Administration Of Ustekinumab Research Articles

The IRE1α/XBP1 pathway sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease.

Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. ER stress is linked to inflammatory bowel disease (IBD). Here, we used cell culture, mouse models, and human specimens to determine whether ER stress in ILC3s affects IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24-hour rhythmic expression pattern of the master ER stress response regulator inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1). Proinflammatory cytokine IL-23 selectively stimulated IRE1α/XBP1 in mouse ILC3s through mitochondrial ROS (mtROS). IRE1α/XBP1 was activated in ILC3s from mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1α deletion in ILC3s (Ire1αΔRorc) showed reduced expression of the ER stress response and cytokine genes including Il22 in ILC3s and were highly vulnerable to infections and colitis. Administration of IL-22 counteracted their colitis susceptibility. In human ILC3s, IRE1 inhibitors suppressed cytokine production, which was upregulated by an IRE1 activator. Moreover, the frequencies of intestinal XBP1s+ ILC3s in patients with Crohn's disease before administration of ustekinumab, an anti-IL-12/IL-23 antibody, positively correlated with the response to treatment. We demonstrate that a noncanonical mtROS-IRE1α/XBP1 pathway augmented cytokine production by ILC3s and identify XBP1s+ ILC3s as a potential biomarker for predicting the response to anti-IL-23 therapies in IBD.

P944 Ustekinumab in refractory Ulcerative Colitis: single-center, real-world experience

Abstract Background Ustekinumab, an anti-interleukin 12/23 agent, was approved by the European Medicines Agency in 2019 as a treatment for moderate-to-severe ulcerative colitis (UC). Limited real-world data is available regarding the utilization of ustekinumab in UC, particularly medication persistence and escalation, which are indicators of medication performance in real-world settings. Our aim was to describe our experience with ustekinumab in refractory UC patients. Methods This was an observational single-center study on UC patients who received at least one intravenous dose of ustekinumab 16 weeks before data analysis due to active UC (Simple clinical colitis activity index (SCCAI)>5). Data regarding disease activity prior to and post-induction were analyzed. Patients were followed up until the last ustekinumab administration. Clinical response to therapy was assessed at 16, 24,52 weeks, and the end of follow-up. Response was defined as SCCAI<4, and remission as SCCAI≤2. Dose adjustment or IV maintenance was considered part of the treatment regimen. Patients who discontinued ustekinumab due to lack of therapeutic effect or worsening of UC were considered failures. When available, colonoscopy data was analyzed. Results Forty-seven patients who received ustekinumab for refractory UC were included. Thirty-eight percent were female, and 34% were former smokers. Median age was 46 [37.5-61.5]; 62% had extensive disease, and 15% had perianal disease. Ninety-three percent received at least one biologic before ustekinumab, and 24% had received a JAK inhibitor. Thirty-eight patients required dose escalation, and 11 were on maintenance IV. Clinical response at week 16 was achieved in 74% and remission in 46%. At 24 and 52 weeks, 65% and 61% were in remission, respectively. At the end of follow-up, 59% of patients had endoscopic remission (Endoscopic Mayo score ≤ 1). Sixty percent continued treatment during a mean follow-up of 12 months [6-21]. No variable was associated with risk of discontinuation. No serious adverse events were reported. Discontinuation of treatment was due to treatment failure in all cases. Conclusion Ustekinumab was effective for induction and maintenance in our cohort of UC patients, although a significant proportion required dose escalation. Drug persistence was higher than 50% during the follow-up. The safety profile of ustekinumab was similar to that in controlled studies and other real-world studies.

P334 The longitudinal analysis of fecal microbiota in response to ustekinumab treatment in patients with Crohn’s disease

Abstract Background Emerging evidence supports that treatment of Crohn’s disease (CD) can alter the intestinal microbiota, which can play a significant role in the pathogenesis and therapeutic outcomes of CD. Ustekinumab (UST) has also been reported to modify the intestinal microbiota during a short-term treatment period. However, the long-term impact of UST treatment on the intestinal microbiota has rarely been studied. Methods We prospectively enrolled patients with CD who were planning to start UST treatment and collected fecal samples before (baseline) and after UST administration at week 20 and week 52. Fecal bacterial taxonomic diversity and composition were analyzed through 16S ribosomal ribonucleic acid (rRNA) gene amplicon sequencing. The difference in the intestinal microbiota between clinical remitters and non-remitters defined by Crohn’s disease activity index (CDAI) was investigated, along with the longitudinal changes in the intestinal microbiota. Results A total of 124 fecal samples acquired from 43 patients were analyzed (median age 30 years, male 76.7%, median CDAI at baseline 183.2). Clinical remission was observed in 34.9% (n=15/43), 61.0% (n=25/41), and 60.0% (n=24/40) at baseline, week 20, and week 52, respectively. Shannon’s alpha diversity index increased significantly at week 20 and week 52 compared to baseline (both P<0.001). Compared to non-remitters, a significant increase of Shannon’s alpha diversity index was also observed among remitters (P=0.044) across all time points, while no significant difference was noted at each time point. The beta diversity analysis based on the Bray-Curtis distance revealed a significant difference among remitters at week 20 (P=0.027), however, there were no significant differences at other time points. Compared to the baseline, the abundance of the Firmicutes phylum was higher at week 20 (P=0.048) and 52 (P=0.019). The Lactobacillus genus (P=0.042), and Lactobacillus gasseri group (P=0.016) were significantly less abundant in remitters, while the Lachnospiraceae family (P=0.017) was more abundant in remitters. At week 20, Bifidobacterium genus (P=0.027) and Bifidobacterium pseudolongum group (P=0.040) were significantly more abundant in remitter while the Lactobacillus genus was less abundant (P=0.009) in remitter (Figure 1). Conclusion The alteration of fecal microbiota after UST treatment may have the potential to serve as a biomarker for predicting clinical remission. Financial Support This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2021R1A2C2095096), the grant (2020IT0012) from the Asan Institute for Life Sciences, Seoul, Korea and the grant (CR 2017-4) from CELLTRION PHARM, Inc., Chungcheongbuk-do, Korea.

