The risk of infection associated with tumor necrosis factor α antagonists: Making sense of epidemiologic evidence

Solomon, Daniel H.; Lunt, Mark; Schneeweiß, Sebastian

doi:10.1002/art.23396

Cited by 38 publications

(35 citation statements)

References 22 publications

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“…However, the magnitude of our observed associations between anti-TNF exposure and infection were consistent with some previously published results [24,25]. As we demonstrated in our analyses, the highest risk of infection associated with anti-TNF initiation was observed in the period following initiation, which suggests a higher risk is in the early period following treatment start [8,26]. …”

Section: Discussionsupporting

confidence: 92%

“…Differences in patient populations, outcome ascertainment and validation, follow-up, and study design may explain the differences between the studies. One ongoing discussion in this area is the prevalent vs. incident user design [26,27]. Briefly, the debate focuses on whether it is appropriate to compare a new user of a therapy (incident user) to a current or ongoing user (prevalent user) because those most susceptible to the adverse reactions or outcomes of interest may no longer be included in the prevalent pool because they discontinued the medication.…”

Section: Discussionmentioning

confidence: 99%

“…Using the IPTW approach, we answered the question: “What is the risk of infection if everyone in our study population had been exposed to anti-TNF treatment versus if everyone had not?”. The statistical method employed changes the scientific question answered, as does how the study population is defined and what comparator is used [26]. Therefore, special attention should be paid when interpreting the results of the present study into the context of what has been published.…”

Section: Discussionmentioning

confidence: 99%

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TNF-<i>α</i> Antagonist and Infection in Rheumatoid Arthritis

Mittleman¹,

Shadick²,

Karlson³

2012

OJRA

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Background Anti-TNF treatment may increase infection risk, although this has been difficult to study because the timing of anti-TNF treatment is driven by disease activity, which may influence infection susceptibility leading to confounding that varies over time. We evaluated the association between anti-TNF initiation in rheumatoid arthritis (RA) patients on disease modifying anti-rheumatic drugs (DMARD) and infection using multiple approaches adjusting for time-varying confounding. Methods 383 anti-TNF-naïve RA patients on ≥1 non-biologic-DMARD at enrollment from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) were followed up to two years. Pooled logistic regressions estimated the association between anti-TNF and infection by including time-varying covariates in the adjusted models and inverse probability treatment weighting (IPTW). Results Adjustment for time-varying disease activity and other suspected confounders yielded non-statistically significant positive associations between anti-TNF start and infection regardless of analytic approach (RRmvar_adj = 2.1, 95% CI: 0.8 – 5.8). Conclusions Incorporating changing clinical status, and treatment indications and consequences, yielded consistently (though not significantly) elevated relative risks of infection associated with anti-TNF initiation. Due to limited statistical power, we cannot draw firm conclusions. However, we have illustrated multiple approaches adjusting for potential time-varying confounding in longitudinal studies and hope to replicate the approaches in larger studies.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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TNF-<i>α</i> Antagonist and Infection in Rheumatoid Arthritis

Mittleman¹,

Shadick²,

Karlson³

2012

OJRA

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“…Patients newly starting medications establish retrospective and prospective analytic cohorts within the Registry, enabling the unbiased evaluation of the safety and effectiveness of therapeutic agents. This “new user” analytic design greatly improves the validity of study results [38, 39]. …”

Section: Discussionmentioning

confidence: 99%

The new Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry: design, rationale, and characteristics of patients enrolled in the first 12 months

et al. 2017

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BackgroundHerein we describe the history, design, and rationale of the new Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry and present the characteristics of patients with juvenile idiopathic arthritis (JIA) enrolled in the first 12 months of operation.MethodsThe CARRA Registry began prospectively collecting data in the United States and Canada in July 2015 to evaluate the safety of therapeutic agents in persons with childhood-onset rheumatic disease, initially restricted to JIA. Secondary objectives include the evaluation of disease outcomes and their associations with medication use and other factors. Data are collected every 6 months and include clinical assessments, detailed medication use, patient-reported outcomes, and safety events. Follow-up is planned for at least 10 years for each participant and is facilitated by a telephone call center.ResultsAs of July 2016, 1192 patients with JIA were enrolled in the CARRA Registry at 49 clinical sites. At enrollment, their median age was 12.4 years old and median disease duration was 2.6 years. Owing to preferential enrollment, patients with systemic JIA (13%) and with a polyarticular course (75%) were over-represented compared to patients in typical clinical practice. Approximately 49% were currently using biologic agents and ever use of oral glucocorticoids was common (47%). The CARRA Registry provides safety surveillance data to pharmaceutical companies to satisfy their regulatory requirements, and several independently-funded sub-studies that use the Registry infrastructure are underway.ConclusionThe new CARRA Registry successfully enrolled nearly 1200 participants with JIA in the first 12 months of its operation. Sustainable funding has been secured from multiple sources. The CARRA Registry may serve as a model for the study of other uncommon diseases.

