Publications

INTRODUCTION: Medicare patients in the United States may face high out-of-pocket (OOP) costs for specialty inflammatory bowel disease (IBD) medications.

METHODS: We conducted a study of Medicare OOP costs for specialty IBD medications between 2020 and 2022 and compared them to incomes of typical Medicare beneficiaries.

RESULTS: In 2022, median OOP costs ranged from 6.4% to 59.2% of annual income for a Medicare patient with approximately median income. Inflation-adjusted OOP costs for most medications increased between 2020 and 2022 though decreased for infliximab and its biosimilars.

DISCUSSION: OOP costs may limit many Medicare beneficiaries' access to specialty IBD medications.

INTRODUCTION: We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD).

METHODS: This study used a retrospective, multicenter, multinational consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions were assessed using time-to-event analysis, and clinical predictors were assessed by using multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation.

RESULTS: A total of 1,113 patients (51.8% female, 90% prior antitumor necrosis factor exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naive patients achieved significantly higher rates of clinical and endoscopic remissions at 63% and 55%, respectively. On multivariable analyses, prior antitumor necrosis factor (hazard ratio, 0.72; 95% confidence interval, 0.49-0.99) and vedolizumab exposure (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77 of 102 (75%) underwent dose optimization, and 44 of 77 (57%) achieved clinical response. An additional 152 of 681 patients (22.3%) were dose-optimized because of primary nonresponse incomplete response to UST, of whom 40.1% (61 of 152) responded. Serious infections occurred in 3.4% of patients while other noninfectious adverse events (lymphoma [n = 1], arthralgia [n = 6], rash [n = 6], headache [n = 3], hepatitis [n = 3], hair loss [n = 3], neuropathy [n = 1], and vasculitis [n = 1]) occurred in 2.4% of patients.

DISCUSSION: UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in biologic-naive patients, and dose escalation may recapture clinical response.

BACKGROUND AND AIMS: The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics.

METHODS: This was a prospective cohort study including patients with inflammatory bowel diseases on maintenance doses of infliximab, vedolizumab, or ustekinumab on monotherapy or combination with a thiopurine or oral methotrexate. We collected 6-TGN concentrations, biomarker levels, and clinical and endoscopic disease activity. The primary outcomes were infliximab, vedolizumab, and ustekinumab concentrations as well as anti-drug antibodies (ADAs).

RESULTS: A total of 369 patients were recruited (113 infliximab, 133 vedolizumab, and 123 ustekinumab). Patients with 6-TGN levels ≥146 pmol per 8 × 108 red blood cells (RBCs), and those receiving combination therapy with thiopurine or oral methotrexate had significantly higher infliximab concentrations when compared with monotherapy (median levels of 17.4 μg/mL on thiopurine with 6-TGN ≥146 pmol per 8 × 108 RBCs, 17.1 on methotrexate, and 3.9 on infliximab monotherapy; P = .001 for both comparisons). However, there was no association between the use of immunomodulators and 6-TGN concentrations with vedolizumab (median levels of 8.8 on thiopurine with 6-TGN ≥152 pmol per 8 × 108 RBCs, 6.8 on methotrexate, and 10.5 on vedolizumab monotherapy; P > .05 for both comparisons) or ustekinumab median concentrations (median levels of 5.0 on thiopurine with 6-TGN ≥154 pmol per 8 × 108 RBCs, 5.2 on methotrexate and 7.0 on ustekinumab monotherapy; P > .05 for both comparisons). Fourteen (12%) patients had anti-infliximab antibodies, while 1 patient had ADAs in each of the other drug cohorts.

CONCLUSIONS: Achieving higher 6-TGN levels or the use of methotrexate improved the pharmacokinetics of infliximab. Conversely, these data do not support the use of combination therapy to augment pharmacokinetics with vedolizumab or ustekinumab.

Many patients with inflammatory bowel disease [IBD] are treated with anti-tumour necrosis factor [TNF] therapies, of which infliximab [IFX] is most commonly used. Loss of response [LOR] to anti-TNF therapy due to immunogenic failure accounts for 20% of subsequent medical intervention and is defined, using a drug-sensitive assay, as low or undetectable concentration of drug with high titres of anti-drug antibodies [ADAb]. We performed a systematic review to investigate the use of a drug-tolerant assay during both induction and maintenance, to monitor patients treated with anti-TNFs. After the search on PubMed, 90 publications were reviewed. Most ADAb detection methods are drug-sensitive, cannot detect ADAb in the presence of drug, and therefore cannot be used close to drug administration when the drug concentration is too high. To overcome this major limitation, several drug-tolerant techniques have been developed and will be discussed in this review. Using drug-tolerant assays, ADAb against IFX or adalimumab [ADM] can be detected during induction and predict primary non-response or LOR. Drug-sensitive assays do not allow detection of ADAb during the induction phase when IFX or ADM concentration is typically high.

