Ustekinumab In Patients Research Articles

Efficacy of biologic and small molecule agents as second-line therapy after exposure to TNF inhibitors in patients with ulcerative colitis: A propensity-matched cohort study.

There is limited real-world data on comparative effectiveness of different biologic or small molecule agents as second-line therapies in patients with ulcerative colitis (UC) with prior exposure to a tumour necrosis factor inhibitor (TNFi). We conducted a retrospective cohort study using TriNetX, a multi-institutional database to assess the efficacy of tofacitinib, vedolizumab and ustekinumab in patients with ulcerative colitis (UC) with prior exposure to a TNFi. Failure of medical therapy was defined as a composite outcome of intravenous steroids or colectomy within 2 years. One-to-one propensity score matching was performed for demographics, disease extent, mean haemoglobin, C-reactive protein, albumin and calprotectin, prior IBD medications and steroid use between cohorts. Among 2141 patients with UC and prior exposure to TNFi, 348 (16.2%), 716 (33.4%) and 1077 (50.3%) were switched to tofacitinib, ustekinumab and vedolizumab, respectively. After propensity-score matching, there was no difference in the composite outcome (aOR: 0.77, 95% CI: 0.55-1.07) but higher risk of colectomy (aOR: 2.69, 95% CI: 1.31-5.50) in the tofacitinib cohort than the vedolizumab cohort. There was no difference in the risk of composite outcome (aOR: 1.29, 95% CI: 0.89-1.86) but higher risk of colectomy (aOR: 2.63, 95% CI: 1.24-5.58) in the tofacitinib cohort than the ustekinumab cohort. The vedolizumab cohort had a higher risk of composite outcome (aOR: 1.67, 95% CI: 1.29-2.16) than the ustekinumab cohort. Ustekinumab might be the preferred second-line therapy over tofacitinib and vedolizumab in patients with UC that were previously exposed to a TNFi.

Ustekinumab in the treatment of acute disseminated pyoderma gangrenosum in a patient with Crohn's disease.

Pyoderma gangrenosum (PG) is an auto-inflammatory dermatosis characterized by lesions that often cause ulcers. We present a case of successful ustekinumab treatment for acute general PG in a 31-year-old woman with coexisting Crohn's disease (CD). For a month, the patient suffered from skin ulcers, two of them deep and necrotic; a histopathological examination revealed PG. Treatment included: methylprednisolone, azathioprine, betamethasone, gentamicin and zincic ointments, antiseptic compresses, and adalimumab therapy. Due to resistance to the implemented treatment, the patient was enrolled in a clinical trial that included the administration of an anti-cytokines drug, ustekinumab. Subsequently, a significant reduction was observed in the severity of symptoms of PG with no relapse. The use of ustekinumab in patients with PG who have an inadequate response to current treatment or cannot receive first-line treatment can be considered. This applies especially to patients with accompanying autoimmune diseases such as CD.

1-Year Comparative Effectiveness of Tofacitinib vs Ustekinumab for Patients With Ulcerative Colitis and Prior Antitumor Necrosis Factor Failure.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Real-world data comparing the effectiveness of tofacitinib to ustekinumab are limited. We compared 52-week outcomes of tofacitinib vs ustekinumab for UC after antitumor necrosis factor (anti-TNF) failure. In this retrospective cohort study, adults initiated tofacitinib or ustekinumab for UC after anti-TNF failure May 1, 2018 to April 1, 2021, at a US academic medical center. The primary outcome was steroid-free clinical remission (SFCR) at 12 and 52 weeks. The secondary outcome was drug survival (ie, time to drug discontinuation due to nonresponse). Adverse events (AEs) were also assessed. Sixty-nine patients initiated tofacitinib, and 97 patients initiated ustekinumab with median follow-up of 88.0 and 62.0 weeks, respectively. After inverse probability of treatment-weighted logistic and Cox regression, there was no association of tofacitinib vs ustekinumab with SFCR at 12 weeks (odds ratio, 1.65; 95% CI, 0.79-3.41), SFCR at 52 weeks (odds ratio, 1.14; 95% CI, 0.55-2.34), or drug survival (hazard ratio, 1.37; 95% CI, 0.78-2.37). Kaplan-Meier analysis demonstrated no separation in drug survival curves. Regression results were similar after excluding patients with prior tofacitinib or ustekinumab exposure. During available follow-up, 17 AEs were reported for tofacitinib (most commonly shingles, n = 4), and 10 AEs were reported for ustekinumab (most commonly arthralgia and rash, each n = 2). Two patients discontinued treatment due to AEs (1 tofacitinib for elevated liver enzymes, 1 ustekinumab for arthralgia). In a real-world UC cohort, tofacitinib and ustekinumab demonstrated similar effectiveness at 52 weeks. Adverse events were consistent with the known safety profiles of these agents.

Development of Antibodies to Ustekinumab Is Associated with Loss of Response in Patients with Inflammatory Bowel Disease.

