Background The risk of subsequent infections in rheumatoid arthritis (RA) patients who receive biologic therapy after a serious infection is unclear.
Objective To compare the subsequent risk of hospitalised infections associated with specific biologic agents among RA patients previously hospitalised for infection while receiving anti-tumour necrosis factor (anti-TNF) therapy.
Methods Using 2006–2010 Medicare data for 100% of beneficiaries with RA enrolled in Medicare, we identified patients hospitalised with an infection while on anti-TNF agents. Follow-up began 61 days after hospital discharge and ended at the earliest of: next infection, loss of Medicare coverage or 18 months after start of follow-up. We calculated the incidence rate of subsequent hospitalised infection for each biologic and used Cox regression to control for potential confounders.
Results 10 794 eligible hospitalised infections among 10183 unique RA patients who contributed at least 1 day of biologic exposure during follow-up. We identified 7807 person-years of exposure to selected biologics—333 abatacept, 133 rituximab and 7341 anti-TNFs (1797 etanercept, 1405 adalimumab, 4139 infliximab)—and 2666 associated infections. Mean age across biologic exposure cohorts was 64–69 years. The crude incidence rate of subsequent hospitalised infection ranged from 27.1 to 34.6 per 100 person-years. After multivariable adjustment, abatacept (HR: 0.80, 95% CI 0.64 to 0.99) and etanercept (HR: 0.83, 95% CI 0.72 to 0.96) users had significantly lower risks of subsequent infection compared to infliximab users.
Conclusions Among RA patients who experienced a hospitalised infection while on anti-TNF therapy, abatacept and etanercept were associated with the lowest risk of subsequent infection compared to other biologic therapies.
- rheumatoid arthritis
- anti-TNF therapy
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Many studies have evaluated the association between various biologic medications and an increased risk of serious infection in rheumatoid arthritis (RA) patients. Some, but not all, suggest that anti-tumour necrosis factor (anti-TNF) therapy increases the risk for serious infections compared to non-biologic drugs.1–13 Although the mechanisms of any increased risks remain unclear, the fact that biologic medications target key components of host immune defences may result in an increased susceptibility to different types of infections.14 Less is known about the comparative risk for anti-TNF medications versus biologics with other mechanisms of action (MOA).
Switching biologics is common in RA, and selecting a specific agent may be impacted by not only the expectation of efficacy but also safety considerations. Indeed, up to one-third of RA patients discontinue their first biologic within 1 year due to lack of efficacy and/or adverse events.15 In the setting of a recent serious adverse event, such as a hospitalised infection, occurring while on anti-TNF therapy, the 2012 American College of Rheumatology (ACR) recommendations suggest changing to a non-anti-TNF biologic.16 This recommendation was based on level C evidence (expert opinion). While clinicians and patients could choose to continue the same biologic or switch to a different anti-TNF, these options were not the preferred choices in the ACR recommendations.
Given limited evidence on the association between serious infection and biologic therapies in high risk RA patients, such as those experiencing a recent serious infection, the aim of this study was to evaluate the risks of subsequent hospitalised infections associated with specific biologic agents and associated with switching to a different MOA versus continuing anti-TNF therapy. The study population focused on RA patients recently hospitalised with an infection while receiving anti-TNF therapy.
Study design and data sources
This cohort study used 2006–2010 data for all Medicare beneficiaries with RA, obtained from the Centers for Medicare and Medicaid Services (CMS). Medicare is a national health insurance programme in the USA that provides medical and pharmacy benefits to more than 50 million elderly people (aged ≥65), individuals under age 65 with disabilities and individuals with end stage renal disease.17 RA patients with significant limitations in function are potentially eligible for disability benefits that include Medicare coverage after approximately 2 years.18 Data included demographics, inpatient, outpatient, prescriptions, and claims for infusions given in provider offices and hospital-based outpatient infusion centres. CMS and the Institutional Review Board of the University of Alabama at Birmingham approved the study.
