INTRODUCTION
Monoclonal antibodies (mAbs), considered to be one of the fastest-growing group of drugs, are engineered molecules developed in order to restore, enhance, or mimic the responses of the immune system.[1] And currently, they are being utilized in the management of autoimmune disorders, hematological and malignancies, viral illnesses (including COVID-19), and also as an antiplatelet therapy.
Rituximab is one such mAb which was launched in 1997 after its due approval from the United States Food and Drug Association (US FDA) for the management of non-Hodgkin’s lymphoma,[2] and since then its use has been approved in the management of various other conditions such as moderate-severe rheumatoid arthritis (2006), chronic lymphocytic leukemia (2010), follicular lymphoma and pemphigus vulgaris (2011), and recently in 2019 for granulomatosis with polyangiitis and microscopic polyangiitis in children.[2,3] The mechanism by which this chimeric human/murine mAb exerts its effect is essentially by targeting the CD20 antigen expressed on the surface of pre- and mature B lymphocytes. This then activates the complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity pathways, eventually resulting in the lysis of B lymphocytes.[3-5] And the commonly encountered adverse effects of rituximab are infusion reactions, neutropenia, lymphopenia, infection and HBV reactivation.[3]
Because of its ability to cause lysis of B lymphocytes, this mAb is now being routinely used for the management of certain off-label indications (implying use in a medical condition that has not been approved by FDA, but healthcare providers use).[6] As per a systematic review, there are approximately 30 off-label diseases in which rituximab is being used, the most common being renal transplant (single dose of 35–500 mg), autoimmune hemolytic anemia, and immune thrombocytopenia. The commonly used doses in such indications were 500 mg twice 1–2 weeks apart for neuromusculoskeletal and skin diseases and 100 mg weekly for 4 weeks in hematological disorders.[7]
Using this mAb in each and every aforesaid situation may create an undue economic burden on both the user and healthcare system. In such circumstances, the use of biosimilars might abate this trouble. As World Health Organization defines, biosimilars are biotherapeutic products similar in terms of quality, safety, and efficacy to already licenced reference biotherapeutic products.[8] And the advantage of these biosimilars is the economic relief they offer by their low-cost option, especially to the middle- and lower-income groups, hence improving access to biologics for all patients.[9,10] Since the patent on rituximab has expired (in September 2016 in the USA and in February 2013 in Europe), more of its affordable biosimilars are now available. To name a few: rituxan, mabthera, truximab, ruxience, reditux, and ritucad are available.[11,12]
Considering how well rituximab has fared in the market and thus has been declared a blockbuster drug, accessibility to its affordable biosimilars will expand its use for off-label indications exponentially.[13] According to the reports by America’s Health Insurance Plans, between 2012 and 2014, 20.8% of rituximab’s use was for off-label indications, while authors of a cross-sectional retrospective study observed that the off-label use of rituximab increased by over 4600% during the course of study.[14,15]
Since the data regarding off-label use of rituximab in Indian setting are limited, the authors planned for a retrospective study to collect and compare the indicated and off-label uses of rituximab in tertiary care hospitals of Central India.
METHODS
This was a retrospective cross-sectional study, wherein data were collected from All India Institute of Medical Sciences, Raipur, and Balco Medical Centre, Raipur, Chhattisgarh, India. Due approval for this study was obtained institutional ethics committee (IEC) vide Letter No. 1344/IEC-AIIMSRPR/2020 dated November 13, 2020, following which the head of Balco Medical Centre was approached for permission to collect and analyze the patients’ records. The data of those patients who had received at least one infusion of rituximab between January 01, 2019, and December 31, 2021, in the above-mentioned hospitals were collected. And since this was a retrospective record-based study, patients’ consent was waived off. The study was conducted in complete adherence to the principles of the declaration of Helsinki.
The data collection was performed by three of the authors. For this observational study, no sample size was calculated, and all the patients’ records that were complete were included. Their demographic and clinical information along with comorbidities were noted. The patients were then divided into two groups; one group of patients who received rituximab for USFDA-approved indication (Non-Hodgkins lymphoma, Wegner granulomatosis, microscopic polyangiitis, chronic lymphocytic leukemia, pemphigus vulgaris, rheumatoid arthritis), and the other group which received rituximab for “off-label indication” (other uses apart from the indicated ones).
The primary outcome of the study was the proportion of patients receiving rituximab for approved indications. Other endpoints were to compare the characteristics of patients who received rituximab for approved and off-label indications. Furthermore, factors associated with the use of approved indications were also analyzed. The burden of comorbidities was calculated using 19-point Charlson comorbidity index.[16]
The data were presented as mean (for continuous variables) and percentage (for categorical variables). Characteristics of patients have been compared between groups with unpaired t-test/Chi-squared test. A multiple logistic regression model was applied to assess factors associated between approved indications and all possible patient characteristics using Graphpad Prism 9 (trial version). P < 0.05 was considered statistically significant.