Ustekinumab Decreases Circulating Th17 Cells in Ulcerative Colitis.

Objective T helper (Th) cells play a central role in the pathogenesis of ulcerative colitis (UC). The present study analyzed the changes in circulating T cells by administration of ustekinumab (UST), an interleukin-12/23p40 antibody. Methods CD4 T cells were isolated from peripheral blood at 0 and 8 weeks after UST treatment, and we analyzed the proportion of CD4 T cells by flow cytometry. Clinical information and laboratory data were obtained at 0, 8, and 16 weeks. Patients We evaluated 13 patients with UC who received UST for the induction of remission between July 2020 and August 2021. Results The median partial Mayo score improved from 4 (1-7) to 0 (0-6) (p<0.001) with UST. Among serological parameters, albumin concentrations, C-reactive protein concentrations, the sedimentation rate, and leucine-rich alpha 2 glycoprotein concentrations showed significant improvement with UST. A flow cytometric analysis of circulating CD4 T cells showed that the percentage of Th17 cells was significantly decreased by UST treatment in all patients (1.85% to 0.98%, p<0.0001). Th1 cells were significantly increased by UST treatment (9.52% to 10.4%, p<0.05), but Th2 and regulatory T cells were not significantly different. The high-Th17 subgroup had a significantly better partial Mayo score than the low-Th17 subgroup at 16 weeks after UST treatment (0 vs. 1, p=0.028). Conclusion Treatment with UST decreases circulating Th17 cells, suggesting that this change may be related to the anti-inflammatory effect of UC.

A novel nomogram for predicting endoscopic remission in refractory Crohn's disease with ustekinumab administration.

Ustekinumab (UST) is a human IgG1 monoclonal antibody that targets to the share p40 subunit of interleukin-12(IL-12) and IL-23. Evidence has shown that UST therapy is well tolerated and effective in inducing clinical response in refractory CD(Crohn's disease) and dose escalation is effective in recapturing response in over half of the patients. However, no predictive factor has been reported to be helpful for UST treatment in clinical practice. Additionally, there were few reports about therapeutic drug monitoring (TDM) of UST administration in China due to its late launch time in Chinese market and lack of experience in clinical use. Herein, we establish and validate the first UST-trough concentrations (TCs) -related nomogram in China for predicting endoscopic remission in refractory CD to facilitate clinical decision making.

Administration Details of Genetically Engineered Biologic Drug (Ustekinumab) in Children with Psoriasis and Comorbid Metabolic Syndrome or in Case of Previous Biological Therapy Failure: Case Studies

Background. Psoriasis is a chronic immune-mediated disease with multifactorial nature. It often requires administration of genetically engineered biologic drugs. They have a number of features and risks that depend on various factors. The results of ustekinumab administration as a drug of choice in patients with comorbid metabolic syndrome in a child with Down syndrome, as well as a case of inefficacy of previous biologic therapy with inhibitors are considered.Clinical cases description. Two clinical cases of ustekinumab administration in children with severe psoriasis have been described. In the first case, we had to choose systemic therapy for the child suffering from Down syndrome and having complex comorbid background: obesity and steatohepatitis. The second case was interesting due to the family history of psoriasis in the patient, who received methotrexate for a long time, and then etanercept with subsequent loss of efficacy and severe disease aggravation without any pathogenetic therapy.Conclusion. Ustekinumab is the favorable genetically engineered biologic drug (according to the studies results and the clinical cases data) for children with severe psoriasis who have comorbid pathologies and who require the change in biologic agent due to its inefficacy.

