One-year risk of serious infection in patients treated with certolizumab pegol as compared with other TNF inhibitors in a real-world setting: data from a national U.S. rheumatoid arthritis registry

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes persistent synovial inflammation. When not treated adequately, active RA can lead to progressive joint damage, significant pain, disability, and reduced quality of life [1, 2]. The chronic inflammation inherent to RA has consequences that go beyond the damage to the musculoskeletal system. Compared with the general population, RA is associated with substantial morbidity and premature mortality, which is attributed mainly to serious infection, cardiovascular disease, and certain types of cancer [3‐5]. The substantial disease burden of RA underscores the importance of effective therapy.

Tumor necrosis factor inhibitors (TNFi), often the first class of biologic therapy prescribed to patients with RA, have been demonstrated to reduce disease activity and improve clinical, radiographic, and functional outcomes [6]. Effective control of disease activity with TNFi has been linked with a reduced risk of cardiovascular disease [7, 8]. Conversely, the immunosuppressive effect of TNFi has raised concerns over an increased risk of infection [9], although the magnitude of this risk remains a topic of intense debate [10‐21]. The impact of TNFi on the incidence of cancer is also unclear [11, 22‐25].

Overall, it is difficult to assess the risks associated with TNFi therapy, owing to the influence of patients’ demographic characteristics, clinical history, and concomitant immunomodulatory treatments. Furthermore, in clinical practice, drugs with similar therapeutic indications can be prescribed selectively to patients with different baseline prognoses, a phenomenon termed channeling bias [26]. Consequently, the line of TNFi therapy may also influence the safety risks observed in clinical practice.

Certolizumab pegol (CZP), a PEGylated, Fc-free TNFi, is approved for the treatment of adult patients with moderate to severe active RA [27]. Currently, there is limited evidence on the safety of CZP compared with other TNFi drugs in the context of U.S. clinical practice. The objective of this prospective, observational cohort study was to examine the 1-year incidence of serious infectious events (SIEs) during CZP use compared with other TNFi drugs (golimumab, etanercept, adalimumab, and infliximab), with and without a methodological approach accounting for channeling bias in patients with moderate to severe RA enrolled in the Consortium of Rheumatology Researchers of North America (Corrona) registry. The 1-year risk of malignancies and cardiovascular events (CVEs) was also assessed, owing to their importance for decision-making in clinical practice.

When initiating TNFi therapy in RA, rheumatologists need to carefully balance the potential clinical benefits of treatment with the anticipated risks in each individual patient in light of their demographic characteristics, clinical history, and concomitant medications. Excepting a recently completed head-to-head randomized controlled trial (RCT) comparing the efficacy and safety of CZP and adalimumab, in which investigators reported no clinically significant differences between the two drugs [33], there is a paucity of head-to-head RCTs comparing the safety of TNFi drugs in RA. Observational studies therefore provide a valuable source of comparative safety data.

Using data from the Corrona registry, we compared the safety of CZP with other TNFi as a group (golimumab, etanercept, adalimumab, and infliximab). As with any registry study, channeling bias can arise from the fact that clinicians prescribe treatment not at random but based on personal clinical experience and their patients’ clinical characteristics [26]. To overcome this limitation, we assessed safety outcomes in two cohorts: (1) all patients initiating CZP or other TNFi therapy and (2) the subset of patients matched by PS. In the unmatched population, the rate of SIEs was approximately 50% higher in the CZP group than in the other TNFi group. After using the PS-matched model to minimize channeling bias and resolve clinically significant baseline differences between CZP and other TNFi initiators, the risk of SIEs associated with each group was no longer distinguishable.

The contrasting results in the unmatched and PS-matched cohorts highlight the need to consider baseline patient differences when comparing the risk of AEs between TNFi drugs prescribed at different stages in the course of RA. CZP was prescribed later in the line of therapy than other TNFi. Consequently, patients initiating CZP were, on average, older and had longer disease duration, more active disease, and more functional impairment than patients initiating treatment with other TNFi. This probably explains the higher rate of SIEs in the unmatched CZP group because older age, high disease activity, and disability have previously been identified as risk factors for serious infection in RA [9, 34‐38].

Meta-analyses of RCTs have demonstrated that the different TNFi drugs available in RA are equally efficacious at reducing disease activity [18]. Therefore, on the basis of clinical efficacy alone, there has been relative equipoise among rheumatologists regarding which therapy to choose as first and subsequent lines of treatment [39]. However, the safety of TNFi therapy, particularly with regard to infection, continues to be debated. The authors of the first published meta-analysis of serious infection in RA detected an association with TNFi treatment [11], but subsequent meta-analyses performed with greater sample sizes have produced discordant results [14, 15, 17, 18, 20]. Similarly, whereas researchers in some observational studies have reported an association between TNFi and the risk of serious infection [10, 13, 19], others did not find a clear link [12, 16, 21]. In a large meta-analysis of RCTs in which authors compared the safety of all five TNFi drugs across multiple diseases, CZP was associated with higher odds of serious infection than adalimumab, etanercept, and golimumab [40]. However, the diseases and patient populations captured in this meta-analysis differed substantially between drugs, and no correction was made for placebo exposure, which makes the results difficult to interpret. It is known that the background risk of SIEs varies greatly across diseases [37, 41], and even within indications it is strongly dependent on study inclusion criteria and baseline patient characteristics [35]. By contrast, a recent head-to-head clinical trial comparing the efficacy and safety of CZP with adalimumab in patients with RA provided direct evidence of a comparable safety profile for the two drugs, including a similar incidence of serious infection [33].

