FormalPara Key Points

Biosimilar products of rituximab were not associated with an increased risk of hospitalization for anaphylactic shock or serum sickness following injections, either at initiation, at switch, or over time.

Clinicians should take into account hypersensitivity reaction risk factors regardless of the product, biosimilar or originator.

1 Introduction

Rituximab is a monoclonal antibody that targets the CD20 protein on B lymphocytes. The European Medicines Agency (EMA) granted market approval for rituximab in 1998 and this molecule has been extensively used since then in various pathologies, including non-Hodgkin lymphoma, chronic lymphoid leukemia in hematology [1], and inflammatory disorders such as rheumatoid arthritis [2], granulomatosis with polyangiitis [3] and pemphigus vulgaris [4]. In terms of safety, adverse effects include hematologic and cardiac disorders, infections, and hypersensitivity reactions such as anaphylactic shock and serum sickness [5, 6].

Biosimilar products entered the European market in 2017, lowering the cost of rituximab treatment [7]. The active substance of biosimilars is highly similar to the originator’s. Biosimilar products are approved provided that data demonstrating biosimilarity to the reference product include physiochemical, non-clinical (mostly in vitro studies), pharmacokinetic and pharmacodynamic studies, and generally one comparative phase III clinical trial to demonstrate their bioequivalence, i.e. efficacy and safety [8,9,10]. Rituximab biosimilars have been widely used since then, especially to treat rituximab-naïve patients [11, 12].

Since 2019, following alerts from pharmacovigilance centers, the Department of Pharmacovigilance at the French National Agency for Medicines and Health Products Safety (ANSM) has been documenting cases of severe hypersensitivity reactions in patients treated with rituximab biosimilars, notably after switching from originator to biosimilar product. Several case reports described the same reactions, for rituximab [13] or infliximab injections [14]. In an initiation context, the risk of hypersensitivity reaction has been proven to be highest at first rituximab injection [5, 15]. In addition, switch from originator to biosimilar product may lead to an excess risk of hypersensitivity reaction [16,17,18], potentially due to pre-sensitization to originator product and development of antidrug antibodies. Thus, although this signal was not identified during the clinical trials carried out on biosimilar rituximab products, it could now be assessed in real-world studies thanks to longer follow-up and a wider study population [19].

The aim of the present study, carried out on a real-world database covering 5 years of experience, was then to assess the association between rituximab biosimilar use (versus originator use) and anaphylaxis or serum sickness in various contexts, among rituximab-naïve patients and among switchers, at first injection and over time.

2 Methods

2.1 Data Source

We used data from the French National Health Data System (SNDS); the SNDS covers almost the totality (> 99%) of the French population—68 million residents. Each person is identified by a unique and anonymous number. The SNDS records comprehensive outpatient (procedures and pharmacy deliveries of reimbursed drugs) and inpatient (pharmacy deliveries of expensive drugs, procedures performed during hospital stays, and discharge diagnoses coded according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10]) reimbursement information since 2006. The SNDS also contains sociodemographic information on sex, age, place of residence, and vital status, among others. Patients’ status for 100% reimbursement of care related to a severe and costly long-term disease (LTD) is recorded and LTD diagnosis is coded according to the ICD-10. The SNDS has been extensively used to conduct pharmacoepidemiological studies, especially on the use, safety, and effectiveness of health products [20,21,22,23].

2.2 Study Periods and Populations

We included every patient who had at least one delivery of rituximab (Anatomical Therapeutic Classification [ATC] code L01FA01, brand names and additional information are presented in Online Resource Table 1) from 1 October 2017 (date of the commercialization of the first biosimilar of rituximab) to 31 December 2021. The term ‘originator’ was chosen to designate the reference medicine product, as opposed to the biosimilar product.

A first cohort of initiators was constituted, gathering originator or biosimilar rituximab new users (i.e. having no delivery of rituximab in the past 2 years before the considered delivery—the 2-year threshold was chosen to account for the long half-life of rituximab). The index date was set to the first rituximab delivery date. Initiations occurring with simultaneous deliveries of both biosimilar product and originator product were excluded. There were two groups of exposure—originator and biosimilar. The reference group was the originator group. Exposure was either studied at first injection, or over time.

A second cohort was created, gathering patients who had a least one delivery of originator rituximab within a 2-year time span before the study start date and still under treatment or during the study period, and who switched from originator rituximab to any biosimilar product of rituximab during the study period. The index date was set to the first biosimilar delivery date. Switches occurring with simultaneous deliveries of both biosimilar product and originator product were excluded. To take into account the history of originator deliveries and patient characteristics, and to build an appropriate comparator group for the switching patients, switchers were matched to non-switchers, with up to two patients still treated with the originator product on age (in categories), sex, number of deliveries of rituximab in the past 2 years (1–3 or ≥ 4) and pathology (hematology, inflammatory/immune dysfunction disorders, multiple pathologies, undetermined). Switchers that could be matched with only one non-switcher were kept, but non-matched switchers were excluded. The index date for the non-switcher was set on the date of the rituximab delivery that matched the switcher index date.

