Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development.

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with various malignancies, however, they are associated with a wide range of immune-related toxicities affecting many organs, including the liver. Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a distinctive form of drug induced liver injury (DILI), that differs from most DILI types in presumed underlying mechanism, incidence, and response to therapeutic interventions. Despite increased awareness of ILICI and other immune-related adverse effects of ICIs reflected by recent guidelines for their management in post marketing clinical practice, there is lack of uniform best practices to address ILICI risk during drug development. As efforts to develop safer and more effective ICIs for additional indications grow, and as combination therapies including ICIs are increasingly investigated, there is a growing need for consistent practices for ILICI in drug development. This publication summarizes current best practices to optimize the monitoring, diagnosis, assessment, and management of suspected ILICI in clinical trials using ICI as a single agent and in combination with other ICIs or other oncological agents. It is one of several publications developed by the IQ DILI Initiative in collaboration with DILI experts from academia and regulatory agencies. Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, ILICI detection, approach to a suspected ILICI signal, causality assessment, hepatic discontinuation rules and additional medical treatment.

Risk of malignancy in children with juvenile idiopathic arthritis not treated with biologic agents.

OBJECTIVE: To estimate the relative risk of incident cancer diagnosis among patients with juvenile idiopathic arthritis (JIA) compared to patients without JIA. METHODS: A cohort of biologics-naive patients diagnosed with JIA between 1998 and 2007 and a matched cohort of comparators without JIA were assembled from the PharMetrics Patient-Centric Database. The primary outcome was any incident malignancy, excluding nonmelanoma skin cancer and carcinoma in situ. Claims profiles of patients with any cancer-related diagnosis codes were reviewed to determine outcomes. Incidence rates and 95% confidence intervals (95% CIs) of cancer were calculated and compared between cohorts using Cox proportional hazards regression. Standardized incidence ratios (SIRs) for each cohort compared to the general population were calculated using reference rates from the US Surveillance, Epidemiology, and End-Results (SEER) program. RESULTS: The JIA and non-JIA cohorts included 3,605 and 37,689 patients, respectively, with a mean age of 11 years. The incidence rates of cancer were 67.0 (95% CI 1.3-132.5) cases/100,000 person-years (PY) for JIA and 23.2 (95% CI 12.2-34.2) cases/100,000 PY for non-JIA. The risk of cancer associated with biologics-naive JIA was elevated (hazard ratio 2.8, 95% CI 0.9-8.3). The JIA cohort had a significantly elevated SIR of 4.0 (95% CI 2.6-6.0); the non-JIA cohort SIR was not significantly above SEER rates (SIR 1.4, 95% CI 0.6-2.6). CONCLUSION: We found a nearly 3-fold increased risk of cancer in biologics-naive JIA patients, which approached significance despite the small number of outcomes. This finding suggests an elevated underlying risk of cancer in this disease population.

Infliximab treatment shifts the balance between stimulatory and inhibitory Fcgamma receptor type II isoforms on neutrophils in patients with rheumatoid arthritis.

OBJECTIVE: Human neutrophils express both activating and inhibitory Fcgamma receptors (FcgammaR), and their relative expression determines the inflammatory response to immune complexes. Tumor necrosis factor alpha (TNFalpha) up-regulates the expression of stimulatory FcgammaRIIa on neutrophils in vitro, and amplifies immune complex-induced activation of neutrophils in vivo. This study was undertaken to determine whether TNFalpha blockade in patients with rheumatoid arthritis (RA) alters the balance of activating FcgammaR and inhibitory FcgammaR and thereby decreases inflammation. METHODS: We used fluorescence-activated cell sorting and Western blotting to examine FcgammaR expression on neutrophils in 24 patients with RA, preceding their first infusion of infliximab and immediately prior to >or=3 subsequent infusions. RESULTS: In 13 of 24 patients (54.2%), there was a decrease in the expression of the predominant activating FcgammaR, FcgammaRIIa, after treatment with infliximab, an effect that persisted over >or=3 months of treatment. Although prior to initiation of infliximab therapy the inhibitory FcgammaR, FcgammaRIIb, was undetectable in neutrophils from 23 of 24 patients with RA, FcgammaRIIb protein was detected by Western blotting in 9 patients (37.5%) at the time of the third infliximab infusion. The induction of inhibitory FcgammaRIIb was always associated with decreased levels of FcgammaRIIa, and improvement following infliximab therapy, measured using the Health Assessment Questionnaire, was significantly associated with down-regulation of FcgammaRIIa. CONCLUSION: Our findings indicate that TNFalpha inhibition may reduce inflammation in patients with RA by restoring the balance of activating and inhibitory FcgammaR and thereby raising the threshold for immune complex-mediated activation of neutrophils.

