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Abstract

Background:

Biosimilar biologic disease-modifying antirheumatic drugs (bDMARDs) are increasingly used in clinical practice; however, real-world evidence regarding safety outcomes is currently limited. Denmark has rapidly implemented biosimilars through nationwide mandatory switches, introducing infliximab biosimilars CT-P13 in 2015 and GP1111 in 2019.

Objectives:

To investigate the incidence of serious safety outcomes among Danish real-world arthritis patients (including biosimilar-to-biosimilar switchers) during the first year of infliximab biosimilar GP1111 treatment.

Methods:

Patients with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis initiating GP1111 during April 1, 2019–April 1, 2022 were identified in the nationwide DANBIO registry. Comorbidities at treatment start (=baseline) and safety outcomes (major adverse cardiac events (MACE), venous thromboembolic events (VTEs), deaths, severe allergic reactions, and serious infections) during 1-year follow-up were captured through linkage to nationwide registries by using diagnoses registered from hospital contacts. Each safety outcome was assessed separately in the overall GP1111 cohort and in five sub-cohorts (based on bDMARD treatment history). We calculated 1-year crude and age- and sex-adjusted incidence rates (IRs) of each safety outcome. Furthermore, baseline factors associated with risks were assessed in the overall cohort.

Results:

In total, 2132 patients initiating GP1111 treatment were included, whereof 1534 (72%) were infliximab-biosimilar-to-biosimilar switchers. For the overall cohort, adjusted IRs for MACE, VTEs, death, and allergic reactions were very low (⩽1.0/100 person-years). For serious infections, the adjusted IR was 3.2 (95% confidence interval (CI) 2.5–4.2) for the overall cohort, varying across sub-cohorts (IRs 2.1–5.6). Prior serious infection increased risk of serious infection (hazard ratio = 2.06 (95% CI 1.19–3.57), whereas other baseline factors, including biologic treatment history did not. Due to few events, similar analyses were not presented for other safety outcomes.

Conclusion:

This study demonstrated that 1 year of treatment with biosimilar infliximab GP1111 was safe regardless of treatment history. The rate of serious infections was comparable to originator tumor necrosis factor inhibitors.

Keywords

Introduction

Biologic disease-modifying antirheumatic drugs (bDMARDs) have transformed treatment options and improved the disease course in patients with inflammatory arthritis. The high costs, however, have been a significant financial burden for healthcare systems, creating an incentive for the development of biosimilar drugs.^1–3 Biosimilars are highly similar versions of the originator bDMARDs and entered the market nearly a decade ago as cost-effective alternatives. They are increasingly available in routine care leading to different treatment scenarios, including switching within biosimilars from the same originator (biosimilar-to-biosimilar switches).^3,4

Denmark is known globally for its rapid implementation of biosimilars with several mandatory switches based on national treatment guidelines.^5–7 For infliximab, CT-P13 was the first available biosimilar in 2015, followed by GP1111 in 2019, which led to repeated nationwide biosimilar switches to reduce costs, as previously described in Nabi et al.,⁶ Glintborg et al.,⁸ Jensen et al.⁷

Despite the increased use and growing evidence, the immunogenicity and safety of biosimilar drugs remain a concern, leading to reluctance among some clinicians and patients.^4,9 RCTs and open-label extension studies of infliximab biosimilars have shown no new safety signals compared to the originator.^10–15 However, while the safety of single switches (i.e., between originator and the corresponding biosimilar) is relatively well studied, the evidence regarding switches between biosimilars of the same originator and other switch scenarios remains limited, especially in more heterogeneous patient populations.^9,15 Previous studies of biosimilar treatment effectiveness in real-world patients have indicated that patient-related factors (e.g., treatment history and disease activity at the time of switching) impact treatment effectiveness,^6,8,16 whereas their role regarding safety outcomes remains unclear. Thus, the need for comprehensive high-quality real-world data to provide insights into biosimilar use and safety in routine clinical practice has been highlighted.^4,9,15,17

Danish patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) are monitored routinely and prospectively in the nationwide registry DANBIO.¹⁸ The Danish research infrastructure allows linkage at the individual level of clinical data from DANBIO with other comprehensive, near-complete nationwide registries for information regarding, for example, hospital contacts, use of prescription medicine, thus providing a unique opportunity to explore safety outcomes in routine care.^18–20

The aim of this study was to investigate the incidence of serious safety outcomes in real-world patients with RA, PsA, or axSpA initiating treatment with the infliximab biosimilar GP1111. Outcomes included major adverse cardiac events (MACE), venous thromboembolic events (VTEs), death, severe allergic reactions, and serious (hospitalized) infections during the first year of GP1111 treatment.

Methods

Study design

This was an observational cohort study based on prospectively collected data from nationwide registries.

Setting and data sources

Eligible patients were identified in the DANBIO registry. DANBIO is a Danish clinical quality registry in rheumatology, established in the year 2000, which covers >95% of adults with inflammatory diseases treated with biological or targeted (b/ts-) DMARDs in routine care.^18,21 By use of the unique Danish civil registration number, DANBIO data were enriched with patient-level information regarding comorbidities and all hospital contacts (in- and outpatient) from the Danish National Patient Registry (DNPR), use of prescription medicine from the Danish National Prescription Registry, vital status from the Danish Civil Registry, and death from the Cause of Death Register (Supplemental Table S1).^19,20,22 Findings are reported in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement.²³

Study population

Patients with a clinical diagnosis of RA, PsA, or axSpA, who initiated GP1111 treatment between April 1, 2019 (date, where Zessly was listed as the first-line infliximab in national treatment guidelines²⁴) and April 1, 2022 (time of data-cut) were identified in the DANBIO registry (Figure 1). Date of GP1111 treatment start was defined as baseline (=index date).

