Granulocyte colony-stimulating factor-associated aortitis in the Japanese Adverse Drug Event Report database.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) is the standard-of-care therapy for chemotherapy-associated neutropenia in patients with malignancies. Recent case reports have implied that G-CSF treatment may be associated with the development of aortitis, but the precise nature of the relationship is unclear. We investigated the association between G-CSF and risk for aortitis in patients with various malignancies. METHODS: We performed an observational study of 102,014 subjects with malignant neoplasms documented in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and February 2018. The adjusted odds ratio (OR) and 95% confidence interval (CI) for aortitis in patients treated and not treated with G-CSF were estimated using multivariate logistic regression with R software. RESULTS: Among the 102,014 subjects, 25 developed aortitis. Of the 3409 and 98,630 subjects treated and not treated with G-CSF, 16 (0.47% [95% CI; 0.27, 0.76]) and 9 (0.01% [0.00, 0.02]) developed aortitis, respectively. Multivariate logistic regression indicated an association between G-CSF and aortitis (adjusted OR 45.87 [19.16, 109.8], p < 0.001). The values for filgrastim, pegfilgrastim, and lenograstim were 0.25% (0.07, 0.63), 1.58% (0.79, 2.81), and 0.24% (0.05, 0.69), respectively. CONCLUSION: G-CSF treatment was associated with a signal of increased risk for aortitis among patients with malignant neoplasms. Three different G-CSF agents were associated with such risk, implying that it is a class effect. However, we do not recommend changing G-CSF prescriptions, because our results may have been influenced by the limitations of the JADER database and because the benefit of G-CSF treatment outweighs the potential risk.

Drug-associated progressive multifocal leukoencephalopathy in multiple sclerosis patients.

OBJECTIVE: To investigate characteristics of multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients associated with drugs other than natalizumab since our experience in other disease-modifying drugs (DMD) is still limited. METHODS: This is a descriptive observational study within the FAERS database, registered between July 2015 and June 2017. RESULTS: The primary cohort for the analysis consisted of 100,921 MS patients (mean (standard deviation (sd)) age, 48.9 (12.8) years, 20.9% male). Among them 786 (0.78%) developed PML. The adjusted odds ratio of PML for each drug was as follows; natalizumab 115.72 (95% CI; 83.83, 159.74), fingolimod 4.98 (3.64, 6.81) followed by dimethyl fumarate 1.77 (1.2, 2.62) and rituximab 3.22 (1.07, 9.72). The median time from the start of suspected drugs to the onset of PML for natalizumab and other agents were 1463 and 178 days, respectively. The proportion of PML appeared higher in Japan (2.4%) compared to that in the United States (0.24%). CONCLUSION: The reporting proportion of PML was relatively higher in natalizumab followed by fingolimod, dimethyl fumarate and rituximab. Other characteristics of PML associated with DMDs, including the time to onset and differences in reporting among countries, are described.

EGFR-TKI-Associated Interstitial Pneumonitis in Nivolumab-Treated Patients With Non-Small Cell Lung Cancer.

Importance: Nivolumab and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are now the standard-of-care therapies in non-small cell lung cancer (NSCLC). Although EGFR-TKIs are well understood and have well-defined safety profiles, our experience with immune checkpoint inhibitors is still growing, particularly regarding the use of combinations of different classes of antitumor agents, including both the concomitant and sequential use of such agents. Objective: To determine whether nivolumab increases EGFR-TKI-associated interstitial pneumonitis (IP). Design, Setting, and Participants: A database study of 20 516 participants with NSCLC in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, performed between April 2015 and March 2017. Main Outcomes and Measures: We compared the incidence of EGFR-TKI-associated IP in patients receiving and not receiving nivolumab treatment. Results: The mean (SD) age of participants treated with EGFR-TKI, with and without nivolumab, was 64.4 (15.5) and 68.9 (11.8) years, respectively, and the proportion of men was 40.0% and 53.8%, respectively. Of the 20 516 participants with NSCLC, 985 cases (4.80%; 95% CI, 4.51-5.10) developed IP. Of 5777 patients treated with EGFR-TKI, 265 developed IP (4.59%; 95% CI, 4.06-5.16). Of 70 patients treated with both EGFR-TKI and nivolumab, 18 developed IP (25.7%; 95% CI, 16.0-37.6). The adjusted odds ratio for an interaction between EGFR-TKI and nivolumab was 4.31 (95% CI, 2.37-7.86; P < .001), suggesting the existence of an interaction. When we further stratified the patients by treatment with and without nivolumab, the odds ratio of EGFR-TKI-associated IP in cases with and without nivolumab treatment was 5.09 (95% CI, 2.87-9.03) and 1.22 (95% CI, 1.00-1.47), respectively. Conclusions and Relevance: We found a higher proportion of reports of IP for nivolumab in combination with EGFR-TKI vs treatment with either drug alone. Owing to the limitations of this study, the results warrant further confirmation. However, careful consideration should be given to the possibility of an increased risk of IP when EGFR-TKI is administered in combination with nivolumab, including concomitant and sequential use, and careful monitoring for IP is recommended.

