Comparison of ustekinumab, infliximab and combination therapy in moderately to severely active ulcerative colitis - a study protocol of a randomized, multicenter, head-to-head COMBO-UC trial.

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a complex etiology that affects the large intestine. Characterized by chronic, bloody diarrhea, UC can lead to severe complications, including an increased risk of colorectal cancer. Despite advancements in conservative treatment, including biologics like anti-TNF agents and ustekinumab (UST), many patients do not achieve full remission. Dual targeted therapy (DTT) combining infliximab (IFX) and UST is a promising approach to improve treatment outcomes. Methods: This prospective, randomized, multicenter, head-to-head controlled trial will evaluate the efficacy and safety of UST, IFX, and combination therapy (UST + IFX) in 172 patients with moderate to severe active UC across eight gastroenterology centers in Poland. The study includes a 14-16 week remission induction period followed by a 52-week maintenance phase. Patients will be randomly assigned to one of three treatment arms: IFX monotherapy, UST monotherapy, or IFX + UST combination therapy. Primary endpoint is clinical and endoscopic remission post-induction. Secondary endpoints include clinical response, biochemical remission, histological remission, and quality of life assessments using the Inflammatory Bowel Diseases Questionnaire and 36-Item Short Form Survey. Safety will be monitored through adverse event and serious adverse event reporting. Discussion: This trial aims to determine whether combining IFX and UST can achieve higher remission rates and better long-term outcomes compared to monotherapy. The results could provide crucial insights into the optimal use of biologic agents in UC treatment, potentially establishing DTT as a standard therapy. The study's design, including extensive follow-up and robust endpoint measures, will contribute to understanding the therapeutic potential and safety profile of this combination therapy.

No Impact of Concomitant Medications on Efficacy and Safety of Biologics and Small Molecules for Ulcerative Colitis.

BACKGROUND AND AIMS: While participants with inflammatory bowel diseases (IBD) in clinical trials of biologics and small molecule drugs (henceforth, advanced therapies) frequently receive several medications concomitantly, it is unclear how they modify treatment effect. METHODS: Through an individual patient data pooled analysis of ten clinical trials of advanced therapies for moderate-to-severe ulcerative colitis (UC), we assessed whether concomitant exposure to corticosteroids, immunomodulators, 5-aminosalicylates, proton pump inhibitors (PPIs), histamine receptor antagonists (H2RA), opiates, antidepressants, and antibiotics modified the effect of the intervention on treatment efficacy and safety outcomes, using modified Poisson regression model. RESULTS: Of 6044 patients (4280 receiving intervention, 1764 receiving placebo), several received concomitant corticosteroids (47%), immunomodulators (28%), 5-aminosalicylates (68%), PPIs (14%), H2RAs (2%), opiates (7%), antidepressants (6%), and/or antibiotics (5%). After adjusting for confounders and examining treatment efficacy of intervention vs. placebo, we observed no impact of concomitant exposure to corticosteroids (ratio of relative risk of drug vs. placebo with vs. without concomitant exposure: RRR, 0.81 [95% CI,0.63-1.06], 5-aminosalicylates (RRR, 1.04[0.78-1.39]), PPIs (RRR, 0.87 [0.61-1.22]), H2RAs (RRR, 1.72[0.97-14.29]), opiates (RRR, 0.90[0.54-1.49]), antidepressants (RRR, 1.02[0.57-1.83]), and antibiotics (RRR, 0.72[0.44-1.16]) on likelihood of clinical remission. Concomitant exposure to immunomodulators was associated with lower likelihood of achieving clinical remission (RRR, 0.73[0.55-0.97]), particularly with non-TNF antagonists. CONCLUSIONS: In clinical trials of advanced therapies for UC, baseline concomitant exposure to multiple commonly used class of medications does not impact treatment efficacy or safety. These findings directly inform design of regulatory clinical trials with respect to managing concomitant medications at baseline.

Comparative Efficacy and Safety of Ustekinumab and Secukinumab in the Treatment of Generalized Pustular Psoriasis: A 48-Week Retrospective Cohort Study with Genetic Background Analysis.

