A Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose escalation study to evaluate the safety and pharmacokinetics/pharmacodynamics of PF-06835375, a C-X-C chemokine receptor type 5 directed antibody, in patients with systemic lupus erythematosus or rheumatoid arthritis.

BACKGROUND: The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF­06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18-70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03-6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3-10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant. RESULTS: In total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t1/2 ranged from 3.4-121.4 h (SAD cohorts) and 162.0-234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3-99.3%/62.4-98.7% [SAD] and 91.1-99.6%/89.5-98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375. CONCLUSIONS: These data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03334851.

Ustekinumab in paediatric patients with moderately to severely active Crohn's disease: UniStar study long-term extension results.

OBJECTIVES: To assess the efficacy, safety, immunogenicity, and pharmacokinetics through 240 weeks of ustekinumab treatment in paediatric patients from the long-term extension (LTE) of the phase 1, double-blind UniStar trial. METHODS: Paediatric patients with moderately to severely active Crohn's disease (CD) were randomised 1:1 and stratified by body weight (<40 or ≥40 kg) to low- or high-dose intravenous ustekinumab followed by a subcutaneous maintenance dose at Week 8. At Week 16, patients were eligible to enter the LTE at the discretion of the investigator and continued maintenance dosing every 8 weeks up to Week 240. RESULTS: Of the 34 patients who entered the LTE, 25 patients with evaluable data completed Week 48, and 41.2% (14/34) achieved clinical remission at Week 48. Among the 24 patients with Week-0 C-reactive protein (CRP) levels ≥3 mg/L, 29.2% (7/24) achieved normalisation of CRP at Week 48, while imputing missing data as failures. Through Week 240, the most common adverse events were infections (n = 28) and gastrointestinal disorders (n = 26). The most common serious adverse event was worsening of CD (n = 6). Only one patient had detectable antibodies to ustekinumab. Median serum ustekinumab concentrations remained consistent through Week 48, were detectable through Week 224, and trended lower in patients <40 kg. CONCLUSIONS: Efficacy and pharmacokinetics through 1 year and safety and immunogenicity through 4 years of ustekinumab treatment in paediatric patients with CD were generally comparable to those previously reported in adults.

Outcomes in Adult Inflammatory Bowel Disease Clinical Trials: Assessment of Similarity Among Participants with Adolescent-Onset and Adult-Onset Disease.

BACKGROUND AND AIMS: Most pediatric IBD studies are performed after medications are approved in adults and the majority of participants in these studies are adolescents. We hypothesized that adolescent-onset IBD is not fundamentally different than adult-onset IBD. If this is correct, the value of delaying access to novel drugs in adolescents becomes questioned. METHODS: Data from 11 randomized, double-blind, placebo-controlled adult phase 2 and 3 trials of 4 biologics were analyzed. Participants were categorized as having adolescent- or adult-onset disease (diagnosed 12 to <18, or ≥18 years). Multivariable modelling explored the association between age at diagnosis and response to treatment after adjustment for disease duration, extent, and severity at baseline. Data from dose arms were pooled to evaluate similarity of therapeutic response between adolescent- and adult-onset IBD within the same trial (not between doses or across trials). Ratios of odds ratios between the two groups were evaluated. RESULTS: Data from 6,283 study participants (2,575 with Crohn's disease [CD], 3,708 with ulcerative colitis [UC]) were evaluated. Of 2,575 study participants with CD, 325 were 12-<18 years old at diagnosis; 836 participants (32.4%) received placebo. Of 3,708 participants with UC, 221 were 12-<18 years old at diagnosis; 1,212 (33%) were receiving placebo. The majority of the ratios of ORs were within two-fold, suggesting that responses in adolescent and adult-onset participants are generally similar. CONCLUSION: Data presented lend support for extrapolating efficacy of biologics from adults to adolescents with IBD, which would facilitate earlier labeling and patient access.

A standardized scoring system for conflict of interest determination and mitigation for AASLD-sponsored continuing medical education events.