The purpose of this study was to investigate the relationship between anti-drug antibodies detected by a drug-tolerant assay and loss of response (LOR) to therapy in a cohort of patients with IBD being treated with ustekinumab. This retrospective study consecutively enrolled all adult patients with moderate to severe active IBD who had at least 2 years of follow-up after ustekinumab was initiated. LOR was defined as CDAI > 220 or HBI > 4 for Crohn's disease (CD) and partial Mayo subscore > 3 for ulcerative colitis (UC) and with a modification in disease management. Ninety patients were included (78 CD and 12 UC; mean age 37 years). Median levels of anti-ustekinumab antibodies (ATU) were significantly higher in patients with LOR compared to those with ongoing clinical response (15.2 µg/mL-eq CI (7.9-21.5) and 4.7 µg/mL-eq CI (2.1-10.5), respectively; p = 0.04). The area under the ROC curve (AUROC) for ATU in predicting LOR was 0.76. The optimal cut-off point for identifying patients with LOR was 9.5 µg/mL-eq with a sensitivity of 80% and specificity of 85%. Uni- and multivariate analyses showed that serum ATU ≥ 9.5 µg/mL-eq (hazard ratio (HR) 2.54, 95%CI (1.80-5.93)), p = 0.022, prior vedolizumab (HR 2.78, 95%CI (1.09-3.34), p = 0.019) and prior azathioprine (HR 0.54, 95%CI (0.20-0.76), p = 0.014) exposures were the only factors independently associated with LOR to UST. In our real-life cohort, ATU was identified as an independent predictor of LOR to ustekinumab in patients with IBD.

Evaluation of the LFA-REAL clinician-reported outcome (ClinRO) and patient-reported outcome (PRO): prespecified analysis of the phase III ustekinumab trial in patients with SLE

ObjectiveThe Lupus Foundation of America Rapid Evaluation of Activity in Lupus (LFA-REAL) system is a novel and simple SLE disease activity instrument, consisting of a tandem clinician-reported (ClinRO) and patient-reported...

Comparison of the Persistence of Anti-TNF Agents and Ustekinumab in Patients with Crohn’s Disease: A Study Based on the Korean National Database

Biologics play an important role in the treatment of moderate to severe Crohn's disease (CD). Ustekinumab was approved for such patients in the Republic of Korea on 1 December 2018. Therefore, we need to compare the efficacy of ustekinumab and anti-TNF inhibitors. We compared one-year persistence rates between anti-TNF inhibitors and ustekinumab in moderate-to-severe CD patients using Korean National Health Insurance Service data from 1 December 2016 to 30 November 2021. We also analysed the risk factors for the non-persistence of biologics. The one-year persistence rates with index therapy in bio-naïve and bio-experienced patients were 87.7% and 69.7% for infliximab (p < 0.001), 85.1% and 72.8% for adalimumab (p < 0.001), and 92.1% and 89.8% for ustekinumab (p = 0.333), respectively. The risk factors for non-persistence were older age, non-use of an immune modulator, and previous biologic exposure in both the infliximab and adalimumab groups. The one-year persistence rate of ustekinumab was higher than that of anti-TNF inhibitors in bio-naïve patients (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.35-0.81; p = 0.003) and bio-experienced patients (HR 0.32; 95% CI 0.22-0.45; p < 0.001). Ustekinumab was superior in bio-naïve CD patients compared to anti-TNF inhibitors. However, the follow-up time was relatively short; further studies should continuously collect and analyse data.

Pretreatment serum monocyte chemoattractant protein-1 as a predictor of long-term outcome by ustekinumab in patients with Crohn's disease.

Ustekinumab has been proven to be effective for treatment of patients with Crohn's disease; however, 30-40% of patients have been reported to lose clinical response within 2years. We aimed to evaluate the efficacy of ustekinumab and identify predictors of short-term and long-term efficacy in Crohn's disease. Patients with Crohn's disease receiving their first ustekinumab infusion in our hospital between June 2017 and September 2020 were prospectively enrolled. Concentrations of serum cytokines and chemokines were measured using a multiplex bead array assay. Fifty-nine Crohn's disease patients were enrolled in this study. Among 34 clinically active patients, 38.2% achieved a clinical response at week 8. None of the assayed factors were associated with short-term clinical response. Cumulative persistence rates of ustekinumab were 77.6% at 1year and 58.9% at 2years. Univariate Cox regression analysis revealed that Harvey-Bradshaw Index scores at baseline, concomitant immunomodulator treatment, and concentrations of interferon gamma-induced protein-10, monocyte chemoattractant protein-1 (MCP-1), and interleukin (IL)-1RA, IL-4, IL-6, and IL-8 were significantly associated with loss of efficacy. Multivariate Cox regression analysis found that biologic naïve status (hazard ratio [HR]: 0.1191, 95% confidence interval [CI]: 0.02458-0.5774) and MCP-1 concentrations (HR: 1.038, 95% CI: 1.015-1.062) were significantly and associated with loss of sustained efficacy for ustekinumab treatment. Our findings suggest that pretreatment serum MCP-1 analysis, combined with a history of biologic use, could be a novel biomarker for predicting the long-term efficacy of ustekinumab in patients with Crohn's disease.