Purpose: Recent studies have shown that novel biologics may provide significant clinical benefits for patients with generalized pustular psoriasis (GPP). Ustekinumab and secukinumab have been approved in Japan for GPP treatment in adult patients. However, the differences in efficacy and safety of these two drugs in GPP are not known. Aim: Based on the genetic background, we aimed to compare the efficacy and safety of secukinumab and ustekinumab in patients with GPP. Methods: Patients with moderate to severe GPP who were treated with ustekinumab/secukinumab at our department from July 2019 to May 2022 were included in this study and followed up for 48 weeks. The difference in efficacy between ustekinumab and secukinumab was evaluated by assessing changes in body temperature, laboratory indices, recovery of skin lesions, and changes in quality of life. Additionally, we collected patients' saliva for genotyping and explored the effect of CARD14 genetic mutations on clinical efficacy. Results: A total of 65 patients (32 adults and 33 children) with moderate to severe GPP were included in this study. 31 patients received ustekinumab therapy, and 34 patients were treated with secukinumab. Secukinumab demonstrated superiority to ustekinumab, as evidenced by a higher GPPASI 90 response at week 2. Additionally, the efficacy of ustekinumab and secukinumab was found to be independent of the presence of the CARD14 mutation. Conclusion: Secukinumab is superior to ustekinumab in rapidly clearing the skin and improving health-related quality of life. Moreover, the responses to ustekinumab/secukinumab in patients were not influenced by CARD14 gene mutations.

Comparative real-world outcomes between ustekinumab, infliximab, and adalimumab in bio-naïve and bio-experienced Crohn's disease patients: a retrospective multicenter study.

BACKGROUND: Numerous studies have compared the efficacy of ustekinumab (UST) and anti-TNF agents [infliximab (IFX) or adalimumab(ADA)] in moderate to severe Crohn's disease (CD) patients. This study aims to compare the efficacy of UST, IFX, and ADA while differentiating between bio-naïve and bio-experienced patients, which is an underexplored aspect, particularly in Asia. METHODS: We conducted a retrospective multi-center study from 2012 to 2023, categorizing patients into bio-naïve and bio-experienced groups. We evaluated clinical remission rates after induction therapy and clinical outcomes, including CD-related hospitalization, intestinal resection, and drug discontinuation during maintenance therapy. RESULTS: Among the 214 bio-naïve CD patients, 60 received UST, 108 received IFX, and 46 received ADA. After 1:1 propensity score matching between UST and anti-TNF agents groups, 59 patients were analyzed in each group (45 in the IFX group and 14 in the ADA group). We found no significant differences in clinical remission rates (P = 0.071), CD-related hospitalization (P = 0.800), intestinal resection (P = 0.390), or drug discontinuation (P = 0.052) between the UST, IFX, and ADA groups in bio-naïve CD patients. In bio-experienced CD patients, with 35 in the UST group and 13 in the anti-TNF agents group, the UST group showed a lower risk of drug discontinuation (P = 0.004) than the anti-TNF agents group. CONCLUSIONS: This study suggests that UST, IFX, and ADA are equally effective in bio-naïve CD patients, while in bio-experienced patients, mostly with previous exposure to anti-TNF agents, UST may offer superior drug durability.

Comparison of the Effectiveness of Vedolizumab and Ustekinumab in Patients with Ulcerative Colitis: A Real-World Retrospective Study.

Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine. Data on the comparative effectiveness of biological therapies such as vedolizumab (VDZ) and ustekinumab (UST) remain limited. This retrospective study compared the effectiveness and safety of VDZ and UST in UC patients. Between November 2018 and November 2023, 106 patients were included: 64 received VDZ and 42 received UST. Bio-failure was significantly higher (p = 0.005) in the UST group versus the VDZ group. The remission rates at 6, 22, and 54 weeks in VDZ group were 51.6%, 61.3%, and 66.7%. The remission rates at 8, 24, and 56 weeks in the UST group were 66.7%, 65.0%, and 66.7%, respectively. Both treatments were comparable in inducing and maintaining clinical remission over 54-56 weeks, with no significant differences observed in the Lichtiger clinical activity index. Subgroup analyses highlighted the potential short-term effectiveness of UST among cases of bio-failure and a white blood cell level ≥ 9000/µL. Safety profiles were generally favorable, with no significant adverse events. Usutekinumab demonstrated effectiveness as a salvage therapy in patients who failed VDZ. Despite the increased disease severity in the UST group compared to the VDZ group, both groups demonstrated similar remission rates, suggesting UST shows significant efficacy even in moderate to severe UC.