Continuing medical education (CME) is essential to increase the knowledge, skills, and professional performance of health care providers. To keep the content of CME relevant and balanced, conflict of interest (COI) determination and mitigation is essential. While the Accreditation Council for Continuing Medical Education provides oversight and guidelines, each organization that sponsors CME programs has its own protocol for COI. To standardize and simplify the American Association for the Study of Liver Diseases' approach to COI, we propose a standardized COI disclosure scoring system for all CME programs to notify the audience of any conflicts and how such conflicts can be mitigated.

Biosimilars for Rheumatoid Arthritis: Riding the 2023 Wave [Podcast].

This article discusses some of the queries and concerns that patients may have about initiating or switching to treatment with a biosimilar for rheumatoid arthritis following the US 2023 release of several biosimilars of the adalimumab reference product, also known by the brand name, Humira. The article also covers the difference between a generic medicine and a biosimilar, and the clinical evidence to support the safety and efficacy of adalimumab biosimilars in patients with rheumatoid arthritis.

Janus kinase inhibitors: efficacy and safety.

PURPOSE OF REVIEW: Janus kinase inhibitors (JAKi) have been available for the treatment of rheumatoid arthritis (RA) since 2012 and are indicated for patients with active disease despite csDMARD therapy. Efficacy and safety, as demonstrated in the clinical trials, was similar to biologics. A recent post marketing trial suggested safety concerns with the JAKi, which will be reviewed. RECENT FINDINGS: A post marketing Food and Drug Administration (FDA) mandated open-label randomized clinical trial of tofacitinib 5 and 10 mg twice daily (b.i.d.) compared with adalimumab and etanercept was conducted in RA patients on background methotrexate who were at a high risk for cardiovascular disease. This was a noninferiority study evaluating the incidence of major adverse cardiovascular events (MACE) and malignancy with the therapies. Noninferiority for both doses of tofacitinib was not achieved with a numerical increase in MACEs and malignancy with tofacitinib compared to the TNF inhibitors. A dose-dependent increase in venous thromboembolism (VTE) risk with tofacitinib was observed. The findings from this study resulted in the FDA and European Medicines Agency (EMA) restriction of use for all Jaki to RA patients who had failed TNF inhibitors. SUMMARY: JAK inhibitors are effective treatments for RA. Issues have been raised regarding safety in patients with an increase in cardiovascular risk and VTE risk resulting in the need for risk stratification.

A Treat-to-Target Strategy Guided by Pan-Enteric Evaluation in Children With Crohn's Disease Improves Outcomes at 2 Years.

BACKGROUND AND AIMS: It is uncertain whether a treat-to-target approach could be an effective strategy for improving outcomes in children with Crohn's disease (CD). Previously, we reported mucosal healing (MH) and deep remission rates throughout the intestinal tract by performing 3 pan-enteric capsule assessments and using a treat-to-target strategy over 52 weeks in children with CD. This report describes the outcomes of this approach at 104 weeks. METHODS: Children with known CD who completed the 52-week protocol repeated pan-enteric capsule endoscopy (PCE) at 104 weeks. Results at weeks 52 and 104 were compared, and long-term outcomes between patients, with and without MH, were calculated using an intention-to-treat analysis of clinical relapse, need for steroids, treatment escalation, hospitalization, and surgery. RESULTS: Of the previous study cohort of 48 patients, 46 (96%) were available for this extension study (28 [61%] of 46 with MH and 18 [39%] of 46 without MH at 52 weeks). When evaluated at 104 weeks, MH was maintained in 93% of patients with MH at 52 weeks. In the intention-to-treat analysis, complete MH at 52 weeks was associated with reduced risk of steroid use (log-rank P < .0001), treatment escalation (log-rank P < .0001), hospitalization (log-rank P < .0001), and clinical relapse (log-rank P < .0001). CONCLUSIONS: When a PCE-based, treat-to-target strategy is employed, MH is sustainable (93%) over a 1-year period and is correlated with improved patient outcomes, including reduced need for steroids, treatment escalation, hospitalization, and clinical relapses at 104 weeks.ClinicalTrials.gov number: NCT03161886.