RESULTS
For the said assessment period, a total of 79 patient records were analyzed. Of these, 35 were from AIIMS Raipur and 44 from Balco Medical Centre Raipur. Most of the patients were males (55.7%; 44 out of 79). Among them, 61 (77.2%) patients had received rituximab for USFDA-approved indication while 18 (22.8%) had received rituximab for an off-label indication [Table 1]. Out of 61 patients who received rituximab for approved indications, 38 belonged to the Balco Medical Centre. The patients who received rituximab for approved indications were significantly older, more likely to be male, and had malignancy as comorbidity (P < 0.05). Though not statistically significant, the burden of comorbidities was found to be higher among patients who received rituximab for an approved indication.
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Table 1: Clinical and demographic characteristics of patients with rituximab infusion
On further analysis, the authors observed that among the approved indications for the use of rituximab, oncological indications were most common, followed by pemphigus vulgaris and rheumatoid arthritis [Table 2]. And the most frequent oncological condition for which rituximab was prescribed was non-Hodgkin’s lymphoma. While on the other hand, autoimmune diseases [such as autoimmune hemolytic anemia (AIHA), systemic lupus erythematosus (SLE) and idiopathic thrombocytopenic purpura (ITP)] were the most common off-label indications encountered among these records [Table 2].
Table 2: Indications of rituximab
Multiple factors (patients’ age, sex, Charlson comorbidity index score, and the presence of comorbidities) were analyzed using multiple logistic regression so as to determine the relationship between these factors and the use of rituximab for an approved indication. Among these factors, advanced age (AOR = 1.04, 95% CI = 0.99–1.1), male sex [AOR = 2.55, 95% CI = 0.74–9.33] were identified to have that plausible relation with the use for approved indications. The high burden of disease was not associated with the approved use of rituximab (AOR = 0.66; 95% CI = 0.35–1.25). The presence of comorbidities (diabetes: AOR = 1.37, 95% CI = 0.1879–13.74, malignancy: AOR = 9.39, 95% CI = 1.463–76.12) was also found to be associated with a higher likelihood of rituximab use for an approved indication. The association of all the factors was statistically not significant except malignancy (P = 0.02) [Table 3].
Table 3: Factors affecting the use of rituximab for approved indications
DISCUSSION
The present retrospective, cross-sectional study involved analysis of 79 medical records of patients receiving rituximab infusion during 2019–2021. In the study, it was found that most of the patients were receiving rituximab for its approved indications; however, upon scrutinizing the data, it was clearly evident that more patients in BMC received rituximab for approved indications. The difference is attributable to the different hospital settings as BMC is a dedicated cancer hospital while AIIMS Raipur is a multi-speciality tertiary care center catering to numerous varieties of patients. The extent of off-label use of rituximab in our study was ~23% which is similar to the findings of previous studies;[15,17,18] however, the off-label use is reported to be very high in few studies.[19,20] In a study from India, the off-label use of rituximab was not observed in 2011.[21]
The authors observed that the use of rituximab for approved indications was associated with higher age and male sex. As the most common FDA-approved indication of rituximab is oncologic, the patients were likely to be older. The authors did not observe an association of high comorbidity score with the use of rituximab for approved indications. It was not in coherence with the previous study.[15] The disease, non-Hodgkin’s lymphoma, more prevalent among males, has been found to be the most common indication approved for the use of rituximab, and probably that is the reason why in our study as well we could better associate the use of rituximab for an approved condition with male gender.[22] The patients receiving rituximab for off-label indications were younger, female sex with less comorbidities, and autoimmune diseases were the major indications. The association of female sex can also be explained by the fact that females are much more prone to autoimmune diseases, and autoimmune diseases constitute the most common off-label indications of rituximab.[23] The most common approved indication was non-Hodgkin’s lymphoma, which is in excellent agreement with the previous studies.[15,18] Autoimmune disorders were the most common off-label indications which are similar to the previous study.[18]
Due to the less number of patients and relatively smaller duration of study, it is not possible to draw a conclusion regarding the change in usage pattern over time. A significant rise in off-label use of rituximab is observed which is going to increase further as low-cost biosimilars are increasingly available.[12] Further, the patients with diseases with limited therapeutic options may get benefitted.
Limitations
The present study indicates the usage pattern of rituximab in two hospitals which is relatively less while the duration of three years can further be increased. Due to the smaller number of patients, the generalizability is less. Despite the limitations, the study is among the very few studies which have assessed the usage pattern of rituximab.
CONCLUSIONS
Rituximab is approved for numerous indications and is used for unapproved indications also. The majority of patients received it for approved indications. Autoimmune disorders were the most common cause of off-label use. Increased age, male sex, malignancy, and diabetes were associated with the use of rituximab for approved indication.
Declaration of patient consent
The authors certify that they have obtained all the necessary permission for retrospective analysis of data. The patients were not interacted and study was carried out using the medical records. The data anonymity has been maintained.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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