Predictive factors of the clinical efficacy of ustekinumab in patients with refractory Crohn's disease: tertiary centers experience in Japan.

Therapeutic efficacy of ustekinumab in the real-world data is limited in patients with refractory Crohn's disease (CD). In addition, factors predictive of better therapeutic efficacy of ustekinumab remains unsolved in CD. We aimed to evaluate therapeutic efficacy of ustekinumab in patients with refractory CD and to identify the factors associated with the efficacy of ustekinumab. We retrospectively analyzed the clinical data of 72 patients treated with ustekinumab for refractory CD. Therapeutic efficacy was assessed at weeks 8, 26, 52, and 104 on the basis of dual remission, defined as the combination of Crohn's Disease Activity Index < 150 and CRP < 0.3mg/dL, and factors predictive of the induction and maintenance of dual remission were investigated. The cumulative continuation rates and safety of ustekinumab were assessed. The dual remission rates at weeks 8, 26, 52, and 104 were 31.9%, 37.9%, 47.5%, and 42.6%, respectively. A short disease duration (≤ 2years) and higher baseline serum albumin levels (≥ 3.1g/dL) were positively associated with dual remission at weeks 8 and 52. Meanwhile, higher serum CRP levels (≥ 1.19mg/dL) were negatively associated with dual remission at week 8. The cumulative ustekinumab continuation rate was favorable, and no severe adverse events were found. A short disease duration and higher baseline serum albumin levels might be predictive of favorable therapeutic efficacy of ustekinumab in refractory CD. Induction efficacy appears to be lower in patients with higher serum CRP levels.

P457 Treatment duration of ustekinumab in patients with Crohn’s disease (CD) and psoriasis (PSO) – real-world evidence from German claims data

Abstract Background Ustekinumab is a monoclonal antibody approved for the treatment of inflammatory diseases such as Crohn’s disease (CD) or psoriasis (PSO). Real-world evidence about treatment persistence of patients treated with ustekinumab is scarce. This retrospective observational study uses German claims data to analyse average treatment duration of ustekinumab in CD and PSO patients in a real-world setting. Methods Patients with at least two confirmed outpatient diagnoses or one inpatient diagnosis of Crohn’s disease (ICD-10 code: K50*) between 01/01/2016 and 30/06/2020 and a subsequent incident prescription of ustekinumab (ATC code: L04AC05) between 01/01/2017 and 30/06/2020 were identified in the AOK PLUS database, a sickness fund with more than 3.4 million patients from the states of Saxony and Thuringia in the eastern part of Germany. Similarly, patients with at least two outpatient diagnoses or one inpatient diagnosis of psoriasis (ICD-10 code: L40*) between 01/01/2010 and 30/06/2020 and an incident prescription of ustekinumab between 01/01/2011 and 30/06/2020 were identified. Treatment durations were quantified by assessing the time from the first ustekinumab prescription until treatment discontinuation. Discontinuation was defined as a gap of at least 90 days between the end date of the last prescription and the date of the next prescription or switch to another biologic agent. Deaths were counted as treatment discontinuations, and patients were censored at the end of follow-up or disenrolment from the sickness fund. Stockpiling was taken into account (i.e., accumulated medications were assumed to be taken consecutively), and hospitalizations were considered as a part of treatment. Treatment duration was explored in a Kaplan-Meier analysis. Results A total of 251 CD and 848 PSO patients with incident ustekinumab treatment were identified. 39 CD (15.5%) and 375 PSO patients (44.2%) discontinued treatment during the study period (median follow-up: 16.1 and 44.9 months; total patient years: 383.6 and 3338.7 for CD and PSO, respectively). For CD, median time to treatment discontinuation was not reached, as most patients were still on treatment at the end of the follow-up period; for PSO, median time to treatment discontinuation was 51.5 months (Table 1 &amp; Figure 1). Conclusion Our results provide real-world evidence of ustekinumab treatment duration in patients with CD and PSO in Germany. A low proportion of CD patients discontinuing treatment over the available follow-up period and a median treatment duration of more than four years for PSO indicate that ustekinumab treatment persistence is high in these patient groups.

P579 Real-world comparison of effectiveness between tofacitinib and ustekinumab in patients with ulcerative colitis exposed to at least one anti-TNF agent: results from the TORUS study

