % failed to achieve remission, compared with 84.2 % in the placebo group. The absolute risk reduction was 25.4 % (13.8 % vs. 37.1 %), and the NNT was 4. A recent meta-analysis of RCTs found that 54 % of patients receiving oral steroids failed to achieve remission compared with 79.0 % of patients randomized to placebo. The likelihood of failure to achieve remission was significantly reduced with steroid therapy (relative risk (RR) = 0.65; 95 % CI 0.45–0.93) [55].

Patients with severe UC require hospitalization and intravenous corticosteroids. In a study from Oxford, 49 patients with severe UC were treated with a 5-day course of IV prednisolone (60 mg/day) and rectal hydrocortisone (100 mg twice daily) during the period between 1969 and 1973. Thirty-six patients (74 %) were in complete remission at the end of the 5-day course, 4 (8 %) showed clinical improvement but no remission and required surgery within the next 6 weeks, and 9 (18 %) required emergent surgery after 5 days of treatment [56]. The same group reported their results in an additional 100 courses of the same regimen in 87 patients with severe UC, treated during the period between 1974 and 1978. 60 % of the attacks responded swiftly to the regimen; in 15 %, there was improvement; and in 25 %, failure to respond resulted in emergency colectomy [57]. More recent studies have reported remission rates of 50–61 % [58–60].

A French retrospective study assessed factors predictive of failure of intravenous corticosteroid therapy, defined as colectomy before day 30, intravenous cyclosporine, or death. On multivariate analysis, severe endoscopic lesions (defined as extensive deep ulcerations, mucosal detachment on the edge of these ulcerations, well-like ulcerations, and/or large mucosal abrasions) were associated with an increased risk of failure (P = 0.007). The presence of Truelove and Witts’ criteria for severe disease (P = 0.018) and an attack that had lasted more than 6 weeks (P = 0.001) were also independent predictors of failure. Patients with severe endoscopic lesions and Truelove and Witts’ criteria for severe disease had a failure rate of 86 %, whereas those with severe endoscopic lesions and moderate disease by the Truelove and Witts’ criteria had a failure rate of 50 % [61]. An English prospective study evaluated clinical parameters predictive of surgery in 51 consecutive episodes of severe colitis by the Truelove and Witts’ criteria. All patients were treated with intravenous and rectal hydrocortisone. In addition, 14 of 51 patients were treated with intravenous cyclosporine. There was complete response in 21 episodes (<or = 3 stools on day 7, without visible blood), incomplete response in 15 (>3 stools or visible blood on day 7, but no colectomy), and colectomy on that admission in 15. Patients with more than eight stools on day 3, or a stool frequency between three and eight together with a CRP >45 mg/l, had an 85 % risk of colectomy during the hospitalization [62].

Corticosteroids are available in oral, intravenous, and topical formulations. Oral corticosteroids are indicated in mild to moderate UC when a patient is flaring despite maximal 5-ASA use [63]. Recommended dosing is prednisone 40–60 mg (or its equivalent) until clinical remission (not response) is achieved, usually in 7–14 days [64]. The rapidity of the taper is dictated by how quickly the patient responds. Common errors are starting the prednisone taper as soon as the patient begins to improve, rather than waiting for the patient to achieve clinical remission tapering too quickly in a patient who responded slowly, and tapering too slowly in a patient who promptly entered remission. Generally, prednisone is tapered by 5–10 mg each week until 20 mg, then by 2.5–5 mg each week. However, the importance of individualizing the taper cannot be overemphasized. Patients should not be treated with a “standard” taper and should be instructed to contact their physician periodically regarding the dose changes. On the basis of two RCTs, extended-release budesonide (Uceris^® 9 mg; Santarus, San Diego, CA, USA) was recently approved in the USA for the induction of remission in patients with active, mild to moderate UC [65, 66]. The formulation (budesonide in a multimatrix (MMX) of hydrophilic and lipophilic excipients) was designed to deliver the agent to the colon and thus minimize systemic absorption.

Accepted intravenous steroid therapies include methylprednisolone 20 mg every 8 h, hydrocortisone 100 mg every 8 h, or prednisolone 30 mg every 12 h. There is no difference between intravenous bolus delivery and 24-h continuous infusions [67]. Intravenous corticosteroids are administered until clinical remission is achieved—only then should the patient be switched to an oral form. During their hospitalization, patients with severe UC should be monitored for dehydration, electrolyte abnormalities, anemia, and signs of toxicity and megacolon. If no improvement is seen after 5–7 days, then surgical consultation is sought, and the patient is offered the options of cyclosporine, infliximab, or surgery. Common management errors in the hospitalized patient include prematurely switching to oral steroids, not employing topical 5-ASA and steroid therapies, omitting measures to prevent venous thromboembolism, not feeding the patient, underestimating the severity of the disease, and therefore delaying surgical consultation.