Low muscle mass is associated with efficacy of biologics in Crohn's disease.

BACKGROUND: Low muscle mass (LMM) can be a frequent complication in Crohn's disease (CD). We attempted to explore the effect of LMM on the efficacy of biologics in patients with CD. METHODS: The retrospective cohort study included moderate-to-severe CD patients treated with infliximab or ustekinumab, and appendicitis patients as control. The skeletal muscle area (SMA) of L3 was assessed to evaluate the patients' muscle mass. After propensity score matching, the impact of LMM on drug efficacy was assessed in CD patients. RESULTS: A total of 269 patients with CD and 172 appendicitis patients were included. The CD group had lower skeletal muscle density and BMI, and a higher risk of developing LMM than the control group. BMI (OR = 0.48, p < 0.001) and previous use of biologics (OR = 2.94, p = 0.019) were found to be independently associated with LMM. LMM was found to be associated with a decrease in clinical response (at weeks 8-14), clinical remission (at weeks 8-14, 24-30 and 52) and biochemical remission (at week 52). At weeks 24-30 and 52, LMM was independently associated with loss of response (LOR). We found LMM could be a predictor of lower clinical remission at week 30, lower clinical remission at week 52 and a higher LOR rate at week 30 in infliximab. While in ustekinumab, LMM was associated with lower endoscopic remission at week 24, biochemical remission at week 52 and a higher LOR rate at weeks 24 and 52. CONCLUSIONS: The prevalence of LMM was higher in the CD group compared to the control group. For CD patients with LMM, the efficacy of infliximab and ustekinumab was relatively poor in both the short-term and long-term.

Treatment efficacy and patient satisfaction of ustekinumab compared with tumor necrosis factor-alpha inhibitors in Chinese patients with moderate-to-severe psoriasis: a real-world study.

BACKGROUND: Ustekinumab is an interleukin (IL)-12/IL-23 inhibitor for the treatment of moderate-to-severe psoriasis. OBJECTIVE: This real-world study compared ustekinumab and tumor necrosis factor-alpha inhibitors (TNFis) in Chinese moderate-to-severe psoriasis patients. METHODS: Patient health records of 110 moderate-to-severe psoriasis patients initiating or switching biologics were reviewed, with 31 patients receiving ustekinumab (ustekinumab group) and 79 patients receiving TNFis (TNFi group). RESULTS: Compared with TNFi group, psoriasis area and severity index (PASI)-75 response rate at month 6 (M6) were elevated (87.1% versus 65.8%, p = 0.026) in the ustekinumab group, whereas the rates at month 1 (M1) and month 3 (M3) and PASI-90 response rates at M1, M3, and M6 only showed an increasing trend (all p > 0.050) in the ustekinumab group than the TNFi group. By subgroup analyses, ustekinumab (versus TNFi) was more effective in patients with biologics therapy history than those without. Compared with the TNFi group, the ustekinumab group had lower dermatology life quality index scores and higher patient satisfaction scores at M3 and M6 (all p < 0.050). CONCLUSION: Chinese moderate-to-severe psoriasis patients treated with ustekinumab have a better treatment response at 6 months with improved quality of life and patient satisfaction after 3-6 months of treatment when compared to TNFi.

Recent clinical evidence on nutrition, novel pharmacotherapy, and vaccination in inflammatory bowel diseases.