Post-Marketing Safety Surveillance of Tofacitinib over 9 Years in Patients with Psoriatic Arthritis and Rheumatoid Arthritis.

INTRODUCTION: The safety of tofacitinib in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) has been demonstrated in clinical studies of ≤ 4 and 9.5 years, respectively. Post-marketing surveillance (PMS) data for tofacitinib from spontaneous and voluntary adverse event (AE) reports have been published for RA, but not PsA. To inform the real-world safety profile of tofacitinib in PsA, we evaluated AE reports submitted to the Pfizer safety database (including RA data for context). METHODS: Endpoints included AEs, serious AEs (SAEs), AEs of special interest (AESIs; serious infections, herpes zoster, cardiovascular events, malignancies, venous thromboembolism), and fatal cases. Exposure was estimated using IQVIA global commercial sales data. Number, frequency, and reporting rates (RRs; number of events/100 patient-years' [PY] exposure) were summarized by indication and formulation (immediate release [IR] 5 or 10 mg twice daily], modified release [MR] 11 mg once daily, or all tofacitinib). The data-collection period differed by indication (PsA: 14 December 2017 [US approval, IR/MR] to 6 November 2021; RA: 6 November 2012 [US approval, IR] to 6 November 2021; MR approval, 24 February 2016). RESULTS: A total of 73,525 case reports were reviewed (PsA = 5394/RA = 68,131), with 20,706/439,370 PY (PsA/RA) of exposure. More AEs were reported for IR versus MR (IR/MR: PsA = 8349/7602; RA = 137,476/82,153). RRs for AEs (IR/MR: PsA = 59.6/113.4; RA = 44.0/64.8) and SAEs (PsA = 8.1/13.6; RA = 8.0/9.5) were higher with MR versus IR. AE RRs (RA) in the first 4 years after IR approval were 95.9 (IR; 49,439 PY) and 147.0 (MR; 2000 PY). Frequency of SAEs, AESIs, and fatal cases was mostly similar across formulations and indications. The most frequently-reported AE Preferred Terms (PsA/RA) included drug ineffective (20.0%/17.8%), pain (9.7%/10.6%), condition aggravated (9.9%/10.5%), headache (8.8%/7.9%) and, for PsA, off-label use (10.5%/3.4%). CONCLUSIONS: Tofacitinib PMS safety data from submitted AE reports were consistent between PsA and RA, and aligned with its known safety profile. Exposure data (lower MR versus IR; estimation from commercial sales data), reporting bias, reporter identity, and regional differences in formulation use limit interpretation.

A Randomized, Double-Blind, Sham-Controlled, Clinical Trial of Auricular Vagus Nerve Stimulation for the Treatment of Active Rheumatoid Arthritis.

OBJECTIVE: Preliminary evidence suggests that vagus nerve stimulation (VNS) may have some benefit in patients with rheumatoid arthritis (RA); however, prior studies have been small and/or uncontrolled; this study aimed to address that gap. METHODS: This randomized, double-blind, sham-controlled trial enrolled patients aged 18 to 75 years with active RA who had failed conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and were naïve to biologic and/or targeted synthetic DMARDs. All patients received an auricular vagus nerve stimulator and were randomized 1:1 to active stimulation or sham. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Secondary endpoints included mean changes in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI). RESULTS: A total of 113 patients (mean age 54 years; 82% female) enrolled, and 101 patients (89.4%) completed week 12. ACR20 response at week 12 was 25.0% for active stimulation versus 26.9% for sham (difference vs. sham, -1.9; 95% CI, -18.8, 14.9, P = 0.823). The least square mean ± SE change in DAS28-CRP was -0.95 ± 0.16 for active stimulation and -0.66 ± 0.16 for sham (P = 0.201); in HAQ-DI it was -0.19 ± 0.06 for active stimulation and -0.02 ± 0.06 for sham (P = 0.044). Adverse events occurred in 17 patients (15%); all were mild or moderate. CONCLUSION: Auricular VNS did not meaningfully improve RA disease activity. If VNS with other modalities is pursued in the future for the treatment of RA, larger, controlled studies will be needed to understand its utility.

