Abstract
Objective To determine whether higher serum exposure during subcutaneous (SC) abatacept (ABA) treatment was associated with an increased infection risk in adult patients with early rheumatoid arthritis (RA).
Methods Data from Assessing Very Early Rheumatoid Arthritis Treatment-2 (AVERT2; ClinicalTrials.gov: NCT02504268), a randomized, placebo-controlled study in anticitrullinated protein antibody–positive patients with early RA, were analyzed. A post hoc population pharmacokinetic (PPK) analysis was performed. The association between steady-state ABA concentration exposures (ie, steady-state time-averaged serum concentration, steady-state trough serum concentration, steady-state maximum serum concentration) and first infection was evaluated using Kaplan-Meier plots of probability vs time receiving treatment and Cox proportional hazards models.
Results The PK model of SC ABA was defined as a linear 2-compartment model with first-order absorption and elimination, and higher body weight was the only covariate with a clinically relevant effect in the final PPK model. Infections occurred in 330/693 patients treated with ABA + methotrexate (MTX; 47.6%; 11/693 [1.6%] with serious infections) and 134/301 of those treated with ABA placebo + MTX (44.5%; 4/301 [1.3%] with serious infections). Exposure-response analysis demonstrated no exposure relationship for an increased risk of first infection for patients with concomitant use of MTX and glucocorticoids (GCs) during the induction period, baseline GC use, or higher-than-median body weight (> 70 kg) at baseline.
Conclusion This exposure-response analysis of AVERT-2 showed no increase in the risk of first infection, regardless of ABA exposure level, in patients with RA treated with SC ABA. Similarly, no effect on the risk of first infection was found for concomitant MTX and GC use in patients with RA treated with SC ABA + MTX.
Plain Language Summary
Rheumatoid arthritis (RA) is a long-lasting autoimmune disease. Infections are common in RA. Some infections can cause hospital visits or death. It is important to study how different doses of treatments for RA may affect the risk of infections. This study looked at abatacept (ABA), a treatment option for RA, and whether higher doses led to more infections in patients with RA.
Our study had 2 parts. It used data from the original Assessing Very Early Rheumatoid Arthritis Treatment-2 (AVERT-2) study, where patients with RA were treated with 2 drugs: ABA and methotrexate. In part 1, we combined results from AVERT-2 with results from 12 other studies. We did this to see what factors might affect ABA levels in patients with RA taking ABA and methotrexate. In part 2, we used results from AVERT-2 to see if higher ABA doses would lead to more infections in patients with RA.
In part 1, we found that body weight affects how long ABA stays in the body. In part 2, we found that higher ABA doses did not lead to more infections. We also found that taking a steroid at the beginning of the study or taking methotrexate with a steroid during the study did not lead to more infections. Patients who weighed more than 70 kg at the beginning of the study did not have more infections than those who weighed less than 70 kg. These results may help doctors pick the best dose of ABA for treatment of patients with RA.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that has a substantial societal impact in terms of cost, disability, and lost productivity.1 Observational and population-based studies in patients with RA have shown an approximately 2-fold increase in hospitalization risk due to infection compared to individuals without RA.2,3 Patients with RA also have an increased risk of mortality from infection4-6; therefore, consideration of treatment options in light of the infection risk is important.
