Risk of hospitalisation for serious bacterial infections in patients with rheumatoid arthritis treated with biologics. Analysis from the RECord ...
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Risk of hospitalisation for serious bacterial infections in
patients with rheumatoid arthritis treated with biologics.
Analysis from the RECord linkage On Rheumatic Disease
study of the Italian Society for Rheumatology
G. Carrara1, A. Bortoluzzi2, G. Sakellariou3, E. Silvagni2, A. Zanetti1,
M. Govoni2, C.A. Scirè1,2
Epidemiology Research Unit, Italian Society for Rheumatology, Milan, Italy;
1
2
Rheumatology Unit, Department of Medical Sciences, University of Ferrara, Italy;
3
Chair and Division of Rheumatology, IRCCS Policlinico San Matteo Foundation,
University of Pavia, Italy.
Abstract
Objective
The aims of this study were to define the risk of serious bacterial infections in patients receiving specific biological
disease-modifying anti-rheumatic drugs (bDMARDs) and evaluating the effect of concomitant synthetic DMARDs
(sDMARDs) in a large population-based sample of rheumatoid arthritis (RA) deriving from an administrative health
database.
Methods
Data were extracted from health databases of Lombardy Region, Italy (2004–2013), as a part of the RECord-linkage
On Rheumatic Diseases (RECORD) study. Patients with RA treated with approved bDMARDs were included.
Hospitalisations for bacterial infections were evaluated by hospital discharge forms. The association between drug
exposure and infections was assessed by survival models, with time-dependent covariates. Results are presented as
hazard ratios (HR) and 95%CI, crude and adjusted for pre-specified confounders (sex, age, disease duration,
Charlson Comorbidity Index, previous biologics, previous infections, use of methotrexate, leflunomide,
corticosteroids, non-steroidal anti-inflammatory drugs).
Results
4,656 RA patients with at least one bDMARD prescription were included, for a total of 7,601 biological courses;
3,603 (77.4%) women with a mean (SD) age of 55.8 (12.7) years. Crude incidence rate of hospitalised infection ranged
from 0.14 to 2.95 per 1000 person-years. After multivariable adjustment, abatacept users (HR 0.29, 95%CI 0.10–0.82)
had significantly lower risk of infections compared to etanercept. Concurrent treatment with methotrexate (0.72, 0.52–0.99)
reduced the overall risk of infection while glucocorticoids increased it (1.09 per mg/day, 1.06–1.11).
Conclusion
In RA patients treated with bDMARDs, abatacept was associated with the lowest risk of infections; overall risk was
mitigated by concomitant methotrexate and increased by glucocorticoids in a dose-dependent manner.
Key words
biological disease-modifying anti-rheumatic drugs, rheumatoid arthritis, bacterial infections,
synthetic disease-modifying anti-rheumatic drugs
Clinical and Experimental Rheumatology 2019; 37: 60-66.
Clinical and Experimental Rheumatology 2019Infectious risk in patients with bDMARDs / G. Carrara et al.
Greta Carrara, Stat* Introduction of comorbidities or a higher disease ac-
Alessandra Bortoluzzi, PhD* The introduction of biologic disease- tivity correlate with higher number of
Garifallia Sakellariou, PhD modifying anti-rheumatic drugs (b- infections also in this patients (18). Fi-
Ettore Silvagni, MD
DMARDs) for the treatment of rheu- nally, glucocorticoids (GCs) have con-
Anna Zanetti, Stat
Marcello Govoni, MD matoid arthritis (RA) has allowed a sistently been related to increasing the
Carlo Alberto Scirè, MD, PhD better disease control in patients non- risk of infections (19), also in patients
*These authors made an equal responsive to synthetic DMARDs receiving bDMARDs, with a dose-re-
contribution. (sDMARDs), leading to better disease lated effect (20, 21).