Population Pharmacokinetics and Exposure–Response Analyses of Ustekinumab in Patients With Moderately to Severely Active Crohn's Disease

Ustekinumab, a fully human immunoglobulin G1κ monoclonal antibody that antagonizes human interleukin-12/23p40, is an effective therapy for several immune-mediated inflammatory diseases, including Crohn's disease (CD). This work characterizes the population pharmacokinetic (PK) and exposure-response (E-R) relationships of ustekinumab in patients with CD using data from four Phase IIb/III clinical studies. Serum ustekinumab concentration-time data from 1673 patients after IV and/or SC administration of ustekinumab were fitted simultaneously using nonlinear mixed effects modeling to develop a population PK model, which was subsequently used to evaluate simulation scenarios. Logistic regression E-R models were used to assess relationships between serum ustekinumab concentrations and clinical remission after induction (n=1910) and maintenance (n=387) treatment. Ustekinumab PK properties are well described by a two-compartment model with first-order absorption and elimination. Typical values of PK parameters for a 70-kg patient were: clearance, 0.192 L/d; volume of distribution at steady state, 4.62 L; and intercompartmental clearance, 0.287 L/d. Ustekinumab terminal elimination t1/2 was 19days, and bioavailability after SC administration was 78.3%. Ustekinumab clearance was not affected by coadministration of immunosuppressive agents or corticosteroids. Body weight, serum albumin, and C-reactive protein (CRP) concentrations, tumor necrosis factor (TNF) antagonist failure status, sex, race (Asian vs non-Asian), and anti-ustekinumab antibody status significantly affected ustekinumab disposition; however, the effects of these covariates on ustekinumab exposure were not clinically relevant. The population PK model predicts that a milligram/kilogram dosing approach will result in lower ustekinumab exposure in patients with lower body weight. A positive E-R relationship was established between ustekinumab concentration and efficacy outcomes. The treatment effect of ustekinumab after induction therapy was more pronounced among patients with higher baseline CRP concentrations relative to those with lower values. In patients with CD, ustekinumab disposition after IV and SC administration was biexponential and consistent with those in patients with ulcerative colitis. Prior treatment with TNF antagonists or the concomitant use of immunosuppressive agents or corticosteroids had no effect on ustekinumab disposition. None of the covariates that affected ustekinumab clearance had a clinically meaningful impact on ustekinumab exposure. E-R models support recommended posology of ustekinumab in adults with CD; however, an ∼6 mg/kg IV induction dose in pediatric patients with lower body weights may not provide exposure that matches that in adult patients. gov identifiers: NCT00771667, NCT01369329, NCT01369342, and NCT01369355.

The Long-Term Clinical Effectiveness of Ustekinumab in Antitumor Necrosis Factor-Experienced Crohn's Disease Patients.

BackgroundCrohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology. Ustekinumab (UST), an interleukin (IL)-12 and IL-23 antibody, has been approved in the recent years to treat IBD, both Crohn’s disease and ulcerative colitis. This study clarifies the long-term effectiveness of ustekinumab (UST) in antitumor necrosis factor (anti-TNF) refractory Crohn’s disease in Middle Eastern patients.MethodsA retrospective review study, including 30 refractory or medication-intolerant patients with Crohn’s disease, was conducted at a tertiary care center in Riyadh, Saudi Arabia. The patients were started on ustekinumab and followed up for at least 52 weeks. Follow-up was performed on weeks 12, 24, and 52. Data related to demographic and laboratory parameters, the dosing schedule of ustekinumab administration, and the Harvey-Bradshaw index (HBI) were collected. Clinical remission and response rates were assessed. Statistical analysis was performed using SPSS Statistics version 28.0 (IBM Corp., Armonk, NY, USA). A statistical significance threshold of p < 0.05 was adopted.ResultsThe mean age of the study subjects was 34.2 ± 17.9 years (95% confidence interval (CI): 27.5-40.9), with a mean disease duration of 10.6 ± 4.9 years (95% CI: 8.8-12.5). Of our cohort, 56.7% failed two biologics during their disease course, and about 20% failed three different biologics. The percentage of patients who used thiopurines was 76.7%, while 6.7% used methotrexate. Concurrent immunomodulators were used by 58.6% of the patients. Corticosteroids were given to 13.3% of the patients. Intravenous induction of UST at 6 mg/kg was used for 90% of the patients, while only 10% used a 260 mg subcutaneous dose. At week 12, 73.3% of the patients had a clinical response, and 66.7% achieved clinical remission. Corticosteroid-free remission, clinical response, and clinical remission showed a decreasing percentage trend between weeks 12 and 24 compared to week 52 where a spike was observed in all aforementioned parameters. The clinical response rate at week 52 was 76.7%. The p-values from cross-tabulation were significant for clinical response and remission when comparing week 12 to weeks 24 and 52.ConclusionUstekinumab presents a safe and effective treatment option in moderate to severe Crohn’s disease patients with previous exposure to multiple biologics.

Paradoxical Reactions to Biologicals in Chronic Inflammatory Systemic Diseases.