Figure 1.

Study population and definitions of the sub-cohorts according to previous bDMARD treatment history.

Patients were stratified into five mutually exclusive sub-cohorts according to prior bDMARD treatment history. This was done to account for potential baseline differences in disease activity and other clinical characteristics that may influence safety outcomes (Figure 1). Patients who had performed an infliximab biosimilar-to-biosimilar switch (termed B2B-switchers) from CT-P13 to GP1111 (details provided in Figure 1) were further subclassified into those with a previous switch from originator infliximab to CT-P13 (originator-experienced, cohort A), and those without (originator-naïve, cohort B), also previously described in Nabi et al.⁶ The remaining GP1111-treated patients were subclassified by any prior infliximab treatment (infliximab-experienced, cohort C), those with any previous non-infliximab bDMARD treatment (infliximab-naïve, but bDMARD-experienced, cohort D) or previously bDMARD naïve (cohort E). Patients in cohort C included infliximab-experienced patients (originator and/or biosimilar), of which some had performed an infliximab B2B-switch but did not meet the specific criteria for cohort A and cohort B for various reasons (e.g., due to calendar time, a switch interval ⩾120 days, or having received another bDMARD between the infliximab treatments).

Outcomes

The safety outcomes assessed in this study were MACE, VTEs, death, severe allergic reactions, and serious infections. Safety outcomes were identified based on hospital contacts (in- or outpatient) from the DNPR registry using International Classification of Diseases, tenth revision codes (ICD-10) (definitions provided in Supplemental Table S2). Serious infections were restricted to hospital contacts due to infections lasting ⩾24 h to capture only severe cases requiring hospitalization.

The primary study outcomes were 1-year crude and age- and sex-adjusted incidence rates (IRs) of the above-mentioned safety outcomes during GP1111 treatment assessed in the overall cohort and in sub-cohorts A–E. The key secondary outcome was baseline factors associated with the risk of safety outcomes during GP1111 treatment in the overall cohort.

Follow-up

Patients were followed up for 1 year. Each safety outcome was followed up on and assessed separately. Exposure time was defined as the number of days from baseline to the first of the following: safety outcome of interest, discontinuation of treatment (=first missed dose irrespective of reason), end of follow-up, emigration, data-cut, or death (except when death was the outcome of interest, in which case it was considered an event). Treatment pauses of less than 90 days with no other bDMARD used in between and no occurrence of safety outcomes were disregarded.

Covariates

The following baseline covariates were retrieved: (1) From DANBIO: age (years), sex (female/male), disease duration (years), body mass index, current smoker (yes/no), prior bDMARD treatment history including originator infliximab treatment duration (years), prior biosimilar infliximab CT-P13 treatment duration (years), number of prior non-infliximab bDMARD treatments (0/1/⩾2), concomitant methotrexate (yes/no), C-reactive protein (CRP; mg/L), physician global assessment (Visual Analogue Scale (VAS), 0–100), and patient-reported outcomes: fatigue (VAS 0–100), global assessment (VAS 0–100), pain (VAS 0–100), and functional status (Health Assessment Questionnaire; 0–3). Disease activity was evaluated by specific measures, for RA and PsA: Disease Activity Score-28 joint (DAS28)-CRP, Clinical Disease Activity Index; for AxSpA: Bath Ankylosing Spondylitis Indices of Disease Activity (0–10) and BAS functional status (0–10), Ankylosing Spondylitis Disease Activity Score (ASDAS). Disease remission (yes/no) was defined as DAS28 <2.6 (RA and PsA) and ASDAS <1.3 (axSpA). (2) From the DNPR: diagnosis (in- or outpatient) of cancer ever (yes/no) or any of the following during a 10-year period prior to baseline (yes/no): serious infection, knee/hip prosthesis, pulmonary disease, diabetes, chronic kidney disease, inflammatory bowel disease (IBD), liver disease, myocardial infarction, cerebrovascular disease, thromboembolic disease, and/or coagulopathy (ICD-10 codes and definitions provided in Supplemental Table S1). From this, an “any comorbidity (⩾1)” variable was defined (yes/no). (3) From the national prescription registry: at least one dispensed prescription within 1 year prior to baseline (yes/no) and included nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, oral corticosteroids, aspirin, and statins (Anatomical Therapeutic Chemical Classification codes provided in Supplemental Table S1).

Statistical analyses

All statistical analyses were performed using RStudio (version2024.04.2+764). p-Values <0.05 were considered statistically significant. No formal power analysis was conducted as all available patients in DANBIO initiating GP1111 in the specified timeframe were included in the study. Some stratifications could not be made due to small cohort sizes, and due to the General Data Protection Regulations (GDPR), patient numbers greater than zero but below 4 were reported as <4.²⁵

Baseline characteristics were presented as medians (ranges) or numbers (percentages) for continuous and categorical variables, respectively, and were stratified by indication (RA/PsA/axSpA). The availability of baseline variables was reported. Crude IRs of safety outcomes were presented as events/100 Person Years (PY) with 95% confidence intervals (CI). Crude IRs were adjusted for age and sex using Poisson regression. Due to very few events across cohorts, it was not considered meaningful to perform further adjustments.