Using multiple imputation of real-world data to estimate clinical remission in pediatric inflammatory bowel disease.

Aim: To evaluate the performance of the multiple imputation (MI) method for estimating clinical effectiveness in pediatric Crohn's disease in the ImproveCareNow registry; to address the analytical challenge of missing data. Materials & methods: Simulation studies were performed by creating missing datasets based on fully observed data from patients with moderate-to-severe Crohn's disease treated with non-ustekinumab biologics. MI was used to impute sPCDAI remission statuses in each simulated dataset. Results: The true remission rate (75.1% [95% CI: 72.6%, 77.5%]) was underestimated without imputation (72.6% [71.8%, 73.3%]). With MI, the estimate was 74.8% (74.4%, 75.2%). Conclusion: MI reduced nonresponse bias and improved the validity, reliability, and efficiency of real-world registry data to estimate remission rate in pediatric patients with Crohn's disease.

Safety profile of upadacitinib over 15 000 patient-years across rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and atopic dermatitis.

OBJECTIVE: To evaluate the long-term safety profile for upadacitinib across rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and atopic dermatitis (AD). METHODS: Safety data from clinical trials of upadacitinib 15 mg and upadacitinib 30 mg (AD only) for treating RA, PsA, AS and AD as of 30 June 2021 were analysed; some RA and PsA studies included adalimumab and methotrexate as active comparators. Treatment-emergent adverse events (TEAEs) were presented by disease as exposure-adjusted event rates per 100 patient years (E/100 PY). RESULTS: The analysis included 6991 patients (RA, n=3209; PsA, n=907; AS, n=182; AD, n=2693) who received at least one dose of upadacitinib, representing 15 425 PY of exposure (maximum duration 2.75-5.45 years) across diseases. Rates (E/100 PY) of any TEAE (205.5-278.1) and TEAE leading to discontinuation (4.5-5.4) were similar across diseases; serious TEAEs were numerically higher in patients with RA and PsA. Rates of herpes zoster (1.6-3.6), non-melanoma skin cancer (0-0.8) and elevations in creatine phosphokinase levels (4.4-7.9) were higher with upadacitinib than with active comparators in the RA and PsA populations. Deaths (0-0.8), serious infections (0-3.9), major adverse cardiovascular events (0-0.4), venous thromboembolism (<0.1-0.4) and malignancies (0.3-1.4) were observed, with rates generally lowest in AS and AD. Increased rates of acne were observed in patients with AD only. CONCLUSIONS: Findings from this analysis demonstrate that upadacitinib is generally well tolerated with observed differences in safety profiles likely reflective of varying patient characteristics across RA, PsA, AS and AD populations. TRIAL REGISTRATION NUMBERS: NCT02675426, NCT02706951, NCT02706847, NCT02629159, NCT02706873, NCT03086343, NCT03104374, NCT03104400, NCT03178487, NCT03569293, NCT03568318 and NCT03607422.

Increasing liver stiffness is associated with higher incidence of hepatocellular carcinoma in hepatitis C infection and non-alcoholic fatty liver disease-A population-based study.

