January's Paper of the Month is 'Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis' which looks into the efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23.
Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis
Sands BE, Sandborn WJ, Panaccione R, O'Brien CD, Zhang H, Johanns J, Adedokun OJ, Li K, Peyrin-Biroulet L, Van Assche G, Danese S, Targan S, Abreu MT, Hisamatsu T, Szapary P, Marano C; UNIFI Study Group
N Engl J Med. 2019;26;381(13):1201-1214
What is known on the subject
Ulcerative colitis is a chronic inflammatory disease of the colon and rectum. Approximately one fifth of patients with UC will require surgery during the course of their disease. While a total proctocolectomy offers definitive treatment, its operative morbidity and risk of postoperative poor quality of life drive development of new medications to prevent surgery.
What this study adds
Ustekinumab (Stelara, Janssen Biotech) is a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23. The UNIFI trial is a phase 3 trial of ustekinumab that included patients with moderate-to-severe ulcerative colitis. The UNIFI trial included an 8-week randomized induction trial and a 44-week randomized withdrawal maintenance trial (representing 52 weeks of treatment). Both were double-blind, placebo-controlled trials conducted from August 2015 through August 2018 under one protocol at 244 sites worldwide.
The results from the UNIFI trial showed that 57.2% of patients with ulcerative colitis that was refractory to biologics had a clinical response to intravenous ustekinumab (6 mg per kilogram of body weight) 8 weeks after initiation of induction therapy. Maintenance of clinical response was achieved in 64.8% of the patients who received the 90-mg subcutaneous dose of ustekinumab every 8 weeks and in 55.0% of those who received the same ustekinumab dose every 12 weeks, as compared with 38.6% of those who received placebo. The higher rates of clinical remission were achieved in patients who either had not previously received biologic agents or had a response to previous treatment with biologics. Rates of clinical remission were similar in the sub-group of patients with ulcerative colitis that was refractory to anti-TNF therapy and vedolizumab. Two deaths before week 44 (one attributed to haemorrhage from esophageal varices and one from acute respiratory distress syndrome [ARDS]) and a further death after week 44 (a patient with failure to thrive had a cardiac arrest) occurred among patients receiving ustekinumab. Cancer occurred in 7 of 825 patients who received ustekinumab (1 each of prostate, colon, renal papillary, and rectal cancer and 3 non-melanoma skin cancers). Four patients who received ustekinumab presented with potential opportunistic infections: cytomegalovirus colitis (in 2 patients during maintenance), legionella pneumonia (in 1 patient during induction), and concurrent ophthalmic and oral herpes simplex infections (in 1 patient during maintenance). Two major cardiovascular events occurred in patients underwent ustekinumab treatment.
The authors concluded that
“Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis.”
Implications for colorectal practice
Ustekinumab is becoming one of the biologics for treatment of ulcerative colitis, however new algorithms are needed to position this new generation of drugs correctly. Although complete remission is the ultimate treatment goal for all patients underwent medical treatment, surgery still remains as the ultimate treatment for ulcerative colitis.