In a sensitivity analysis, the exposure time was defined as number of days from baseline to the first of following: safety outcome of interest, discontinuation of GP1111 (=first missed dose irrespective of reason) + 90 days, end of follow-up, emigration, data-cut, or death (except when death was the outcome of interest, in which case it was considered an event). The +90-day period after discontinuation was added to capture safety outcomes occurring during treatment washout.

Cox proportional hazard (PH) regression analysis was conducted to explore potential baseline risk factors associated with safety outcomes. The analysis was performed for the overall cohort with sub-cohort (A–E) included as a covariate. Results were only presented for serious infections due to the low number of events for the other safety outcomes. Adjustment was done according to a priori-defined variables inspired by a clinical prediction model for serious infections in bDMARD-treated patients developed in a previous DANBIO study.²⁶ The included baseline variables were: age group (<40, 40–49, 50–59, 60–69, ⩾70 years), sex, history of previous infection, diabetes, pulmonary disease, IBD, myocardial infarction (all within the last 10 years before treatment start), and use of oral glucocorticoid within the last year. All variables included in the analyses were complete. The PH assumption was validated using Schoenfeld residual testing.²⁷ The global test yielded a p-value of 0.75, indicating no violation of the PH assumption and supporting the appropriateness of the model.

Results

In total, 2132 patients in five sub-cohorts initiated GP1111 treatment and were included (Table 1, Supplemental Tables S3 and S4). Overall, patients were 44–62 years old with a median disease duration ranging from 6 to 11 years across the different indications (RA, PsA, and axSpA). The number of patients in DAS28/ASDAS disease remission varied by indication: 55% in RA, 54% in PsA, and 30% in axSpA, respectively (Supplemental Table S3). Additionally, 23% of patients had at least one comorbidity and 14% used oral corticosteroids during the previous year (Supplemental Table S3).

Table 1.

Baseline characteristics of different GP1111 users stratified by previous bDMARD treatment history and by indication, overall n = 2132.