In patients with RA, the increased risk of serious infection could be a result of the immunomodulatory effects of the disease, multimorbidity, or treatment-related factors such as the use of immunosuppressive drugs (eg, steroids or disease-modifying antirheumatic drugs [DMARDs]) that increase susceptibility to infections.2,3 Previous RA studies examining the effects of different classes of immunosuppressive therapy on infection rates have reported varying results. A retrospective study noted that long-term high doses of glucocorticoids (GCs; > 10 mg/day) were associated with a high risk of serious infections.7 The British Society for Rheumatology (BSR) Biologics Register for RA reported a relationship between biologic drug exposure and risk of infection for tumor necrosis factor inhibitors (TNFi) and interleukin 6 inhibitors (IL-6i).8
With recent advancements, immunosuppressive RA treatments are more effective in controlling disease activity and joint damage in many patients. However, infections are the most commonly reported adverse events (AEs) in patients with RA treated with immunosuppressives such as biologics, and their safety—particularly the risk of infection—remains a concern. In a previous study of juvenile patients with polyarticular-course juvenile idiopathic arthritis (pcJIA), no association was found between higher serum levels of abatacept (ABA) and the incidence of infection following treatment with subcutaneous (SC) or intravenous (IV) ABA.9 However, this association has not been evaluated for patients with RA who are older and have different comorbidities and disease characteristics, such as frailty.10,11
This analysis aimed to determine whether higher serum ABA exposure—defined by steady-state time-averaged serum concentration (Cavg,ss), steady-state trough serum concentration (Cmin,ss), and steady-state maximum serum concentration (Cmax,ss)—during treatment with SC ABA was associated with an increased risk of first infection in adult patients with RA. It also aimed to characterize the pharmacokinetic (PK) profile of ABA and the effects of covariates on variability in PK variables when ABA is administered in combination with methotrexate (MTX). The relationship between ABA exposure and safety, as measured by the number and seriousness of infections, was evaluated.
METHODS
Patient population and study design. Assessing Very Early Rheumatoid Arthritis Treatment-2 (AVERT-2; ClinicalTrials. gov: NCT02504268) was a phase IIIb, randomized, double-blind, placebo-controlled study that assessed the efficacy of SC ABA + MTX in achieving remission in patients with early RA. Briefly, SC ABA (125 mg) + MTX or ABA placebo + MTX was administered weekly to patients with early, active RA who were MTX-naïve and anticitrullinated protein antibody (ACPA)-positive.12 Remission was defined as Simplified Disease Activity Index (SDAI) ≤ 3.3 at week 24. The AVERT-2 study comprised 2 stages: induction (56 weeks) and deescalation (48 weeks). The current analysis focuses on the induction period (IP) of AVERT-2 (Supplementary Figure S1, available with the online version of this article). The full study design has been published previously.12 During the IP, patients were randomized (3:2) to once-weekly doses of SC ABA 125 mg + MTX or ABA placebo + MTX for 56 weeks. The starting dose of MTX was 7.5-15 mg/week. By week 8, the dose was titrated to ≥ 15 mg, as tolerated, and as per local practice and regulations. Patients maintained a consistent dose once stabilization was achieved, and changes in dose were not permitted after week 12 except for a decrease in dose to a minimum of 10 mg/week because of toxicity or intolerance.
Patients were enrolled from 174 sites in 30 countries. Patients aged ≥ 18 years with early RA (for ≤ 6 months, diagnosed per the American College of Rheumatology [ACR] and European Alliance of Associations for Rheumatology [EULAR] 2010 criteria) who were ACPA-positive and DMARD-naïve were eligible for the study if they had a tender joint count ≥ 3, a swollen joint count (SJC) ≥ 3, C-reactive protein > 3.0 mg/L or erythrocyte sedimentation rate ≥ 28 mm/h, and baseline SDAI score > 11.12
Assessments and statistical analyses. An additional subanalysis of AVERT-2 involved PK analyses of a subset of patients for whom ≥ 1 PK sample was collected during the IP and assessed for serum concentration. PK samples were obtained before study drug administration to determine serum ABA concentrations at day 1, week 4, week 8, week 12, week 24 (day 169), and week 52 (day 365) of the IP.
Data from the AVERT-2 PK subanalysis were used to perform a population PK (PPK) analysis (ie, a study of drug levels based on dose and frequency interval per unit body size) to characterize the ABA serum concentration–time profile and assess the effects of covariates on variability in PK variables in adult patients with RA who received SC ABA + MTX. PPK analysis of SC and IV ABA with standard treatment has been previously characterized.13 The previously developed base model, including 5 phase II and 7 phase III clinical studies of IV ABA, was updated to add the phase III AVERT-2 PK analysis (with SC ABA) to assess the PPK of SC ABA + MTX in patients with RA (Supplementary Table S1, available with the online version of this article). The PPK analysis dataset was prepared by pooling the assembled datasets containing ABA serum concentrations from the 12 clinical studies and clinical data collected in AVERT-2. Dataset records corresponding to missing serum ABA concentrations or missing sample collection times were retained in the analysis dataset but flagged and excluded from the analysis.
