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 Table of Contents  
Year : 2018  |  Volume : 13  |  Issue : 1  |  Page : 20-25

Safety and efficacy of an Anti-CD20 Monoclonal antibody (RedituxTM) In Indian patients with seropositive rheumatoid arthritis

1 Department of Rheumatology, Army Hospital (Research and Referral), New Delhi, India
2 Department of Rheumatology, Command Hospital, Lucknow, Uttar Pradesh, India
3 Centre for Chronic Disease Control, Public Health Foundation of , Gurugram, Haryana, India
4 Department of Rheumatology, Command Hospital, Pune, Maharashtra, India
5 Department of Rheumatology, Command Hospital, Kolkata, West Bengal, India

Date of Web Publication26-Feb-2018

Correspondence Address:
Dr. Vivek Vasdev
Department of Rheumatology, Army Hospital (Research and Referral), Delhi Cantt, New Delhi - 110 010
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_98_17

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Background: Rituximab (RTX), an anti-CD 20 monoclonal antibody is one of the first line biological disease-modifying anti-rheumatoid drug indicated for the treatment of rheumatoid arthritis (RA) in patient's refractory to conventional Synthetic DMARDs (csDMARDs). Limited data are available about the safety and efficacy of biosimilar version of this molecule. In this study, we assessed the clinical efficacy and safety profile of biosimilar RTX, RedituxTM.
Methods: In this prospective study, 36 adults with moderate disease activity measured by the European League Against Rheumatism (EULAR) disease activity score (DAS28-erythrocyte sedimentation rate [ESR] ≥3.2), who had failed conventional therapy with at least 2 csDMARDs were initiated on RTX, 1000 mg, given on day 0 and day 15, after taking informed consent. Biomarkers including ESR, C reactive protein, Immunoglobulin G and M (IgG, IgM) and DAS28-ESR scores were measured at baseline and repeated at 2, 4, 8, 12, 16, 20, and 24 weeks. The primary endpoint was attaining EULAR good/moderate response.
Results: DAS28-ESR score showed a statistically significant decline at 24 weeks (P < 0.001). Seventy-five percent patients showed an EULAR moderate response while 25% showed no EULAR response at 24 weeks posttreatment. IgG and IgM levels declined by 24.9% (P < 0.001) and 37% (P = 0.020) at end of 24 wks. However, there were no infections noted during the period of study. The most common adverse event was infusion reaction seen in 16.6% of patients.
Conclusions: RTX is a safe and effective drug for the management of seropositive RA with results comparable with the original molecule. No serious adverse effects were noted in the study except for mild infusion reactions and fall in immunoglobulin levels.

Keywords: Biosimilar, csDMARDs, immunoglobulin, Indian, rheumatoid arthritis, Rituximab

How to cite this article:
Hegde A, Vasdev V, Shanmuganandan K, Singh K, Kartik S, Kumar A. Safety and efficacy of an Anti-CD20 Monoclonal antibody (RedituxTM) In Indian patients with seropositive rheumatoid arthritis. Indian J Rheumatol 2018;13:20-5

How to cite this URL:
Hegde A, Vasdev V, Shanmuganandan K, Singh K, Kartik S, Kumar A. Safety and efficacy of an Anti-CD20 Monoclonal antibody (RedituxTM) In Indian patients with seropositive rheumatoid arthritis. Indian J Rheumatol [serial online] 2018 [cited 2021 Jan 28];13:20-5. Available from:

  Introduction Top

The introduction of biological disease-modifying anti-rheumatoid drugs (bDMARDs) has revolutionized the treatment of rheumatic illnesses. Rituximab (RTX) is a potent anti-CD20 monoclonal antibody, which is 20% mouse and 80% human protein,[1] and accomplishes B-cell killing chiefly by antibody-dependent cell-mediated cytotoxicity, complement-mediated cytotoxicity, and apoptosis of CD20 + ve B cells.[2],[3] It has proven efficacy and safety in the treatment of rheumatoid arthritis (RA), however, the cost of this molecule remains a limiting factor. The impetus globally has thus been to develop follow-on or “biosimilar” versions of this reference (originator or innovator) molecules to reduce cost. A biosimilar is defined as a biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product” with similarity defined as “the absence of a relevant difference in the parameter of interest.”[4]