Biological agents that contain substances affecting the immune system are increasingly being used to treat chronic inflammatory systemic diseases. Aside from the expected adverse effects, they can also induce unexpected paradoxical reactions (PR). A reaction is called paradoxical when a substance that is generally therapeutically effective induces the opposite of what is intended, with the new appearance or exacerbation of inflammatory changes in the skin and other organs. The paradoxical reactions that have been described since 1997 are presented here on the basis of the available literature on the main types of chronic inflammatory systemic disease, which was retrieved by a selective search in the PubMed and Google Scholar databases. Many studies and registers to date contain no mention of paradoxical reactions. Anti-TNF-alpha treatment for patients with ankylosing spondylitis leads to paradoxical reactions in 19 per 1000 patient years, compared to 11 per 1000 patient years with conventional treatment; the corresponding frequency for paradoxical psoriasis in patients with other chronic inflammatory systemic diseases are 1.04-3.68 versus 1.45 per 1000 patient years. Paradoxical reactions tend to be more common with anti-TNF-alpha treatment than, for example, with the administration of ustekinumab, vedolizumab, and other agents. It is unclear whether some drugs have been noted to cause PR more commonly than others because of varying times since their approval, differences in immunogenicity, and differences between their target structures. Paradoxical reactions induced by biological agents are a problem confronting physicians in multiple specialties. They need to be distinguished from infectious and neoplastic diseases and from autoimmune conditions of other types. The treatment options for paradoxical reactions include local treatment, symptomatic therapy, prednisolone administration, and the discontinuation or switching of the biological agent, although some patients will react with a further paradoxical reaction to a different biological agent that is used instead.

Ustekinumab pharmacokinetics after subcutaneous administration in swine model.

BackgroundDue to multiple similarities in the structure and physiology of human and pig skin, the pig model is extremely useful for biological drug testing after subcutaneous administration. Knowledge of the differences between subcutaneous injection sites could have a significant impact on the absorption phase and pharmacokinetic profiles of biological drugs.ObjectivesThis study aimed to analyze the impact of administration site on pharmacokinetics and selected biochemical and hematological parameters after a single subcutaneous administration of ustekinumab in pigs. Drug concentrations in blood plasma were analyzed by enzyme-linked immunosorbent assay. Pharmacokinetic analyses were performed based on raw data using Phoenix WinNonlin 8.1 software and ThothPro v 4.1.MethodsThe study included 12 healthy, female, large white piglets. Each group received a single dose of ustekinumab given as a 1 mg/kg subcutaneous injection into the internal part of the inguinal fold or the external part of the inguinal fold.ResultsThe differences in absorption rate between the internal and external parts of the inguinal fold were not significant. However, the time of maximal concentration, clearance, area under the curve calculated between zero and mean residence time and mean residence time between groups were substantially different (p > 0.05). The relative bioavailability after administration of ustekinumab into the external part of the inguinal fold was 40.36% lower than after administration of ustekinumab into the internal part of the inguinal fold.ConclusionsHealthy breeding pigs are a relevant model to study the pharmacokinetic profile of subcutaneously administered ustekinumab.

Real-world long-term effectiveness of ustekinumab in Crohn's disease: results from the ENEIDA registry.

Data on the long-term administration of ustekinumab in recommended doses are limited. To assess the real-world, long-term effectiveness of ustekinumab in refractory Crohn's disease (CD). Multi-centre study of CD patients starting ustekinumab at the recommended dose, followed for 1year. Values for the Harvey-Bradshaw Index (HBI), endoscopic activity, C-reactive protein (CRP), and faecal calprotectin (FC) were recorded at baseline and at weeks 26 and 52. Demographic and clinical data, previous treatments, adverse events (AEs) and hospitalisations were documented. Potential predictors of remission were examined. A total of 407 patients were analysed. The initial maintenance dose of 90mg SC was administered every 12, 8 and 4weeks in 56 (14%), 347 (85%) and 4 (1%) patients, respectively. After 52weeks, treatment was discontinued in 112 patients (27.5%). At baseline, 295 (72%) had an HBI >4 points. Of these, 169 (57%) and 190 (64%) achieved clinical remission at weeks 26 and 52, respectively. FC levels returned to normal in 44% and 54% of patients at weeks 26 and 52, and CRP returned to normal in 36% and 37% of patients at weeks 26 and 52, respectively. AEs were recorded in 60 patients. The use of fewer previous anti-TNFα agents and ileal localisation were associated with clinical remission, and endoscopic severity was associated with poor response. No factors correlated with endoscopic remission. After 52 weeks, ustekinumab demonstrated effectiveness in inducing clinical and endoscopic remission in patients with refractory CD.

A Case of Meningococcal and HSV-2 Meningitis in a Patient Being Treated with Ustekinumab for Pityriasis Rubra Pilaris.