The PPK model was developed with the analysis dataset in 3 steps: (1) reestimating the previously developed base PPK model using a pooled dataset of 13 studies with PK data from patients with RA; (2) assessing the effect of selected covariates on ABA clearance and volume using a single round of forward selection; and (3) performing backward elimination on covariates added to the model during the first round of forward selection. The final model was evaluated using a prediction-corrected visual predictive check. Finally, simulations were performed to obtain summary measures of exposures for each patient with RA in the analysis dataset. The final PPK model and individual participant PK variables described above were used as a basis for these simulations. No sensitivity analyses were performed.
The exposure-response relationship (ie, the study of the relationship between drug concentration and infection rate) between ABA exposure and the probability of first infection in MTX-naïve patients during the AVERT-2 IP by treatment arm (ABA + MTX vs ABA placebo + MTX) was analyzed. Safety endpoints considered in the exposure-response analysis were the first infection, regardless of seriousness, and the first serious infection. Covariates considered in the exposure-response analysis were baseline age, baseline body weight, sex, race, baseline GC use, and concomitant MTX and GC use.
ABA trough serum concentration at steady state (Cmin,ss) was used as the primary exposure measure,13 along with both maximum serum concentration (Cmax,ss) and time-averaged serum concentration (Cavg,ss). The association between steady-state ABA exposure measures (Cavg,ss, Cmin,ss, Cmax,ss) and time to first infection (response) was explored using Kaplan-Meier (KM) plots of the probability of first infection vs time on treatment, by ABA exposure quartiles. The effect of low vs high ABA serum concentrations was assessed by exposure quartiles; quartiles of ABA exposure were generated based on drug concentrations at steady state. Cox proportional hazards models were used to test the significance of ABA exposure as predictors of time to first infection (significance level of 0.05). Infection diagnosis was based on the investigator’s clinical judgment and/or culture of an organism (if available). Opportunistic infections (OIs) were defined, per a previous study,14 as specific pathogens or presentations of pathogens that indicate the likelihood of an alteration in host immunity in the setting of biologic therapy. As a higher risk of opportunistic infection, particularly tuberculosis (TB), is well recognized with the use of biologic therapies in arthritis,15 latent TB was also considered an OI and was confirmed with a positive tuberculin test or interferon-γ release assay.
RESULTS
Study population. From the AVERT-2 study, 693 patients receiving ABA + MTX (of 994 study patients) had evaluable PK data (mean age 49.3 [SD 12.8]; female, n = 538 [77.6%]; Table 1). During the AVERT-2 IP, 103 (14.9%) patients discontinued treatment, mostly due to AEs (n = 32), lack of efficacy (n = 20), and patient requests to discontinue (n = 16; data not shown).
Baseline patient demographics and disease characteristics of the PK analysis AVERT-2 study population.
For the PPK analysis, a total of 15,378 samples (80.5%) from 3050 patients (97.1%) with available ABA serum concentrations were included in the pooled analysis of the 13 clinical studies. Baseline characteristics of the pooled population and covariates for the PPK analysis are summarized in Supplementary Table S1 (available with the online version of this article). Mean patient age across studies was 50.9 (SD 12.9) years and 79.7% (n = 2430) were female.
PPK analysis. In PK-evaluable patients from AVERT-2, baseline mean study exposure was 373.5 (SD 66.2) days for those receiving ABA. Baseline mean prednisone equivalent dose was 6.7 (SD 3.7) mg/day. The baseline mean MTX dose was 9.7 (SD 3.1) mg/week (Table 1). During the IP period, the mean MTX dose was 11.5 (SD 2.8) mg/week from week 1 through week 7 and 15.5 (SD 3.7) mg/week from week 8 through week 24. Despite mandatory MTX titration to ≥ 15 mg/week, MTX dosing was missed or not conducted in accordance with the protocol for some patients, which resulted in lower overall mean MTX doses. The median SDAI score was 36.9 (IQR 27.5-48.2). A summary of ABA PK variables and exposures in AVERT-2 is provided in Table 2.