In India, few studies have attempted to study the effect of originator RTX in RA like Narayanan et al. (In 12 patients who failed antitumor necrosis factor alpha).[5] Safety and efficacy studies with biosimilar RTX in Indian patients with RA are few, namely, by Santhanam et al. (13 patients with RA refractory to at least 2 conventional synthetic DMARDs (csDMARDs),[6] Bhati and Bandyopadhyay (retrospective study of 39 patients with at least 2 csDMARD failure),[7] and Roshique and Ravindran et al. (21 patients with biologic naïve RA).[8] Review of the literature reveals that repeated courses of RTX have resulted in secondary hypogammaglobulinemia[9] and low baseline Immunoglobulin G (IgG) level has been identified as an independent risk factor in the French Registry.[10] However, none of the Indian studies have monitored serial immunoglobulin titers to address this safety aspect. The primary objective of our study was to test the safety and efficacy profile of biosimilar RTX (Reditux) in Indian patients with seropositive RA refractory to csDMARDs.

  Methods Top

This is a prospective observational (non-randomized) study evaluating the safety and efficacy of Reditux (RTX) in patients with seropositive RA.

Patients and data collection

A total of 36 individuals with moderate to severe Rheumatoid arthritis, classified as per 2010 ACR/European League Against Rheumatism (EULAR) criteria,[11] who were attending a tertiary care hospital in North India, were recruited, both from the rheumatology outpatient clinic and the inpatient ward. Individuals were recruited for the study over a period of 18 months from June 2013 to December 2014. All patients recruited were above 16 years of age, had seropositive RA (rheumatoid Factor and/or anti-citrullinated protein antibody positive) and active disease, defined by a disease activity score in 28 joints (DAS 28) ≥3.2, despite having been on at least 2 csDMARDs in optimal doses (Methotrexate 20 mg/wk or Leflunomide 20 mg OD or Sulfasalazine 1 g BD or Hydroxychloroquine 300 mg OD) for at least 3 months. Steroids (prednisolone or equivalent (<10 mg/day) and nonsteroidal anti-inflammatory drugs were permitted if their doses had remained stable for at least 4 weeks and 2 weeks respectively, before enrollment. The patients should not have been exhibited bDMARDs before recruitment in the study. The exclusion criteria comprised of patients harboring active infection, demyelinating disease, positive HBsAg status, and pregnant or lactating women.

A questionnaire was administered to all 36 patients enrolled in the study to collect information regarding demographic, and behavioral factors, and past and present health status of the patients. All patients underwent baseline clinical and laboratory evaluation. The baseline history was recorded to include features as enumerated in 2010 ACR/EULAR classification criteria for RA. Clinical evaluation included the estimation of the tender joint count and the swollen joint count.

Two doses of Reditux, 1000 mg each, were given intravenous at 0 and 15 days. All patients were given premedication with Injection Methylprednisolone Sodium Succinate 125 mg IV before the infusion, along with Tablet Paracetamol 1000 mg and Injection Chlorpheniramine 50 mg intramuscular.

Laboratory parameters comprising of erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) were evaluated at baseline and repeated at 2, 4, 8, 12, 16, 20 and 24 weeks. ESR was measured using the Westergren method. CRP was measured using nephelometer (DN ProSpec, Siemens). The cut-off for CRP was 10 mg/L. Immunoglobulin profile (Comprising IgG and Immunoglobulin M [IgM] levels) was done at baseline, 2, 12, and 24 weeks, using nephelometer (DN ProSpec, Siemens). The normal values for IgG were 7–16 g/L and IgM were 0.7–2.4 g/L. Treatment efficacy was evaluated by estimation of disease activity using the EULAR DAS28-ESR. For the DAS28, cutoff points for high disease activity, moderate disease activity, low disease activity, and remission were 5.1, 3.2, 2.6, and <2.6, respectively. DAS28 scores were analyzed at baseline, 2, 4, 8, 12, 16, 20, and 24 weeks. EULAR response criteria were analyzed at 24 weeks. EULAR good response was defined as a decline in score ≥1.2, resulting in the achievement of low disease activity (DAS28 <3.2). EULAR moderate response was achieved by a decline in the DAS28 by >1.2 (without reaching low disease activity); or by a decline of 0.6–1.2, plus reaching at least moderate disease activity (DAS28-<5.1).[12] The primary outcome was defined as achievement of an EULAR good/moderate response.