Pityriasis rubra pilaris (PRP) is a rare chronic inflammatory papulosquamous dermatosis affecting both adults and children. Six subtypes of PRP have been described. Recently, the management of PRP with biologic immunosuppressive agents regularly used in psoriasis has been supported by several case reports and series. Ustekinumab is an anti-IL12/23 IgG1 kappa human monoclonal antibody. It has been approved for the treatment of Crohn’s disease, plaque psoriasis, psoriatic arthritis and ulcerative colitis. It has also been reported to be effective as an off-label treatment for PRP. Current data are equivocal regarding infectious disease risk with ustekinumab administration. We describe a case of meningococcal and HSV-2 infection of the central nervous system in a patient being treated with ustekinumab for PRP.LEARNING POINTSThe administration of biologic immunosuppressive agents can result in severe life-threatening infections.Research is required on the infection potential of ustekinumab.Physicians should be aware of the possibility of infectious disease when prescribing biologic agents.Vaccination is essential in immunosuppressed adults.

P629 Long-term effectiveness and safety of ustekinumab (UST) in patients with active Crohn’s disease (CD) in real life: Interim analysis of the SUSTAIN study

Abstract Background Post-marketing data are required to confirm the durability and the long-term benefit and safety of UST in CD in clinical practice. Our aims were: (1) to evaluate the retention rate of UST in CD patients and to identify predictive factors of UST discontinuation; (2) to assess UST short-term effectiveness; (3) to analyse the durability of the response to UST in the long-term; and (4) to evaluate the safety of UST in clinical practice. Methods Retrospective, multicentre study (&amp;gt;60 centres). Patients with active CD [(Harvey–Bradshaw (HBI) &amp;gt;4)] that received at least one dose of UST intravenously before July 2018 were included. Clinical activity plus biochemical parameters were assessed at every UST administration. Clinical remission was defined as HBI score ≤4, and clinical response as a decrease in HBI ≥3 points. Loss of efficacy was defined as reappearance of symptoms that led to intensify the treatment dose, add another medication to control CD, switching or surgery in patients with short-term remission. The retention rate of UST treatment and the cumulative incidence of loss of efficacy were evaluated by survival curves, and predictive factors were assessed by Cox-regression. The short-term response was evaluated at week 8 and after the induction (week 16). Factors associated with short-term remission were assessed by multivariate analysis. Adverse events were recorded. Data quality was assured by remote monitoring. Results 331 CD patients have been included up to date (Table 1). The incidence rate of UST discontinuation was 15% per patient-year of follow-up: 8%, 13% and 20% at 6, 12 and 18 months (Figure 1). Previous surgery was the only factor associated with a higher risk of UST discontinuation [Hazard ratio (HR) = 2.03, 95% confidence interval (CI) = 1.1–3.6]. Short-term efficacy is shown in Figure 2. Previous surgery (OR = 0.3, 95% CI = 0.2–0.6) and higher HBI score at baseline (OR = 0.8, 95% CI=0.8–0.9) were associated with an impaired response to UST at week 16. The cumulative incidence of loss of response was 32% per-patient-year of follow-up (Figure 3); A higher HBI score at baseline was associated with a higher risk of losing response (HR = 1.2, 95% CI = 1.1–1.3). Neither the concomitant treatment with immunosuppressants nor the number of previous biologics were associated with UST short- and long-term benefit. Thirty adverse events were reported in 25 (7%) patients (Table 2). Conclusion Sustain is the largest real clinical practice study of UST to treat CD patients with the longest follow-up reported to date. UST was demonstrated to be effective in real-world use in the short and long run. Safety was consistent with the known profile of UST.

2096 Leukocytoclastic Vasculitis Related to Ustekinumab in a Crohn’s Disease Patient

INTRODUCTION: Leukocytoclastic vasculitis (LV) is a single-organ, skin-isolated small vessel vasculitis or angiitis, without systemic vasculitis or glomerulonephritis. This vasculitis is often mediated by immune complex deposition in the small vessels. Many drugs or inflammatory diseases may cause immune complex formation. CASE DESCRIPTION/METHODS: We report a case of a 28-year-old female patient followed in our outpatient clinic since the age of 20-years-old, with colonic Crohn's disease with perianal involvement (A2L2B1p). After the first pregnancy, she became steroid-dependent initiating immunomodulator and biologic therapy with partial response, with persistent perianal disease activity. Due to refractory disease, a diverting ostomy was made and ustekinumab 90 mg (every 8 weeks) was begun with no adverse events. Three years later, she presented painful and palpable purpura in the lower abdomen and both legs. The laboratory study performed to exclude a systemic disease as the cause of cutaneous vasculitis (liver and kidney function tests, serologies and immunological study with serum antibodies, cryoglobulins and serum complement levels) was normal. Ustekinumab was stopped until a diagnosed was achieved. A skin biopsy was performed that showed granulocytic dermatitis associated with the presence of fibrinoid material in the cutaneous small-vessels wall. Therapy with prednisone was started with symptomatic relief and resolution of cutaneous lesions. After this period, a new dose of ustekinumab was administered, with the reappearance of the same cutaneous lesions. The reappearance of cutaneous lesions following ustekinumab administration gave us a cause-effect relationship between the drug and cutaneous disease. Ustekinumab was permanently discontinued, with complete resolution of the cutaneous disease. DISCUSSION: In this report, we describe the first case of LV after a long term exposure to ustekinumab in a patient with IBD. When an adverse drug reaction occurs infrequently, it is unlikely to be detected in premarketing clinical trials. It is therefore important for the physician to recognize and report clinically significant adverse.