The IRs of SIEs reported in the present study are consistent with rates observed in other real-world patient populations. For example, in a retrospective study of medical and pharmaceutical data from a large U.S. health insurer, the rate of hospitalized infections among patients with RA with no prior biologic use was 4.6/100 PY, whereas for patients switching to a new biologic at baseline, an IR of 7.0/100 PY was reported [35]. In a retrospective analysis of Medicare claims data for patients with RA treated with prior biologics, the crude IRs of hospitalized infection during TNFi treatment ranged between 14.1/100 PY (golimumab) and 17.0/100 PY (infliximab; the IR for CZP was 14.2/100 PY) [42]. A prospective observational study using data from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA) reported rates of SIEs ranging from 2.8/100 PY in patients aged < 55 years to 8.3/100 PY in patients aged > 75 years [13].

Regardless of PS matching, there were no important differences in the IRs of malignancies and CVEs between CZP and other TNFi initiators. Interpretation of these results must take into account the infrequent nature of these AEs and the fact that patients in this study were followed for a maximum of 12 months, which may have been too short to detect meaningful risk differences between groups.

Evaluating the impact of TNFi on the risk of cancer in RA is a challenging task. Because most types of cancer occur very rarely, RCTs often lack sufficient power to conclusively assess the risk of malignancy, owing to the short duration of follow-up. Furthermore, patients with RA with a history of cancer tend to be excluded from participation in RCTs [43]. Given the latency of cancer and its potential for reactivation over time, it is important to evaluate the risks of TNFi use in patients with a history of this condition. Approximately 5% of Corrona patients included in our study had a history of prior malignancy. Regardless of PS matching, the IRs of malignancies reported here for CZP and other TNFi initiators were comparable to those previously reported in the BSRBR-RA [43, 44] and the Swedish Biologics Registry [45]. Also consistent with these two registries, nonmelanoma skin cancer was one of the most commonly reported malignancies [46, 47].

Cardiovascular disease is one of the main causes of morbidity and premature mortality in patients with RA [3]. This has been attributed to the direct impact of chronic inflammation on the vascular system and to the secondary effects of physical inactivity [48]. By effectively reducing disease activity, TNFi treatment may help to mitigate the cardiovascular risk associated with RA [7, 8]. In this study, traditional cardiovascular risk factors such as BMI, smoking status, blood pressure, history of cardiovascular disease, and prednisone use were similar at drug initiation between the CZP and other TNFi groups. By contrast, RA disease activity, which is also associated with cardiovascular risk [8, 49, 50], was higher in the CZP group. Nevertheless, the IRs of CVEs we report, which corresponded mainly to myocardial infarction and transient ischemic attack (TIA)/stroke, did not differ substantially between the CZP and other TNFi groups, regardless of PS matching.

A limitation of this study was that patients were followed for a maximum of 12 months after initiation of a particular TNFi. Although SIE rates tend to be highest during the first 6–12 months of TNFi exposure [13, 51], this time frame may not have been sufficient to detect differences in the rates of CVEs or malignancies, owing to the comparative infrequency and longer-term nature of these AEs. Despite this limitation, the rates of malignancy we report were consistent with a recent meta-analysis of observational studies where there were no differences among the five TNFi drugs regarding the overall risk of cancer [52]. Similarly, the rates of myocardial infarction and TIA/stroke were comparable to those previously reported for the Corrona cohort [8]. The rarity of other AEs of interest prevented further analyses; their inclusion in this report was meant to provide a more complete picture of the AEs reported by the study population. Overall, although AEs were assessed over a 1-year period only, the findings of this study are consistent with previously published long-term safety analyses of CZP in RA [53].

A key strength of this study is the fact that we compared safety outcomes for TNFi in U.S. clinical practice using data from a large, nationwide cohort of patients with RA. Because patient characteristics and access to biologic drugs can vary substantially between countries, owing to payer and regulatory differences, it is important to obtain clinical evidence directly relevant to practicing rheumatologists in the United States. It has been demonstrated that patients in Corrona share similar demographic and clinical characteristics with Medicare beneficiaries with claims for rheumatology or RA, suggesting that the results we present may be generalizable to the wider RA population in the United States [54]. Furthermore, we used PS matching to control for baseline patient characteristics that might have influenced the decision to treat with CZP or other TNFi, thereby helping to minimize channeling bias and allowing for a more accurate comparison of the risk of AEs associated with these therapies.

In a PS-matched cohort of patients with moderate to severe RA enrolled in the Corrona registry, there were no differences in the 1-year risk of SIEs, malignancies, and CVEs between patients treated with CZP and those treated with other TNFi.