Eligible patient population and observation period
Patients eligible for this analysis had RA and an ‘index hospitalisation’ with an infection while receiving an anti-TNF therapy (see online supplementary appendix 1). To select this population, we identified patients who experienced hospitalisation with an infection discharge diagnosis in any position (primary or non-primary) on the hospital claim using diagnosis codes from the International Classification of Disease, 9th revision, Clinical Modification (ICD-9-CM). This approach has previously been shown to have high validity to identify confirmed hospitalised infections.19
To increase the homogeneity of patient characteristics and thereby reduce confounding, patients also had to meet these criteria: (1) had at least two ICD-9 codes for RA (ICD-9 714.x) from a physician office visit or hospitalisation at any time preceding the hospital admission date; (2) had no diagnosis of cancer (excluding non-melanoma skin cancer) in the 6 months before the index hospitalisation (patients with cancer might have other infection-related risk factors compared to patients without cancer); (3) were using anti-TNF therapy at the time of admission to the hospital; (4) had an index hospitalisation with length of stay less than 14 days (to avoid excessive heterogeneity in the severity of infections); and (5) were not receiving nursing home care services during the first 60 days following hospital discharge. We used the 6 months before the index hospitalisation discharge date as the baseline period to assess all covariates (eg, demographics, co-morbidities).
We desired greater certainty that patients subsequently hospitalised for an infection had experienced a new infection rather than simply a recurrence of the index infection. We also wanted to allow a ‘washout’ from anti-TNF drug exposures prior to the index hospitalisation. Given these considerations, and in light of the usual dosing frequency of infliximab of 56 days, the ‘index date’ for starting follow-up was 61 days after hospital discharge. Follow-up after each index hospitalisation episode ended at the earliest time of: admission for a new, subsequent hospitalised infection; cancer; death; or the end of the 18-month follow-up period. We censored all follow-up after 18 months because previous studies have reported that infection risk is higher earlier after initiation of biologics.6 ,8
Eligible patients also must have been continuously enrolled with Medicare fee-for-service coverage with hospital, physician and prescription drug plans (ie, part A, B, and D, excluding Medicare Advantage coverage) in the 6 months before the admission date of the index hospitalisation and throughout follow-up.
For each index hospitalisation, we used pharmacy (for injected biologics, ie, etanercept and adalimumab) and procedure claims (for infused biologics, ie, abatacept, infliximab and rituximab) to determine the time-dependent medication exposure for each person-day during follow-up. We determined etanercept or adalimumab exposure based on the days of supply reported for filled prescriptions and assigned exposure as 30 days for abatacept, 56 days for infliximab and 180 days for rituximab based on recommended dosing frequency. For each biologic, we added a 30-day exposure ‘extension’.3 The extension was added because patients who become ill often stop medications, and using an extension captures attributable events that occur shortly after biologic therapy is discontinued.8
We created biologic exposure groups defined by MOA as: restarting the same anti-TNF biologic that the patient was treated with at the time of the index hospitalisation; switched to a different anti-TNF biologic; and switched to a non-anti-TNF biologic. We classified days on which patients had overlapping biologic exposures (ie, concurrent exposure) as exposed to the most recent biologic. There was insufficient use of golimumab, certolizumab and tocilizumab to study these agents independently.
For each index hospitalisation, the outcome was time to first subsequent hospitalised infection. We identified these infections by the use of hospital diagnosis codes for infections in any position using claims-based algorithms that have been validated.4 ,19 Types of hospitalised infections were categorised as: pneumonia and respiratory tract, genitourinary tract, skin and soft tissue, sepsis/bacteraemia, and other.3
Confounder control using an infection risk score
Using previously described methods,5 ,20 ,21 we derived an infection risk score for each index hospitalisation that provided a composite risk to control for infection-related confounding for all factors unrelated to biological therapy using claims from the 6-month baseline (see online supplementary appendix 2). Factors included were demographics, co-morbidities, concurrent medications and health service utilisation. We categorised the infection risk score into deciles21 and removed index hospitalisation episodes with an infection risk score not overlapping between different biologics. Within deciles of the infection risk score, patients treated with each biologic were comparable with respect to their predicted risk for serious infection (see online supplementary appendix 3).
The unit of analysis was biologic-exposed person-days as a time-varying variable. All other covariates were evaluated during the 6-month baseline. We compared baseline characteristics as of the date of each index hospitalisation. For each specific biologic, we calculated the crude incidence of subsequent hospitalised infections.