Schemes of inclusion and follow-up of both cohorts are schematized in Online Resource Fig. 1.

2.3 Patient Characteristics

Sex and age (converted into 10- to 20-year categories) were collected at the index date. Patients without those characteristics were excluded. Corticosteroid delivery 30 days before rituximab injection was also described (excluding the 40 mg of prednisolone systematically administered just before rituximab injection).

Patients’ pathologies were defined at index date, in a two-step process. We first identified pathologies for which rituximab is indicated in France (i.e. non-Hodgkin lymphoma, chronic lymphoid leukemia, rheumatoid arthritis, Wegener granulomatosis, microscopic polyangiitis, and pemphigus vulgaris) thanks to ICD-10 codes for LTD status or any discharge diagnosis linked to a hospitalization within the 5 years preceding the index date. We also identified off-label indications of rituximab (including, among others, lupus [24], multiple sclerosis [25], and kidney disease [26]) with corresponding ICD-10 codes. ICD-10 codes used for these steps are presented in Online Resource Table 2. Finally, we categorized patients’ pathologies as hematology or inflammatory/immune dysfunction disorders according to the first list, and if no pathology was identified, we used the second list. The retained pathology in case of overlap between pathologies was the most recent (based on the start date of the LTD or the start date of hospitalization). A category ‘Multiple pathologies’ was set for non-distinguishable pathologies, and a category ‘Undetermined’ included patients with no diagnosis code in their medical background. After population size estimation, we grouped together the categories ‘Multiple pathologies’ and ‘Undetermined’ under the term ‘Undetermined’ in the analyses as these subgroups were very small.

2.4 Outcome of Interest

The outcome was hypersensitivity reaction, which was defined by ICD-10 codes for anaphylactic shock (ICD-10 codes T78 and T886) or serum sickness (T805/T806). These ICD-10 codes have already been used in other studies [27,28,29,30]. The ICD-10 code for hypersensitivity reaction was retained if the rituximab injection had occurred during the same hospital stay. For the serum sickness code only, the hospital stay could begin no later than 15 days after the rituximab injection.

Duration of hospitalization, transfer to the intensive care unit, and death during hospitalization were documented for patients who experienced an outcome.

History of the outcome was defined as having had at least one hospitalization for an anaphylactic shock or serum sickness coded within the past year before rituximab injection.

2.5 Statistical Analysis

First, the initiation cohort was analyzed. Multivariable logistic regression adjusted for age, sex, year of inclusion, pathology, corticosteroid delivery, and history of the outcome was used to estimate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of biosimilar versus originator rituximab injection associated with the outcome at initiation. To assess the risk of hypersensitivity reaction associated with a rituximab injection over time, we used a multivariable Cox proportional hazards regression with time-dependent exposure and covariates, estimating adjusted hazard ratios (HRs) and 95% CIs of biosimilar versus originator rituximab injection. The model was adjusted for age, sex, year of inclusion and pathology as fixed covariates, and corticosteroid delivery, history of outcome and delivery number (taken as a linear continuous variable) as time-dependent covariates. As a post hoc sensitivity analysis, we changed the definition of initiation, taking a 10-year period without rituximab injection to be treatment-naïve, and repeated the analyses.

Second, we compared matched switchers and non-switchers at index date using a multivariable logistic regression adjusted for age, sex, pathology, number of past rituximab injections, corticosteroid delivery, and history of outcome, giving estimates of adjusted OR and 95% CI of switch versus non-switch associated with the outcome at first injection.

Multivariable Cox proportional hazards regression with time-dependent exposure and covariates was used to estimate the adjusted HR and 95% CI of biosimilar versus originator rituximab injection associated with the outcome during the study follow-up among switchers who remained on biosimilar (they were censored if they switched back to originator) treatment versus non-switchers who remained on originator treatment (they were censored if they switched to biosimilar). The model was adjusted for age, sex, number of past rituximab injections, and pathology as fixed covariates, and corticosteroid delivery, history of outcome, and delivery number as time-varying covariates. As a sensitivity analysis, conditional models were performed, to take into account the matching process.

Kaplan–Meier survival curves without the event were computed for each cohort. The linearity of continuous variables was checked comparing Akaike Information Criterion (AIC) of fractional polynomials of degree 2 with the simple linear model. The risk period modeled in the time-dependent Cox regression was fixed to the 15 days after each rituximab injection, to take into account the time window used for event identification. Patients were censored at switch (originator to biosimilar, or biosimilar to originator), death, 1 year after the last rituximab delivery, or on 31 December 2021, whichever came first. Follow-up stopped at first onset of the outcome. The proportionality of hazards was verified for the main exposure variable with Schoenfeld residuals. Figure 2a, b presented in the Online Resource show some examples of inclusions and follow-ups in the initiation cohort and in the switchers/non-switchers cohort.