Please address correspondence outcomes (1). However, the molecular In clinical practice, the management of
and reprint requests to: targets addressed by these drugs, such patients with RA frequently implies the
Dr Carlo Alberto Scirè, as tumor necrosis factor-α (TNF-α) and administration of multiple concurrent
Reumatologia, lymphocytic function, are involved in treatments but the amount of informa-
Dipartmento di Scienze Mediche, immune response and resistance against tion on the impact of co-medication
Università di Ferrara, infections. Their use has therefore been during treatment with bDMARDs is
Ospedale San Anna,
Via A. Moro 8,
related to an increased risk of infec- limited. Although it has been demon-
44124 Cona (FE), Italy. tions, including intracellular and oppor- strated that patients receiving MTX in
E-mail: c.scire@reumatologia.it tunistic infections, which might be due association with TNF-inhibitors tend to
Received on January 18, 2018; accepted to several factors (2–5). Patients with discontinue treatment less frequently
in revised form on April 11, 2018. RA have an increased infectious risk because of loss of efficacy (22) and of
© Copyright Clinical and compared to general population (6, 7) adverse events (23) and that the rate
Experimental Rheumatology 2019. that is related to disease characteristics, of discontinuation is not significantly
such as extra-articular manifestations, different in patients receiving MTX or
implying a more severe disease, and leflunomide (LEF) co-medication (24,
comorbidities (8). Since bDMARDs are 25), the precise role of concurrent ther-
frequently prescribed to patients with a apies on adverse events – infections
more severe disease, a baseline higher in particular – in patients receiving
risk of infection might be present in bDMARDs is not clearly established.
this group; at the same time, disease- In last decade, the use of large admin-
independent baseline relative risk of istrative health databases (AHD) has
infection (e.g. patients with a lower emerged as a feasible strategy to study
number of comorbidities, patients treat- a consistent number of patients for long
ed with treat-to-target approach (9)) periods, with the availability of com-
could drive bDMARDs prescription, plete data and without loss at follow-up
leading to a complex relationship be- (26, 27).
tween indication and contraindication In this study we aimed to define the
biases. In keeping with these consid- risk of serious bacterial infections in
erations, the comparison with patients patients receiving bDMARDs, evalu-
on sDMARDs-monotherapy yielded ating clinical and demographic fac-
contrasting results, with some studies tors associated with this outcome and
confirming the presence of a consist- exploring the influence of specific bio-
ent increase in risk (10), especially in logic agents and the role of concurrent
the first months of bDMARD treatment sDMARDs and GCs co-medication
(11), whilst other studies showed only a in a large population sample deriving
moderately increased (12) or a compa- from AHD of the Lombardy region in
rable risk (13). Also, differences might Italy.
Funding: this study was supported by exist between the available drugs, with
the Italian Society for Rheumatology. abatacept (ABA) being related to a Materials and methods
Competing interests: A. Bortoluzzi has lower risk of serious infections com- Study design
received fees for sponsorised lectures pared to other bDMARDs (14, 15). This is a retrospective cohort study
and/or partecipation in advisory boards sDMARDs do not seem to lead to more on AHD of Lombardy Region, Italy
from Sanofi; infections, as suggested by the results (>10,000,000 inhabitants).
M. Govoni has received fees for of large observational studies evaluat-
sponsorised lectures and/or partecipation
ing sDMARDs monotherapies (16, 17), Ethics approval and consent
in advisory boards Pfizer, Abbvie, MSD,
Roche, BMS, Sanofi, Lilly, Novartis and with some reports of a decreased rate to participate
Celgene; of infections in patients on methotrex- Access to the data was granted by the
the other authors have declared ate (MTX) and hydroxychloroquine General Directorate of Health for the
no competing interests. (HCQ) (14); nevertheless the presence purpose of the RECORD study proto-
Clinical and Experimental Rheumatology 2019 61Infectious risk in patients with bDMARDs / G. Carrara et al.
col of analysis, a project promoted by Exposure Table I. Clinical and demographic features
the Italian Society for Rheumatology Exposure to bMDARDs was consid- of the population included of 4,656 RA
(SIR), in accordance with national ethi- ered changing during follow-up. A patients.