Summary of abatacept PK variables and exposures in adult patients with RA from the AVERT-2 study (N = 693).a
Steady state of ABA was reached at day 57. From day 57 onward, Cmin,ss concentrations remained consistent over time; the Cmin,ss geometric mean range was 24.0-29.4 μg/mL. The PK model of SC ABA was determined as a linear 2-compartment model with zero-order IV infusion or first-order absorption for SC dosing and first-order elimination. The final PPK model included effects of age, sex, race, baseline body weight, glomerular filtration rate, baseline albumin, MTX use, nonsteroidal antiinflammatory drug use, SJC on clearance, and baseline body weight on volume of the central compartment and volume of the peripheral compartment, as well as a shift in bioavailability for SC dosing. The only covariate with a clinically relevant effect was body weight, affecting clearance and volume.
ABA exposure and infections.
• Overall infections. In the PK-evaluable population of AVERT-2, 78.5% of patients (n = 544/693) had AEs and 7.9% (n = 55/693) had serious AEs, with 1 death (0.1%; Table 3). Overall, infections occurred in a total of 330/693 (47.6%) patients treated with ABA + MTX and 134/301 (44.5%) treated with ABA placebo + MTX during the AVERT-2 IP. No significant exposure-response relationship was observed between steady-state ABA exposure quartiles (Cavg,ss, Cmin,ss, Cmax,ss) and the occurrence of first infection vs placebo (Figure 1A-C) based on the Cox proportional hazards analysis. Comparison of exposure-response models by exposure metric for the evaluation of ABA exposure on time to first infection, regardless of seriousness, showed that no ABA exposures were significant predictors of the time to first infection, indicating no exposure-response relationship (Supplementary Table S2, available with the online version of this article). At the time of first infection, a similar proportion of patients treated with ABA + MTX (42%; 140/330) and ABA placebo + MTX (37%; 50/134) during the AVERT-2 IP were receiving GCs.
Safety summary of AEs in adult patients with RA from the AVERT-2 study.
Kaplan-Meier plots for time to first infection for ABA + MTX vs ABA placebo + MTX: (A) Cavg,ss, (B) Cmin,ss, and (C) Cmax,ss. ABA intervals enclosed in brackets represent quartiles of ABA exposures. P values are given for exposure-response safety models for time to first infection regardless of seriousness. ABA: abatacept; Cavg,ss: steady-state time-averaged serum concentration; Cmax,ss: steady-state maximum serum concentration; Cmin,ss: steady-state trough serum concentration; MTX: methotrexate.
The exposure-response analysis demonstrated that there was no exposure relationship (ie, no separation on KM plots) detected for an increased risk of infections for patients with concomitant use of MTX and GCs during the IP, baseline GC use, and higher-than-median body weight (> 70 kg) at baseline (Figure 2A-C). Although there was some separation in the probability of first infection over time by age (< 65 vs ≥ 65 years) and sex, neither was statistically significant using a log-rank test (P = 0.93 and P = 0.18, respectively; data not shown).
Kaplan-Meier plots for time to first infection by covariates of interest: (A) concomitant MTX and GC use, (B) baseline GC use, and (C) body weight ≥ 70 kg median. GC: glucocorticoid; MTX: methotrexate.
• Serious infections and OIs. Overall, a similar proportion of patients treated with ABA + MTX (1.6%, n = 11 events) and ABA placebo + MTX (1.3%, n = 4 events) experienced ≥ 1 serious infection. Owing to the very low occurrence of serious infections, KM plots were not prepared. Exploratory graphical analyses of the relationships between measures of ABA steady-state exposure and serious infection occurrences (Figure 3A-C) found that the median and range of ABA steady-state exposure measures for patients who experienced serious infections were similar to the values of patients who did not experience serious infections, indicating no apparent exposure-response relationship.