We used Cox regression to estimate the adjusted HR for subsequent hospitalised infection for each biologic compared to every other biologic. We applied the Huber–White ‘sandwich’ variance estimator to control for correlations among the observations nested within the same person.22 The regression models adjusted for the decile of the infection risk score, type of infection at the index hospitalisation, number of previous index hospitalisations, specific anti-TNF used at the time of the index hospitalisation, whether (for anti-TNFs) it was the same drug or a switch between baseline and follow-up, steroid use during baseline, non-biologic disease-modifying antirheumatic drug use during baseline, and concurrent (ie, overlapping around the time of switch) biologic exposure.22
In order to examine the time-varying hazard of infection, we produced a smoothed hazard plot using a publically-available R package ‘muhaz’.23 ,24 Within selected deciles of the infection risk score (lowest, median and highest), we calculated the 1-year adjusted infection rate difference between each biologic and abatacept (referent) using the output from the Cox model (using the ‘Baseline’ statement in SAS).
We conducted three sensitivity analyses: (1) defining the index hospitalisation and subsequent hospitalised infection using only primary diagnosis codes, (2) using a 90-day extension to current exposure, (3) and using a 2-year baseline look back during which no other biologics were identified.
We identified 12 933 eligible index hospitalised infections occurring while patients were exposed to anti-TNF therapy (figure 1). On the date of admission, 3248 patients were receiving etanercept, 2564 adalimumab, 6990 infliximab, 72 certolizumab and 59 golimumab. The most frequent types of index infections were pneumonia/respiratory tract (29.3%), genitourinary tract (23.5%), skin and soft tissue (16.6%) and septicaemia/bacteraemia (11.3%).
After discharge from the index hospitalisation, most patients restarted the same anti-TNF medication (79%); 2% switched to another anti-TNF, 3% initiated a non-anti-TNF biologic, and16% did not receive any biologic over 18 months. Of patients who initially restarted the same anti-TNF agent they had been on at the time of the index hospitalisation, 10% switched to a different biologic during follow-up. Of patients who received any biologic during follow-up, we identified 10 794 index hospitalisations occurring among 10 183 unique RA patients, yielding 7807 person-years of biologic exposure (table 1). In terms of demographics, co-morbidities and common types of infections, we observed similar distributions across the medication exposure groups. Most biologic exposure time occurred within 1 year of drug initiation or restart.
During follow-up, we observed 2666 subsequent hospitalised infection events (table 2). The crude incidence rate of subsequent hospitalised infection ranged from 27.1 to 34.6 per 100 person-years. Compared to those who used the same anti-TNF after the index hospitalisation, the adjusted HR for subsequent hospitalised infection was 0.86 (95% CI 0.72 to 1.03) for non-anti-TNF biologics and 1.10 (95% CI 0.89 to 1.35) for switch to a different anti-TNF biologic. Patients who did not receive any biologic during follow-up had a crude incidence of infection of 40.5 per 100 person-years. The most frequent types of subsequent infection were similar to the most frequent types of index infection; pneumonia was the most common, and the types of infection did not differ by specific drug (not shown).
In drug-specific analyses, abatacept had the lowest crude incidence rate of subsequent hospitalised infection, and etanercept had the highest (table 3). After multivariable adjustment, abatacept (HR: 0.80, 95% CI 0.64 to 0.99) and etanercept (HR: 0.83, 0.72 to 0.97) had significantly lower risks of infection compared to infliximab. The type of infection at the index hospitalisation, biologic switch and specific anti-TNF agent being used at the time of the index hospitalisation were not significantly associated with subsequent hospitalised infection except for baseline etanercept (HR: 1.22, 95% CI 1.08 to 1.38). Within patient risk groups defined as lowest, median, and highest (figure 2), the adjusted infection risk was lowest for abatacept (referent, y axis) and highest for infliximab in the highest risk group, up to an 8/100 person-year difference.
