Risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors

Beukelman, Timothy; Xie, Fenglong; Chen, Lang; Horton, Daniel B.; Lewis, James D.; Mamtani, Ronac; Mannion, M.; Saag, Kenneth G.; Curtis, Jeffrey R.

doi:10.1136/annrheumdis-2017-212613

Cited by 56 publications

(31 citation statements)

References 33 publications

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“…Beukelman et al conducted two studies about the risk of malignancy and biologics and the conclusion of two studies was that children with JIA had an increased rate of incident malignancy compared to children without JIA. However, treatment with biologics did not appear to be further increasing the risk of malignancy [26,27]. In our cohort, we did not observe any malignancy development or death under biologics.…”

Section: Discussioncontrasting

confidence: 62%

The necessity, efficacy and safety of biologics in juvenile idiopathic arthritis

Çakan¹

2019

North Clin Istanbul

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J uvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in children. JIA is arthritis of unknown etiology that begins before the 16th birthday and persists for at least six weeks. JIA is a diagnosis of exclusion and other causes of chronic arthritis should have been excluded before calling a child as having JIA [1-3]. JIA is not a single disease but rather a group of disorders as having chronic arthritis a common feature. Currently used International League of Associations for Rheumatology (ILAR) classification criteria divides JIA into seven subtypes as follows: oligoarticular (persistent or extended) JIA, enthesitis-related arthritis (ERA), ABSTRACT OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in children. Biologics have changed the faith of children with rheumatic diseases. The main objective of this study was to demonstrate the rate of usage, efficacy and safety of biologics in JIA subtypes. METHODS: This retrospective observational cohort study was conducted between May 2010 and September 2017. All children with the diagnosis of JIA and children under a biological agent treatment were recorded into the local registry system. Age, gender, JIA subtype, medications used, the clinical status of the patient, tuberculosis screening results, and side effects observed under biologics were retrieved from the registry. RESULTS: There were 405 patients with the diagnosis of JIA in the cohort. Biologics were used in 123 (30.3%) JIA patients. Subtype frequencies of JIA patients were as follows: persistent oligoarticular JIA (33.6%), enthesitis-related arthritis (29.2%), systemic JIA (13%), rheumatoid factor (RF)-negative polyarticular JIA (13%), extended oligoarticular JIA (4.2%), RF-positive polyarticular JIA (3.4%), psoriatic arthritis (1.8%) and unclassified arthritis (1.8%). The rate of biologic use was high in extended oligoarticular JIA (64.7% of the cases), RF-positive polyarticular JIA (57.1%), psoriatic arthritis (57.1%), RFnegative polyarticular JIA (41.5%), and in systemic JIA (39.6%). Enthesitis-related arthritis (27.1%), persistent oligoarticular JIA (17.6%) and unclassified arthritis (16.6%) patients were the cases that needed a biologic agent in the last order. At the last control, 78.9% of the cases were in remission, while 21.1% of them were active despite biologic treatment. Isoniazid prophylaxis was used in 30.8% of the patients. None of the patients developed active tuberculosis infection under prophylaxis. Adverse events were observed in 18.6% of patients under biologics as recurrent uncomplicated upper respiratory tract infections being the most common. CONCLUSION: Biologics are safe and effective treatment options in children with JIA. Most of the JIA patients with polyarticular involvement require biologics earlier in the disease course. The risk of tuberculosis infection seems not to be increased after appropriate screening and prophylaxis.

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Section: Discussioncontrasting

confidence: 62%

The necessity, efficacy and safety of biologics in juvenile idiopathic arthritis

Çakan¹

2019

North Clin Istanbul

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“…The incidence of Hodgkin lymphoma in post-marketing ETN data for patients aged 0–17 years was 9.5 per 100,000 patient-years, which is higher than the value for patients in the same age range for the general US population recorded in the Surveillance Epidemiology and End Results database (0.9 per 100,000 patient-years) [35]. However, patients with JIA cannot be easily compared with the general population, since both JIA and the extensive pre-treatment with immuno-suppressants, including methotrexate, have been suggested as additional risk factors for lymphoma [36, 37], and a retrospective study of 2000–2014 US claims data did not find an increased risk of malignancies in TNF-treated children with JIA, pediatric inflammatory bowel disease, or pediatric plaque psoriasis [38]. Nevertheless, a possibility must be allowed that the case of Hodgkin lymphoma observed in our study could have been related to the patient’s treatment (methotrexate, ETN, or both).…”

Section: Discussionmentioning

confidence: 99%

Etanercept treatment for extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or psoriatic arthritis: 6-year efficacy and safety data from an open-label trial