Inflammatory bowel diseases (IBD), which enclose Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing inflammatory ailments. Their specific pathogenesis is not completely clarified, the worldwide incidence and prevalence of IBD has been steadily growing, and there is still not a definitive cure. The management of IBD has become more and more targeted, with specific immune mediators identified to be involved in its pathogenesis. Vedolizumab, a humanised monoclonal antibody binding specifically to the α4ß7 integrin, is a gut-selective immunosuppressive biologic drug administered for both CD and UC. With the same indications as vedolizumab, ustekinumab is a fully human IgG1κ monoclonal antibody binding with specificity to the shared p40 protein subunit of human cytokines interleukin (IL)-12 and IL-23. Several selective IL-23p19 monoclonal antibodies (risankizumab, mirikizumab, and guselkumab) have also revealed admirable efficacy and safety in IBD patients. Nutrition is a very important environmental factor associated with the onset and progression of IBD, and the Western diet is considered to contribute to the development of IBD. In this narrative review, our aim is to present an overview of the main results from recent clinical studies on IBD regarding diet, new drug treatments, and also vaccination.

Optimizing outcomes with maintenance IV UST in highly bio-exposed patients with IBD. Efficacy and adjusted regimen in real world.

BACKGROUND AND AIMS: Ustekinumab is an effective treatment for inflammatory bowel diseases. However, some patients do not respond to conventional doses. The aim of the study was to evaluate the effectiveness of intravenous maintenance ustekinumab in patients with secondary failure. METHODS: Single-center, retrospective study in adult patients with intravenous maintenance ustekinumab. The reduction of biochemical activity markers, ustekinumab trough levels and clinical indices of activity were evaluated. Biological remission was defined as the percentage decrease fecal calprotectin ≥80% and/or final fecal calprotectin ≤250 and C reactive protein <5mg/L. RESULTS: Thirty-one patients were included: Crohn's disease 77.4%. All included patients were bio-exposed and 61.3% had carried ≥2 biologics. Pre-intravenous maintenance mean Harvey-Bradshaw Index was 6.5±4.38 vs 5±3.1 at week 8 (p=0.024) vs 4.1±3.1 at week 24 (p=0.019). The median ustekinumab trough level pre-intravenous maintenance was 1.40µg/ml [IQR 2.3] vs 5.35µg/ml [IQR 4.1] at week 8 (p<0.001) vs 4.8µg/ml [IQR 3.9] at week 24 (p<0.001). The pre-intravenous maintenance median fecal calprotectin was 809µg/g [IQR: 2256] vs 423µg/g [IQR: 999] at week 8 (p=0.025) vs 333µg/g [508] (p=0.001) at week 24. At the end of follow-up 48% went into biological remission. The presence of perianal disease was associated with lower biological remission (70.6% vs 27.3%, p=0.025). Median intravenous ustekinumab maintenance time was 8.55 [IQR 23.9] months. In 83.9% of patients no serious infections or malignancy were documented. CONCLUSIONS: The use of maintenance intravenous ustekinumab appears to be an effective and safe strategy that can be evaluated as a salvage treatment especially in highly bio-exposed patients.

New Ustekinumab Biosimilar Candidate FYB202: Pharmacokinetic Equivalence Demonstrated in a Randomized, Double-Blind, Parallel-Group, Single-Dose Trial in Healthy Subjects.

In the RUSTIC trial, pharmacokinetic (PK) similarity between the proposed ustekinumab biosimilar FYB202 and EU-approved (EU-Ref) and US-licensed ustekinumab (US-Ref) as well as between both reference drugs was assessed after a single 45-mg subcutaneous injection. Safety analyses comprised immunogenicity (antidrug antibodies, neutralizing antibodies), adverse events, and local tolerability. Overall, 491 healthy adults were randomized 1:1:1 and observed for up to 112 days; 486 completed the trial, and 478 were included in the PK analysis. All 3 comparisons showed PK similarity, since the 90% confidence intervals of the respective geometric mean ratios for area under the concentration-time curve from time 0 to infinity and maximum serum concentration were contained within the acceptance interval of 80%-125%. No clinically meaningful differences regarding overall safety, immunogenicity, and local tolerability were observed. Notably, after FYB202 administration, in fewer subjects at least 1 positive antidrug antibody result was observed compared to the reference groups (FYB202, 20%; EU-Ref, 42%; US-Ref, 51%). In conclusion, the RUSTIC trial demonstrated equivalent PK characteristics for FYB202 when compared to both EU-Ref and US-Ref ustekinumab and between both reference drugs. It provides the basis for the marketing authorization of FYB202, together with an extensive analytical characterization and the results of a confirmatory efficacy and safety trial in patients with moderate to severe plaque psoriasis.