3151 Ustekinumab Administration Prior to Week Eight Following Induction Improves Symptoms and Maintains Remission of Severe Crohn's Disease: A Case Series

INTRODUCTION: Ustekinumab is a recently approved immunosuppressive agent for management of moderate to severe Crohn's Disease (CD). In trials, dosing was determined at 6 mg/kg for induction with maintenance injection of 90 mg every 8 weeks. Approximately half of the patients in the UNITI Induction trials did not respond to ustekinumab treatment when assessed at 6-8 weeks, and were included in the Maintenance trial with ustekinumab provided at week 8 or 12. Only 30-40% of these patients continued to have remission at maintenance trial conclusion. We present a case series of two CD patients who were initiated on ustekinumab therapy but required a shortened maintenance dose interval to achieve/maintain remission. CASE DESCRIPTION/METHODS: Case 1: A 33 year old female presenting clinically with intermittent abdominal pain, diarrhea, occasional blood in stool &amp; nocturnal symptoms was diagnosed with CD in 2017 via computed tomography of the abdomen combined with colonoscopy revealing terminal ileum aphthous ulceration. Previous therapies included budesonide, prednisone &amp; adalimumab. Ustekinumab induction was initiated on 2/2/2018. However, on 3/20/2018, the patient developed severe abdominal pain consistent with a CD flare. Following, she has received ustekinumab injections every 4-6 weeks to maintain disease remission. Case 2: A 47 year old male initially diagnosed with CD at the age of 22, complicated by emergent colectomy with end ileostomy in 2014 presented with an acute flare consisting of abdominal pain, peristomal fistulas and increased ostomy output. Following evaluation, he underwent surgical correction of fistula, drainage of intraabdominal wall abscess &amp; abdominal wall reconstruction in December 2018. Prior to this, he was treated with sulfasalazine, mercaptopurine, azathioprine along with immunomodulators including infliximab &amp; certolizumab without adequate response. In January 2019, ustekinumab therapy was initiated with standard induction followed by injectable dosing every 4 weeks due to CD severity and physician recommendation. Following this schedule, the patient has had improved ostomy output and symptom control. DISCUSSION: In our experience, shortening the interval of injectable ustekinumab dosing to 4-6 weekly from 8 weeks has proven successful in maintaining remission for patients with severe CD. This subsegment of CD patients was excluded in trials and further investigation is needed to assess long term efficacy of shortened ustekinumab therapy intervals to maintain remission.

Ensuring continuity of care for patients transitioning from intravenous to subcutaneous therapy at a health system owned specialty pharmacy

Background: On 26 September 2016, the FDA approved ustekinumab for the treatment of Crohn’s disease, which uniquely requires administration via two distinctly different methods, induction intravenous infusion followed by maintenance of subcutaneous self-injection. While therapeutically appropriate, the two dosing methods present administrative challenges beyond currently available treatments including verification of insurance coverage for both medical and pharmacy benefit, coordination of medication distribution, and care coordination and communication between the infusion service and specialty pharmacy. To ensure continuity of care, the successful facilitation of this process requires a care system that has experience in managing both infusion and specialty pharmacy medications.Objectives: Describe process and key learnings for complex therapy administration.Methods: In this descriptive analysis we characterize the patient, provider, and dispensing process across multiple sites of care. We highlight common scenarios experienced by patients and summarize unique challenges of coordinating treatment across multiple care settings.Results: Prior to the approval of ustekinumab, Fairview Pharmacy Services identified potential gaps in coordination between different the clinical settings and partnered with the health system, local clinics, and infusion centers to seamlessly coordinate care across medication delivery settings. A designated Specialty Care Coordinator is responsible for performing end-to-end communication and coordination of all activities for patients to ensure the transition between delivery settings does not result in gaps in therapy. Since process implementation, Fairview has successfully coordinated ustekinumab administration for over 200 patients within and external to our health system to ensure all patients received the intravenous induction dose prior to receiving the subcutaneous maintenance dose. In addition, we identified scenarios where lack of coordination can result in disruption to treatment for the patient or medication waste to the healthcare system.Conclusions: Health system owned specialty and infusion pharmacy services are uniquely positioned to facilitate and coordinate a successful transition of complex therapy with minimal disruption across various clinical settings. Fairview Pharmacy Services unique care model and partnerships are equipped to handle both our own patients and those being seen outside the system.