Abstract Background We aimed to compare the effectiveness of tofacitinib and ustekinumab in patients with ulcerative colitis (UC) previously exposed to at least one anti-TNF agent. Methods In this multicenter study, we retrospectively included consecutive UC adult patients previously exposed to at least one anti-TNF agent, with partial Mayo score (pMS) &amp;gt; 2, having who started tofacitinib or ustekinumab between January 2019 and June 2022. The primary endpoint was steroid-free clinical remission (pMS ≤ 2) (CFREM) at week 16 (W16). Secondary endpoints were endoscopic remission (CFREM + Mayo endoscopic score (MES) ≤ 1), and histological remission (CFREM + MES ≤ 1 + Nancy index ≤ 1). Comparisons were performed using propensity score analyses adjusted on potential confounders. Results Overall, 289 patients were included (tofacitinib = 124 patients, ustekinumab = 165 patients). The groups were comparable (tofacitinib vs vedolizumab) for male gender (50.8% vs 43.3%), mean age (40.7 vs 42.9 years), median UC duration (8.6 vs 9.3 years), concomitant use of 5-ASA (13.7% vs 9.7%), steroids (25.0% vs 29.7%), immunosuppressants (7.3% vs 5.5%), and ≥ 2 prior biologics (85.5% vs 82.4%). Tofacitinib group had more pancolitis (55.6% vs 42.4%, p = 0.026) and UC with pMS &amp;gt; 6 (64.5% vs 50.3%, p = 0.016). In our study, 42.1 % of the patients treated with tofacitinib continued using a dose of 10 mgx2/day until W16 while 47.3% of the patients on ustekinumab required dose escalation to 90 mg/4 weeks before W16. After propensity score analysis, the rate of CFREM at W16 was 37.8% and 35.6% in the tofacitinib and ustekinumab arms, respectively arm (p=0.75). CFREM at W16 was achieved in 43.3% vs 57.1% (p = 0.48) after failure of one biologic, 20.7% vs 37.9% (p=0.16) two biologics and 46.7% vs 23.2% (p=0.047) or ≥ 3 biologics, in tofacitinib and vedolizumab arms, respectively. After primary failure to at least one biologic, the rate of CFREM at W16 was 46.3% on tofacitinib vs 25.9% on ustekinumab (p = 0.13). CFREM at W16 was similar with tofacitinib and ustekinumab in case of more severe UC such as pMS ≥ 6 (40.6% vs 41.5%) and CRP &amp;gt; 30 (27.2% vs 33.0%). No predictor of tofacitinib effectiveness has been identified. Factors associated with no CFREM at W16 on ustekinumab were male gender (p=0.035), ≥ 3 prior biologics (p=0.013), prior use of tofacitinib (p=0.03), primary failure to at least one biologic (p=0.013). Endoscopic remission was achieved in 17.0% vs 11.7% (p =0.47) and histological remission in 4.4% vs 7.8% (p=0.32) of the patients treated with tofacitinib and ustekinumab, respectively. Conclusion Tofacitinib and ustekinumab have similar effectiveness in UC after anti-TNF failure. However, the efficacy of ustekinumab could be more impacted by prior therapeutic failures.

P796 Effectiveness and safety of ustekinumab for patients with ulcerative colitis: A single-centre retrospective study

Abstract Background Ustekinumab, a monoclonal antibody directed against the interleukin 12/23 p40 subunit, was approved worldwide in 2020 for the treatment of ulcerative colitis. The efficacy of ustekinumab in inducing and maintaining remission in moderate to severe ulcerative colitis was demonstrated in the phase 3 clinical study, the UNIFI trial; however, real-world data on the effectiveness and safety of ustekinumab for patients with ulcerative colitis is still scarce. We aimed to investigate the real-world effectiveness and safety of ustekinumab in patients with ulcerative colitis. Methods This was a single-centre retrospective study enrolling patients with ulcerative colitis who were aged 16 years or more and administered ustekinumab between March 2022 and March 2022 at Toho University Sakura Medical Center, a tertiary center. Data were extracted by chart review. Ustekinumab was administered as a single intravenous infusion (approximately 6 mg/kg) followed by 90mg subcutaneous injection at week 8 and then by 90mg subcutaneous injection every 8-12 weeks. The endpoints were 1) the proportion of patients achieving symptomatic remission, defined as a rectal bleeding score of 0 and a stool frequency score of 0 or 1 in patient-reported outcome-2 (PRO-2), at week 8, 2) time to discontinuation, and 3) safety during the observation periods. Results We enrolled 53 patients in this study, with a median age of 45 years (interquadrant range: 27-57). Thirty patients (56.6%) were male and 23 (43.4%) were female. The majority of patients (n=39; 73.6%) had extensive colitis. Notably, 21 (38.9%) patients were naïve to advanced therapies. Thiopurines had been administered to 24 (45.3%) patients. Twenty-one (39.6%) patients achieved symptomatic remission at week 8 after a single intravenous infusion. The proportion of patients with symptomatic remission was numerically higher in advanced therapy-naïve patients compared with advanced therapy-experienced patients (47.6% versus 34.4%) (Figure 1). Univariate analysis failed to identify clinical predictors for symptomatic remission at week 8. The time to discontinuation were significantly longer in advanced-therapy naïve patients compared with advanced therapy experienced patients, with a median observation period of 296 days (Figure 2). As for safety, one patient discontinued ustekinumab due to skin disorder. One death due to pneumonia was observed, which was unrelated to ustekinumab. Conclusion Ustekinumab was effective and safe in the real-world setting. Advanced-therapy naïve patients were more likely to continue ustekinumab compared with advanced therapy experienced patients.