Association between acute myelogenous leukemia and thrombopoietin receptor agonists in patients with immune thrombocytopenia.

OBJECTIVE: The development of myeloid malignancies is a concern when administering thrombopoietin receptor (or the myeloproliferative leukemia virus proto-oncogene product, MPL) agonists. Progression from myelodysplastic syndrome (MDS) to acute myelogenous leukemia [AML, 9 (6.12%) AML patients among 147 MDS subjects] was reported in a clinical trial. However, only one (0.15%) case of AML among 653 immune thrombocytopenic purpura (ITP) subjects was reported. Our objective was to determine whether there is currently a safety signal in the FDA files termed Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for AML in ITP patients who receive MPL agonists. METHODS: We conducted a case-controlled study using the FAERS as a source of case and control data. We compared demographic characteristics, such as gender, age and exposure to MPL agonists between AML patients and others among ITP subjects registered between 2002 and 2011. RESULTS: Total of 4,821 ITP subjects were identified, including 62 AML patients. The number of patients treated with romiplostim and eltrombopag was 54 (1.74%) AML patients among 3,102 ITP subjects and nine (1.52%) AML patients among 594 ITP subjects, respectively. It should be noted that all AML patients were exposed to one or more MPL agonists. Another factor associated with AML was male gender. CONCLUSION: We herein report an association between AML and MPL agonist use in ITP subjects. Due to various biases and the incompleteness of the FAERS data, further studies are warranted to determine whether the detected signal is a real risk. Physicians should not alter their prescribing behaviors based on this single preliminary analysis.

Association of hepatitis B with antirheumatic drugs: a case-control study.

BACKGROUND: Though concern of hepatitis B virus (HBV) reactivation by antirheumatic agents has limited therapeutic opportunities in HBV-infected rheumatoid arthritis (RA) patients, the relative risks (RR) among such agents have not been clarified. OBJECTIVE: We compared the reporting of antirheumatic-agent-associated hepatitis B. PATIENTS: We assessed 92 hepatitis B cases and 98,069 controls from a population of 98,161 RA patients registered into the US Food and Drug Administration's (FDA's) adverse event database between 2004 and 2010. MEASUREMENTS: A reporting odds ratio (ROR), a signal suggesting a risk for hepatitis B among antirheumatic agents, was measured. RESULTS: Treatment with corticosteroids [ROR 2.3 (95% confidence interval 1.3-4.0)], methotrexate [4.9 (3.9-6.0)], rituximab [7.2 (5.3-9.9)], tacrolimus [4.2 (1.5-11.9)], or reporting from Japan [2.2 (1.1-4.2)] were associated with higher signal, whereas adalimumab had a lower ROR [0.2 (0.1-0.4)]. LIMITATIONS: There are known limitations of spontaneous reporting, such as underreporting, the Weber effect, reporting bias, indication bias, and limited clinical information such as HBV status. CONCLUSIONS: Adalimumab's low reporting rate is most likely be due to notoriety. However, the possibility that adalimumab might suppress reactivation of HBV cannot be denied. Until the possibility is clarified in well-designed clinical studies, physicians should use adalimumab cautiously in patients with HBV.