BACKGROUND: We examined whether the difficulties of patients with somatoform disorders (SFDs) in integrating medical reassurance can be altered by preventing patients from devaluing reassuring information through defensive cognitive strategies.

METHOD: Patients with SFD (n = 60), patients with major depression (n = 32), and healthy volunteers (n = 37) watched a videotaped doctor's report, which provided medical reassurance for gastroenterological complaints. Subsequently, participants were asked about their perception of the report. In the SFD sample, patients' appraisal of the reassuring was experimentally modulated: In one condition, doubts about the validity of the doctor's diagnostic assessment were triggered; in another condition, the devaluation of medical reassurance was blocked through underscoring the validity of the doctor's diagnostic assessment; and a control condition received no manipulation.

RESULTS: As evident on all outcome variables, patients with SFD had more difficulty integrating medical reassurance than depressed and healthy people. Within the SFD sample, participants from the experimental condition blocking the devaluation of medical reassurance rated the likelihood of an undetected serious disease to be significantly lower than the other two conditions. They also reported less emotional concern and a lower desire to seek the opinion of another doctor.

CONCLUSIONS: By comparing patients with SFD to both a healthy and a clinical control group, the current study suggests that the difficulty in processing reassuring medical information is a specific psychopathological feature of SFD. Furthermore, our results suggest that the integration of medical reassurance can be improved by preventing patients from devaluing reassuring information through dismissive cognitive strategies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

BACKGROUND: The estimated prevalence of bloating is 15 to 30% in the adult US population and is even higher in patients with disorders of gut-brain interaction (DGBIs). Despite this frequency, there is little research into patients who endorse bloating as a predominant symptom. The aim of this study was to better characterize these patients.

MATERIALS AND METHODS: New patients with DGBIs were asked to identify their 3 most predominant symptoms over the preceding 3 months; those who reported bloating were classified as "bloating predominant." Rome IV and symptom-specific questionnaires were administered to assess for the frequency of DGBIs and other predominant symptoms in this patient population. Using univariable and multivariable modeling, we analyzed the associations between bloating predominance, DGBI subtype, and clinical characteristics.

RESULTS: Of the 586 patients surveyed, 242 (41%) reported predominant bloating. Bloating-predominant patients were more likely to be female, younger, and meet the criteria for IBS-mixed (IBS-M), functional constipation, and functional dyspepsia compared with nonbloating-predominant patients. Bloating-predominant patients were also more likely to endorse concurrently predominant constipation, incomplete evacuation, abdominal pain, belching, and/or nausea. On multivariable logistic regression, constipation and abdominal pain severity were positively associated, although depression was negatively associated with predominant bloating.

CONCLUSIONS: Patients with predominant bloating are more likely to have constipation-related symptoms than diarrhea-related symptoms. They are also more likely to have more severe abdominal pain than patients without predominant bloating. These findings help characterize patients with bloating as a predominant symptom and suggest that diagnosing and treating constipation should be considered as first-line treatment.

INTRODUCTION: Exposure-outcome relationship data show that higher infliximab concentrations are associated with better outcomes in patients with Crohn's disease (CD). However, most of these data were derived from adult patients on maintenance therapy. We aimed to investigate the association of infliximab concentrations during and early after induction therapy of infliximab with short-term and long-term clinical outcomes in a pediatric CD population.

METHODS: We conducted a post hoc analysis of the REACH trial which included pediatric patients with moderate-to-severe CD treated with infliximab (n = 103). The investigated outcomes were early clinical remission (CR) defined as a pediatric CD activity index score of ≤ 10, assessed at week 10, and long-term clinical response (LTCR) defined as a decrease from baseline in the pediatric CD activity index score of at least 15 points, with a total score of ≤ 30 and no need for drug discontinuation, assessed at weeks 30 and 54.