Topical corticosteroids are available as foam (hydrocortisone acetate 10 %); each application delivers approximately 900 mg of foam containing 80 mg of hydrocortisone (90 mg of hydrocortisone acetate) and enema (one 60 mL enema delivers 100 mg hydrocortisone) preparations. Topical budesonide formulations are also available in other countries. These options are useful in treating flares in patients with distal or left-sided UC or in those with prominent distal symptoms. The combination of topical 5-ASA and corticosteroids has been shown to be superior to either therapy alone in distal UC [68].

Cyclosporine is a calcineurin inhibitor used as a salvage therapy in patients with severe UC failing intravenous corticosteroids after 5–7 days. In the seminal study by Lichtiger et al. 82 % of patients with severe, steroid-refractory UC treated with intravenous (IV) cyclosporine avoided colectomy in the short term [69]. Based on pooled data from controlled and uncontrolled trials, approximately 80 % of patients respond to IV cyclosporine and avoid colectomy in the short term [70]. However, 88 % of responders will require colectomy at 7 years [71]. Cyclosporine is also effective as first-line therapy in patients with severe UC (in lieu of IV corticosteroids). In a Belgian, double-blind RCT, IV cyclosporine was as effective as IV methylprednisolone in patients with severe UC (response rates of 64 % and 53 %, respectively) [72]. Cyclosporine is administered at a dose of 2 mg/kg/day by continuous IV infusion. The dose is adjusted targeting serum concentrations of 350–500 ng/ml [73]. Dose-dependent toxicities include nephrotoxicity, infection, hypertrichosis, gingival hyperplasia, paresthesias, tremor, and seizures [74]. The risk of seizures is increased in the setting of hypomagnesemia and hypocholesterolemia. Shortly after successful induction with cyclosporine, immunomodulators are started. Steroids are tapered off first, followed by cyclosporine, so that by 4–6 months the patient is in remission on immunomodulators alone. In a study from the University of Chicago, this approach improved long-term success of avoiding colectomy (59 % with vs. 39 % without immunomodulators) [75]. Prophylaxis against Pneumocystis jiroveci (carinii) with trimethoprim-sulfamethoxazole or dapsone should be administered in cyclosporine-treated patients.

Small, open-label studies of tacrolimus, a calcineurin inhibitor-like cyclosporine, showed effectiveness in preventing colectomy in the short term in two-thirds of patients with refractory UC [76, 77]. In a recent randomized, placebo-controlled trial of oral tacrolimus in hospitalized patients with steroid-refractory UC, tacrolimus therapy improved clinical response at week 2 (50 % vs. 13 %; P = 0.003) and mucosal healing (44 % vs. 13 %; P = 0.012) [78].

The thiopurines, 6-mercaptopurine (6-MP) and its pro-drug azathioprine (AZA), modulate immune response through several mechanisms, including inhibition of DNA and RNA synthesis and apoptosis of activated T-cells [79]. 6-MP and AZA are metabolized into the active 6-thioguanine nucleotide (6-TGN) metabolites as well as the inactive metabolites, 6-methylmercaptopurine nucleotides (6-MMPN) and 6-thiouric acid [80]. High 6TGN concentrations lead to leukopenia, where as high 6MMPN concentrations lead to hepatotoxicity. Conversion to the 6-MMPN metabolites is mediated by the enzyme thiopurine methyltransferase (TPMT). The activity of TPMT is largely determined genetically. Alleles conferring high (TPMT ^H) and low enzyme activity (TPMT ^L) are inherited in autosomal, codominant fashion. Approximately 89 % of Caucasians carry only TPMT ^H alleles (TPMT ^H/TPMT ^H) and have normal TPMT activity, 11 % are heterozygous (TPMT ^H/TPMT ^L) and have intermediate activity, and 0.3 % are homozygous for the same TPMT ^L allele (TPMT ^L/TPMT ^L) or are heterozygous with two different low activity alleles (TPMT ^L/TPMT ^L’; compound heterozygotes) and have low or undetectable activity. Measurement of TPMT activity is recommended to determine initial optimal dosage and avoid toxicity. Individuals with low or undetectable activity are generally not treated with the thiopurines, as they invariable develop very high 6-TGN concentrations resulting in neutropenia. Individuals with normal activity are treated with standard doses (6-MP 1–1.5 mg/kg/day or AZA 2.0–3.0 mg/kg/day), whereas those with intermediate activity are given half the standard doses (6-MP 0.5 mg/kg/day or AZA 1.0 mg/kg/day) [81].