Smoothed, unadjusted hazard plots of subsequent hospitalised infection by specific biologic (figure 3) showed that for three anti-TNF biologics, hazards peaked early, and then declined over time. In contrast, the hazard for abatacept was essentially flat and became similar to anti-TNF biologics at approximately 6–9 months. The hazard of rituximab was in between abatacept and anti-TNF biologics and was truncated at 6 months due to the sparsity of data. The 95% CIs for the associated hazard of infection between biologics overlapped one another (not shown).
Sensitivity analyses that defined hospitalised events using only primary diagnosis codes, and those using a 2-year look-back period yielded results similar to the main analysis (not shown). The sensitivity analysis that used a 90-day extension to current exposure rather than 30 days yielded comparable results to those in table 3; the only additional significant differences were for abatacept (HR: 0.85, 95% CI 0.73 to 0.98) and etanercept (HR: 0.88, 95% CI 0.77 to 0.99) users, who had lower risks of subsequent infection compared to adalimumab users.
Among high risk RA patients who experienced a hospitalised infection while on anti-TNF therapy, our results showed that abatacept and etanercept had a significantly lower rate of subsequent infection compared to infliximab. In analyses that grouped drugs by MOA, the subsequent hazard rate of hospitalised infections was not significantly different among patients who remained on the same anti-TNF agent, switched to a different anti-TNF medication, or who switched to a biologic with an alternate MOA, although trends suggested that switching to a non-anti-TNF agent might be preferable. Additionally, we observed that continued use of a previously prescribed anti-TNF agent after a hospitalised infection was common, accounting for 90% of observation time during the 18 months of follow-up.
The 2012 ACR recommendations16 suggest that RA patients on anti-TNF therapy should switch to a non-anti-TNF biologic after a serious adverse event, including hospitalised infections. Evidence in support of this recommendation has been scant. We found that such switching happens infrequently, which is consistent with an earlier report in a younger RA population that most patients continued the same anti-TNF that they were treated with prior to hospitalisation.5 Our results suggest that the ACR recommendation may be appropriate, especially if switching to abatacept, but considering the grouped safety profile of medications defined by a anti-TNF or non-anti-TNF common MOA may not be appropriate.
The absolute incidence rates for a subsequent hospitalised infection ranged from 26 to 36 per 100 person-years, which is appreciably higher than the typical range of hospitalised infections in RA cohorts (3–6/100 person-years)3 ,5 ,7 ,11 ,25 and even in older Medicare patients with RA (10–12/100 person-years).20 Our findings are consistent with previous studies comparing anti-TNF therapies to one another and extend those observations by examining risk versus biologics with other MOAs. The observed higher absolute incidence rate but lower adjusted rate of infection for etanercept users probably reflects channelling of higher risk patients to this agent. All rates of infections were lower than the infection rates among patients not treated with biologics (40.5/100 person-years), which may indicate channelling of the highest risk patients away from all biologics or the possibility that higher-dose glucocorticoids were substituted for biologics, which increases infection risk.26
We found that abatacept had a lower hospitalised infection rate compared to infliximab, consistent with a trial that made a similar comparison.27 The rate of infection for abatacept also was lower but of borderline significance compared to adalimumab in our analysis, although did reach statistical significance in the sensitivity analysis. This result is consistent with a 2-year head-to-head clinical trial showing lower but non-significant serious infection risk for abatacept versus adalimumab.28 Similarly, etanercept had a significantly lower adjusted infection rate compared to infliximab, and in a sensitivity analysis, a lower rate compared to adalimumab. Also concordant with our results, data from the Dutch RA registry and a network meta-analysis found the risk of serious infections in patients treated with etanercept to be lower than with adalimumab or infliximab,29 ,30 although Europe uses less infliximab. The range of absolute risk difference between abatacept and other therapies ranged from <1/100 person-years (etanercept) to a high of 8/100 person-years (infliximab, highest risk group), yielding a number needed to harm (NNH) of up to 13. This NNH and the associated range of risk differences between specific drugs suggest that our results are important clinically. However, the differences between our results and infection rates from other, healthier RA cohorts suggest that drug-specific differences are probably outweighed by patient-related characteristics (eg, age, co-morbidities) and potentially modifiable factors (eg, glucocorticoid dose).