P782 Ustekinumab in Ulcerative colitis: a real-life effectiveness study across multiple Belgian centers (SULTAN)

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon.1 Ustekinumab (UST), a monoclonal antibody against the p40 subunit of interleukin (IL) 12 and 23 has shown in the UNIFI trials to be effective and safe in patients with moderate-to-severe UC.2 Real-life data are still limited.3 The aim of this study was to assess the real-world effectiveness and safety of UST in patients with UC across Belgian hospitals. Methods In this multicentric, retrospective observational study, patients with UC who received UST from September 2020 onwards were included. Clinical and biochemical response was assessed at baseline, week 8, 16 and 52. The primary endpoint was steroid-free remission defined as partial Mayo score of ≤ 2 with no subscore &amp;gt; 1 at week 16. Secondary endpoints included clinical and biochemical response (defined respectively as a decrease in partial Mayo score ≥ 3 points and ≥ 3 plus a decrease in rectal bleeding score ≥ 1 or an absolute rectal bleeding score ≤ 1 and a decline of 50% or more in CRP and/or fecal calprotectin). Results 107 patients with moderate-severe UC (86% patients with ≥ S2 severity) were included across 16 participating centers. Median disease duration was 10 years (1-73y) and 69 (64%) of patients had previously failed 2 or more biologicals. At week 16, 35 patients reached the primary endpoint of steroid-free clinical remission (33%), while 67 had a clinical response (62.6%) (Fig 1). There was a statistically significant decline in partial mayo score (median at baseline 6.0 range (1-9); W16 2.0 (0-9, p&amp;lt;.001), CRP (3.85 mg/L (0.4-181) vs 3.15 (0.88-10.3); p&amp;lt;.001) and calprotectin (1040 (13-6000) vs 300 (3.8-2980); p&amp;lt;.001) (Fig 2 and 3). Biochemical response was seen in 41 patients (38%). No predictors for steroid-free remission could be identified. At the end of follow-up at week 52, 75 patients were still treated with UST (70%). Reasons for discontinuation were primary non-response (N=18 (17%), loss of response (N=8 (7.5%) and adverse events (N=2 (1.9%)). No predictor for UST failure could be identified. Eight patients needed to be referred for colectomy (7.5%). In 7 patients dose optimization via IV reinduction occurred. No difference in occurrence of extra-intestinal manifestations was noted during treatment, severe infections occurred in 1 patient (0.9%). No other new safety signals were observed. Conclusion In this multi-centric, real-life cohort with highly refractory UC patients, UST was associated with a clinical response rate of 63% at 16 weeks while steroid-free remission was achieved in 33% of patients. No important new safety signals were observed.

P652 Therapeutic drug monitoring during induction therapy with Ustekinumab in patients with Crohn’s disease: the key to early identification of patients with inadequate response.

Abstract Background Ustekinumab (UST), an inhibitor of the p40 subunit of interleukins 12 and 23, is approved for the treatment of moderate and severe Crohn disease (CD) but a significant number of patients either partially respond or do not benefit at all. Therapeutic drug monitoring can be used to optimize the efficacy of biological drugs by ensuring adequate exposure to these drugs. The aim of our research was to identify the relationship between serum concentrations of UST during the induction and biochemical remission at week 16 in patients with CD. Methods All CD patients treated with UST included in a local database were identified. Only patients with a fecal calprotectin (FCP) &amp;gt; 250 mg/g were selected. All patients were treated with an initial intravenous induction therapy of UST, followed by subcutaneous maintenance therapy. Disease activity was assessed retrospectively by clinical (Harvey–Bradshaw Index [HBI]) and biochemical parameters (FCP; C-reactive protein (CRP) and Albumin) at Week 0, Week 4, week 8 and week 16. UST trough levels were measured at 4, 8 and 16 weeks using a commercially available validated enzyme-linked immunosorbent assay (ELISA). Main outcome was biochemical remission, defined by a decreased of calprotectin levels more than 80% or an absolute value less than 200 mg/g at week 16. Results Seventy-six patients were included. Patients’ Characteristics at baseline are listed in table 1. Median [IQR] HBI was 5,5 [3-8] at the beginning of treatment. Evolution of biochemical parameters throughout induction is showed in table 2. At the end of the induction phase (week 16), HBI, CRP and FCP decreased significantly from baseline. At this moment HBI was less than 2 in 51% of patients. FCP was available in 63 patients. Biochemical remission was observed in 26/63 (41,3%) patients. Median [IQR] UST serum concentrations were 20,9 μg/mL [13,7–26,3] at w4, 10,1 μg/mL [3,5–7,4] at w8 and 4,1 μg/mL [1,4–3,9] at w16. Quartile analysis demonstrated that 100% and 66% with an UST serum concentration in the highest quartile [Q4], at w4 and w8, achieved a biochemical remission by w16 [p = 0.05 and p &amp;lt;0,02 respectively]. The area under the receiving operating characteristic curve (AUROC) of UST levels to predict biochemical remission at week 4 and week 8 were 0,84 CI95% (0,62-1) and 0,74 CI95% (0,57-0,91) respectively. Conclusion Serum concentrations of UST at week 4 and 8 after intravenous infusion could be used to stratify patients according to the probability of achieving remission. This measurements during induction could be used to optimize treatment of CD.