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“…The problem of comparing prevalent users with switchers without randomization is well described, for example, in the rheumatology literature (ongoing methotrexate users versus those switching to biologic disease-modifying antirheumatic drugs). 20 Such studies are well intentioned and try to answer a clinically relevant question, but randomization is usually necessary to obtain valid estimates when focusing on patients who are not treatment-naïve. It is widely acknowledged that comparing new users of one agent with new users of the comparator agent can substantially reduce such bias in nonrandomized studies.…”

Section: Full-length Articlesmentioning

confidence: 99%

Interpreting the quality of health care database studies on the comparative effectiveness of oral anticoagulants in routine care

Patrick¹,

Schneeweiss²,

Huybrechts³

et al. 2013

CER

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Background: Dabigatran, an oral direct thrombin inhibitor, has now been available for 2 years in the US for the prevention of stroke in patients with nonvalvular atrial fibrillation, and direct Xa inhibitors are also starting to enter the market. Studies examining the effects of new oral anticoagulants in health care databases are beginning to emerge. The purpose of this study was to describe the validity of early published observational studies on the comparative safety and effectiveness of new oral anticoagulants in patients with atrial fibrillation. Methods: We identified published nonrandomized post-marketing studies (articles or conference abstracts or posters) and critically appraised their internal validity, with a particular focus on their ability to control confounding and other biases. Results: Two full-length journal articles, three conference posters, two conference presentation abstracts, and a US Food and Drug Administration analysis form the basis of the early comparative effectiveness and safety experience with new oral anticoagulants. Some published studies exhibit substantial biases and have insufficient precision for several important endpoints. Several studies suffer from biases arising from comparing ongoing users of the older drug, warfarin, who seem to tolerate it, to initiators of the new treatment who may have switched from warfarin or have had no prior experience with anticoagulants. Analyses tended to not adjust or not adjust adequately for confounding, and unsound propensity score application was also observed. Several studies introduced selection bias by excluding patients who died during follow-up and by restricting the study population to those with continuous database enrollment following cohort entry. We describe how these deficiencies can be avoided when studying new drugs. Conclusion:The first published post-marketing observational studies may not be sufficient for decision-makers to assess fully the comparative effectiveness and safety of new oral anticoagulants. These studies have methodologic challenges that can be avoided by using sound pharmacoepidemiologic design and analysis strategies.

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The risk of infection associated with tumor necrosis factor α antagonists: Making sense of epidemiologic evidence

Cited by 38 publications

References 22 publications

TNF-<i>α</i> Antagonist and Infection in Rheumatoid Arthritis

TNF-<i>α</i> Antagonist and Infection in Rheumatoid Arthritis

The new Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry: design, rationale, and characteristics of patients enrolled in the first 12 months

Interpreting the quality of health care database studies on the comparative effectiveness of oral anticoagulants in routine care

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The risk of infection associated with tumor necrosis factor α antagonists: Making sense of epidemiologic evidence

Cited by 38 publications

References 22 publications

TNF-&lt;i&gt;α&lt;/i&gt; Antagonist and Infection in Rheumatoid Arthritis

TNF-&lt;i&gt;α&lt;/i&gt; Antagonist and Infection in Rheumatoid Arthritis

The new Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry: design, rationale, and characteristics of patients enrolled in the first 12 months

Interpreting the quality of health care database studies on the comparative effectiveness of oral anticoagulants in routine care

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Product

Resources

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TNF-<i>α</i> Antagonist and Infection in Rheumatoid Arthritis

TNF-<i>α</i> Antagonist and Infection in Rheumatoid Arthritis