	Infliximab biosimilar-to-biosimilar switchers(CT-P13 → GP1111)						Other GP1111 users
	AOriginator-experienced switchersN = 416			BOriginator-naïve switchersN = 1118			CInfliximab-experienced usersN = 222			DInfliximab-naïve but bDMARD-experienced usersn = 272			EbDMARD-naïve usersN = 104
	RA	PsA	AxSpA	RA	PsA	AxSpA	RA	PsA	AxSpA	RA	PsA	AxSpA	RA	PsA	AxSpA
Number of patients, n	187	67	162	432	201	485	94	42	86	90	71	111	43	24	37
Age, years (IQR)	67 (57–74)	58 (50–65)	51 (44–58)	60 (51–68)	52 (41–59)	42 (33–52)	65 (53–73)	50 (40–62)	42 (34–53)	57 (48–65)	55 (43–61)	44 (37–56)	54 (44–67)	47 (38–58)	37 (31–51)
Female sex, n (%)	141 (75)	25 (37)	36 (22)	296 (69)	108 (54)	171 (35)	69 (73)	25 (60)	36 (42)	71 (79)	49 (69)	52 (47)	31 (72)	12 (50)	15 (41)
Disease duration, years	20 (14–27)	17 (13–25)	18 (12–25)	7 (4–14)	8 (5–14)	4 (3–7)	18 (11–29)	12 (8–18)	10 (4–15)	7 (3–14)	7 (2–13)	4 (1–10)	7 (3–15)	3 (2–6)	1 (0–3)
BMI, kg/m²	24.4 (21.9–28.2)	26.3 (23.9–28.8)	25.2 (22.8–27.5)	25.5 (22.7–30.1)	28.3 (24.4–31.1)	25.7 (22.9–28.2)	25.2 (22.6–27.7)	27.2 (25.5–31.6)	25.9 (23.1–28.6)	24.9 (22.4–28.5)	28.4 (24.4–30.9)	26.2 (23.4–28.0)	25.4 (23.6–28.7)	29.4 (24.3–29.8)	23.7 (22.4–26.7)
Current smoking, n (%)	30 (20)	13 (23)	38 (28)	90 (23)	32 (18)	116 (26)	15 (18)	9 (26)	19 (25)	21 (23)	18 (27)	30 (31)	11 (35)	7 (33)	14 (47)
Prior originator treatment duration, years	8 (6–10)	7 (5–9)	8 (6–10)	–	–	–	8 (5–12)	4 (2–7)	5 (2–10)	–	–	–	–	–	–
Prior CT-P13 treatment duration, years	2 (2–2)	2 (2–2)	2 (2–2)	1 (1–3)	1 (1–2)	1 (1–2)	2 (1–3)	1 (0–2)	0 (0–3)	–	–	–	–	–	–
Concomitant MTX, n (%)	152 (81)	46 (69)	34 (21)	323 (75)	111 (55)	70 (14)	63 (67)	21 (50)	13 (17)	58 (64)	34 (48)	16 (14)	24 (56)	8 (33)	⩽3
Prior non-infliximab bDMARD treatments, n(%) 0 1 ⩾2	168 (90) 15 (8) 4 (2)	50 (76) 7 (10) 10 (14)	136(85) 15 (9) 11 (6)	335 (78) 58 (13) 39 (9)	148 (75) 23 (11) 30 (14)	378(79) 70 (14) 37 (7)	54(58) 16(17) 24 (25)	18(43) 9(21) 15(36)	46(53) 17(20) 23(27)	0 (0) 41(46) 49 (54)	0 (0) 36(51) 35(50)	0 (0) 55(50) 56(50)	–	–	–
Disease activity
In DAS28/ASDAS remission,^a n (%)	118 (82)	45 (80)	54 (42)	206 (58)	104 (66)	146 (37)	38 (49)	10 (31)	11 (18)	5 (7)	7 (14)	0 (0)	5 (15)	⩽3	0 (0)
CRP, mg/L	2 (1–4)	2 (1–4)	2 (1–4)	3 (1–7)	2 (1–4)	3 (1–4)	3 (2–6)	2 (1–5)	3 (1–5)	12 (4–31)	4 (3–9)	5 (2–17)	12 (4–27)	4 (3–8)	–
DAS28	1.9 (1.4–2.4)	2.0 (1.6–2.4)	–	2.4 (1.8–3.3)	2.2 (1.7–2.9)	–	2.6 (1.7–3.4)	3.2 (2.3–4.4)	–	4.8 (4.0–5.5)	4.2 (3.3–4.8)	–	4.6 (3.4–5.2)	3.7 (3.0–4.0)	–
CDAI	2.9 (1.4–5.5)	3.8 (2.2–7.0)	–	5.7 (2.5–10.7)	5.3 (2.2–9.7)	–	7.9 (2.6–12.1)	10.2 (5.3–19.5)	–	20.6 (15.2–28.9)	16.1 (10.5–20.8)	–	18.7 (9.7–24.9)	15.1 (11.8–19.8)	–
BASDAI, mm	–	–	23 (6–37)	–	–	29 (13–52)	–	–	33 (20–63)	–	–	66 (48–77)	–	–	57 (43–72)
BASFI	–	–	24 (9–42)	–	–	23 (10–48)	–	–	47 (17–65)	–	–	57 (36–71)	–	–	37 (20–63)
ASDAS	–	–	1.5 (0.9–2.3)	–	–	1.9 (1.2–2.8)	–	–	2.2 (1.5–3.4)	–	–	3.6 (2.9–4.4)	–	–	3.3 (2.9–4.1)
Swollen joints (28)	0 (0–0)	0 (0–0)	0 (0–0)	0 (0–1)	0 (0–0)	0 (0–0)	0 (0–1)	0 (0–2)	0 (0–0)	4 (2–7)	1 (0–3)	0 (0–0)	2 (1–5)	0 (0–1)	0 (0–0)
Tender joints (28)	0 (0–0)	0 (0–1)	0 (0–0)	0 (0–2)	0 (0–1)	0 (0–0)	0 (0–4)	3 (0–6)	0 (0–1)	6 (3–10)	4 (1–7)	0 (0–2)	4 (2–9)	3 (1–9)	0 (0–2)
Physician global VAS, mm	5 (2–9)	4 (2–11)	4 (1–11)	6 (2–14)	6 (2–10)	5 (2–10)	10 (5–16)	16 (9–23)	12 (3–24)	31 (20–48)	27 (14–37)	23 (15–35)	30 (12–38)	26 (17–53)	20 (1–38)
Patient pain VAS, mm	19 (8–38)	18 (9–43)	21 (7–39)	29 (12–55)	32 (9–57)	25 (9–51)	37 (13–64)	46 (23–76)	46 (20–65)	77 (57–85)	73 (58–85)	69 (49–83)	62 (42–82)	63 (50–79)	67 (35–82)
Patient fatigue VAS, mm	28 (12–57)	31 (18–59)	30 (11–52)	44 (22–69)	59 (19–78)	45 (20–70)	50 (16–74)	70 (39–85)	61 (24–85)	78 (54–90)	79 (68–88)	75 (59–85)	64 (49–80)	71 (57–81)	64 (44–90)
Patient global VAS, mm	20 (8–48)	22 (10–42)	23 (9–43)	36 (14–61)	37 (17–69)	30 (10–57)	44 (16–72)	59 (31–85)	49 (21–76)	79 (64–90)	81 (66–89)	77 (57–86)	75 (56–90)	72 (51–85)	74 (46–93)
HAQ	0.5 (0.1–1.1)	0.4 (0.0–1.0)	0.3 (0.0–0.8)	0.8 (0.3–1.3)	0.8 (0.1–1.1)	0.4 (0.0–0.8)	0.8 (0.3–1.3)	0.8 (0.3–1.5)	0.1 (0.6–1.1)	1.3 (0.9–1.8)	1.1 (0.7–1.6)	0.9 (0.6–1.5)	0.8 (0.6–1.5)	1.0 (0.7–1.3)	0.5 (0.1–0.9)
Comorbidities^b
Cancer, n (%)	7 (4)	4 (6)	⩽3	6 (1)	6 (3)	7 (1)	5 (5)	4 (10)	5 (6)	⩽3	0 (0)	⩽3	⩽3	0 (0)	⩽3
Serious infection, n (%)	39 (21)	15 (22)	35 (22)	99 (23)	44 (22)	76 (16)	27 (29)	13 (31)	25 (29)	16 (18)	14 (20)	22 (20)	11 (26)	⩽3	6 (16)
Knee/hip prosthesis, n (%)	8 (4)	⩽3	0 (0)	25 (6)	4 (2)	5 (1)	5 (5)	⩽3	⩽3	⩽3	0 (0)	0 (0)	⩽3	0 (0%)	0 (0)
Pulmonary disease, n (%)	11 (6)	⩽3	⩽3	18 (4)	10 (5)	13 (3)	5 (5)	4 (9.5)	⩽3	7 (7.8)	5 (7.9)	⩽3	⩽3	0 (0)	0 (0)
Diabetes, n (%)	10 (5)	⩽3	11 (7)	23 (5)	9 (5)	10 (2)	5 (5)	0 (0)	4 (5)	⩽3	⩽3	⩽3	⩽3	0 (0)	⩽3
Chronic kidney disease, n (%)	⩽3	⩽3	⩽3	4 (0.9)	⩽3	⩽3	⩽3	0 (0)	0 (0)	0 (0	⩽3	0 (0)	⩽3	0 (0%)	0 (0%)
IBD, n (%)	4 (2)	⩽3	10 (6)	4 (1)	6 (3)	41 (9)	⩽3	⩽3	12 (14)	⩽3	⩽3	20 (18)	4 (9)	⩽3	13 (35)
Any comorbidity (⩾1), n (%)	46 (25)	17 (25)	37 (23)	102 (24)	47 (23)	82 (17)	31 (33)	26 (62)	29 (34)	17 (19)	14 (20)	25 (23)	13 (30)	⩽3	7 (19)
Use of prescription medicine
NSAIDs, n (%)	58 (31)	15 (22)	46 (28)	151 (35)	77 (38)	187 (39)	26 (28)	14 (33)	40 (47)	43 (48)	37 (52)	73 (66)	16 (37)	9 (38)	25 (68)
Use of anticoagulants, n (%)	30 (16)	7 (11)	17 (11)	54 (13)	13 (7)	20 (2)	23 (25)	⩽3	4 (5)	10 (11)	9 (13)	⩽3	4 (9)	⩽3	⩽3
Oral corticosteroids, n (%)	15 (18)	⩽3	4 (3)	69 (16)	18 (9)	28 (6)	28 (30)	10 (24)	10(12)	44 (49)	16 (23)	29 (26)	22 (51)	⩽3	10 (27)
Aspirin, n (%)	⩽3	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Statins, n (%)	42 (23)	10 (15)	24 (15)	78 (18)	28 (14)	41 (9)	28 (30)	8 (19)	7 (8)	14 (16)	9 (13)	7 (6)	4 (0.3)	⩽3	⩽3