Foeldvari¹,

Constantin

Vojinović

et al. 2019

Arthritis Res Ther

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Background To describe the 6-year safety and efficacy of etanercept (ETN) in children with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA) Methods Patients who completed the 2-year, open-label, phase III CL inical Study I n P ediatric P atients of E tanercept for Treatment of E R A, PsA, and Extended Oligoarthritis (CLIPPER) were allowed to enroll in its 8-year long-term extension (CLIPPER2). Children received ETN at a once-weekly dose of 0.8 mg/kg, up to a maximum dose of 50 mg/week. Efficacy assessments included the JIA core set of outcomes, the JIA American College of Rheumatology response criteria (JIA-ACR), and the Juvenile Arthritis Disease Activity Score (JADAS). Efficacy data are reported as responder analyses using a hybrid method for missing data imputation and as observed cases. Safety assessments included treatment-emergent adverse events (TEAEs). Results Out of 127 patients originally enrolled in CLIPPER, 109 (86%) entered CLIPPER2. After 6 years of trial participation (2 years in CLIPPER and 4 years in CLIPPER2), 41 (32%) patients were still taking ETN, 13 (11%) entered the treatment withdrawal phase after achieving low/inactive disease (of whom 7 had to restart ETN), 36 (28%) discontinued treatment for other reasons but are still being observed, and 37 (29%) discontinued treatment permanently. According to the hybrid imputation analysis, proportions of patients achieving JIA ACR90, JIA ACR100, and JADAS inactive disease after the initial 2 years of treatment were 58%, 48%, and 32%, respectively. After the additional 4 years, those proportions in patients who remained in the trial were 46%, 35%, and 24%. Most frequently reported TEAEs [ n (%), events per 100 patient-years] were headache [28 (22%), 5.3], arthralgia [24 (19%), 4.6], and pyrexia [20 (16%), 3.8]. Number and frequency of TEAEs, excluding infections and injection site reactions, decreased over the 6-year period from 193 and 173.8, respectively, during year 1 to 37 and 61.3 during year 6. A single case of malignancy (Hodgkin’s lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported. Conclusions Open-label etanercept treatment for up to 6 years was safe, well tolerated, and effective in patients with eoJIA, ERA, and PsA. Trial registration ClinicalTrials.gov: CLIPPER, NCT00962741 , registered 20 August, 2009, CLIPPER2, NCT01421069 , registered 22 August, 2011. Electronic supplementary material The online version of this article (10.1186/s13075-019-1916-9) contains supplementary material, which is available to authorized users...

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“…As demonstrated before, incidence rates of the malignancies reported to BIKER are higher than in the general population (10). In a more recent study, they compared patients with JIA who were using TNFi with those who were not using TNFi and found that treatment with TNFi did not appear significantly associated with the development of malignancy (20). In a nationwide cohort study in the United States, Beukelman et al (19) found a threefold increased risk for malignancies in patients with JIA compared with children with ADHD.…”

Section: Discussionmentioning

confidence: 86%

Biologic Therapies in Polyarticular Juvenile Idiopathic Arthritis. Comparison of Long‐Term Safety Data from the German BIKER Registry

Klein

Becker

Minden

et al. 2019

ACR Open Rheumatology

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Objective. Biologics have an important role in the treatment of juvenile idiopathic arthritis (JIA). Long-term safety data are limited. Direct comparison of different agents regarding occurrence of adverse events (AEs), especially of rare events, requires large quantities of patient years. In this analysis, long-term safety with regard to AE of special interest (AESI) was compared between different biologics.Methods. Patients with nonsystemic JIA were selected from the German BIKER registry. Safety assessments were based on AE reports. Number of AEs, serious AEs, and 25 predefined AESIs, including medically important infection, uveitis, inflammatory bowel disease, cytopenia, hepatic events, anaphylaxis, depression, pregnancy, malignancy, and death, were analyzed. Event rates and relative risks were calculated using AEs reported after first dose through 70 days after last dose.Results. A total of 3873 patients entered the analysis with 7467 years of exposure to biologics. The most common AESIs were uveitis (n = 231) and medically important infections (n = 101). Cytopenia and elevation of transaminases were more frequent with tocilizumab (risk ratio [RR] 8.0, 95% confidence interval [CI] 4.2-15, and RR 4.7, 95% CI 1.8-12.2, respectively). Anaphylactic events were associated with intravenous route of administration. In patients ever exposed to biologics, eight malignancies were reported. Six pregnancies have been documented in patients with tumor necrosis factor inhibitors. No death occurred in this patient cohort during observation.Conclusion. Surveillance of pharmacotherapy as provided by the BIKER registry is an import approach, especially for long-term treatment of children. Overall, tolerance was acceptable. Differences between biologics were noted and should be considered in daily patient care.

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Risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors

Abstract: Children diagnosed with JIA, pIBD and pPsO had an increased rate of malignancy compared with the general population, but treatment with TNFi did not appear to significantly further increase the risk compared with no TNFi use. More data are needed about the long-term risks of TNFi use.

Cited by 56 publications

References 33 publications

The necessity, efficacy and safety of biologics in juvenile idiopathic arthritis

The necessity, efficacy and safety of biologics in juvenile idiopathic arthritis

Etanercept treatment for extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or psoriatic arthritis: 6-year efficacy and safety data from an open-label trial

Biologic Therapies in Polyarticular Juvenile Idiopathic Arthritis. Comparison of Long‐Term Safety Data from the German BIKER Registry

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