P525 Real-world effectiveness and safety of ustekinumab in patients with ulcerative colitis: a systematic review and meta-analysis

Abstract Background Knowledge of the real-world effectiveness and safety of tofacitinib for ulcerative colitis (UC) is relevant to confirm the benefit observed in clinical trials. The aim of this systematic review was to summarize reported evidence on the real-world outcomes of ustekinumab for UC and to conduct a meta-analysis of effectiveness and safety data. Methods A systematic search was conducted in electronic databases PubMed, Web of Science, EMBASE, and Science Direct, and conference proceedings until 15 September 2022 for real-world studies evaluating ustekinumab for UC. A random-effects meta-analysis model was used to calculate the pooled rates of clinical and safety outcomes. We evaluated the outcomes at week 8, week 12 to 16, month 6, and month 12. Need for colectomy and adverse events (AE) were reported as percentages and incidence rates (IRs) per 100 patients-year (PY) of exposure. Results Of the 254 citations identified, 19 studies were included with 3786 patients. Sixteen studies reported prior exposure to biologics or JAK inhibitors and included 1003 patients, of whom 92.3% were previously treated with any biologic, 61.1% with both anti-TNF and vedolizumab, and 16.4% with any biologic and tofacitinib (Figure 1). Remission was achieved in 45.4% of patients at week 8 (95% confidence interval 30.1-60.6%), 43.8% (38.4-49.2%) at weeks 12 to 16, 44.6% (35.9-53.3%) at month 6, and 50.6% (36.3-64.8%) at month 12 (Figure 2). Response was achieved in 61.2%, 59.4%, 65.2%, and 76.8% of patients at week 8, weeks 12 to 16, month 6, and month 12, respectively (Figure 3). Corticosteroid-free remission was achieved in 18.7%, 36.8%, 34.5%, and 39% of patients at week 8, weeks 12 to 16, month 6, and month 12, respectively. Endoscopic improvement was achieved in 29.9%, 24.3% %, and 58.2% of patients at weeks 12 to 16, month 6, and month 12, respectively. Almost 30% of the patients needed dose escalation, which was effective in 40% of these patients. The pooled rate of persistence with ustekinumab was 76.9% and 73.3% at month 9 and month 12, respectively. The IRs of colectomy, AE, serious AE, and serious infections were 5.1, 7.9, 1 and 0.5 per 100 PY, respectively (Figure 4). Conclusion The results of this systematic review and meta-analysis of real-world studies confirm the effectiveness of ustekinumab in a highly treatment-refractory population of patients with active moderate-to-severe UC. The acceptable safety data presented here support the positive long-term benefit-risk profile of ustekinumab in the treatment of UC. These real-world effectiveness and safety results were consistent with clinical trials and provide a broader perspective that can be used to aid treatment decisions in a more heterogeneous clinical setting.

Meta-analysis: Real-world effectiveness and safety of ustekinumab in patients with ulcerative colitis.

Evidence on real-world outcomes of ustekinumab for ulcerative colitis (UC) patients is needed. To summarise evidence on the real-world outcomes of ustekinumab for UC and conduct a meta-analysis of effectiveness and safety data. A systematic search was conducted through September 2022 in electronic databases for observational studies evaluating ustekinumab for UC. A random-effects meta-analysis model was used to calculate the pooled effect sizes (percentages or incidence rates [IRs]) of effectiveness and safety outcomes. In all, 19 studies were included with 3786 patients. More than 92% of patients were previously treated with any biologic, 61.1% with both anti-TNF and vedolizumab and 16.4% with any biologic and tofacitinib. Clinical remission was achieved in 45.4% at week 8 (95% CI: 30.1%-60.6%), 43.8% (38.4%-49.2%) at weeks 12-16, 44.6% (35.9%-53.3%) at month 6, and 50.6% (36.3%-64.8%) at month 12. Response was achieved in 61.2%, 59.4%, 65.2% and 76.8% at weeks 8, 12-16, month 6 and 12, respectively. CS-free remission was achieved in 18.7%, 36.8%, 34.5% and 39% at weeks 8, 12-16, month 6 and 12, respectively. Overall, 58.2% of patients had endoscopic improvement at month 12. Almost 30% of the patients needed dose escalation, which was effective in 40% of these patients. The IRs of colectomy, adverse events (AEs), serious AEs and serious infections were 4.8, 7.9, 0.8 and 0.3 per 100 patient-years, respectively. This meta-analysis confirms the effectiveness and safety of ustekinumab in a highly treatment-refractory population of UC patients.