cal requirements. The protocol was ap- patient was considered exposed to a Demographic characteristics
proved by the local ethics committee of specific biological treatment from the
the Pavia University Hospital. No spe- first prescription of the drug until the Mean age (SD, years) 55.8 (12.7)
Female, n (%) 3603 (77.4)
cific consent to participate was needed. last one plus 6 months, to consider the
coverage period of a drug also after Clinical characteristic
Data its withdrawal, or until the first pre-
Data retrieved from the AHD included scription of subsequent drug. Censor- Disease duration, n (%)
≤1 years 1052 (22.6)
demographics (birth date, gender, death ing was defined at treatment stop date >1 to ≤2 years 1137 (24.4)
date or embarkment), drug prescrip- plus drug coverage or until the start of ≥3 to ≤5 years 1090 (23.4)
tions (Anatomic-Therapeutic Chemi- a new bDMARD or death or at the end >5 years 1377 (29.6)
cal - ATC - code, date of drug deliv- of established follow-up. Exposure to a Charlson Comorbidity Index, 1.24 (0.75)
Mean (SD)
ery, quantity), RA certification by a new bMDARD in the same patient was Serious infections in the 24 (0.5)
rheumatologist, outpatient services and defined as a new bDMARD treatment previous year, n (%)
hospital discharge forms (HDF) includ- course. Antibiotic prescription in 877 (18.8)
ing information on time International the previous year, n (%)
Classification of Disease, 9th revision, Outcome
Clinical Modification (ICD-9-CM) di- Hospitalisations for the first bacterial Results
agnoses and Disease Related Group - infection occurred during the exposi- A total of 4,656 RA patients who had at
DRG - codes for the period between 1st tion to each bDMARD were evaluated least one bDMARD delivery for a total
of January 2004 and 31st of December using HDF based on relevant ICD-9- of 7,601 biological treatment courses
2013. CM codes: ICD-9-CM 049* and 320* (exposures), equal to 20,519 person/
are considered for meningitis; 054.3 years (PYs) of exposure, were includ-
Population and 323* for encephalitis; 681*-682* ed. 3,603 were women (77.4 %) with a
Patients with RA were identified for cellulitis; 421* for endocarditis; mean age (SD) at first bDMARD expo-
through rheumatologist certification 481*-482* for pneumonia; 590* for sure of 55.8 (12.7) years and with modal
of disease (co-payment exemption pyelonephritis; 711* for septic arthritis; disease duration of over five years. No
code 006.714.0), based on its previ- 730.0*-730.2* for osteomyelitis and missing data nor lost to follow-up were
ously demonstrated high specificity 038* and 790.7 for bacteraemia (30). registered, nor expected by design.
(96.39%) and sensitivity (77.08%) for A mean (SD) Charlson Comorbidity In-
RA recognition (27), following other Statistical methods dex Score equal to 1.24 (0.75) was esti-
studies with a similar methodology Continuous characteristics are present- mated (Table I). 24 patients (0.5%) had
(28, 29). Patients with RA and at least ed as median and interquartile range a hospitalised infection in the previous
one delivery of bDMARDs (ABA, (IQR) or mean and standard deviation year and 877 (18.8%) a previous course
adalimumab (ADA), certolizumab (SD), when appropriate. For propor- of antibiotic treatment lasting more
(CER), etanercept (ETA), golimumab tions, absolute and relative frequencies than 14 days in the past year (Table I).
(GOL), infliximab (INF), rituximab are reported. The association between Of 7,601 treatment courses, 32.4%
(RTX) and tocilizumab (TCZ)) were bDMARDs exposure and hospitalisa- were with ETA, 22.2% with ADA,
included. Different lines of bDMARD tion for bacterial infections was as- 13.7% with INF, 9.5% with ABA, 7.2%
treatment were considered. The expo- sessed by survival models for compet- with TCZ, 6.7% with RTX, 4.2% with
sure to non-steroidal anti-inflammatory ing risks (death), with time-dependent GOL and 4.0% with CER.
drugs (NSAIDs), specific sDMARDs covariates (Cox proportional hazard Among concomitant immunosuppres-
– including MTX, LEF, cyclosporine models). Results were presented as sive medications, MTX was the most
A (CSA), HCQ or sulfasalazine (SSZ) hazard ratios (HR) and 95% confidence commonly prescribed sDMARD. This
– and daily mean GC dosage (mg per intervals (95%CI), crude and adjusted combination therapy was observed in
day) were defined by the drug delivery for pre-specified confounders (sex, age, 4,942 treatment courses (65% of bio-
recorded in the administrative data- disease duration, Charlson Comorbidity logical treatment courses), especially
base. Number of previous courses of Index (31), concomitant use of MTX, in association with TNF-inhibitors.