Numbers are median (IQR) unless otherwise stated. Based on the following ICD10 codes: For RA: M05.9, M06.0, M06.9, M13.0, for PsA: M073.A, M073.B, and for axSpA: M45.9, M46.1, M46.8, M46.9, also in combination with M02.9, M07.2, M07.3, M07.4, M07.5, and/or H20.0. Numbers <4 cannot be reported due to GDPR regulations. Baseline is in time-window −90 days to +6 days according to GP1111 start date.

Remission defined as DAS28 <2.6 (RA, PsA), ASDAS <1.3 (AxSpA).

Comorbidities included (0–10 years prior to baseline and 0-ever for cancer): serious infections, knee/hip prosthesis, pulmonary disease (including chronic obstructive pulmonary disease/asthma and interstitial lung disease), diabetes, myocardial infarction, liver disease, kidney disease, IBD, thromboembolic events, cerebrovascular disease and/or coagulopathy, and cancer.

ASDAS, Ankylosing Spondylitis Disease Activity Score; axSpA, axial spondyloarthritis; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, BAS Functional Index; bDMARD, biologic disease-modifying antirheumatic drugs; BMI, body mass index; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, disease activity score in 28 joints; GDPR, General Data Protection Regulations; HAQ, Health Assessment Questionnaire; IBD, inflammatory bowel disease; ICD, International Classification of Diseases; IQR, interquartile range; MTX, methotrexate; NSAIDS, nonsteroidal anti-inflammatory drugs; PsA, psoriatic arthritis; RA, rheumatoid arthritis; VAS, Visual Analogue Scale (0–100).

Stratified by treatment history (Table 1), the originator-experienced and originator-naïve infliximab B2B switchers (cohort A + B) had the highest percentage of patients in baseline disease remission, and few patients used oral corticosteroids. In comparison, the infliximab-experienced patients in cohort C had intermediate disease duration (10–18 years), and higher disease activity and comorbid burden. The infliximab-naïve but bDMARD-experienced users (cohort D) had the highest disease activity across all sub-cohorts, the highest prevalence of pulmonary disease, and greatest use of NSAIDs and oral corticosteroids during the previous year. The bDMARD-naïve GP1111 users in cohort E also had high disease activity, frequent use of NSAID and oral steroids, and many current smokers (Table 1).

Safety outcomes during follow-up

Major adverse cardiac events

In the overall GP1111-treated population, the number of MACE events was 19 (Table 2). Patients with MACE had a median age of 66.4 (56.3–74.5) years, and 63% were male (Supplemental Table S4). The overall age- and sex adjusted IR of 1.0 (95% CI 0.7–1.7) per 100 PY (Table 2). MACE events occurred in B2B-switchers (cohort A and B), with the highest IR among the originator-experienced B2B-switchers (age- and sex-adjusted IR 2.2 (1.1–4.3) per 100 PY; Table 2, Figure 2).

Table 2.

IRs of serious safety outcomes during the first year of GP1111 treatment in the overall cohort and sub-cohort A–E.