Impact of Temperature on Injection-Related Pain Caused by Subcutaneous Administration of Ustekinumab: A Three-arm Crossover Open-label Randomized Controlled Trial

Background: Adherence to subcutaneous biologic agents for the treatment of psoriasis can be negatively influenced by injection pain.Objective: To explore the differences in injection site pain when patients are pre-treated with heat or cold, versus no pre-treatment prior to administration of a subcutaneous biologic agent.Methods: In an observational cohort study, patients receiving subcutaneous injections of ustekinumab were randomly assigned to receive pretreatment with ice, heat, or no intervention over three visits. Post-dose, patients rated pain on a 100 mm visual analogue scale (VAS).Results: There was an increase in the VAS score for both heat (2.51, P=0.30) and ice (3.33, P=0.16), compared to no intervention. No differences were found between the two intervention groups (-0.83, P=0.73). On average, females had the same VAS scores with ice compared to that of no intervention (-0.12, P=0.97) and a non–significant decrease of 3.29 points (P=0.38) with heat. Males had increased pain scores by 5.65 points (P=0.07) with ice and by 6.39 points (P=0.04) with heat.Limitations: Pain is a subjective measurement and objective quantification is difficult.Conclusions: On average, neither heat nor cold application reliably reduced pain. Our results do not support the application of heat or cold prior to ustekinumab injection.

Erythrodermic Psoriasis Improved by Ustekinumab: A Report of Two Cases.

Dear Editor: Erythrodermic psoriasis is a severe form of psoriasis, presenting as prominent erythema rather than thick scales, affecting the entirebody including the face, trunk, extremities, and nails. The disease poses a therapeutic challenge, and numerous treatment choices have been examined1. Ustekinumab (Stelara; Jannssen Biotech Inc., Horsham, PA, USA) is a human monoclonal antibody targeting the p40 subunit shared by interleukin (IL)-12 and IL-23. This biological agent has shown good efficacy against plaque-type psoriasis and emerging effectiveness in a variety of inflammatory skin diseases such as atopic dermatitis2. Erythrodermic psoriasis has been an exclusion criterion in studies evaluating the efficacy of ustekinumab for psoriasis, but recently, a few reports have proven its efficacy in treating erythrodermic psoriasis3,4,5. Herein, we report 2 cases of erythrodermic psoriasis that successfully improved following ustekinumab treatment. A 42-year-old man presented with a 7-year history of erythrodermic psoriasis and a 5-year history of psoriatic arthritis. He was previously treated with cyclosporine A, methotrexate, and narrow band ultraviolet B phototherapy. The treatments were interrupted due to liver enzyme elevation and low efficacy. The patient was treated with ustekinumab 45 mg subcutaneously at 0, week 4, and every 12 weeks thereafter. The patient was also diagnosed with latent pulmonary tuberculosis by the QuantiFERON-TB Gold In-Tube test (Cellestis Limited, Carnegie, VIC, Australia). He was concurrently treated with isoniazid 300 mg/day for 6 months and has not experienced a recurrence of tuberculosis to date. At week 28, his Psoriasis Area and Severity Index (PASI) score decreased from 64.8 (baseline) to 9.6 (Fig. 1). The psoriasis aggravated temporarily during discontinuation of the treatment for 5 months and he promptly recovered upon restarting ustekinumab injections. His arthritis symptoms improved slightly, but the improvement was not sufficient for him to stop taking oral sulfasalazine and steroid for the arthralgia. Fig. 1 A 42-year-old man presented with whole body erythema with scanty scales. He responded well to ustekinumab (A: baseline, B: 28 weeks after the treatment, C: 76 weeks after the treatment). The second case is a 26-year-old man suffering from erythrodermic psoriasis for 10 years. Therapies with conventional systemic agents and anti-tumornecrosis factor were discontinued due to lack of efficacy. Four months after the first administration of ustekinumab (45 mg), the patient achieved 75% improvement of the PASI score from 50.9 (baseline) to 4.4 (Fig. 2A, B). Currently, the patient has received treatment for 112 weeks, and is maintaining a PASI 90 improvement (Fig. 2C). Fig. 2 A 26-year-old man. (A) Baseline: normal skin islands are noticeable within the diffuse erythroderma. Clinical improvement was significant and sustained (B) 28 weeks after the treatment and (C) 112 weeks after the treatment, respectively. Both patients are currently on treatment, and show sustained responses without any adverse reactions or exacerbations. Although further studies are needed to evaluate the efficacy and safety of ustekinumab, it is likely that ustekinumab can be an effective therapeutic option for patients affected by erythrodermic psoriasis where other treatments have failed.