bDMARDs, age at the start of each bD- LEF, GCs, NSAIDs, number of previ- Combination therapy with LEF has
MARD course, the presence of a previ- ous biologics and previous infections). been observed in 776 (10.2%) expo-
ous hospitalised infection (in the year All the analyses were performed using sures, and a concomitant prescription
before starting the first bDMARD) and the Stata11 software (STATA Corpora- of another sDMARD (CSA, HCQ or
the presence of an antibiotic treatment tion, College Station, Texas, USA) and SSZ) was found during exposure to
course of at least 14 days occurred in R Statistical Software (Foundation for biologics in 21.4% of cases (Table II).
the previous year was also recorded. Statistical Computing, Vienna, Austria). We identified 181 hospitalised infec-
62 Clinical and Experimental Rheumatology 2019Infectious risk in patients with bDMARDs / G. Carrara et al.
Table II. Biological exposures, person-years and concomitant medications.
bDMARDs All ETA ADA INF CER GOL ABA RTX TCZ
Biological treatment courses, 7,601 2,462 (32.4) 1,687 (22.2) 1,042 (13.7) 306 (4.0) 322 (4.2) 724 (9.5) 507 (6.7) 551 (7.2)
n (%)
Person years 20,519 8,296 4,851 3,199 406 451 1404 984 928
Mean (SD) number of 0.64 (1.02) 0.36 (0.70) 0.42 (0.72) 0.28 (0.70) 1.10 (1.52) 1.06 (1.37) 1.36 (1.16) 1.14 (1.22) 1.35 (1.35)
previous bDMARD
**NSAIDs, n (%) 5,550 (73) 1,864 (75.7) 1,257 (74.5) 832 (79.8) 201 (65.7) 191 (59.3) 476 (65.7) 334 (65.9) 395 (71.7)
**MTX, n (%) 4,942 (65.0) 1,562 (63.4) 1,125 (66.7) 851 (81.7) 184 (60.1) 205 (63.7) 448 (61.9) 258 (50.9) 309 (56.1)
**LEF, n (%) 776 (10.2) 289 (11.7) 205 (12.2) 92 (8.8) 27 (8.8) 29 (9) 58 (8) 37 (7.3) 36 (6.5)
**sDMARD (CSA,HCQ, 1,627 (21.4) 538 (21.9) 345 (20.5) 220 (21.1) 62 (20.3) 82 (25.5) 168 (23.2) 90 (17.8) 122 (22.1)
SSZ), n (%)
**Mean(sd) GCs dosage 2.57 (3.66) 2.34 (3.55) 2.42 (3.18) 2.74 (3.9) 2.18 (2.83) 2.53 (4.02) 2.77 (3.35) 3.66 (5.29) 2.73 (3.57)
(mg/day)
**Concomitant medications. ABA: abatacept; ADA: adalimumab; CER: certolizumab; ETA: etanercept; GOL: golimumab; INF: infliximab; RTX: rituxi-
mab; TCZ: tocilizumab; bDMARDs: biological disease-modifying anti-rheumatic drugs; NSAIDs: non-steroidal anti-inflammatory drugs; sDMARDs:
synthetic disease-modifying anti-rheumatic drugs; MTX: methotrexate; LEF: leflunomide; CSA: cyclosporine A; HCQ: hydroxychloroquine; SSZ: sulfa-
salazine; GCs: glucocorticoids.
tions (68 with ETA, 52 with ADA, 26 Table III. Type of infections reported in our study.
with INF, 4 with ABA, CER and GOL,
Type of infection n events/person years Incidence rate (x 1000) (95%CI)
13 with RTX and 10 with TCZ) yield-
ing to an overall incidence of 8.82 Pneumonia 61/20,661 2.95 (2.26, 3.79)
cases per 1000 person/years. The types Bacteraemia 52/20,711 2.51 (1.88, 3.29)
of infections are shown in Table III. Cellulitis 27/20,721 1.30 (0.86, 1.90)
Septic arthritis 22/20,746 1.06 (0.66, 1.61)
Pneumonia followed by bacteraemia
Osteomyelitis 13/20,764 0.63 (0.33, 1.07)
and cellulitis were the most common Pyelonephritis 10/20,740 0.48 (0.23, 0.89)
types of infections observed. Meningitis 8/20,762 0.39 (0.17, 0.76)
The primary results of the study are Encephalitis 3/20,763 0.14 (0.03, 0.42)
described in Table IV and V. Table IV Endocarditis 3/20,764 0.14 (0.03, 0.42)
shows the factors associated with hos-
Table IV. Factors associated with hospitalised infection among RECORD RA patients.