Abatacept steady-state exposure measures by occurrence of serious infections: (A) Cavg,ss, (B) Cmin,ss, (C) Cmax,ss. Boxes indicate the 25th, 50th, and 75th percentiles; whiskers indicate 5th to 95th percentiles. Asterisks and squares indicate data points outside this range. Cavg,ss: steady-state time-averaged serum concentration; Cmax,ss: steady-state maximum serum concentration; Cmin,ss: steady-state trough serum concentration.
A total of 10/693 patients (1.4%) in the PK-evaluable population experienced OIs, with the following incidence rates (IR) per 100 patient-years: overall, 1.4 (95% CI 0.76-2.62); oral candidiasis, 0.85 (95% CI 0.38-1.88); ophthalmic herpes, 0.14 (95% CI 0.02-1.00); latent tuberculosis, 0.14 (95% CI 0.02-1.00); esophageal candidiasis, 0.14 (95% CI 0.02-1.00); and tuberculosis, 0.14 (95% CI 0.02-1.00).
Immunogenicity. Antidrug antibodies (ADAb) to ABA were observed during the trial. During the initial treatment period, 12/664 patients (1.8%) developed antibodies (titer 10-210), of which 6 (0.9%) were CTLA4-specific. In the posttreatment period, antibodies were detected in 12/53 patients (22.6%; titer 10-508). Neutralizing antibodies (NAb) were assessed on anti-ABA antibody–positive samples that were eligible for NAb analysis (CTLA4 specificity and ABA serum concentrations ≤ 1 μg/mL) using a validated in vitro cell-based bioassay. Of the 18 patients who were positive for CTLA4-specific antibodies, 14 were tested for NAbs and 5 were positive; NAb positivity was not associated with infusion reactions or immune-related AEs.
DISCUSSION
This analysis of the AVERT-2 IP, including PPK and exposure-response analyses, showed no increase in the risk of first infection in patients with RA, regardless of ABA exposure. The exposure-response analysis detected no exposure relationship for an increased risk of infections for patients with concomitant use of MTX and GCs during the IP, baseline GC use, and higher-than-median body weight (> 70 kg) at baseline. The findings of this updated PPK analysis including the AVERT-2 study were consistent with those reported in prior population analyses of ABA PK in adults with RA.13 The PK model of SC ABA was defined as a linear 2-compartment model with first-order absorption and elimination, and higher body weight was the only covariate with a clinically relevant effect. Infections occurred at a similar rate between patients treated with ABA + MTX (47.6%; serious infections 1.6%) and ABA placebo + MTX (44.5%; serious infections 1.3%).
SC ABA administered at a dose of 125 mg/week in combination with oral MTX was generally safe and well tolerated in this AVERT-2 study analysis. The overall proportion of serious infections was low (1.6%), and no apparent association between ABA steady-state exposure and risk of serious infections was found. Similar to the findings of this study, a previous post hoc analysis of 2 clinical trials in patients with pcJIA found that the use of MTX and biologic DMARD (bDMARD) combination therapy does not increase the risk of serious AEs, serious infections, or death compared with bDMARD monotherapy.9 In the 2-year head-to-head ABA Versus Adalimumab (ADA) Comparison in Biologic-Naïve RA Subjects With Background MTX (AMPLE) trial,16 a similar proportion of patients experienced serious infections with ADA + MTX vs ABA + MTX (2.7% vs 2.2%, respectively), both of which were slightly higher than the proportion of serious infections (1.6%) reported in AVERT-2. Further, 63.2% of patients receiving ABA + MTX and 61.3% receiving ADA + MTX in the AMPLE study had an infection, both of which are greater than the 47.6% treated with ABA + MTX who had infections in this study. Despite the differences in occurrence of infections, the planned MTX dose for both studies was similar (≥ 15 mg in the current AVERT-2 study and 15-20 mg/week in the AMPLE study).15 However, in the AMPLE patient population, the duration of active disease was longer, prior DMARD therapy was higher, and drug exposure levels were not examined. In contrast, more patients experienced infectious AEs with increasing MTX doses (≤ 20 mg/week) in the prospective CONCERTO ADA trial.17 These findings are important, indicating a difference in infection rates, particularly for serious infections, when considering other drug exposures and patient population factors.