Cost per responder for vedolizumab and ustekinumab in Crohn’s disease patients after failure of TNF-α inhibitors in Italy

Background: The aim of this economic evaluation was to compare the cost per responder between vedolizumab and ustekinumab in patients with Crohn’s disease (CD) after failure of tumor necrosis factor-α inhibitors in Italy. Methods: Clinical efficacy was assessed using the results of an Italian large multicentre observational retrospective cohort study. The aim of the study was to compare the effectiveness of ustekinumab and vedolizumab as second line therapy in Crohn’s disease patients in which tumour necrosis factor-α inhibitors failed. Clinical efficacy of vedolizumab and ustekinumab was measured by clinical response and clinical remission. Treatment costs were based on the number of administrations at 26 or 52 weeks. Cost per responder, based on clinical efficacy and clinical response, was used as a cost-effectiveness indicator. Results: Regardless of the clinical efficacy measure used and the treatment duration considered, the cost per responder was consistently lower for vedolizumab compared with ustekinumab on all clinical measures. Considering the clinical response, the cost per responder at 26 weeks was € 15,640 for vedolizumab and € 23,667 for ustekinumab and at 52 weeks was € 23,927 for vedolizumab and € 30,820 for ustekinumab. Considering the clinical remission, the cost per responder at 26 weeks was € 22,832 for vedolizumab and € 33,786 for ustekinumab and at 52 weeks was € 29,488 for vedolizumab and € 46,847 for ustekinumab. Sensitivity analysis confirmed the validity of results. Conclusion: These results suggest that vedolizumab is a cost-effective option compared with ustekinumab from the perspective of the Italian health service in patients with CD after failure of TNF-α inhibitors.

A Retrospective Cohort Study of Clinical Features and Treatment Patterns With Ustekinumab in Patients With Crohn Disease Utilizing a Health Care Database in Japan.

Biologics are used to treat moderate-to-severe Crohn disease (CD). In Japan, ustekinumab was approved for reimbursement for CD treatment in 2017. However, limited information describes utilization of ustekinumab in real-world settings. To describe treatment patterns and clinical outcomes of patients with CD treated with ustekinumab in Japan. A retrospective cohort drug utilization study was conducted using the Japan Medical Data Center employment insurance database. Patients with a diagnosis of CD who initiated treatment with ustekinumab (International Classification of Disease, Tenth Revision [ICD-10] K50.x) from January 1, 2017, to September 30, 2020, were enrolled. Eligible patients were followed up until disenrollment or study end (September 30, 2020). A total of 622 patients with CD initiated ustekinumab during the study period; 45.7% had no prior history of biologic use (bio-naive) and 54.3% had previously received ≥1 biologic (bio-experienced); 82.8% of patients received an induction dose of whom 97.5% received a dose within the recommended range (260-520 mg) and 90.8% of patients received their first maintenance dose within a 42- to 70-day interval. Median treatment duration was 14.8 months and 90.2% remained on ustekinumab at study end. Compared with the 12-month period prior to ustekinumab initiation, surgical procedures decreased by 88.0%, gastrointestinal complications by 64.6%, enteral nutrition requirements by 41.9%, and CD-related hospitalizations by 62.6% within 12 months after commencing ustekinumab. These first real-world data from Japan, where ustekinumab has been used longest for CD treatment, shows that a majority of patients initiated ustekinumab as per the recommended label. Indirect evidence of clinical impact could be relevant in other settings in Asia.

Effectiveness and safety of ustekinumab in bio-naïve Crohn's disease patients: a multicentre observational retrospective study.

Clinical trials have demonstrated the efficacy and safety of ustekinumab in Crohn's disease (CD). However, more data are necessary on the effectiveness of ustekinumab in bio-naïve patients in real-life studies. The aim of our study was to evaluate the effectiveness and safety of ustekinumab in patients with CD refractory or intolerant to conventional therapy and without previous exposure to biological drugs. We performed a nationwide, observational, retrospective, multicentre study including patients with CD, in which ustekinumab was used as the first biological drug. The corticosteroid-free clinical and biological response and remission were analysed at weeks 16, 24, 52 and 72. Clinical remission was defined as Harvey-Bradshaw index ⩽ 4 and biological remission as a faecal calprotectin (FC) <250 mg/g and C-reactive protein (CRP) <5 mg/L. Moreover, the persistence of the treatment and any adverse events were assessed. In all, 84 patients were included in the study, males and females were equally distributed, with a median age of 63 years [interquartile range (IQR): 51-75] and a median disease duration of 6.8 years [IQR: 3.6-17.0]. The majority (86.9%) of patients were treated with ustekinumab as monotherapy, without concomitant immunosuppressive medication. The proportion of patients in corticosteroid-free clinical remission or response at weeks 16, 24, 52 and 72 was 93.3% (56/60), 86.8% (46/53), 82.2% (37/45) and 71.4% (30/42), respectively. CRP returned to normal values in 47.6%, 43.2%, 50% and 52.4% of patients at weeks 16, 24, 52 and 72, respectively. Similarly, FC was normalized in 45.5%, 45.5%, 48.6% and 50% of patients at weeks 16, 24, 52 and 72, respectively. The cumulative probability of remaining on ustekinumab treatment was 84.8% (95% confidence interval: 73.3-91.6) after 72 weeks. Ustekinumab was discontinued in 10 patients (11.9%) within 72 weeks of follow-up. Reasons for discontinuing treatment were lack of response (n = 4), adverse events (n = 4) and death (n = 2). There were no discontinuations because of stable remission. Ustekinumab was effective and safe in Spanish bio-naïve CD patients, showing a quicker and more durable response than obtained in patients with previous biological treatment. In this cohort of bio-naïve patients starting on ustekinumab, the average age was high. Effectiveness and safety of ustekinumab in Crohn's disease patients not previously exposed to other biological therapies Evidence on the use of ustekinumab in biological naïve real-world patients is scarce. Here, we present real-world data evaluating the effectiveness and safety of ustekinumab in 84 bio-naïve patients from 17 Spanish hospitals. We report high rates of both clinical and biological remission. Moreover, after 1 year, 90.4% of patients remained being treated with ustekinumab. The safety profile of ustekinumab in these patient population was favourable. In conclusion, our results show that in patients with CD, ustekinumab could be considered as first-line therapy.