Serious safety outcomes	Overall population of GP1111-treated patientsn = 2132	Infliximab B2B switchers(CT-P13 → GP1111)		Other GP1111 users
Serious safety outcomes	Overall population of GP1111-treated patientsn = 2132	AOriginator-experienced switchersn = 416	BOriginator-naïve switchersn = 1118	CInfliximab-experienced usersn = 222	DInfliximab-naïve but bDMARD-experienced users n = 272	EbDMARD-naïve usersn = 104
MACE
Number of events, n	19	9	10	0	0	0
Number of PY	1846	395	1007	190	181	73
Crude IR/100 PY (95% CI)	1.0 (0.7; 1.6)	2.3 (1.1; 4.4)	1.0 (0.5; 1.8)	–	–	–
Age- and sex-adjusted IR^a	1.0 (0.7; 1.7)	2.2 (1.1; 4.3)	1.0 (0.5; 1.9)	–	–	–
VTEs
Number of events, n	11	0	7	0	<4	<4
Number of PY	1848	399	1007	190	180	73
Crude IR/100 PY (95% CI)	0.6 (0.3; 1.1)	–	0.7 (0.3; 1.5)	–	–	–
Age- and sex-adjusted IR^a	0.6 (0.3; 1.0)	–	0.7 (0.3; 1.4)	–	–	–
Deaths
Number of events, n	9	–	–	–	–	–
Number of PY	1851	–	–	–	–	–
Crude IR/100 PY (95% CI)	0.5 (0.3; 1.0)	–	–	–	–	–
Age- and sex-adjusted IR^a	0.6 (0.3; 1.4)	–	–	–	–	–
Severe allergic reactions
Number of events, n	16	0	10	0	4	<4
Number of PY	1848	399	1006	190	181	73
Crude IR/100 PY (95% CI)	0.9 (0.5; 1.4)	–	1.0 (0.5; 1.8)	–	2.2 (0.8; 5.9)	–
Age- and sex-adjusted IR^a	0.9 (0.5; 1.4)	–	1.1 (0.6; 2.0)	–	2.5 (0.9; 6.9)	–
Serious infections^b
Number of events, n	58	13	27	4	12	⩽4
Number of PY	1838	392	1003	191	180	73
Crude IR/100 PY (95% CI)	3.2 (2.5; 4.1)	3.3 (1.9; 5.7)	2.7 (1.8; 3.9)	2.1 (0.8; 5.6)	6.7 (3.8; 11.8)	–
Age- and sex-adjusted IR^a	3.2 (2.5; 4.2)	2.9 (1.7; 5.1)	2.7 (1.8; 4.0)	2.1 (0.8; 5.5)	5.6 (3.1; 10.0)	–

Due to a low number of events, event counts and IRs are not reported for all sub-cohorts.

Serious infections were defined as hospital contacts with >24 h of hospitalization. Numbers <4 cannot be reported due to GDPR regulations.

bDMARD, biologic disease-modifying antirheumatic drugs; CI, confidence interval; GDPR, General Data Protection Regulations; IRs, incidence rates; MACE, major adverse cardiac events; PY, person years; VTEs, venous thromboembolic events.

Figure 2.

Age- and sex-adjusted incidence rates for safety outcomes in each sub-cohort. Results not shown for cohort E and for deaths due to the very low number of events.

Venous thromboembolic events

The overall incidence of VTEs was low (n = 11, age- and sex-adjusted IR 0.6 (0.3–1.0)) and was mainly observed in the originator-naïve switchers (cohort B; Table 2, Figure 2). Patients with VTE had a median age of 58.8 (39.9–73.8) years, and 55% were female (Supplemental Table S4).

Deaths

The total number of deaths was low (n = 9, median age 73.1 (66.2–80.1) years) with an overall adjusted IR of 0.6 (0.3–1.4) per 100 PY (Table 2, Supplemental Table S4). Results for sub-cohorts could not be presented due to GDPR regulations.

Severe allergic reactions

The total number of severe allergic reactions was 16 with a crude IR 0.9 (0.5–1.4) per 100 PY for the overall cohort (Table 2). They mainly occurred among the originator-naïve B2B-switchers (cohort B) and the infliximab-naïve but bDMARD-experienced patients (cohort D), with the highest IR in cohort D (age- and sex-adjusted IR 2.5 (0.9–6.9) per 100 PY; Table 2, Figure 2).

Serious infections

Serious infection was the most frequently observed adverse event (n = 58, median age 57.0 (46.1–69.9 years, 64% female; (Supplemental Table S4) with an adjusted IR of 3.2 (2.5–4.2) per 100 PY for the overall cohort. The IR varied across sub-cohorts (adjusted IRs of 2.1–5.6 per 100 PY) with the highest rate among the infliximab-naïve but bDMARD-experienced patients (cohort D; Table 2, Figure 2). The most common type of infections were pneumonia and other respiratory infections (31%), followed by erysipelas and other skin infections (19%; Table 3).

Table 3.

Distribution of serious infections in GP1111-treated patients.

Type of infections	Events in the overall population of GP1111 usersN = 2132
Pneumonia and other respiratory infections, n (%)	18 (31.0)
Erysipelas and other skin infections, n (%)	11 (19.0)
Unspecified bacterial infections, n (%)	8 (13.8)
Sepsis, n (%)	6 (10.3)
Gastrointestinal infection (bacterial or viral), n (%)	6 (10.3)
Urinary tract and kidney infections, n (%)	4 (6.9)
Other, n (%)^a	5 (8.7)
Total, n (%)	58 (100)

Includes hepatitis, COVID-19, and septic arthritis.