In the current study, the higher proportion of patients with detectable ADAb posttreatment aligns with the method of action of the drug (ie, interference with T cell costimulation), which may have inhibited development of ADAb during the treatment period; this finding aligns with a previous study where ABA was withdrawn.18 Although the proportion of patients with detectable ADAb was higher in the posttreatment period (1.8% vs 22.6%), the titers in these patients were low, with values ≤ 175 for CTLA4-specific antibodies.
Owing to their immunomodulatory effect, GCs are associated with a higher risk of infection19,20; this effect is dependent on dose and duration of use. Long-term use of higher GC doses (> 10 mg/day prednisone equivalent) are reported to more than double the risk of serious infections.7 Higher doses of GCs increase the risk substantially more than conventional synthetic DMARDs (csDMARDs), biologics, or Janus kinase inhibitors.20 In line with this, the most recent EULAR guidelines on RA management recommend considering short-term use of GCs when initiating or changing csDMARDs, with rapid tapering and discontinuation of GCs when clinically feasible.21 The ACR guidelines recommend against the use of high-dose, long-term GCs for the same reason.22 In the AVERT-2 study, the mean prednisone equivalent dose was 6.7 mg/day, which has been associated with an increased risk of infection.7 Importantly, results of the exposure-response analysis demonstrated there was no exposure-response relationship detected for an increased risk of infections with concomitant use of MTX and GCs with ABA during the IP, baseline steroid use, and higher-than-median body weight (> 70 kg) at baseline during the AVERT-2 IP. It has been reported extensively in the literature that use of GCs is associated with an increased risk of infection in a dose-dependent manner.7,20 For reasons that are not clear, we were not able to demonstrate a similar risk of GC use in the current study population.
A higher number of OIs were found in this study (n = 10, 1.4%; IR 1.41, 95% CI 0.76-2.62) compared with a pooled analysis of 16 ABA clinical trials including AVERT-2, in which OIs were observed in 0.2% of the pooled population (n = 4; IR 0.17, 95% CI 0.050.43).23 Oral candidiasis showed the highest incidence (n = 6; 0.9%), vs 0 cases in the previous pooled analysis.
Previous analyses on other DMARDs, reported only in abstract form from the BSR, have noted mixed results for exposure-response relationships across drug classes. In contrast with the reported findings, a relationship was reported between drug exposure for several biologics and risk of infection8; of note, the BSR population analyzed was comparable in size (n = 703) with the AVERT-2 study (n = 693). The BSR analysis assessed the TNFi etanercept, ADA, certolizumab, and infliximab, as well as the IL-6i tocilizumab, but did not differentiate results for the different drug classes. The BSR study population was older than the current population (mean 58 [SD 12] years vs 49.3 [SD 12.8] years), with a similar proportion of women (74% vs 77.6%). Other factors that influence the risk of infection and may have contributed to the difference in findings between the 2 studies (eg, presence of extraarticular manifestations of RA, leukopenia, and comorbidities24) were not reported. A metaanalysis of 18 randomized controlled trials (n = 8808) on the safety of TNFi showed no increase in the risk of serious AEs with recommended doses of TNFi, but a 2-fold increase in the risk of serious infections with high-dose TNFi (2-3 times the recommended dose).25 ABA is associated with a low number of infections26 compared with TNFi. Our current study in patients with RA showed that higher ABA exposure does not increase the risk of first infection compared with lower ABA exposure, which is also supported by our previous study in patients with pcJIA.9
When a given therapy fails to demonstrate efficacy for management of RA symptoms, therapeutic drug level monitoring may provide insight into why the therapy failed, and may provide an opportunity for personalized dosing, considering other individual patient factors like weight, disease duration, and activity. However, routine drug level monitoring may be wasteful without providing additional clinical information,27 especially for drugs that show no increase in efficacy or have safety issues and/or infections associated with increases in exposure. Compared with the BSR study,8 which used concentration-effect curves with patient drug levels available in 2 national prospective RA cohorts to determine low/normal vs high drug levels, this study used steady-state exposure measures (Cavg,ss, Cmin,ss, Cmax,ss), which are reliable indicators for treatment of chronic conditions like RA. In this study, steady state was achieved at 57 days, which should be considered in the context of previous findings from the AMPLE trial showing that the time course of clinical efficacy was similar between ABA + MTX and ADA + MTX.16 None of the 3 exposure measures evaluated in this analysis showed any relationship with increased infection. Regarding ABA, immunogenicity does not appear to affect systemic exposures of ABA while on treatment,28 which increases the reliability of these results.