Immunopathogenetic mechanisms of action of ustekinumab, a new drug for the treatment of psoriatic arthritis and psoriasis

The paper analyzes the data available in the literature on the mechanisms of action of ustekinumab (UST), a new medication to treat activepsoriatic arthritis (PsA) and psoriasis. UST is a human IgG1κ monoclonal antibody (mAb). The mechanism of action of the drug is described; UST is shown to effectively neutralize interleukin 12- (IL12) and IL-23-mediated responses in humans, but not to affect the immune response mediated by cytokines or cellular activity. The paper considers the results of clinical trials of UST used to treat psoriasis and psoriatic arthritis, among them there are PSUMMIT-1 and 2 which included 615 patients with active PsA. Long-term treatment with UST is noted to exhibit an increasing clinical efficacy. At week 52 of treatment, all the patients are shown to have 58% ACR20 responses, 34.2% ACR50 responses, 19.6% ACR70 responses, and 69% PASI75 responses. There is evidence that UST therapy slows down joint radiographic progression in patients with active PsA. Trends in the body mass index (BMI) of psoriatic patients treated with UST are comparatively analyzed; at this time the use of the drug contributes to a significantly smaller increase in BMI than that the other mAb-based drug infliximab, which is relevant in patients with PsA, whose obesity lowers the clinical effect of anticytokine therapy. It is concluded that the results of UST administration confirm successful targeted therapy with mAb-based drugs that effectively reduce the severity of clinical manifestations in psoriasis and psoriatic arthritis presumably through local changes in the expression of cytokines in the skin or synovium; however, but it is necessary to perform further fundamental studies and clinical trials of this class of drugs aimed at blocking the biological effects of certain cytokines.

RESULTS OF USTEKINUMAB TREATMENT IN PATIENTS WITH PSORIATIC ARTHRITIS IN THE RUSSIAN FEDERATION ACCORDING TO THE DATA OF PSUMMIT 1 AND PSUMMIT 2

Psoriatic arthritis (PsA) is a chronic inflammatory disease of the joints, vertebral column, and entesises, which is associated with psoriasis. T helper type 17 cells (Th-17) play a leading role in the development of inflammation in psoriasis and PsA so different biologicals affecting interleukins (IL) 17 and 23 are being intensively investigated. Randomized, placebo-controlled Phase III PSUMMIT 1 (NCT01009086, EudraCT 2009-012264-14) and PSUMMIT 2 (NCT01077362, EudraCT 2009-012265-60) studies were undertaken to evaluate the efficiency and tolerability of ustekinumab (UST) treatment in PsA patients. Subject s and methods. The PSUMMIT 1 study covered 152 Russian patients with active PsA (≥5 tender and ≥5 swollen joints; C-reactive protein ≥3 mg/l) who were randomly (using the dynamic centralized randomization method on the basis of an interactive vocal response algorithm) divided into three groups (at a 1:1:1 ratio): 1) subcutaneous UST 45 mg; 2) UST 90 mg; 3) placebo (PL) at baseline, 4 weeks later, and then every 12 weeks). After 16 weeks the patients showing a less than 5% reduction in the number of tender and swollen joints were given UST 45 mg (if they belonged to the PL group) or 90 mg (if they were in the UST 45-mg group). The PL-receiving patients were given UST 45 mg at weeks 24 and 28 and then every 12 weeks. The treatment duration was 2 years. A therapeutic response was estimated by theAmericanCollege of Rheumatology (ACR) response criteria. The PSUMMIT 2 study enrolled 40 Russian patients who had previously received or were currently receiving disease-modifying anti-rheumatic drugs and/or nonsteroidal anti-inflammatory drugs and tumor necrosis factor-α inhibitors. The patients were randomized to the groups of those receiving UST 45 mg or 90 mg or PL at baseline and at week 4, then once every 12 weeks. The last dose of UST was given at week 40. The follow-up lasted until week 60. Result s and discussion. In the PSUMMIT 1 study, 24-week administration of UST 45 mg and 90 mg significantly more frequently ensured a 20% improvement according to the ACR criteria than that of PL (39.2; 44.0, and 15.7%, respectively; p < 0.01); the therapeutic response persisted until week52. In the PSUMMIT 2, following 24 weeks, the UST 45-mg and 90-mg groups considerably more often showed a 20% improvement according to the ACR criteria than the PL group (64.3, 57.1, and 16.7%, respectively; p < 0.01); the therapeutic response persisted until week 52. Among 150 Russian patients taking UST, on the average, for 45.1 weeks in the PSUMMIT 1 study, 62 (41.3%) were observed to have adverse events (AE) that were serious in 6 (4.0%). Among 40 PsA patients who participated in the PSUMMIT 2 study inRussia, AEs were seen in a total of 25 (62.5%) patients, serious AEs being absent. Conclusion. The results of the PSUMMIT 1 and PSUMMIT studies in the Russian population indicated that UST treatment contributed to a significant reduction of PS symptoms and exhibited a good tolerability. DOI: http://dx.doi.org/10.14412/1995-4484-2015-125-133