Statistical analysis

Univariate analyses, such as frequency (percentage) and mean (standard deviation), were reported to summarize the baseline characteristics of the participants. Bivariate analyses, such as two-way tables of frequency, were conducted to examine the relationships between RTX therapy and changes in various biomarkers such as IgG and IgM. We analyzed the change in IgG, IgM at 2, 12, and 24 weeks from baseline, and DAS28-ESR scores over 2, 4, 8, 12, 16, 20, and 24 weeks in response to the RTX treatment. Paired t-test and repeated measures ANOVA were used to report the statistically significant changes in DAS28-ESR, IgG, and IgM over the study period. All analyses were performed in STATA (version 12.0 SE; StataCorp, TX, USA). All analyses were conducted on complete case analysis basis with no imputation of missing data. A two-sided P < 0.05 was used to indicate statistical significance for all tests.

Ethical approval

The institutional ethics committee and scientific committee approved this study, and written informed consent for participation in the study was obtained from all enrolled patients.

  Results Top

The age group of patients varied from 28 to 66 years. The mean age of study participants was 47.2 years (SD-9.1). The male:female ratio was 1:5. The mean disease duration was 10.75 years (SD-6.89). Other baseline characteristics are given in [Table 1]. All 36 consenting patients in our study completed the study protocol (100%). There were no dropouts or loss to follow-up.
Table 1: Baseline characteristics of study patients

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The assessment of csDMARD use at baseline revealed 80.56% of patients to be on the drug methotrexate, 47.22% patients were on Hydroxychloroquine Sulfate, 25% patients were on Sulfasalazine, and 14% patients were on Leflunomide. 29 (81%) patients had failed dual csDMARDs whereas 9 (25%) had failed triple DMARDs before recruitment in the study. The mean treatment period with csDMARD before the study was 8.4 years.

Effects on Rituximab on disease activity score 28-erythrocyte sedimentation rate and European league against rheumatism response

The mean DAS28-ESR score at baseline was 5.92 (95% CI 5.65–6.18). Mean DAS scores declined significantly after the first dose of RTX to 4.84 (95% CI-4.54–5.13, P < 0.001) at 2 weeks and 3.66 at 12 weeks (95% CI 3.37–3.94, P < 0.001). At 24 weeks, mean DAS28 scores rose to 4.01. This rise in titers was statistically significant when compared to scores at 12th week (P< 0.04). However, compared to DAS28 scores at baseline, they were still significantly low (95% CI 3.58–4.44, P < 0.001). Thus, the DAS28 scores declined by 32% from baseline levels. The DAS28 response to RTX has been depicted in [Figure 1].
Figure 1: Serial changes in DAS28-ESR over 24 weeks post Reditux. DAS28-ESR: Disease activity score 28 joints-erythrocyte sedimentation rate

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The assessment of EULAR response criteria at 24 weeks revealed that 27 patients (75%) achieved an EULAR moderate response (ΔDAS >1.2), whereas 09 patients (25%) showed no response (2 patients having a ΔDAS >0.6 < 1.2, 7 patients showing a ΔDAS <0.6).

Effects on immunoglobulin levels

The mean IgG level at baseline was 14.9 g/l (95% CI 13.51–16.33). The IgG levels declined significantly after the first dose of RTX to 12.3 g/l at 2 weeks (95% CI 11.27–13.38, P = −0.0005), 11.6 g/l at 12th week (95% CI 10.41–12.66, P < 0.001), and 11.5 g/l at 24th week (95% CI 10.41–12.66, P < 0.01). The serum immunoglobulin G levels declined by 24.83% compared to baseline levels at 24 weeks.