BACKGROUND & AIMS: Both non-alcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection commonly result in hepatic fibrosis and may lead to cirrhosis. This study aims to determine the incidence of HCC in patients with HCV or NAFLD complicated by advanced fibrosis, inferred from measurements of liver stiffness. METHODS: Using Veterans Affairs (VA) Informatics and Computing Infrastructure (VINCI), we identified a nationwide cohort of patients with an existing diagnosis of HCV or NAFLD with liver transient elastography (TE) testing from 2015 to 2019. HCC cases, along with a random sample of non-HCC patients, were identified and validated, leading to calculation of incidence rates for HCC after adjustment for confounders. RESULTS: 26,161 patients carried a diagnosis of HCV and 13,629 were diagnosed with NAFLD at the time of testing. In those with HCV, rates of HCC increased with liver stiffness with incidences of 0.28 (95% CI 0.24, 0.34), 0.93 (95% CI 0.72, 1.17), 1.28 (95% CI 0.89, 1.79), and 2.79 (95% CI 2.47, 3.14)/100,000 person years for TE score ranges <9.5 kPa, 9.5-12.5 kPa, 12.5-14.5 kPa and >14.5 kPa, respectively, after a median follow-up of 2.3 years. HCC incidence also increased with higher TE liver stiffness measures in NAFLD after a median follow-up of 1.1 years. CONCLUSION: In this retrospective cohort, the incidence of HCC in HCV and NAFLD increases with higher TE liver stiffness measures, confirming that advanced fibrosis portends risk in viral and non-viral fibrotic liver diseases. Additional comparative studies are needed to determine the optimal cut point of TE liver stiffness to inform HCC screening guidelines and approaches.

Increasing Prevalence and Racial Disparity of Alcohol-Related Gastrointestinal and Liver Disease During the COVID-19 Pandemic: A Population-Based National Study.

OBJECTIVES: One consequence of social distancing during the coronavirus disease 2019 (COVID-19) pandemic was an increase in alcohol use disorders. We postulated that this would be associated with a rise in alcohol-related gastrointestinal and liver disease. METHODS: Using Explorys Inc., an aggregate of electronic health records from US health care systems from 1999 to June 2021, we identified patients with "alcoholic hepatitis," "inflammation of pancreas caused by alcohol," and "alcoholic gastritis," based on Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT). We compared patients utilizing health care during the pandemic to those before it. RESULTS: We identified 8,445,720 patients treated from June 21, 2020 to June 20, 2021 ("COVID cohort") and 65,587,860 patients treated before this ("pre-COVID cohort"). African American patients were more likely to be treated for all causes during COVID-19 [odds ratio (OR): 1.65; P <0.0001]. Alcoholic hepatitis (OR: 2.77), alcoholic pancreatitis (OR: 3.67), and alcoholic gastritis (OR: 1.70) (for each, P <0.0001) were more likely in all patients in the COVID cohort. African Americans in the COVID cohort were more likely to be diagnosed with alcoholic hepatitis (OR: 2.63), alcoholic pancreatitis (OR: 2.17), and alcoholic gastritis (OR: 3.09) [for each, P <0.0001]. CONCLUSIONS: The prevalence of alcohol-related liver and gastrointestinal disease increased during COVID-19. We suspect these increases are associated with increased alcohol use disorder resulting from the stress of social isolation. These data suggest COVID-19 disproportionately affected African Americans in overall health care utilization and increased burden of alcoholic gastrointestinal and liver disease.

Influenza Adverse Events in Patients with Rheumatoid Arthritis, Ulcerative Colitis, or Psoriatic Arthritis in the Tofacitinib Clinical Development Programs.