Relationship between serum NR2a antibodies and cognitive dysfunction in systemic lupus erythematosus.

OBJECTIVE: To assess the association between serum NR2a antibodies and cognitive dysfunction in systemic lupus erythematosus (SLE). METHODS: The study population consisted of English-speaking adults who met American College of Rheumatology (ACR) criteria for SLE and had at least 1 serum sample stored in the Hospital for Special Surgery Autoimmune Registry and Repository. Demographic and clinical information was obtained, and patients completed the neuropsychological test battery recommended by the ACR, the Center for Epidemiologic Studies Depression Scale, and the Spielberger State-Trait Anxiety Inventory. Cognitive impairment was defined as scores >1.5 SD below the mean of age-matched published normative data on at least 2 neuropsychological tests. Sera were tested for NR2a antibodies by enzyme-linked immunosorbent assay. Performance on neuropsychological tests was compared between NR2a-positive and NR2a-negative patients. RESULTS: Of the 93 patients, 24 (25.8%) were positive for NR2a antibodies. Of the 48 patients who were cognitively impaired based on test results, 31% were positive for NR2a antibodies, compared with 20% of those who were not cognitively impaired (P = 0.24). Among antibody-positive patients, the mean +/- SD number of neuropsychological tests with abnormal results was 2.3 +/- 2.2, compared with 2.0 +/- 1.8 in the antibody-negative group (P = 0.59). Similar nonsignificant differences were found when impairment was defined using a more stringent definition (i.e., test scores >2.0 SD below the mean) and using a neuropsychologist's clinical ratings. No association was detected between NR2a antibody positivity and depressive symptoms (P = 0.73) or anxiety (P = 0.42). CONCLUSION: No significant association was found between NR2a antibody positivity and cognitive dysfunction, depressive symptoms, or anxiety. These results indicate that the presence of these antibodies alone does not have a direct effect on cognitive functioning or any other neuropsychiatric manifestation of SLE.

Physician treatment preferences in rheumatoid arthritis of differing disease severity and activity: the impact of cost on first-line therapy.

OBJECTIVE: To conduct a pilot study to identify rheumatologists' treatment preferences for first-line rheumatoid arthritis (RA) therapy and determine whether pharmacoeconomic variables modify physician choice(s). METHODS: A questionnaire describing 3 different RA scenarios was mailed to American College of Rheumatology members within 4 geographic regions of the US. Physicians were asked to identify their choice(s) of first-line therapy for each of the cases, first taking cost into consideration, second without considering the influence of cost, and third identifying the therapy that would be chosen for either themselves or a family member. RESULTS: Three hundred seventy-five questionnaires out of a total of 994 (37.7%) were returned between 3/12/00 and 4/25/00. Hydroxychloroquine was the most commonly cited medication for a mild disease activity/severity presentation, and methotrexate for a moderate-to-severe disease activity/severity presentation. For the severe disease activity/severity presentation, when cost was not considered, 217 (65%) rheumatologists included new disease-modifying antirheumatic drugs (leflunomide, etanercept, and infliximab) in their choice of first-line agents; this number decreased to 47 (14%) when cost was a consideration. CONCLUSION: Pharmacoeconomics appear to play a dominant role in rheumatologists' choice of treatment regimens, at times contrary to the physician's perception of the effectiveness of a drug. Future studies should address physician preferences in more depth with respect to cost and its various components.