This study had notable strengths and limitations. The patient population included a globally representative pool (30 countries), and patients were selected from a large number of study sites (174 sites) and randomized. This study was further strengthened by an extensive PPK study, with approximately 15,000 PK samples from 3050 patients pooled from 13 clinical studies. One limitation is that the generalizability to the overall RA population may be limited, as the data evaluated in this analysis were obtained from patients with early RA, active disease, and poor prognostic factors. Differences in age, race and ethnicity, weight, and other factors (eg, renal function) may also contribute to limited generalizability to other populations. Additionally, no data on disease outcomes or comorbidities were reported in this analysis, although disease outcomes for the AVERT-2 study were reported elsewhere.12 Disease severity in RA is potentially associated with both infection risk and medication exposures,19 as higher disease activity has been associated with a higher probability of developing infections in patients with RA.29 The patient population in this analysis showed severe disease (SDAI 38.7 and Disease Activity Score in 28 joints based on C-reactive protein 5.6; Table 1) at baseline, possibly because they were newly diagnosed with RA (disease duration ≤ 6 months) and DMARD-naïve. As such, the infection risk in this analysis may have been influenced by the disease duration (short history of RA) and disease activity of the study population. Finally, data were not reported on the proportion of patients receiving GCs, disease activity status, ABA concentrations in relation to efficacy, and prednisone dose at the time of serious infection occurrence; therefore, we were unable to infer any relation between these factors and the occurrence of serious infections. This analysis does not include data on repeat infections or serious infectious events and the relationship to drug levels. Future analyses could focus on these points, including the effects of BMI on infection rates, the dosage of GCs in relation to the infection incidence rate, and NAb concentrations between the ABA arms with or without MTX.
PK and exposure-response analyses of the AVERT-2 study showed no association between ABA exposure and risk of first infection. Similarly, no effect on the risk of first infection was found for concomitant MTX and GC use during the AVERT-2 IP in patients with RA treated with SC ABA + MTX. ABA + MTX was generally well tolerated with no exposure-dependent effects of ABA on infection risk. To allow clinicians to make better evidence-based decisions regarding biologic treatment options for RA, reassessing the relationship between exposure levels of TNFi/IL-6i/other bDMARDs and the risk of infection, while identifying ways to improve access to testing, would be helpful.
ACKNOWLEDGMENT
The authors acknowledge the support of Sandra Overfield with protocol management, Prema Sukumar and Renfang Hwang with data management, and Margarita Askelson with statistical support. Professional medical writing and editorial assistance were provided by Candice Dcosta, MSc, at Caudex, a division of IPG Health Medical Communications, and were funded by Bristol Myers Squibb.
