Infliximab is an IV-administered, chimeric monoclonal antibody against TNFα for the treatment of UC, as well as rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, and Crohn’s disease [14]. In the UC population, the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2) found patients with moderately to severely active UC who received infliximab were more likely to have a clinical response than those receiving placebo. Each study was a double-blind, placebo-controlled trial evaluating infliximab at a dose of 5–10 mg/kg of body weight or placebo administered at weeks 0, 2, and 6 and then every 8 weeks through week 22 in ACT 2 and week 46 in ACT 1 [15]. TNFα-naïve patients with active moderate-to-severe UC who had failed or were intolerant to conventional therapies were included. Concomitant medication remained stable throughout each study, except for corticosteroid therapy, which was tapered after week 8. The primary endpoint of each trial was clinical response at week 8.

In ACT 1, 69.4% of patients receiving 5 mg/kg (84 of 121) and 61.5% of patients receiving 10 mg/kg (75 of 122) had a clinical response at week 8, compared with 37.2% of patients receiving placebo (45 of 121, P < 0.001 for both comparisons). In ACT 2, 64.5% of patients receiving 5 mg/kg (78 of 121) and 69.2% of patients receiving 10 mg/kg (83 of 120) had a clinical response at week 8, compared with 29.3% of patients receiving placebo (36 of 123, P < 0.001 for both comparisons). Clinical remission and mucosal improvement occurred in a higher proportion of patients treated with infliximab compared with placebo in both ACT 1 and ACT 2 trials at weeks 8, 30, and 54 and weeks 8 and 30, respectively (P ≤ 0.009 for all comparisons). Incidence of infliximab antibody formation at week 54 in ACT 1 was 6.1% (14 of 229 patients) and 6.4% (12 of 188 patients) at week 30 in ACT 2. In ACT 1, infusion reactions occurred in 10.7% (13 patients) in placebo group, 9.9% (12 patients) of 5 mg/kg group, and 12.3% (15 patients) of 10 mg/kg group (P = 1.00). In ACT 2, incidence of infusion reactions was 8.1% (10 patients) in placebo group, 11.6% (14 patients) in the 5 mg/kg group, and 11.7% (14 patients) of the 10 mg/kg group (P = 0.37). At week 54 in ACT 1, 35.4% of patients with anti-infliximab antibodies had an infusion reaction compared with 9.8% of patients with negative or inconclusive antibody testing (5 of 14 and 21 of 215, respectively). At week 30 in ACT 2, 50% of patients with anti-infliximab antibodies had an infusion reaction compared with 9.7% of patients with inconclusive or lack of antibodies (6 of 12 and 17 of 176, respectively), suggesting that patients with positive tests for antibodies were more likely to develop infusion reactions than those without antibodies. Infliximab was generally well tolerated , and incidence of adverse events and infections was similar for both patients treated with drug and placebo.

Long-term infliximab maintenance therapy for UC was evaluated during the ACT 1 and ACT 2 extension studies, in which patients who achieved a benefit from infliximab continued to receive up to three additional years of therapy [16]. Of 484 infliximab-treated patients in ACT 1 and ACT 2, 229 patients continued to receive infliximab in the extension studies. Of the 229 patients in the infliximab group, 70 (30.6%) discontinued infusions: 24 (10.5%) due to an adverse event, 11 (4.8%) due to lack of efficacy, 1 (0.4%) required colectomy, and 34 (14.8%) for other reasons. The primary intent of the efficacy analysis was to evaluate maintenance of efficacy. At week 0 of the extension study, 42.4% (97 of 229 patients) had no disease activity, and at week 152, 54.6% (125 of 229 patients) had no disease activity. For patients with mild or no disease activity, the proportion was 76.9% (176 of 229 patients) at week 0 and 89.5% (205 of 229 patients) at week 152. Based on these results from the intention-to-treat analysis, efficacy was maintained in both subgroups. Of note, patients who discontinued the study due to trial termination or for other reasons had the last available observation carried forward.

Safety was reported as events per 100 patient-years, for any patient who received at least one infusion of infliximab (N = 230), with a mean treatment duration of 1.99 years in the extension studies. Overall rates of adverse events were 506 per 100 patient-years, and infliximab was discontinued secondary to an adverse event at a rate of 4.63 patients per 100 patient-years of therapy. Infusion reactions occurred at a rate of 7.25 patients per 100 patient-years (36 of 230 patients). Only three patients experienced serious infusion reactions. Five malignancies were diagnosed during the extension studies, including adenocarcinoma of the lung, breast cancer, prostate cancer, basal cell carcinoma, and skin cancer of the nose and forearm (1.01 patients per 100 patient-years of therapy). No new or unexpected safety data compared to previous data on safety of infliximab was reported during the extension studies.