INTRODUCTION: This post hoc analysis evaluated influenza adverse events (AEs) across rheumatoid arthritis (RA), ulcerative colitis (UC), and psoriatic arthritis (PsA) tofacitinib clinical programs. METHODS: Available data from phase 1, randomized phase 2/3/3b/4 clinical trials (completed by 2018), and long-term extension (LTE) studies (up to May 2019) in patients with RA, UC, and PsA were included [randomized or Overall (phase 1-3b/4 and LTE studies) tofacitinib cohorts]. Incidence rates (IRs; events per 100 patient-years) of combined influenza AEs (seasons 2004/2005 to 2018/2019) were analyzed, including by tofacitinib dose [5 or 10 mg twice daily (BID)] and age (< 65 versus ≥ 65 years). Logistic regression models evaluated risk factors for influenza AEs in the RA Overall tofacitinib cohort. RESULTS: In randomized cohorts, combined influenza AE IRs were generally similar across tofacitinib, adalimumab, methotrexate, and placebo groups, across indications. Among Overall tofacitinib cohorts, combined influenza AE IRs with tofacitinib 5/10 mg BID, respectively, were higher in the UC (3.66/5.09) versus RA (2.38/2.19) and PsA (1.74/1.29) cohorts. IRs were generally similar across tofacitinib dose and age groups. Most influenza AEs were nonserious and did not require changes to tofacitinib treatment. Significant risk factors for influenza AEs in patients with RA were geographic region, baseline oral corticosteroid and methotrexate use, and tofacitinib dose. CONCLUSIONS: In the RA, UC, and PsA clinical programs, combined influenza AE IRs were highest in UC, while in each indication they were generally similar across tofacitinib, placebo, and comparator groups. Influenza AEs were predominantly nonserious and not associated with changes to tofacitinib treatment. TRIAL REGISTRATION NUMBERS: NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612, NCT01877668, NCT01882439, NCT01976364.

Commentary on Cohen et al.: Role of Clinical Factors in Precision Medicine Test to Predict Nonresponse to TNFi Therapies in Rheumatoid Arthritis.

A 2021 study described the development and validation of a blood-based precision medicine test called the molecular signature response classifier (MSRC) that uses 23 features to identify rheumatoid arthritis (RA) patients who are likely nonresponders to tumor necrosis factor-α inhibitor (TNFi) therapy. Both the gene expression features and clinical components (sex, body mass index, patient global assessment, and anti-cyclic citrullinated protein) included in the MSRC were statistically significant contributors to MSRC results. In response to continued inquiries on this topic, we write this letter to provide additional insights into the contribution of clinical components to the MSRC on the Network-004 validation cohort.

Accuracy of Ultrasound Elastography and Fibrosis-4 Index (FIB-4) in Ruling Out Cirrhosis in Obese Non-Alcoholic Fatty Liver Disease (NAFLD) Patients.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of advanced liver disease in the USA. Liver biopsy, the gold standard diagnostic test for evaluating liver fibrosis, is associated with significant risk and expense. The accuracy of ultrasound elastography and Fibrosis-4 index (FIB-4) in the obese NAFLD population is unknown. We aimed to compare the accuracy of ultrasound elastography and FIB-4 to liver biopsy in ruling out cirrhosis in NAFLD patients at a tertiary, transplant referral center in the US. METHODS: We retrospectively evaluated 93 patients with a mean age of 53 years (SD: 13 years) who underwent liver ultrasound elastography and liver biopsy, and additionally calculated their FIB-4 at the time of biopsy. We compared the liver stiffness measurement (LSM) obtained from ultrasound elastography and FIB-4 with the pathology results for ruling out cirrhosis. RESULTS: 85% of the patients were white, 53% were female, average BMI was 34.7 (SD: 6.7), 52% had diabetes, and 53% had hypertension. For biopsy-proven cirrhosis (prevalence 15%), a cut-off value of 12.5 kilopascals (kPa) for F4 had a sensitivity of 92% and a specificity of 54%. Values below this threshold excluded cirrhosis with 98% certainty. Compared to FIB-4, ultrasound elastography showed higher accuracy in ruling out cirrhosis (92% vs. 80% sensitivity, 98% vs. 95% negative predictive value (NPV), respectively). CONCLUSION: To our knowledge, this is the first study in a tertiary transplant referral center in the USA to show that ultrasound elastography was superior to FIB-4 and can be used as a reliable screening test to rule out cirrhosis in obese NAFLD patients at a 12.5 kPa cut-off. Therefore, helping to avoid the risk and expense associated with liver biopsy.

Plain language summary of the VOLTAIRE-RA in patients with moderate-to-severe rheumatoid arthritis.