The mean baseline IgM level was 2.2 g/l (95% CI 1.37–2.92), which declined insignificantly at 2 weeks to 1.7 g/l (95% CI 1.19–2.28, P = 0.08) and 1.4 g/l at 12 weeks (95% CI 1.12–1.67, P = 0.06). At 24 weeks, the levels remained at 1.4 g/l (95% CI 1.15–1.71, P = 0.05). The serum immunoglobulin M levels thus declined by 37% at 24 weeks. The results are depicted in [Figure 2].
Figure 2: Serial changes in IgG and IgM levels in gm/L post Reditux at 24 weeks. IgG: Immunoglobulin G, IgM: Immunoglobulin M

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Treatment related adverse events

Adverse events (AEs) were infrequent. The most common noninfectious AE were infusion reactions, which was seen in six patients (16.6%). All of these reactions occurred during the first infusion of RTX. The AEs comprised headache (two patients) and itching in the throat, flushing of face and itching in skin (four patients). Temporary cessation of infusion for 15 min improved the symptoms, and restarting the infusion at a slower rate did not cause recurrence.

One patient (2.7%) developed reduced serum IgG levels, and five (13%) patients developed reduced serum IgM levels below lower limit of normal at 24th week. However, none of these patients with hypogammaglobulinemia had a manifestation of infection during the period of the study. There were no cases of reactivation of hepatitis B or tuberculosis during the duration of the study. [Figure 3] summarizes the adverse effects seen in our study.
Figure 3: Adverse effects of Reditux seen in our study

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  Discussion Top

The average disease duration of illness before recruitment in our study was similar to that of the patients enrolled in the DANCER study (12 years), REFLEX study (12 years) and the SERENE study (7 years).[13],[14],[15]

The mean DAS28 score of the study population (5.9) was comparable with the mean DAS28 scores enrolled in the landmark RTX trials in RA, namely, DANCER (6.7), REFLEX (6.9), SERENE (6.49), MIRROR (6.7),[13],[14],[15],[16] and Tsiakalos et al. (6.6).[17] Attainment of moderate EULAR response in our study at 24 weeks was similar to those of the DANCER study[13] wherein 75.6% of the pts achieved an EULAR good/moderate response.(Moderate response - 63.4%, Good response - 12.17%). Similarly, in the REFLEX study,[14] DAS 28 scores were statistically significant (P< 0.0001) between treatment groups at every time point from week 8 to week 24 with 50% achieving EULAR moderate response and 15% achieving a good response. The SERENE study[15] also showed a significant DAS28 response in the form of adjusted mean change in DAS28-ESR score from baseline of −1.69 (P< 0.0001, when compared to placebo) at 24 weeks with 51.1% achieving EULAR moderate response and 17.4% patients EULAR good response. Similarly, the study by Tsiakalos et al.[17] also showed a significant fall in DAS28 levels in response to RTX at 24 weeks. DAS28 levels in this study declined from 6.6 at baseline to 5.69 at 8 weeks (P< 0.01), 4.95 at 16 weeks (P< 0.05), and 4.42 at 24 weeks (P< 0.0001). In Indian studies with Reditux, Roshique, and Ravindran[8] showed that DAS28-ESR showed a significant fall at 12 weeks (6.08 vs. 2.54) while Bhati and Bandyopadhyay[7] also showed similar heartening results (DAS28-ESR 7.27 at baseline vs. 5.46 at 24 weeks). Our study has this revelation that there was a significant reduction in disease activity at 24 weeks consistent with the landmark studies as well the Indian studies. In consonance with other studies, the disease activity starts an upward trend at 20 weeks thereby indicating that RTX needs to be administered at week 24 as a protocol. A comparative graph of EULAR responses achieved by our study versus other landmark studies is shown in [Table 2]. [Table 3] shows comparable DAS28-ESR scores at 6 months post-RTX in Indian studies along with the percentage of patients achieving remission, low, moderate, and high disease activity at the end of 24 weeks post-RTX.
Table 2: Comparison of European league response against rheumatism response, Percentage of patients with low immunoglobulin G and immunoglobulin M levels at 24-week post-rituximab across published studies

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Table 3: Comparison of disease activity across Indian studies at 24-week post-Reditux

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The assessment of the fall in immunoglobulin levels post-RTX in DANCER study[13] revealed that although the mean immunoglobulin levels declined after RTX infusion, however, they remained above the laboratory lower limit of normal at all times, with the greatest change from baseline levels occurring in the IgM levels, which was similar to the findings of our study. Likewise, in the REFLEX study,[14] mean immunoglobulin levels remained within normal levels in all patients throughout the 24 weeks of study, however fewer patients had low immunoglobulin levels (5.5% low IgM, <1% low IgG) below the lower limit of normal in the posttreatment period. In the SERENE study,[15] 1.3% and 6.6% had low IgG and IgM levels, respectively. The MIRROR study,[16] showed results similar to ours in the form of mean IgG and IgM levels declining from baseline levels in all groups before stabilizing at weeks 8–24. The study by Tsiakalos et al.[17] also revealed that mean IgG and IgM declined moderately during follow-up but continued to remain within normal levels throughout the study, which was similar to our findings. The above findings have been summarized in [Table 2].