Results from the Cox regression analysis are shown in Figure 3 for serious infection during GP1111 treatment. The only significant association observed was increased risk for patients with a previous serious infection (hazard ratio 2.06 (95% CI 1.19–3.57)), whereas previous treatment history (i.e., treatment sub-cohort) was unassociated.

Figure 3.

Baseline variables associated with risk of serious infection during GP1111 treatment, results from Cox proportional hazard analysis. All patients (n = 2132) were included in the analysis (no missingness for data on covariates).

In the sensitivity analysis, adding a +90-day wash-out period for treatment discontinuation, the results for all safety events remained largely similar. These could not be presented due to patient confidentiality (GDPR regulations) as they would allow identification of the hidden patient numbers in the primary analysis.

Discussion

In this real-world observational study, we investigated the risk of various serious safety outcomes among >2100 patients with inflammatory arthritis initiating treatment with the infliximab biosimilar GP1111. Patients were stratified into five sub-cohorts based on their bDMARD treatment history to account for differences in disease burden, which might influence safety outcomes. Overall, the 1-year incidence of safety outcomes was low across sub-cohorts, with serious infections being the most common safety outcome.

Safety has been one of the main concerns regarding biosimilar use, as it may potentially differ compared to that of the originator drug due to minor differences in molecular structure, formulation of buffers, or excipients.²⁸ GP1111 was approved in 2018 based on phase III trials in previously infliximab-naïve patients with RA randomized to either GP1111 or originator infliximab.^11,12 The extrapolation to other indications, for example, PsA and axSpA, could be challenged by differences in clinical factors such as age, genetics, comorbidities, concomitant medication, which could potentially influence the effectiveness and safety.^29,30 Most of the available evidence regarding the safety of biosimilars has focused on early infliximab biosimilars, especially CT-P13, assessed in RCT studies with limited follow-up and highly selected patients.^31–35 Other registry-based and post-marketing studies on infliximab biosimilars have reported no new major safety concerns. However, these have mainly been conducted in patients with IBD or RA, and with GP1111 studies limited to IBD populations.^36–39

The current study included a large prospective and unselected real-world nationwide cohort with high coverage and data completeness. We investigated the incidences of MACE, VTEs, severe allergic reactions, and serious infections during the first year of treatment with GP1111. The majority (72%) of patients were B2B-switchers, reflecting high compliance with the Danish nationwide policy with extended use of biosimilars (i.e., mandatory non-medical switches). Overall, safety events were few and in line with those found in previous studies of patients treated with originator tumor necrosis factor (TNF) inhibitors. The observed IR of MACE in our study of 1.0 (0.7–1.7)/100 PY was comparable to rates from previous studies, ranging from IRs 0.3 (0.2–0.4) to 0.8 (0.8–0.9) for RA and PsA patients treated with originator or biosimilar TNF-inhibitor.^40–43 The IR in our analysis was slightly higher in originator-experienced patients (cohort A), where other risk factors (e.g., long disease duration and consequently a prolonged chronic systemic inflammation, diabetes, smoking) may have contributed. However, due to the low number of events, it was not possible to further adjust for these potential confounders.

For VTEs, the 1-year IR was low at 0.6 (0.3–1.0)/100 PY, consistent with findings from other real-world studies. Thus, a Swedish study in 19,950 TNFi-treatment courses (including both originators and biosimilars) in patients with RA reported an age- and sex adjusted IR of 0.5 (95% CI 0.5–0.6) per 100 PY,⁴⁴ while another study reported IRs ranging from 0.6 to 0.8 per 100 PY in different bDMARD-treated patient groups.⁴⁵

The overall IR of severe allergic reactions in our study was 0.9 per 100 PY, but slightly higher in patients with failure of one or several previous bDMARDs (i.e., the infliximab-naïve, but bDMARD-experienced patients, cohort D). Patients in this cohort had the highest baseline disease activity, more pulmonary diseases, and more use of NSAIDs and oral steroids within the previous year, and the increased risk may thus be attributed to their complex clinical profile. Similar findings were reported in a Japanese post-marketing surveillance study of 794 RA patients initiating treatment with the infliximab biosimilar CT-P13. In this study, patients were stratified into three groups based on treatment history (infliximab originator-treated, non-infliximab bDMARD-treated, bDMARD-naïve) and the overall IR of infusion reactions was 8.7 per 100 PY, ranging from 4.3 to 24.2 per 100 PY, highest among the previously non-infliximab bDMARD-treated patients, as in our study.³⁹ The study captured all types of infusion reactions and may therefore not be fully comparable to our findings. Thus, we defined allergic reactions based on hospital contacts (in- and outpatient) with ICD-10 coded diagnoses, which is likely to identify severe and not mild to moderate allergic reactions.

The 1-year IR of serious infections in our study was 3.2 per 100 PY with respiratory infections being the most frequently observed. Previous studies have compared the IR of serious infection among infliximab biosimilar versus infliximab-originator treated patients and reported IRs of (3.4–4.1 per 100 PY) and (2.7–2.9 per 100 PY), respectively.^46,47 In another study on CT-P13,³⁹ patients were stratified into sub-groups based on previous bDMARD treatment history, in which the IRs of serious infections ranged from 4.6 to 9.7 per 100 PY, comparable with our findings. In our study, patients with previous non-infliximab bDMARD failure (i.e., cohort D) had a slightly higher IR of serious infections (IR 5.7 (3.1–10.0)), probably reflecting that cohort D consisted of more frail patients (channeling bias). In contrast, patients in, for example, cohort A represented a selected “healthy-user population,”⁴⁸ as patients in this cohort had tolerated long-term infliximab treatment, including a prior biosimilar switch. The lower risk of safety outcomes in this group may thus represent time-dependent depletion of high-risk patients (e.g., those who had previously discontinued due to serious adverse events). Similarly, despite the few reported events, patients in cohort E potentially reflected patients with an atypical clinical presentation, as infliximab was their first-line bDMARD despite that the Danish national guidelines recommended adalimumab as the first biologic drug of choice.²⁴

The results from the Cox analysis, adjusted for clinical variables inspired by a Danish risk model,²⁶ indicated that the treatment sub-cohort was not associated with the risk of serious infection. Prior serious infection at baseline was the only significant predictor, suggesting risks to be primarily driven by underlying patient characteristics rather than the treatment history. Due to a few safety events, no further adjustments could be made.