WHAT IS THIS SUMMARY ABOUT?: Here, we summarize the results from the VOLTAIRE-RA study, originally published in the journal Annals of the Rheumatic Diseases. The VOLTAIRE-RA study looked at how effective and safe BI 695501 is in treating people with rheumatoid arthritis (also known as RA). BI 695501 is a biosimilar whose reference product is adalimumab (known by the brand name Humira). A biosimilar is one that is made to be very similar to, and less expensive than the original biologic, also known as the reference product. The VOLTAIRE-RA study aimed to show that BI 695501 is as effective and safe as Humira in treating people with moderate-to-severe RA. WHAT WERE THE RESULTS?: Participants of the VOLTAIRE-RA study took either Humira for 24 weeks and then switched to taking BI 695501 for a further 24 weeks, or BI 695501 for 48 weeks. The participants treated with BI 695501 and Humira had very similar outcomes in terms of reducing symptoms, as well as experiencing side effects. This was also seen for those participants who switched from taking Humira to BI 695501. WHAT DO THE RESULTS MEAN?: These results show that both Humira and BI 695501 could be used to treat people with RA as very similar treatment outcomes could be expected. Clinical Trial Registration: NCT02137226 (ClinicalTrials.gov).

Switching Between Adalimumab Reference Product and BI 695501 in Patients with Chronic Plaque Psoriasis (VOLTAIRE-X): A Randomized Controlled Trial.

BACKGROUND: BI 695501 is an FDA-approved biosimilar to adalimumab reference product (RP). VOLTAIRE-X was a randomized clinical trial to assess outcomes with a biosimilar monoclonal antibody in line with the FDA requirements for designation as an 'interchangeable' biosimilar. OBJECTIVE: The aim of this study was to assess whether multiple switches between adalimumab RP and BI 695501 lead to equivalent pharmacokinetics and a similar safety and immunogenicity profile compared with continuous adalimumab RP. METHODS: We conducted a phase III, double-blind, randomized controlled trial between July 19, 2017, and April 16, 2019. There were 49 investigational sites across Europe and North America. Of 323 screened patients with moderate-to-severe chronic plaque psoriasis, 259 were treated with adalimumab RP during the run-in period. Of these, 118 and 120 were randomized to the continuous or switching arms, respectively. Interventions consisted of a run-in period with adalimumab RP 80 mg subcutaneously (SC) on Day 1, then 40 mg SC every other week (EOW) Weeks 2-12. Patients were then randomized to receive adalimumab RP 40 mg EOW Weeks 14-48 (continuous arm) or BI 695501 40 mg Weeks 14 and 16, adalimumab RP 40 mg Weeks 18 and 20, and BI 695501 40 mg EOW Weeks 22 to 48 (switching arm); all interventions were given SC. Primary endpoints were pharmacokinetics parameters, area under the plasma concentration-time curve (AUCτ,30-32) and maximum observed drug plasma concentration (Cmax,30-32), measured after the third switch during the Week 30-32 dosing interval. RESULTS: 238 patients (mean [standard deviation] age 44.9 [13.8]; 66.0% male) were treated in the switching (n = 118) or continuous arms (n = 120). Adjusted mean Cmax,30-32 was 7.08 and 7.00 µg/mL in the switching and continuous treatment arms, respectively; adjusted mean AUCτ,30-32 was 2025.8 and 1925.9 µg h/mL. Point estimate for mean ratio for AUCτ,30-32 was 105.2% (90.2% confidence interval [CI] 96.6-114.6), and 101.1% (90.2% CI 93.3-109.7) for Cmax,30-32. Both CIs were within a predefined bioequivalence range of 80.0-125.0%. Treatment-emergent adverse events led to discontinuation in 0.8% and 1.7% of patients in the switching and continuous treatment arms, and Psoriasis Area and Severity Index (PASI) scores were highly similar in the two arms across the entire trial period. CONCLUSIONS: Pharmacokinetic equivalence was demonstrated, with highly similar efficacy and immunogenicity, and comparable safety observed in patients with chronic plaque psoriasis who received either adalimumab RP continuously or who switched between adalimumab RP and BI 695501. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03210259 (registered July 2017); Eudract.ema.europa.eu: 2016-002254-20.