pitalisation with a definite bacterial
infection: age at exposure (HR 1.04, Crude HR (95%CI) Adjusted HR (95%CI)
95%CI 1.02, 1.05) and the presence
of infections in the previous year (HR Female 0.72 (0.52, 1) 0.68 (0.49, 0.94)
Age (time-related) 1.04 (1.03, 1.05) 1.04 (1.02, 1.05)
1.52, 95%CI 1.06, 2.18) were related Charlson Comorbidity Index 1.36 (1.2, 1.55) 1.14 (0.93, 1.39)
to a significantly increased risk of se- Disease duration
vere infections, while the female gen- Disease duration >1 to ≤2 years 1.45 (0.91, 2.33) 1.39 (0.84, 2.30)
der was associated with a lower risk Disease duration ≥3 to ≤5 years 1.69 (1.08, 2.66) 1.52 (0.93, 2.47)
Disease duration >5 years 1.50 (0.93, 2.42) 1.63 (0.98, 2.73)
(HR 0.68, 95%CI 0.49, 0.94). The con- bDMARD (previous) 0.97 (0.81, 1.16) 0.98 (0.79, 1.21)
comitant treatment with NSAIDs and Infections (year before first bDMARD) 1.51 (1.07, 2.14) 1.52 (1.06, 2.18)
sDMARDs (LEF or other sDMARDs) Concomitant medication
did not result in an increased risk of MTX* 0.69 (0.51, 0.95) 0.72 (0.52, 0.99)
LEF* 0.84 (0.49, 1.47) 0.82 (0.47, 1.43)
hospitalisation for bacterial infections
sDMARDs others* (CSA,HCQ, SSZ) 0.76 (0.39, 1.47) 0.82 (0.42, 1.59)
while the use of MTX, compared with GCs° 1.09 (1.07, 1.12) 1.09 (1.06, 1.11)
bDMARD monotherapy, reduced the NSAIDs 1.37 (0.89, 2.11) 1.2 (0.77, 1.87)
risk by 28% (HR 0.72, 95%CI 0.52,
*compared to bDMARDs monotherapy; °for each increase of 1 mg/day. bDMARDs: biologic disease-
0.99). Prednisone equivalent prescrip-
modifying anti-rheumatic drugs; sDMARDs: synthetic disease-modifying anti-rheumatic drugs; MTX:
tion correlates to an increased risk of methotrexate; LEF: leflunomide; CSA: cyclosporine A; HCQ: hydroxychloroquine; SSZ: sulfasalazine;
9% for each daily mg (HR 1.09, 95%CI GCs: glucocorticoids; NSAIDs: non-steroidal anti-inflammatory drugs; HR: Hazard Ratio; CI: confi-
1.06, 1.11). dence interval.
When directly comparing biologic
agents to one another using Cox pro- adjusted HR for infection was equal The adjusted HRs and 95%CI for each
portional hazard models, potential to 0.29 (95%CI 0.10, 0.82) for ABA, bDMARD compared with ETA and the
confounders were controlled (Table while it was not significantly differ- clinical and demographic factors asso-
V). Considering ETA as reference, the ent compared to other bDMARDs. ciated with hospitalisation for a defi-
Clinical and Experimental Rheumatology 2019 63Infectious risk in patients with bDMARDs / G. Carrara et al.
Table V. Events, person years (PYs), crude and adjusted HR for hospitalised infection com- sociation with age. On the other hand,
pared to Etanercept. women showed a slightly reduced risk.
Biologic Events PYs Incident rate Crude HR Adjusted HR
This finding is not supported by previ-
exposure *1000 PY (95%CI) (95% CI) (95%CI)* ous studies and needs to be tested in
different populations (34).