Renal Dysfunction in a Patient With Crohn's Disease During Ustekinumab Treatment: A Case Report and Review of the Literature.

Ustekinumab is a first-line drug for Crohn's disease. However, little is known about its potential adverse effects on renal function. We present the case of a 42-year-old man with Crohn's disease who developed chronic renal dysfunction during ustekinumab treatment, which resolved after discontinuing ustekinumab. The findings underscore the importance of close monitoring of renal function in patients receiving ustekinumab, particularly those with preexisting kidney disease or risk factors for renal dysfunction.

Induction and maintenance of mucosal healing in Crohn's disease with ustekinumab in clinical practice across all care levels in Germany (MUCUS).

The impact of ustekinumab (UST) on mucosal- and fistula healing and extraintestinal manifestations (EIM) in Crohn's disease (CD) were not fully elucidated in the registration trials. In this prospective, multicenter study (EudraCT number: 2017-005151-83) we evaluated the German label real-world-effectiveness of UST to achieve the primary endpoint of combined clinical and endoscopic response at week 52 and several secondary endpoints. Of 79 screened we enrolled 52 patients (female n = 28, bionaïve n = 13, biologic n = 39). At week 52 (per protocol analysis), 52% (n = 13/25) of patients achieved the primary endpoint [50% (n = 3/6) in the bionaïve, 45.5% (n = 5/11) biologic, 62.5% (n = 5/8 ) multiple biologics cohorts, respectively with age as independent predictor [OR 95% CI 0.933 (0.873, 0.998) p = 0.043], 60% (n = 15/25) achieved endoscopic response [50% (n = 3/6) in the bionaïve, 54.5% (n = 6/11) biologic, 75% (n = 6/8) multiple biologics cohorts, respectively], 36% (n = 9/25) achieved endoscopic remission [50% (n = 3/6) in the bionaïve, 27.3% (n = 3/11) biologic, 37.5% (n = 3/8) multiple biologics cohorts, respectively], 48% (n = 12/25) achieved mucosal healing [50% (n = 3/6) in the bionaïve, 36.4% (n = 4/11) biologic, 62.5% (n = 5/8) multiple biologics cohorts, respectively]. All achieved a fistula response and 33.3% (n = 1/3) in the multiple biologics group fistula remission at week 52. EIM decreased (week 0 28.2% vs. week 52 8%). CRP, FCP, PRO-2, EQ-5D-5L improved throughout. 36 patients (69.2%) experienced ≥ 1 treatment emergent adverse event, in 8 (15.4%) cases rated as severe and in 5 (9.6%) leading to UST discontinuation, but no very severe events or deaths. The effectiveness of UST was better than in the registration trials.

Tofacitinib for Pityriasis Rubra Pilaris: A Case Report.

Purpose: At present, we have entered the era of using biological agents and small molecule targeted drugs to treat diseases. Although there have been many reports of biological agents treating pityriasis rubra pilaris recently, the clinical application of the JAK inhibitors in the treatment of pityriasis rubra pilaris has been rarely reported, and there is a lack of evidence on the safety and efficacy of these drugs. We explore the use of the JAK inhibitor tofacitinib in the treatment of pityriasis rubra pilaris with significant efficacy and no significant side effects, providing new ideas for the clinical treatment of pityriasis rubra pilaris. Methods: We cover a case of pityriasis rubra pilaris treated with the JAK inhibitor tofacitinib, which showed significant efficacy without any adverse effects. Results: This case report showed that the JAK inhibitor tofacitinib had significant clinical efficacy in the treatment of pityriasis rubra pilaris. We speculated that the treatment of pityriasis rubra pilaris with the JAK inhibitors may be related to blocking the activation of the JAK/STAT pathway, thereby blocking the high expression of cytokines IL-17, IL-12/IL-23, IL-23, TNF-α. Conclusion: The JAK inhibitor tofacitinib can become a new option for treating pityriasis rubra pilaris.

Proactive Therapeutic Drug Monitoring of Ustekinumab Is Associated With Increased Drug Persistence in Patients With Inflammatory Bowel Disease.