RCTs [82–84] and observational studies [85–87] have found the thiopurines effective in maintaining steroid-free remission in patients with steroid-dependent UC. The thiopurines are also useful in patients experiencing frequent flares despite maximal 5-ASA therapy. Long-term therapy is required since 87 % of patients with refractory UC relapse once treatment is discontinued [75]. Due to their slow onset of action, the thiopurines are not used as inductive therapies. A recent meta-analysis reported a nonsignificant trend for benefit from thiopurine induction therapy in patients with active UC (RR = 0.85; 95 % CI = 0.71–1.01) [88].

Leukopenia (frequently, but not always, associated with high 6-TGN concentrations) and transaminitis (frequently, but not always, associated with high 6-MMPN concentrations) are reversible with dose adjustments. Pancreatitis occurs in 1–2 % of patients, usually in the first 6–8 weeks of treatment. Other adverse effects include nausea, emesis, malaise, rash, arthralgias, and myalgias [89]. These may not recur on switching to the alternate thiopurine. Only pancreatitis and fever are absolute contraindications to future use of the alternate thiopurine. Other risks associated with thiopurines include infections (especially in combination with corticosteroids and/or anti-TNF agents) [90] and lymphoma [91].

Oral methotrexate was not effective in a double-blind, randomized, Israeli trial in patients with active, steroid-requiring UC [92]. Mycophenolate mofetil inhibits lymphocyte proliferation by blocking guanine synthesis. Mycophenolate was less effective than AZA in a small, open-label trial in patients with active UC [93].

Infliximab (IFX) is a chimeric monoclonal antibody that targets tumor necrosis factor (TNF)-α, an inflammatory cytokine central to IBD pathogenesis. IFX is approved for the induction and maintenance of clinical remission in adults and children with moderately to severely active UC who have had an inadequate response to conventional therapy. IFX is therefore used in patients with (a) steroid-dependent disease failing thiopurines, (b) steroid-refractory disease, (c) intolerance to 5-ASA and thiopurines, and (d) severe UC requiring hospitalization. IFX is administered as an intravenous infusion at a dose of 5 mg/kg at weeks 0, 2, and 6 for induction, and then every 8 weeks for maintenance.

In two large, phase III trials, IFX led to 61–69 % response and 31–47 % remission rates at 8 weeks [94]. This benefit was maintained through 54 weeks with 44–45 % response and 34–35 % remission rates in IFX-treated patients compared to 20 % and 16 % of placebo-treated patients, respectively. Combination IFX and AZA therapy has been shown to result in higher rates of clinical remission in moderate to severe UC compared to monotherapy (40 % vs. 22–24 %) [95]. Similar results were reported with combination therapy in active Crohn’s disease [96], likely reflecting the reduced formation of antibodies against IFX in patients also receiving AZA.

IFX has proven effective as salvage therapy in severe, steroid-refractory UC. Treatment with IFX decreased the need for colectomy among hospitalized patients with severe fulminant UC and failing intravenous steroids [97, 98]. Nonetheless half of patients eventually required colectomy at 5 years [99]. In a recent study that compared IFX to cyclosporine in patients with severe, steroid-refractory UC, IFX demonstrated comparable rates of clinical response at 1 week (86 % vs. 84 %) and need for colectomy (23 % vs. 18 %) [100]. IFX may also be used in hospitalized patients as first-line therapy (in lieu of IV corticosteroids) [101].

An important question concerns the possibility of third-line therapy in patients who have failed cyclosporine or IFX. A French retrospective study examined patients treated between 2000 and 2008 with cyclosporine followed by IFX (n = 65) and with IFX followed by cyclosporine (n = 21) [102]. The median (±standard error) follow-up time was 23 (7) months. During the study period, 49 patients failed to respond to the second-line rescue therapy and underwent a colectomy. The probability of colectomy-free survival (61 ± 5 % at 3 months and 41 ± 6 % at 12 months) was similar in the two groups. Eight serious infections occurred during first-line therapy in seven patients, including two bacterial central-line infections, two cases of Clostridium difficile infection, two cases of cytomegalovirus viremia, one viral pericarditis, and one esophageal candidiasis. All infections had resolved by the time rescue therapy was started. During rescue therapy, nine serious infections occurred in nine patients (cyclosporine → IFX, n = 7; and IFX → cyclosporine, n = 2), and there was one fatal pulmonary embolism. In our opinion, the risk-benefit ratio favors colectomy over second-line rescue therapy in patients who have failed cyclosporine or infliximab after also having failed intravenous steroids. Patients who elect second-line therapy should be advised that they have a 60 % chance of colectomy at 1 year and a significant risk of infection.