All extractions from the SNDS were carried out using SAS Enterprise Guide software version 9.4 (SAS Institute, Inc., Cary, NC, USA); analyses were performed with R version 3.5.2 [31], using multiple packages, including dplyr [32], ggplot2 [33] and survival [34].

3 Results

The study flow chart is presented in Online Resource Fig. 2.

3.1 Initiation

Biosimilar initiators represented 81% of the initiation cohort (n = 74,289) compared with 19% of originator rituximab initiators (n = 17,605). Rituximab biosimilar initiations increased rapidly from 2017 (n = 823, 15% of rituximab initiations) to 2021 (n = 18,904, 94% of rituximab initiations). Patients’ characteristics were similar between biosimilar and originator initiators (Table 1). Of the 425 patients who experienced a hypersensitivity reaction at first injection, 86 were originator initiators (0.49% of the originator initiators) and 339 were biosimilar new users (0.46% of the biosimilar initiators). The adjusted OR of biosimilar versus originator rituximab initiation associated with the outcome was 1.04 (95% CI 0.80–1.34), underlying no statistically significant increased risk of hypersensitivity in the biosimilar group compared with the originator group at initiation, as the 95% CI contained 1. Past corticosteroid delivery had a preventive effect on hypersensitivity reactions, with an adjusted OR of 0.55 (0.43–0.71), history of hypersensitivity reaction was associated with an increased risk of event (OR 11.68 [7.29–18.69]), and increased age was associated with a decreased risk of outcome (Table 2 and Online Resource Table 3).

Table 1 Initiation cohort characteristics at baseline
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Table 2 Estimation of the association between rituximab injection by product type and hypersensitivity reaction in the initiation cohort, at first injection and over time
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Over time, 628 patients experienced a hypersensitivity reaction at the time of a rituximab injection, of whom 123 were originator users (0.70% of the originator initiators) and 505 were biosimilar users (0.68% of the biosimilar initiators). Survival curves of biosimilar and originator had an important overlay, with a p value of the log-rank of 0.98, showing no difference in the risk of severe hypersensitivity reactions following the injection (Fig. 1). Compared with originator use, biosimilar injection was not associated with the outcome, with an HR of 1.15 (95% CI 0.93–1.42), demonstrating no statistically significant increased risk of hypersensitivity in the biosimilar group compared with the originator group at each injection. We found similar associations as for the logistic model regarding the covariates, with, in addition, a decrease in the risk of event with the number of injections (incremental adjusted HR 0.80 [0.73–0.89]) [Table 2 and Online Resource Table 4].

Fig. 1
figure 1

Kaplan–Meier survival curve without the outcome and confidence bands for the initiation cohort

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The sensitivity analysis is presented in Online Resource Table 5, with consistent results with the main results.

3.2 Switch

A total of 17,123 patients who had a switch from originator to biosimilar were matched to non-switchers, with 7536 (42%) switchers matched to two patients and 9587 (54%) matched to one patient, for a total of 24,659 non-switchers. Only 796 (4%) of the switchers could not be matched and were thus excluded from the study. Characteristics of switchers and matched non-switchers were similar thanks to the matching process (Table 3).

Table 3 Switch cohort characteristics at baseline
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A total of 42 included patients experienced the outcome at the index date, of which 28 were non-switchers (0.11% of the non-switchers) and 14 were switchers (0.08% of the switchers). A switch was not associated with an increased risk of hypersensitivity reaction (adjusted OR 0.74 [0.39–1.42]). Corticosteroid delivery association was not significant (adjusted OR 0.82 [0.41–1.64]), but history of outcome and age < 19 years at inclusion were associated with an increased risk of outcome (with adjusted OR of 20.45 [7.59–55.12] and 4.11 [1.34–12.67], respectively). Having had a history of at least four injections in the past 2 years decreased the risk of hypersensitivity reaction, with an adjusted OR of 0.45 (0.22–0.92) compared with having had fewer than three past injections (Table 4 and Online Resource Table 7).

Table 4 Estimation of the association between rituximab injection by product type and hypersensitivity reaction in the switch cohort, at first injection and over time
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Over the study follow-up, 93 patients experienced the outcome, of whom 51 were non-switchers still treated with rituximab originator (0.20% of the non-switchers), and 42 were switchers still treated with rituximab biosimilar (0.24% of the switchers). Survival curves of switchers and non-switchers had an important overlay, with a p-value of the log-rank of 0.53, showing no difference in the risk of severe hypersensitivity reactions following the injection (Fig. 2). Biosimilar injections were not associated with an increased risk of hypersensitivity reaction (adjusted HR 1.06 [0.70–1.62]). Regarding covariates, we found the same associations as for the first injection model (Table 4 and Online Resource Table 8).