The smoothed hazard plot indicated that the time-dependent risks of subsequent hospitalised infection for patients exposed to anti-TNFs were comparable to one another. These findings are compatible with studies suggesting an early increased risk for anti-TNF agents that declines over time.6 ,8 The pattern was different for abatacept, which was flat and eventually achieved parity with other biologics. Perhaps further accentuating these differences, the substantial majority of anti-TNF users in the analysis were restarting therapy with a medication that they had been on, whereas most abatacept and rituximab users were new users.
Strengths of our study include the large number of high-risk RA patients that allowed us to inform the clinically-relevant question of how to best treat patients who experience a serious infection while receiving anti-TNF therapy. A limitation of our observational study is that patients were not randomly assigned to treatments; therefore, patients might have differed in their risk for serious infections at baseline. Specifically, patients at higher risk of subsequent infection might have been more likely to be changed to abatacept or rituximab rather than resume anti-TNF therapy. However, table 1 and online supplementary appendix 2 did not provide much evidence for such channelling, although abatacept users were somewhat more likely to use prednisone; even if such channelling occurred, it would be expected to attenuate results towards the null. We used administrative data that lacked detailed information on RA disease severity and some clinical factors (eg, smoking). Thus, misclassification and residual confounding are possible. Additionally, we had relatively modest amounts of exposure to rituximab and only 38 hospitalised infections, yielding some imprecision in the risks associated with this agent. Medical records were not available to confirm infections, although the claims-based algorithms used have been shown to have good positive predictive values.19 ,31 Our multivariable adjustment for prior biologic use may be incomplete due to the short 6-month look-back period, although our sensitivity analysis addressed this. Finally, Medicare patients are generally older, and these results may not be generalisable to younger, healthier RA patients.
In conclusion, we found that among RA patients who experienced a hospitalised infection while receiving anti-TNF therapy, most of them continued to use the same anti-TNF agent, and a small proportion switched to another biologic. Comparing individual biologics, abatacept and etanercept had the lowest rate of subsequent hospitalised infection. These findings provide new evidence for clinical management of high risk RA patients and suggest that drug-specific guidance may be more appropriate when making safety-based recommendations, rather than simply lumping drugs together based on MOA. Further studies are needed to investigate the balance of harms and effectiveness simultaneously in key patient subgroups to optimise personalising medication choices for individual patients.
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Handling editor Tore K Kvien
Contributors Conception and design: HY, FX, ED, EBL, JRC. Acquisition of data: HY, ED, FX, LC, JRC. Analysis and interpretation of data: HY, ED, FX, JRC. Drafting manuscript: HY. Critical revision of manuscript for important intellectual content: HY, FX, ED, LC, EBL, JDL, KGS, TB, KW, JWB, JRC. Statistical analysis: HY, FX, JRC. Obtaining funding: JRC, KGS, ED. Administrative, technical or material support: HY, FX, ED, LC, EBL, JDL, KGS, TB, KW, JWB, JRC. Study supervision: JRC.
Funding This work was supported by the Agency for Healthcare Research & Quality (R01 HS018517). HY was supported by grant 1 K12 HS021694 from the Agency for Healthcare Research and Quality, Rockville, Maryland, USA.
Competing interests Disclosures for unrelated work. JRC: research grants and/or consulting: Abbott, Amgen, BMS, Centocor, Crescendo, CORRONA, Pfizer, Roche/Genetech, UCB. ED: research grants: Amgen. JDL: research grants: Amgen. JDL: research grants: Pfizer, Prometheus, Lilly, Shire, Nestle, Janssen, AstraZeneca, Amgen, Consulting: Centocor, Shire, Takeda. KGS: research grants: Ardea, Regeneron, Svient, Takeda/Consulting fees: Ardea, Regeneron, Savient:Takeda. TB: research grants: Genentech and Biogen IDEC/Consulting fees: Novartis Pharmaceutical Corporation, Pfizer Inc.. KW: research grants: Pfizer, Inc/consulting fees: Pfizer, UCB, Genentech, Regeneron. JWB: research grants: BMS, Pfizer.
Ethics approval University of Alabama at Birmingham approved this study.
Provenance and peer review Not commissioned; externally peer reviewed.
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