Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results of the UNIFI Long-Term Maintenance Study.

INTRODUCTION: Ulcerative colitis (UC) is a chronic condition that may require long-term treatment. We report the final efficacy and safety results of the UNIFI long-term extension study of ustekinumab in patients with UC through 4 years. METHODS: Ustekinumab induction responders who completed 44 weeks of maintenance treatment and agreed to enter the long-term extension continued their subcutaneous maintenance therapy (90 mg ustekinumab every 8 or 12 weeks [q8w or q12w] or placebo). Starting at week 56, randomized patients could receive dose adjustment to 90 mg q8w. Symptoms and adverse events were assessed through the study; endoscopic assessment was conducted at week 200. RESULTS: Of the 348 patients randomized to subcutaneous ustekinumab at maintenance baseline (q8w and q12w combined), 55.2% were in symptomatic remission at week 200. A greater proportion of biologic-naive patients (67.2% [117/174]) were in symptomatic remission than those with a history of biologic failure (41.6% [67/161]). Among patients in symptomatic remission at week 200, 96.4% were corticosteroid-free. Of the 171 patients with endoscopic evaluation at week 200, 81.6% (71/87) in the q12w group and 79.8% (67/84) in the q8w group had endoscopic improvement. From weeks 156 to the final safety visit (up to week 220), no deaths, major adverse cardiovascular events, or tuberculosis occurred in patients receiving ustekinumab. Nasopharyngitis, UC worsening, and upper respiratory tract infections were the most frequently reported adverse events. DISCUSSION: The long-term efficacy of ustekinumab maintenance in patients with UC was confirmed through 4 years. No new safety signals were observed. ClinicalTrials.gov number NCT02407236.

Efficacy and Safety of Maintenance Ustekinumab for Ulcerative Colitis Through 3 Years: UNIFI Long-term Extension.

BACKGROUND AND AIMS: The UNIFI long-term extension [LTE] study reports the efficacy and safety of subcutaneous 90 mg ustekinumab through 3 years of maintenance therapy. METHODS: Patients randomised to ustekinumab every 12 weeks [q12w] or every 8 weeks [q8w] at maintenance baseline [N = 348] and randomised ustekinumab-treated patients in the LTE [N = 284] were evaluated. Symptomatic remission [Mayo stool frequency = 0/1, rectal bleeding = 0] was assessed. Safety included all LTE patients [N = 188 placebo and N = 457 ustekinumab]. RESULTS: Among patients randomised to the ustekinumab q12w and q8w groups at maintenance baseline, 54.1% and 56.3% achieved symptomatic remission at Week 152, respectively. Overall, 20% of patients discontinued ustekinumab, 10% of biologic-naïve and 30% of biologic-exposed patients. Among patients in symptomatic remission at Year 3, 94.6% and 98.0% of patients were also corticosteroid free, respectively. Corticosteroid-free symptomatic remission rates in the ustekinumab q12w and q8w groups were 51.2% and 55.1% at Week 152, respectively. Remission rates were higher for biologic-naïve patients than for those with a history of biologic failure. Biochemical evidence of response was demonstrated by stable, decreased C-reactive protein and faecal calprotectin measurements over 3 years. From Weeks 96 to 156, no deaths, major adverse cardiovascular events, or tuberculosis occurred. Nasopharyngitis, ulcerative colitis, and upper respiratory tract infection were most frequently reported. One ustekinumab-treated patient with a history of basal cell carcinoma [BCC] reported two BCCs. One patient in the q8w ustekinumab group, who was receiving concomitant 6-mercaptopurine, experienced serious adverse events of neutropenic sepsis and oral herpes. CONCLUSIONS: Efficacy of ustekinumab in patients with ulcerative colitis was confirmed through 3 years. No new safety signals were observed.

Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy.