Adalimumab is a SC-administered, recombinant human antibody against TNFα approved for the treatment of UC, in addition to rheumatoid arthritis, juvenile idiopathic arthritis, hidradenitis suppurativa, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, and Crohn’s disease [17]. The first trial to evaluate the safety and efficacy of adalimumab in UC was the Ulcerative Colitis Long-Term Remission and Maintenance with Adalimumab (ULTRA 1) . This 8-week, multicenter, randomized, double-blind, placebo-controlled study assessed adalimumab for the induction of clinical remission in anti-TNFα-naïve patients with moderate-to-severe UC despite concurrent therapy with corticosteroids and/or immunomodulators [18]. A second multicenter, randomized, double-blind, placebo-controlled clinical trial, ULTRA 2, was performed to further evaluate the efficacy and safety of adalimumab in patients with moderate-to-severe UC and gather long-term data [19].

The ULTRA 1 study protocol originally included one adalimumab group of patients receiving adalimumab 160 mg at week 0, 80 mg at week 2, 40 mg at weeks 4 and 6 (ADA160/80), and placebo. However, the study protocol was amended to include a second induction group of adalimumab 80 mg at week 0 and 40 mg at weeks 2, 4, and 6 (ADA80/40). Patients in the study continued to receive adalimumab 40 mg SC every 2 weeks through week 52 in an open-label phase. There were two intention-to-treat analyses, one including patients under the amended study protocol (ITT-A3, N = 390) and a second intention-to-treat population including all patients under the original protocol and amendments (ITT-E, N = 575). In the ITT-A3 population, 18.5% of patients in the ADA160/80 arm, 10% of patients in the ADA80/40 arm, and 9.2% of patients in placebo arm achieved primary efficacy endpoint of clinical remission at week 8 (P = 0.031, P = 0.833 versus placebo, respectively). Adalimumab treatment was generally well tolerated at both induction doses, and overall safety profile was comparable to placebo. The findings of ULTRA 1 trial demonstrated that ADA160/80 was safe and effective for induction of remission of moderate-to-severe UC.

The ULTRA 2 trial randomized 494 patients with moderate-to-severe active UC despite concurrent corticosteroid and/or immunomodulator therapy to adalimumab or placebo. Unlike ULTRA 1, prior treatment with infliximab was allowed if it had been discontinued due to loss of response or drug intolerance for greater than 8 weeks, and approximately 40% of the total study population had prior infliximab exposure. Patients w ere randomized 1:1 to ADA160/80 or placebo after stratification by prior anti-TNFα exposure. The primary efficacy endpoint was rate of clinical remission at weeks 8 and 52. At week 8, 16.5% of patients treated with adalimumab achieved clinical remission compared with 9.3% receiving placebo (P = 0.019). Similarly, at week 52 patients treated with adalimumab achieved a significantly higher rate of clinical remission (17.3% versus 8.5%, P = 0.004). At week 52, both anti-TNFα-naïve and experienced patients achieved clinical remission at significantly higher rates compared with placebo arms (22% versus 12.4%, P = 0.029 and 10.2% versus 3%, P = 0.039, respectively). Whereas, at week 8 only patients who were anti-TNFα naïve had a statistically significant rate of clinical remission compared with placebo group (21.3% versus 11%, P = 0.017). In secondary endpoint analyses, significantly more patients treated with adalimumab compared with placebo achieved clinical response at week 8 (50.4% versus 34.6%, P < 0.001) and week 52 (30.2% versus 18.3%, P = 0.002). Adalimumab-treated patients also achieved mucosal improvement more often than placebo-treated patients (week 8, 41.1% versus 31.7%, P = 0.032, and week 52, 25% versus 15.4%, P = 0.009). Overall, adalimumab treatment had a similar safety profile to placebo.

The ULTRA 2 trial was designed to permit patients with inadequate response to initial treatment to switch to open-label adalimumab 40 mg every other week at week 12 or later and weekly adalimumab 40 mg for patients who continued to demonstrate inadequate response. After week 12, 31.7% (39 of 123) of week 8 responders and 61.6% (77 of 125) of week 8 nonresponders switched to open-label adalimumab. Furthermore, 16.3% (20 of 123) and 38.4% (48 of 125) escalated to weekly adalimumab for responders and nonresponders, respectively [20]. Remission, response, and mucosal improvement rates at week 52 for prior week 8 responders were 20%, 45%, and 45%, respectively, compared with 2.1%, 25%, and 29.2%, respectively, for prior week 8 nonresponders. These results indicate that escalation to weekly adalimumab dosing may be beneficial for both patients who initially respond to induction dosing and then lose response, as well as patients who are primary nonresponders. Weekly dosing was not associated with a greater risk of adverse events.