Etanercept 68 8296 8.2 (6.4, 10.4) Ref (1.0) Ref (1.0) When evaluating the impact of con-
Adalimumab 52 4851 10.7 (8, 14.1) 1.27 (0.88, 1.82) 1.37 (0.95, 1.96)
comitant medications, concurrent treat-
Infliximab 26 3199 8.1 (5.3, 11.9) 0.98 (0.62, 1.54) 0.96 (0.60, 1.56)
Certolizumab 4 406 9.9 (2.7, 25.2) 0.93 (0.34, 2.55) 1.31 (0.48, 3.58) ment with sDMARDs did not lead to
Golimumab 4 451 8.8 (2.4, 22.7) 0.84 (0.31, 2.32) 1.09 (0.37, 3.21) an increased risk of infection. On the
Abatacept 4 1404 2.8 (0.8, 7.3) 0.3 (0.11, 0.83) 0.29 (0.10, 0.82) contrary, MTX was related to a re-
Rituximab 13 984 13.2 (7.0, 22.6) 1.4 (0.77, 2.55) 0.95 (0.48, 1.91) duction of infectious risk, as already
Tocilizumab 10 928 10.8 (5.2, 19.8) 1.09 (0.56, 2.12) 1.24 (0.59, 2.61)
reported in previous studies (23), con-
*Adjusted for pre-specified confounders (gender, age, disease duration, NSAIDs, number of previous firming the benefits of combination
bDMARDs, Charlson Comorbidity Index, infections and antibiotic prescription for 14 days in the treatment over hospitalised bacterial
previous year); HR, hazard ratio; CI, confidence interval. infections. A previous report gave sim-
ilar results, with patients treated with
nite bacterial infection are summarised biologics included in large registries bDMARDs combined to MTX, alone
in Figure 1. (32). Pneumonia and bacteraemia were or with other sDMARDs, experiencing
the most incident infections, consist- less frequently severe adverse events.
Discussion ently with previous observational stud- A possible explanation for this could
In this large retrospective cohort, in- ies reporting a higher risk of hospitali- be a better control of disease activity
cluding 4,656 patients with RA treated sation for pneumonia (14, 33). resulting in lower number of adverse
with bDMARDs with complete data When examining the predictors of se- events related to RA, including infec-
deriving from AHD, the incidence rate vere infections in a multivariate model, tions. Moreover, due to the limited
for serious infections requiring hos- as expected older age and previous detail in clinical information available
pitalisation was 8.82/1000 PYs. The severe infections were related to a in the AHD, channelling bias cannot
demographical and clinical features higher risk. In the adjusted analyses, be fully excluded, with MTX being
of this sample are comparable to those comorbidities were only marginally as- administered to fitter subjects. In our
of populations of patients treated with sociated with infection due to their as- study, also LEF, CSA, HCQ and SS-
Fig. 1. Risk of hospitali-
sation for bacterial infec-
tions in RA patients treated
with biologics.
The figure shows the ad-
justed hazard ratio (HR)
and 95%CI for all bD-
MARDs (abatacept - ABA,
adalimumab - ADA, cer-
tolizumab - CER, goli-
mumab - GOL, infliximab
- INF, rituximab - RTX,
tocilizumab - TCZ) com-
pared with etanercept
(ETA) and the clinical and
demographic factors asso-
ciated with hospitalisation
for bacterial infections.
64 Clinical and Experimental Rheumatology 2019Infectious risk in patients with bDMARDs / G. Carrara et al.
Zwere not related to an increased risk in any position, with the possibility of tion. These findings should ideally be
of infection. Previous researches in this having included infections accidentally confirmed in large observational stud-
field have indirectly shown conflicting recognised during hospitalisations not ies with complete clinical information.
results, with both similar persistence related to the infection itself. Howev-
on anti-TNF in combination with ei- er, this possible overestimation is not Acknowledgements
ther MTX or LEF (25, 35) and higher likely to differentially misclassify in- The authors are grateful to the General
discontinuation rates with LEF combi- fections in differently exposed patients. Directorate of Health of the Lombardy
nation (24), although none of these re- The different burden of prescribed bD- Region for making available the ad-
ports considered hospitalised bacterial MARDs (being ETA, ADA and INF the ministrative data for the purpose of the
infections as outcome. Consistently most prescribed ones in our RA sample) RECORD study.
with many studies including both pa- could have influenced our results; to
tients on sDMARDs and bDMARDs, this regard, GOL, CER and non TNF- References
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