RESULTS: Based on multivariable logistic regression analysis, higher week 10 infliximab concentrations were independently associated with CR at week 10 (odds ratio: 1.54; 95% confidence interval: 1.06-2.22; P = 0.022) and LTCR at week 30 (odds ratio: 1.62; 95% confidence interval: 1.12-2.36; P = 0.010). Receiver operating characteristic analysis identified week 10 infliximab concentration thresholds of ≥7.1 μg/mL and ≥6.5 μg/mL to be associated with CR at week 10 and LTCR at week 30, respectively.

DISCUSSION: Higher postinduction infliximab concentrations are associated with both short-term and long-term favorable clinical outcomes in pediatric patients with CD. Tailoring dosing during induction to achieve higher infliximab exposure may lead to better outcomes in pediatric patients with CD.

Psoriasis is a recurring, immune-mediated dermatological disorder. Many therapeutic agents are available for the treatment of psoriasis, including immunosuppressants and biologic treatments with immunosuppressant action. The employment of nanotechnology allows drug tailoring to achieve dermal targeting, improve efficacy and minimize undesirable effects. Here we discuss the use of the topical route in combination with nano-based drug delivery systems containing immunosuppressants for the management of psoriasis. This review is based on articles selected from 2011 to 2022, using the keywords "Psoriasis" AND "Immunosuppressants" AND "Nano*" in the main databases. Fifty-seven articles were retrieved, although only forty-two matched the inclusion criteria. Nanocarriers such as liposomes, ethosomes, niosomes, solid lipid nanoparticle, nanostructured lipid carriers and microspheres containing immunosuppressive drugs (methotrexate, cyclosporine, tacrolimus, and etanercept) were identified. The main findings of these studies are related to the improved in vitro/ex vivo permeation/penetration and therapeutic efficacy of nanoparticles in vitro and in vivo, compared to the drug in solution. Based on the studies discussed in this review, encapsulation in several types of nanocarriers decreases toxicity, dose, and dose frequency. Furthermore, it enables specific targeting of the active drug, pointing to the possibility of improving topical therapy for psoriasis. In conclusion, nanoformulations represent a novel and promising tool for psoriasis treatment.

INTRODUCTION: Nocebo effects are believed to influence the rate of reported adverse events (AE) and subject withdrawal in both the treatment and placebo groups of randomized clinical trials (RCT). Neuromodulators are commonly prescribed to treat disorders of gut-brain interaction (DGBI), but adherence to these medications is often limited by side effects such as headache, dry mouth, fatigue, and altered bowel habits. We performed a systematic review and meta-analysis to assess the proportion and risk difference of patients who experienced side effects leading to withdrawal in the placebo arm vs the treatment arm of RCT of neuromodulators for DGBI. We also sought to estimate the risk of developing any AE in the placebo arm of these studies and the rate of specific individual AEs.

METHODS: We searched MEDLINE, Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials Searches to identify RCT that included terms for DGBI and for commonly prescribed neuromodulators. We calculated pooled proportions of patients experiencing an AE leading to withdrawal in the active treatment group vs the placebo group with 95% confidence intervals (CI), the pooled proportions of patients experiencing any AE, the pooled proportions of patients experiencing specific AE such as dizziness and headache, the pooled proportions of patients experiencing severe AE, and corresponding pooled risk differences with 95% CI.

RESULTS: There were 30 RCT included representing 2,284 patients with DGBI. Twenty-seven RCT reported data on AE leading to withdrawal. The pooled proportion of total patients with AE leading to withdrawal in the placebo group was 4% (95% CI 0.02-0.04). The pooled proportion of patients with AE leading to withdrawal who received neuromodulators was 9% (95% CI 0.06-0.13). In the 12 studies reporting data on patients experiencing at least 1 AE, the pooled proportion of patients experiencing any AE in the placebo group was 18% (95% CI 0.08-0.30), compared with 43% (95% CI 0.24-0.63) in the neuromodulator group. Thus, approximately 44% of the rate of withdrawal (0.04/0.09) and 42% of the rate reporting any side effects (0.18/0.43) in the neuromodulator group may be attributed to nocebo effects in the right context. Subgroup analysis by sex, medication class, risk of bias, and specific DGBI revealed differing withdrawal rates. There was no statistically significant difference in patients experiencing individual AE of dizziness, headache, or diarrhea. Rates of dry mouth, fatigue, and constipation were higher in treatment groups compared with those in placebo groups.

DISCUSSION: Patients with DGBI in RCT randomized to placebo groups frequently experience AE and AE that lead to withdrawal consistent with a strong nocebo effect. Nonspecific AE such as dizziness, headaches, and diarrhea occurred similarly in patients receiving placebo compared with those receiving neuromodulators.