Our study provides valuable insights supporting the safety of the infliximab biosimilar GP1111 across different patient cohorts, ranging from patients with multiple infliximab biosimilar switches to infliximab- and other bDMARD-naïve patients. Overall, the findings were reassuring with a low incidence of safety outcomes among patients regardless of previous treatment history. The observed difference across the cohorts likely reflects the underlying differences in patient-related factors, including disease activity, comorbidity burden, and concomitant medication, rather than the biosimilar itself. This overall supports the Danish biosimilar strategy, in which >90% of patients comply with the mandatory switches according to the nationwide guidelines. Findings were contextualized within data from the existing literature, as a direct comparison of safety risks with originator infliximab or other TNF-inhibitors was beyond the study aim and would introduce significant biases, for example, calendar time bias and selection bias due to evolving switch practices and prescription patterns. Furthermore, an assessment of long-term safety events, for example, malignancy, would be interesting for future research, but was not within the scope of this study.

Strengths and limitations

The study has its strengths and limitations. The study is based on high-quality clinical prospective data on a large, unselected cohort from rheumatology routine care, further enriched with data from virtually complete national registries. Limitations include the risk of residual confounding and the reporting of associations and not causal relationships due to the observational study design. Also, for infections, only hospitalized events (defined as hospital contacts ⩾24 h) were included. Therefore, surveillance bias or misclassification cannot be ruled out, where fragile patients may be hospitalized for less severe infections, potentially impacting the observed infection rates. The use of concomitant glucocorticoid is a known risk factor for serious infections⁴⁹ and was adjusted for in our analysis. The information regarding oral corticosteroid use was obtained from the national drug registry based on dispensed prescriptions. However, there may be unmeasured use due to medication provided in-clinic as intra-muscular or intra-articular injections, which are typically registered in DANBIO but were not available for the current study. Furthermore, only allergic reactions resulting in a hospital contact (in- or outpatient) were identified, thereby likely reflecting only the severe cases and not all infusion reactions. Anti-drug antibodies were not measured as part of the current study.

Conclusion

This observational study included >2100 real-world Danish patients with inflammatory arthritis treated with GP1111 in routine care and demonstrated low incidences of VTEs, MACE, severe allergic reactions, and death during 1-year follow-up. The incidence of serious infections was comparable to previous reports on originator TNF inhibitors. Our findings support the use of biosimilar infliximab GP1111 in routine care.

Supplemental Material

sj-docx-1-tab-10.1177_1759720X251393114 – Supplemental material for Safety outcomes in 2132 Danish patients with inflammatory arthritis treated with biosimilar infliximab (GP1111) in routine care

Supplemental material, sj-docx-1-tab-10.1177_1759720X251393114 for Safety outcomes in 2132 Danish patients with inflammatory arthritis treated with biosimilar infliximab (GP1111) in routine care by Hafsah Nabi, Kasper Yde Jensen, Rasmus Westermann, Oliver Hendricks, Dorte Vendelbo Jensen, Anne Gitte Loft, Søren Andreas Just, Jens Kristian Pedersen, Kamilla Danebod, Heidi Lausten Munk, Salome Kristensen, Ada Colic, Pia Høger Thygesen, Mette Ammitzbøll, Stavros Chrysidis, Frank Mehnert, Niels Steen Krogh, Merete Lund Hetland and Bente Glintborg in Therapeutic Advances in Musculoskeletal Disease

Supplemental Material

sj-docx-2-tab-10.1177_1759720X251393114 – Supplemental material for Safety outcomes in 2132 Danish patients with inflammatory arthritis treated with biosimilar infliximab (GP1111) in routine care

Supplemental material, sj-docx-2-tab-10.1177_1759720X251393114 for Safety outcomes in 2132 Danish patients with inflammatory arthritis treated with biosimilar infliximab (GP1111) in routine care by Hafsah Nabi, Kasper Yde Jensen, Rasmus Westermann, Oliver Hendricks, Dorte Vendelbo Jensen, Anne Gitte Loft, Søren Andreas Just, Jens Kristian Pedersen, Kamilla Danebod, Heidi Lausten Munk, Salome Kristensen, Ada Colic, Pia Høger Thygesen, Mette Ammitzbøll, Stavros Chrysidis, Frank Mehnert, Niels Steen Krogh, Merete Lund Hetland and Bente Glintborg in Therapeutic Advances in Musculoskeletal Disease

Footnotes

Acknowledgements

We are grateful to all patients and Danish Departments of Rheumatology that contribute to the DANBIO registry and Niels Steen Krogh, ZiteLab, for the preparation of raw data. The preliminary data was presented at EULAR 2025.

Declarations

ORCID iD

Hafsah Nabi

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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