Footnotes
CONTRIBUTIONS
PE: study conception and design, data interpretation, writing original draft, draft revision; RF: study conception and design, data analysis, data interpretation, writing original draft, draft revision; RW: study conception and design, data acquisition, data analysis, data interpretation, writing original draft, draft revision; KL: study conception and design, data acquisition, data analysis, data interpretation, writing original draft, draft revision; YT: study conception and design, data analysis, data interpretation, writing original draft, draft revision; VB: study conception and design, data acquisition, data analysis, data interpretation, writing original draft, draft revision; COB: study conception and design, data acquisition, data analysis, data interpretation, writing original draft, draft revision; TWJH: data analysis, data interpretation, writing original draft, draft revision; GC: data analysis, data interpretation, writing original draft, draft revision; VP: study conception and design, data acquisition, data analysis, data interpretation, writing original draft, draft revision; BM: study conception and design, data acquisition, data analysis, data interpretation, writing original draft, draft revision; KFM: data analysis, data interpretation, writing original draft, draft revision; JP: data analysis, data interpretation, writing original draft, draft revision; WDH: study conception and design, data acquisition, data analysis, data interpretation, writing original draft, draft revision; DW: study conception and design, data acquisition, data analysis, data interpretation, writing original draft, draft revision.
FUNDING
This study was sponsored by Bristol Myers Squibb.
COMPETING INTERESTS
PE has been a consultant for AbbVie, Boehringer Ingelheim, BMS, Eli Lilly, Galapagos, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, and Samsung; and has received grant/research support from AbbVie, BMS, Eli Lilly, Novartis, Pfizer, Roche, and Samsung. RF has been a consultant for Amgen, AbbVie, Arthrosi, BMS, Eli Lilly, Galapagos, Galvani, Gilead, GSK, Novartis, Pfizer, and Vyne; and has received grant/research support from Amgen, AbbVie, Arthrosi, AstraZeneca, Biosplice, BMS, Eli Lilly, Gilead, GSK, Horizon, Novartis, Pfizer, Regeneron, and UCB. RW has been a shareholder and worked as an employee (at the time of analysis) for BMS. KL, VP, and BM are shareholders and employees of BMS. YT has received speakers bureau fees from AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, GSK, Mitsubishi-Tanabe, and Pfizer; and grant/research support from AbbVie, Asahi-Kasei, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, and Takeda. VB has been a consultant for AbbVie, BMS, and Pfizer; and received grant/research support from BMS (to institution). COB has been a consultant for AbbVie, BMS, Eli Lilly, Janssen, Pfizer, Sanofi; and received grant/research support from BMS. TWJH has received speakers bureau fees, been a consultant for, and/or received grant/research support from Ablynx, Abbott, Biotest AG, BMS, Crescendo Bioscience, Eli Lilly, Epirus, Galapagos, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB. GC has received speakers bureau fees from AbbVie, Amgen, BMS, Eli Lilly, Janssen, Pfizer, and Sandoz; been a consultant for AbbVie, Amgen, BMS, Pfizer; and received grant/research support from Pfizer. KFM and JP have been consultants for BMS; and are employees of Cognigen Division, a Simulations Plus company. DW has been a consultant for Black Diamond Network, Joule, and Syneos; and been an employee of BMS. WDH worked as an employee (at the time of analysis) for BMS.
ETHICS AND PATIENT CONSENT
The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice Guideline, and the International Society for Pharmacoepidemiology Guidelines for Good Epidemiology Practices. All patients provided written informed consent before enrollment. At each study site, the protocol and patients’ informed consent were reviewed and received institutional review board/independent ethics committee approval before initiation of the study. The laws and regulatory requirements of all countries participating in this study were adhered to. The study protocol and patient enrollment materials were approved according to local law in each participating country before initiation of the study.
DATA AVAILABILITY
Bristol Myers Squibb’s policy on data sharing may be found at https://www.bms.com/researchers-and-partners/clinical-trials-and-research/disclosure-commitment.html.
PLAIN LANGUAGE SUMMARY
The plain language summary of this article is also included as online supplementary material.
- Accepted for publication December 18, 2024.
- Copyright © 2025 by the Journal of Rheumatology
This is an Open Access article, which permits use distribution and reproduction without modification provided the original article is correctly cited and is not used for commercial purposes.
REFERENCES
SUPPLEMENTARY DATA
Supplementary material accompanies the online version of this article.