The most common adverse effects were infusion reactions that were seen in 16.6% of patients, all of which occurred during the first infusion of RTX, and within the 1st hour of infusion. This incidence is much lower compared to the results of the REFLEX[14] (29%) and DANCER[13] studies, wherein 38% of the patients had infusion reactions while on concomitant glucocorticoids. Similar to our findings, the Indian study by Roshique and Ravindran[8] noted infusion reactions in 10% of their patients without any serious adverse reactions. None of our patients had any infusion reactions during subsequent infusions. This was in agreement with the above studies wherein very few infusion reactions were seen in subsequent infusions. Methotrexate, in this study, was used as the baseline DMARD in 80.56% of the patients, which could have attenuated the development of human anti-chimeric antibodies, which in turn possibly could have reduced the incidence of reactions.

Low IgG levels (<6 g/L) have been known to be associated with serious infections.[10] In our study, it was observed that although IgG levels fell to <5 g/L in one patient, none of the patients had any serious infections. These results are similar to the findings in the Indian studies by Narayanan et al.,[5] Santhanam et al.,[6] Bandopadhyay et al.[7] and Roshique and Ravindran[8] thereby implying that RTX could thus find use as a first line biological therapy in India in view of the excellent safety profile in comparison with other bDMARDs.

One of the important limitations of the study was the short-term duration of the study. Twenty-four weeks are inadequate to assess long-term safety and efficacy. Long-term results will be needed to confirm these initial findings.

B cell depletion with RTX is a cost-effective and potent therapeutic modality in the management of seropositive RA who have an inadequate response to csDMARDs, with results similar to those of the originator molecule. The incidence of infusion-related reactions with RTX is few and minor in nature. Significant fall in immunoglobulin levels although observed, does not predispose to infection.

Financial support and sponsorship

The biologics used in this study were provided free to the patients by the Government of India, and all laboratory investigations were carried out in the hospital laboratory free of cost.

Conflicts of interest

There are no conflicts of interest.

  References Top

Cohen MD, Keystone E. Rituximab for rheumatoid arthritis. Rheumatol Ther 2015;2:99-111.  Back to cited text no. 1
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World Health Organization. Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs); 2009. Available from: [Last accessed on 2017 Jul 20].  Back to cited text no. 4
Narayanan K, Bhakuni DS, Garg OP. Experience with rituximab in rheumatoid arthritis. Indian J Rheumatol 2009;4:136-7.  Back to cited text no. 5
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Bhati M, Bandyopadhyay S. Efficacy and safety of an anti-CD20 monoclonal antibody (Reditux™) for the treatment of patients with moderate to severe rheumatoid arthritis following the failure of conventional synthetic disease-modifying anti-rheumatic drugs. Clin Rheumatol 2016;35:1931-5.  Back to cited text no. 7
Roshique KK, Ravindran V. Efficacy and safety of a biosimilar rituximab in biologic naïve patients with active rheumatoid arthritis. Clin Rheumatol 2015;34:1289-92.  Back to cited text no. 8
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Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390-400.  Back to cited text no. 13
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Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ, et al. Efficacy and safety of different doses and retreatment of rituximab: A randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study evaluating Rituximab's efficacy in MTX iNadequate rEsponders (SERENE)). Ann Rheum Dis 2010;69:1629-35.  Back to cited text no. 15
Rubbert-Roth A, Tak PP, Zerbini C, Tremblay JL, Carreño L, Armstrong G, et al. Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: Results of a phase III randomized study (MIRROR). Rheumatology (Oxford) 2010;49:1683-93.  Back to cited text no. 16
Tsiakalos AP, Avgoustidis NK, Moutsopoulos HM. Rituximab therapy in Greek patients with rheumatoid arthritis. Biologics 2008;2:911-6.  Back to cited text no. 17


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]

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