BACKGROUND: The ongoing UNIFI long-term extension evaluates subcutaneous ustekinumab for moderate-to-severe ulcerative colitis (UC) from weeks 44 through 220. AIMS: To assess efficacy (through week 92) and safety (through week 96) during the long-term extension METHODS: Overall, 399 responders to intravenous ustekinumab induction and who were randomised to maintenance therapy were treated in the long-term extension (115 received subcutaneous placebo, 141 received ustekinumab 90 mg every 12 weeks [q12w], and 143 received ustekinumab 90 mg q8w). Placebo treatment was discontinued at unblinding after week 44. Partial Mayo scores were collected every 12 weeks and at each dosing visit after unblinding. Safety was evaluated throughout. RESULTS: Among all patients randomised in maintenance, symptomatic remission rates (stool frequency = 0/1; rectal bleeding = 0) at week 92 were, 64.5% and 67.6% in the ustekinumab q12w and q8w groups, respectively. Among randomised patients treated in the long-term extension, 78.7% and 83.2% of patients receiving q12w and q8w, respectively, attained symptomatic remission at week 92; >95% of patients in symptomatic remission at week 92 were corticosteroid-free. Both ustekinumab groups maintained efficacy through week 92. From weeks 44 to 96, adverse events (AEs) per hundred patient-years (PY) of follow-up for combined ustekinumab vs placebo were: 255.68 vs 267.93; serious AEs, 9.34 vs 12.69; malignancies (including non-melanoma skin cancers), 0.93 vs 1.49; and serious infections, 2.33 vs 2.99. One patient with multiple comorbidities who received one ustekinumab dose after dose adjusting from placebo experienced a fatal cardiac arrest. CONCLUSIONS: The efficacy of ustekinumab in patients with UC was sustained through 92 weeks. No new safety signals were observed (ClinicalTrials.gov number, NCT02407236).

Outcomes of bone density measurements in coeliac disease.

AIM: Some guidelines recommend that patients with newly diagnosed coeliac disease undergo bone density scanning. We assessed the bone density results in a cohort of patients with coeliac disease. METHODS: We searched bone density reports over two 5-year periods in all patients from Auckland District Health Board (2008-12) and in patients under 65 years from Counties Manukau District Health Board (2009-13) for the term 'coeliac.' RESULTS: Reports for 137 adults listed coeliac disease as an indication for bone densitometry. The average age was 47 years, body mass index (BMI) 25 kg/m(2), and 77% were female. The median time between coeliac disease diagnosis and bone densitometry was 261 days. The average bone density Z-score was slightly lower than expected (Z-score -0.3 to 0.4) at the lumbar spine, total hip and femoral neck, but 88-93% of Z-scores at each site lay within the normal range. Low bone density was strongly related to BMI: the proportions with Z-score <-2 for BMI <20, 20-25, 25-30, and >30 kg/m(2) were 28%, 15%, 6% and 0% respectively. CONCLUSIONS: Average bone density was normal, suggesting that bone density measurement is not indicated routinely in coeliac disease, but could be considered on a case-by-case basis for individuals with strong risk factors for fracture.

New Zealand Society of Gastroenterology Guidelines for the Management of Refractory Ulcerative Colitis.

The management of patients with ulcerative colitis who are dependent on corticosteroid for control of symptoms, or refractory to corticosteroids or standard immunosuppressive therapy, is challenging. The development of newer medical therapies has increased the options for managing patients in this situation, but access and funding remain limited. This guideline summarises the literature regarding this situation and provides guidance as to the management of refractory colitis in the New Zealand setting.

Terminal ileal photography or biopsy to verify total colonoscopy: does the endoscope agree with the microscope?

BACKGROUND: Various modalities exist to document the extent of colonoscopy, including a terminal ileum (TI) biopsy, which is considered the criterion standard by some authorities. A TI biopsy adds to procedure costs, is potentially hazardous, and the detection of pathology in routinely acquired biopsy specimens of a macroscopically normal TI is limited. A safer, less costly alternative for documenting total colonoscopy is desirable. OBJECTIVE: To evaluate the effectiveness of TI photography as a means of documenting total colonoscopy. We also assessed the diagnostic yield of TI biopsies in patients with a macroscopically normal TI. DESIGN: Prospective, observational study. SETTING: District general hospital in the United Kingdom. PATIENTS: A total of 232 unselected patients undergoing colonoscopy, TI intubation, photography, and biopsy. MAIN OUTCOME MEASUREMENTS: Independent, experienced endoscopists were asked to state whether villi (and, therefore, TI entry) were "definitely," "probably," or "definitely not" depicted in TI photographs. This was compared with TI histology as a means of verifying total colonoscopy. The diagnostic yield of biopsy specimens from a macroscopically normal TI was determined. RESULTS: Reviewers agreed that villi were "definitely present" in 93.8%, "probably present" in 5.9%, and "definitely not" present in 0.3% of cases, with excellent interobserver agreement (kappa value = 0.778, P < .0001). TI photographs "definitely" depicting villi (93.8%) did not differ significantly from histology confirming TI mucosa (96.1%, P = .285). Microscopic evidence of pathology was only detectable in 2.3% of patients with an endoscopically normal TI. CONCLUSIONS: TI photography is an effective, safe, and cost-effective means of documenting total colonoscopy. Routine biopsy of a "normal" TI has a low diagnostic yield.