Real-World Data on Short-Term and Long-Term Treatment Results of Ustekinumab in Patients with Steroid-Resistant/Dependent Ulcerative Colitis

Introduction: Ustekinumab is an IgG1 kappa monoclonal antibody directed against the common p40 subunit of interleukin-12 and interleukin-23, which activate Th1- and Th17-mediated immune responses, respectively. It has proven efficacy for the treatment of moderate to severe ulcerative colitis (UC) in the UNIFI phase III clinical trial; however, data on its efficacy in the real world are limited. In this study, we aimed to assess the real-world efficacy of ustekinumab. Methods: This observational study included 30 patients with UC who received ustekinumab from April 2020 to April 2022. We examined demographic information, disease type and activity (Mayo score, partial Mayo score [PMS]), use of biologics, concomitant use of predonisolone (PSL), 8-week ustekinumab clinical response rate, remission induction rate, 44- and 152-week remission maintenance rate, continuation rate, and 44-week steroid-free remission rate. The primary outcomes were the short- and long-term efficacy of ustekinumab. Results: Included patients (53% women; mean age: 41.2 years [16–80 years]) had an average disease duration of 86 weeks. The Mayo score (median) was 7.4 and the PMS was 5.4. Two (7%), 24 (80%), and four (13%) patients had a Mayo endoscopic subscore (MES) of MES1, MES2, and MES3, respectively. The median serum CRP was 1.0 mg/dL. Five patients had no history of biotherapy (naive), while eight and 17 had a history of one and two or more biologic agents, respectively. Eight patients were PSL-resistant and 22 were PSL-dependent. The 8-week clinical response rate was 73% and the clinical remission induction rate was 70%. The remission maintenance rates at 44 and 152 weeks were 67% and 63%, respectively. The ustekinumab retention rate was 67% (86-week mean follow-up period). Regarding biologic failure cases, the clinical response rate in the failure group with up to one biologic agent (including naive cases) was 84.6%, which was higher than the 58.0% rate in the failure group with two or more biologic agents (p = 0.06). Steroid-free remission rates at 44 and 152 weeks were 63% each. In the logistic regression analysis parameters for discontinuation of ustekinumab, only PMS remained significant after multivariate analysis (p = 0.018). Conclusion: Our study showed short-term and long-term ustekinumab effectiveness, especially with comparative low disease activity.

Comparative Safety and Effectiveness of Biologic Therapy for Crohn’s Disease: A CA-IBD Cohort Study

We compared the safety and effectiveness of tumor necrosis factor α (TNF-α) antagonists vs vedolizumab vs ustekinumab in patients with Crohn's disease (CD) in a multicenter cohort (CA-IBD). We created an electronic health record-based cohort of adult patients with CD who were initiating a new biologic agent (TNF-α antagonists, ustekinumab, vedolizumab) from 5 health systems in California between 2010 and 2017. We compared the risk of serious infections (safety) and all-cause hospitalization and inflammatory bowel disease-related surgery (effectiveness) between different biologic classes using propensity score (PS) matching. As compared with TNF-α antagonists (n= 1030), 2:1 PS-matched, ustekinumab-treated patients with CD (n= 515) experienced a lower risk of serious infections (hazard ratio [HR], 0.36; 95% CI, 0.20-0.64), without any difference in the risk of hospitalization (HR, 0.99; 95% CI, 0.89-1.21) or surgery (HR, 1.08; 95% CI, 0.69-1.70). Compared with vedolizumab (n= 221), 1:1 PS-matched, ustekinumab-treated patients with CD (n= 221) experienced a lower risk of serious infections (HR, 0.20; 95% CI, 0.07-0.60), without significant differences in risk of hospitalization (HR, 0.76; 95% CI, 0.54-1.07) or surgery (HR, 1.42; 95% CI, 0.54-3.72). Compared with TNF-α antagonists (n= 442), 2:1 PS-matched, vedolizumab-treated patients with CD (n= 221) had a similar risk of serious infections (HR, 1.53; 95% CI, 0.84-2.78), hospitalization (HR, 1.32; 95% CI, 0.98-1.77), and surgery (HR, 0.63; 95% CI, 0.27-1.47). High comorbidity burden, concomitant opiate use, and prior hospitalization were associated with serious infections and hospitalization in biologic-treated patients with CD. In a multicenter cohort of biologic-treated patients with CD, ustekinumab was associated with a lower risk of serious infections compared with TNF-α antagonists and vedolizumab, without any differences in risk of hospitalization or surgery. The risk of serious infections was similar for TNF-α antagonists vs vedolizumab.