Fig. 2
figure 2

Kaplan–Meier survival curve without the outcome and confidence bands for the switch cohort

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Sensitivity analyses are presented in Online Resource Table 4, and the results were consistent with the main results.

3.3 Details on Patients Who Experienced Hypersensitivity Reactions

Patients who experienced the event of interest are described in Table 5. In both the initiation and switch cohorts, the outcome was mainly due to an anaphylactic shock (around 75% of events). Events occurring in the initiation cohort tended to be more severe than in the switch cohort: 28–30% of initiating cases were transferred in the intensive care unit, while only 24% in the switch cohort were transferred; the outcome of the hospitalization in which the event occurred was death in 18–20% of cases in the initiation cohort, but only 14–16% of cases in the switch cohort. The length of hospital stay tended to be longer at inclusion versus over time.

Table 5 Details on patients who experienced hypersensitivity reactions
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4 Discussion

In this two-cohort study based on the French National Health Data System, we did not show an increased risk of hypersensitivity reaction associated with the injection of rituximab biosimilar compared with rituximab originator, neither in an initiation or switch context, nor for the first injection or over time.

This result is consistent with clinical trials [8,9,10, 35], observational studies, and systematic reviews dealing with monoclonal antibodies or fusion proteins [36,37,38,39,40,41,42], in which the authors showed no difference between the biosimilar product and originator product in terms of safety and immunogenicity, and in particular regarding hypersensitivity reactions, at either initiation or switch [16, 18, 43]. However, these studies were small and thus could not detect the rare events we were able to study.

One may hypothesize that the pharmacovigilance signal raised by the ANSM might be due to the fast scale-up of rituximab biosimilar initiations, which replaced originator rituximab initiation almost completely by 2019, as shown in Online Resource Fig. 3a. As hypersensitivity reactions, and especially severe reactions, occurred mainly during the first injection of rituximab in our study, the fast increase of biosimilar initiations might have provoked disequilibrium in the number of reported cases of hypersensitivity in biosimilar new users versus originator users. In addition, there might be a detection bias in pharmacovigilance reports due to a particular focus on novel products such as biosimilars. Indeed, the number of cases of hypersensitivity has remained fairly constant since biosimilar rituximab market approval (as shown in Online Resource Fig. 3b).

Our study has several strengths. First, as the study was based on an exhaustive database, we were able to include almost every patient living in France and to identify every event of interest. Second, the problem of compliance often blamed on medico-administrative databases does not apply here because the treatment is taken at a hospital facility. Third, indication bias, often argued in observational studies, is very limited in our case, as originator and biosimilar products are considered interchangeable (as demonstrated by the fast adoption of the biosimilar products). Finally, we found some known and documented associations between the covariates and the outcome: protective effect of corticosteroids, highest risk at initiation and decreasing risk afterwards [5], and increased risk in patients with a history of outcome and in children [44].

On the other hand, we should discuss the potential limitations of this study. First, as the event is quite rare, the study might not be powered enough to exclude a weak association between the exposure to biosimilars and the outcome, in particular for the switch analyses, showing large 95% CIs. In addition, due to this issue, we did not adjust on complementary risk factors such as medical exposures, for example some antibiotics or proton pump inhibitors [45], or comorbidities such as asthma [29]. Nevertheless, the consistency of the results in the analyses and the sensitivity analyses gives confidence in the study’s conclusions. Additionally, as the study was carried out on a national level and on an exhaustive database, this limitation should not be significant. Furthermore, due to the medico-administrative nature of the database, clinical information such as treatment indication is not systematically recorded; we used algorithms and proxies to categorize patients’ pathologies (i.e. delivery of rituximab with a history of LTD or hospitalization with a specific ICD-10 code). Our algorithm could be improved, especially to reduce the number of patients with an undetermined pathology. In addition, the category ‘Multiple pathologies or pathology undetermined’ was inexplicably associated with the outcome, and we did not find an increased risk of hypersensitivity reaction in patients with inflammatory/immune dysfunction disorders as previously found [46]. However, the group category ‘Multiple pathologies or pathology undetermined’ was very small (less than 5% of initiators and 2% of switchers/non-switchers), and excluding it from the analyses did not change the OR and HR estimates.

5 Conclusion

The results of this study are reassuring regarding the use of rituximab biosimilars, in the context of fast scale-up and political incentives to prescribe biosimilar products. Further real-world studies may still also be carried out with other biosimilar products and studying other product-specific adverse effects to confirm that biosimilar initiation or originator to biosimilar switching does not lead to an increase in signals.