Efficacy and safety data for long-term use of adalimumab was reported for patients enrolled in the ULTRA 1 and 2 trials. Colombel et al. evaluated 600 of the 1094 patients enrolled in ULT RA 1 and 2 who received at least one dose of adalimumab (ADA Randomized Set) and found that 199 patients remained on adalimumab at week 208 [21]. Long-term remission rates and mucosal improvement rates over time were analyzed using nonresponder imputation (NRI), whereby patients with missing data were assumed not to have achieved the endpoint. For the ADA Randomized Set, rate of remission per partial Mayo score was 24.7% (148 of 600 (NRI)), and mucosal improvement was 27.7% (166 of 600 (NRI)) at year 4. Authors also evaluated the maintenance efficacy of adalimumab through week 156, for 588 patients who enrolled in the open-label extension, ULTRA 3, from ULTRA 1 and 2 (ADA Extension Set). Three hundred and sixty patients remained on adalimumab through week 156 in ULTRA 3. Long-term remission with mucosal improvement per partial Mayo score was 63.6% (NRI) at week 156 (of 242 patients who entered in remission) and 59.9% (NRI) at week 144 (of 409 patients who entered with mucosal improvement).

Safety data was reported for patients receiving at least one dose of adalimumab in ULTRA 1, 2, and 3 (N = 1010 patients or 2338 patient-years of exposure). Rates of serious adverse events per 100 patient-years of exposure were similar to or lower than that observed in prior studies. The overall rate was 30.7 events per 100 patient-years for week 52 of ADA 160/80/40 compared with a rate of 17.7 events per 100 patient-years for all ADA. During the ULTRA 3 study, three events of B-cell lymphoma occurred; however all patients had prior or current thiopurine use. Serious adverse e vents included, but were not limited to, two cases of cytomegalovirus colitis, one serious tuberculosis infection, one cardiorespiratory arrest, and one right ventricular failure. No new or unexpected safety data compared to previous data on safety of adalimumab was reported during the extension studies.

Golimumab is a fully humanized, SC-administered antibody against TNFα that is approved for the treatment of UC and also for rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis [22–27]. In the UC population, the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment-Subcutaneous (PURSUIT-SC) study evaluated the safety and efficacy of induction therapy with SC golimumab [28]. This multicenter, randomized, double-blind, placebo-controlled trial concluded that induction with SC golimumab 200/100 mg and 400/200 mg at weeks 0 and 2 was effective in inducing clinical response, clinical remission, and mucosal improvement in patients with moderately to severely active UC. The study also found that induction therapy was well tolerated with a safety profile consistent with other anti-TNFα therapies.

Specifically, this integrated phase 2 and 3 clinical trial enrolled patients with moderate-to-severe UC who were intolerant or refractory to oral 5-aminosalicylates, oral corticosteroids, azathioprine, and/or 6-mercaptopurine but naïve to anti-TNFα antagonists. In the phase 2 dose-finding portion of the trial, 169 subjects were randomized 1:1:1:1 to SC placebo or golimumab 100/50 mg, 200/100 mg, or 400/200 mg at weeks 0 and 2. In the phase 3 study, 774 subjects were randomized 1:1:1 to receive SC placebo, golimumab 200/100 mg, or 400/200 mg at weeks 0 and 2. At week 6, 51.0% and 54.9% of the golimumab 200/100 mg and 400/200 mg patients were in clinical response, compared to 30.3% of placebo patients. This result was statistically significant and met the primary endpoint of the study (P < 0.0001). Additionally, significantly more patients on golimumab 200/100 mg or 400/200 mg reached clinical remission as compared to placebo (17.8%, 17.9%, and 6.4% respectively, P < 0.0001). Significantly more patients on golimumab 200/100 mg or 400/200 mg also attained mucosal improvement. 42.3% on golimumab 200/100 mg (P < 0.0014), 45.1% on golimumab 400/200 mg (P < 0.0001), and 28.7% on placebo had mucosal improvement. Golimumab was generally well tolerated with an adverse event profile similar to placebo. Serious adverse events and serious infections were rare [28].