BACKGROUND: There are limited data on the role of proactive therapeutic drug monitoring (TDM) of ustekinumab (UST) in patients with inflammatory bowel disease (IBD). This study investigated the efficacy and safety of proactive TDM in IBD patients treated with subcutaneous (sc) UST. METHODS: This was a retrospective single-center cohort study. Consecutive patients with IBD who received maintenance subcutaneous (sc) UST therapy and underwent TDM from January 2017 to February 2023 were eligible for inclusion. Patients were followed through May 2024 or until drug discontinuation or an IBD-related surgery. Patients underwent either at least one proactive TDM or reactive TDM only. Survival analysis was performed to evaluate drug persistence, defined as no need for drug discontinuation due to loss of response, serious adverse event (SAE) or an IBD-related surgery, and IBD-related hospitalizations. RESULTS: The study population consisted of 83 patients (proactive TDM, n = 46) of whom 67 (81%) had Crohn's disease. Patients who had at least one proactive TDM had higher drug persistence (Log-rank P < .001) and less IBD-related hospitalization (Log-rank P = .012) compared to patients undergoing only reactive TDM. In multivariable COX proportional hazard regression analysis, at least one proactive TDM was associated with increased drug persistence (hazard ratio [HR]: 5; 95% confidence interval [95% CI], 2-10; P < .001) and decreased IBD-related hospitalization (HR: 0.24; 95% CI, 0.07-0.83; P = .024). There was no SAE reported. CONCLUSIONS: This retrospective study showed that proactive TDM is associated with increased drug persistence and decreased IBD-related hospitalization in IBD patients treated with sc UST.

There is still limited information regarding the role of therapeutic drug monitoring (TDM) other than antitumor necrosis factor biologics. This study showed that proactive TDM is associated with increased drug persistence and decreased inflammatory bowel disease (IBD)-related hospitalization in patients with IBD treated with ustekinumab.

High serum levels of ustekinumab are associated with better clinical outcomes during maintenance treatment for inflammatory bowel disease.

Background: Ustekinumab (UST) is an effective treatment option in Crohn's disease (CD) and ulcerative colitis (UC). However, it still remains unclear if therapeutic drug monitoring could be helpful to guide clinicians. Objectives: The aim of our study was to analyze the relationship between UST through levels (USTTL) and clinical outcomes in real-world inflammatory bowel disease (IBD) patients. Design: We performed a unicentric retrospective study including patients with IBD under UST treatment with at least one level determination. Methods: The following variables were analyzed at the initiation of UST and at each USTTL measurement: clinical response and remission using the Harvey-Bradshaw Index (HBI) for CD and the Partial Mayo Score (pMayo) for UC; biochemical response and remission using fecal calprotectin and C-reactive protein, among others. Two periods were considered: P1 (time between induction and the first determination of USTTL) and P2 (time between USTTL1 and the second determination of USTTL). Results: We included 125 patients, 117 with CD. In P1, 62.4% of patients were on subcutaneous maintenance, and the median USTTL1 was 3.1 µg/mL (1.6-5.3). In 44.8% of CD patients (48/117), clinical remission was achieved, with USTTL1 significantly higher than those who did not achieve remission (3.7 µg/mL (2.3-5.4) vs 2.3 µg/mL (1.1-5.2); p = 0.04). In the 46 patients with two determinations, statistically significant differences were found between variables in P2 versus P1: clinical remission (73.9% vs 21.7%; p = 0.001); USTTL (7.2 µg/mL (4.7-11.7) vs 3.4 µg/mL (1.9-6.4); p < 0.001), HBI (4 (4-4.3) vs 8 (4-9); p < 0.001), pMayo (1 (1-3.3) vs 4.5 (3-5); p = 0.042), and corticosteroid use (26.1% vs 41.3%; p = 0.024). Receiver-Operating-Characteristic (ROC) curves were calculated for clinical remission in P2, with USTTL cutoff value of 6.34 µg/mL for clinical remission and a high rate of intensified patients (98%). Conclusion: High serum levels of UST were associated with clinical remission during treatment for IBD under intensification treatment, with a cutoff point of 6.3 µg/mL.