After successful induction, IFX is continued as scheduled, maintenance therapy. Infusion reactions occur in approximately 10 % of patients and are mitigated by concomitant immunomodulatory therapy or IV hydrocortisone before the infusions [103]. The most important risk concerns infections, particularly opportunistic infections with intracellular pathogens, including M. tuberculosis, histoplasmosis, coccidiomycosis, listeriosis, and others. Testing for latent tuberculosis is mandatory before initiation of therapy. Reactivation of the hepatitis B virus may also occur; hence serologies should be evaluated prior to treatment. Other side effects include hepatotoxicity, worsening of heart failure, drug-induced lupus, and demyelinating disorders, such as multiple sclerosis and optic neuritis. The risk of lymphoma does not appear to be increased [104]. Contraindications to treatment include active infection, untreated latent tuberculosis, preexisting demyelinating disorder, moderate to severe heart failure, and current or recent malignancy.

Adalimumab (ADA) is a humanized monoclonal antibody against TNF-α, which was approved after IFX. ADA is administered by subcutaneous injections of 160 mg at week 0 and 80 mg at week 2 for induction, followed by 40 mg every other week for maintenance.

Two small, open-label studies demonstrated that ADA was well tolerated and beneficial for patients with UC including those who had lost response or had developed intolerance to IFX [105, 106]. More recently, two large RCTs evaluated the efficacy of ADA in moderate to severe UC. A multicenter RCT was conducted in North America and Europe in anti-TNF-naïve patients who received ADA 160/80 (160 mg at week 0, 80 mg at week 2, 40 mg at weeks 4 and 6), ADA 80/40 (80 mg at week 0, 40 mg at weeks 2, 4, and 6), or placebo [107]. More patients were in remission at week 8 in the ADA 160/80 group compared to placebo (18.5 % vs. 9.2 %). There was no difference between the ADA 80/40 group compared to placebo (10.0 % vs. 9.2 %). The second RCT evaluated ADA for the induction and maintenance of clinical remission in 494 patients who had moderate to severe UC and an inadequate response to corticosteroids and/or immunosuppressants [108]. Remission rates were higher in the ADA group than in the placebo group at week 8 (16.5 % vs. 9.3 %) and week 52 (17.3 % vs. 8.5 %). Remission rates were lower in patients who had previously received an anti-TNF agent versus those who were anti-TNF naïve. Rates of serious adverse events were similar between ADA and placebo groups in both studies.

ADA is an option in patients who have experienced loss of response to IFX due to the development of antibodies against IFX. ADA may be preferred over IFX by some patients due to its subcutaneous administration. Recent regulatory approval of golimumab offers another treatment option for patients with ulcerative colitis.

Golimumab is a newer, fully human, subcutaneously administered anti-TNF antibody. A randomized placebo-controlled trial evaluated induction therapy with golimumab in anti-TNF-α-naïve patients with moderate to severe ulcerative colitis [144]. Patients had a Mayo Score of 6–12 points (with an endoscopic subscore≥2 points) and had failed conventional medical therapy with oral mesalamine, oral corticosteroids, and AZA/6-mercaptopurine, or had been unable to taper corticosteroids without recurrence of disease activity. Golimumab was more efficacious than placebo in inducing clinical response, clinical remission and mucosal healing at week 6, and in improvising quality of life [144]. Responders from this trial were eligible for the subsequent, 52-week-long maintenance trial [145]. Golimumab was more efficacious than placebo in maintaining clinical response and remission and in achieving mucosal healing and corticosteroid-free clinical remission [145].

Controlled trials of antibiotics have demonstrated no therapeutic benefit when added to intravenous steroids [109, 110]. However, protocols outlining treatment regimens for severe colitis generally include broad-spectrum antibiotics for patients with signs of toxicity or with worsening symptoms despite maximal medical therapy [111]. Nicotine transdermal patches are effective in active UC, though less so than 5-ASA [112–114]. There is no evidence for its use as maintenance therapy. Side effects include lightheadedness, dermatitis, and nausea.

Two RCTs found the probiotic preparation VSL#3 (a combination of eight live, freeze-dried bacterial strains, including four strains of Lactobacilli, three strains of Bifidobacterium , and Streptococcus thermophilus) effective in inducing remission in UC patients failing oral 5-ASA [115, 116]. The evidence on other probiotics is more limited. Antidiarrheal agents are useful in decreasing diarrhea but are contraindicated in severe disease given the risk of toxic megacolon. Dietary arachidonic acid may play a role in the development of UC [117]. However, at the present time, there is no recommended diet specific for UC patients. Physicians may suggest that their patients identify foods that aggravate their disease and eliminate them from their diet. Controlled studies of total parenteral nutrition (TPN) for patients with severe colitis have shown no benefit, so that TPN is limited to patients who are unable to eat or have significant malnutrition [118, 119].