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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 3  |  Page : 311-321

Expert Panel consensus statements on the optimal usage of rituximab for the management of rheumatoid arthritis in India


1 Department of Rheumatology, Yashoda Hospitals, Secunderabad, Telangana, India
2 Centre for Rheumatology, Kozhikode, Kerala, India
3 Department of Rheumatology, Mazumdar Shaw Medical Center, Bengaluru, Karnataka, India
4 Department of Rheumatology, Apex Center of Rheumatology, Pune, Maharastra, India
5 Department of Rheumatology, KIMS Hospitals, Secunderabad, Telangana, India
6 Department ent of Rheumatology, Apollo Gleneagles Hospital, Kolkata, West Bengal, India
7 Department of Rheumatology, Vikram Hospitals, Bengaluru, Karnataka, India
8 Department of Rheumatology, Radiant Medical Centre, Kolkata, West Benga, India
9 Department of Rheumatology, Sri Ramachandra Medical Center, Chennai, Tamilnadu, India
10 Rheumatic Disease Clinic, Mumbai, Maharashtra, India
11 Department of Rheumatology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
12 Department of Rheumatology, Sir Gangaram Hospital, New Delhi, India
13 Arthritis and Rheumatology Clinic, New Delhi, India
14 Department of Rheumatology, Calcutta Medical Research Institute, GD Hospital and Diabetes Research Institute, Nightingale Hospital, Kolkata, West Bengal, India

Date of Submission14-Mar-2021
Date of Acceptance25-Jun-2021
Date of Web Publication21-Sep-2021

Correspondence Address:
Dr. Vinod Ravindran
Centre for Rheumatology, Kozhikode, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_69_21

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  Abstract 


Pharmacological management of rheumatoid arthritis (RA) includes synthetic and biological disease-modifying antirheumatic drugs (DMARDs). Biological DMARDs, also referred to as “biologics,” rapidly retard progression of the joint damage seen in RA. Rituximab is a well-established biologic for the management of RA with several biosimilar versions available. This document presents the consensus statements on the usage of rituximab for the management of RA developed by a group of 14 experienced rheumatologists from India. This expert panel identified areas of interests, collated and summarized relevant literature, developed, debated and refined and revised the statements which were voted upon at relevant stages. Subsequently, a wider consultative process including voting on the draft statements involved 18 more rheumatologists from across India. The approved final version has 28 consensus statements related to the following seven areas of rituximab therapy in RA, namely, contraindication, pretreatment screening, treatment schedule, evaluation of response, safety, and research agenda for future. It is envisaged that these consensus statements would help in optimizing the usage of rituximab in RA not only in India but also in other countries and benefit all stakeholders.

Keywords: B cell depletion therapy, biological, biosimilar, disease-modifying antirheumatic drugs, rheumatoid arthritis, rituximab


How to cite this article:
Talari K, Ravindran V, Kumar P, Patil P, Mouli SC, Bandyopadhyay S, Dharmanand BG, Ray A, Rajeshwari S, Amin SN, Oak J, Chaturvedi V, Malaviya AN, Mukherjee S. Expert Panel consensus statements on the optimal usage of rituximab for the management of rheumatoid arthritis in India. Indian J Rheumatol 2021;16:311-21

How to cite this URL:
Talari K, Ravindran V, Kumar P, Patil P, Mouli SC, Bandyopadhyay S, Dharmanand BG, Ray A, Rajeshwari S, Amin SN, Oak J, Chaturvedi V, Malaviya AN, Mukherjee S. Expert Panel consensus statements on the optimal usage of rituximab for the management of rheumatoid arthritis in India. Indian J Rheumatol [serial online] 2021 [cited 2021 Dec 6];16:311-21. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/3/311/322898


  Introduction Top


Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease, with progressive polyarthritis and resultant disability as major features. In due course, extra-articular manifestations affecting the skin, eyes, heart, kidneys, and lungs may ensue. If left untreated it may lead to bony erosions, weakening of ligaments and subsequently joint deformities. The clinical manifestations of this disease is attributed to close interaction between cells, soluble mediators, autoantibodies, and signal transduction pathways of the innate and adaptive immune system, which are involved at various stages of RA.[1]

Treatment for RA aims at reducing joint inflammation and pain, maximizing joint function, and preventing joint destruction and deformity. The pharmacological management of RA includes synthetic and biological disease-modifying antirheumatic drugs (DMARDs). Biological DMARDs, also referred to as “biologics,” rapidly retard progression of the joint damage seen in RA.[2] Biologics are recognized as a more “direct, defined, and targeted” treatment modality. This consensus document pertains to rituximab, which is a well-established biologic for the management of RA.[3]

Rituximab is a monoclonal antibody directed at the CD20 molecule present on the surfaces of some B cells.[4] It is a chimeric product that comprises around 80% human and 20% mouse protein. Rituximab induces a near-complete depletion of the B cell population in the peripheral circulation of patients with RA, which typically lasts for 6–9 months.[5] Repopulation primarily occurs via naïve B cells, whereas memory B cells can stay depleted for more than 2 years.[5] The exact mechanism for B cell depletion resulting in clinical efficacy in RA is not completely known.[4] However, B cell antigen presentation ability, B cell production of cytokines, and B cell production of autoantibodies such as rheumatoid factor (RF) are considered to be responsible for mediating these effects.

Clinical studies report that RA affects approximately 0.28%–0.7% of adult population in India.[6] With new drugs being approved in RA, there are several treatment strategies for a patient who is drug naïve or has had inadequate response to either conventional synthetic or biologic DMARDs. There are also several biosimilars available in India.[7] In such a scenario, it appears reasonable to build a consensus on optimal usage of rituximab for the Indian patients with RA. Therefore, the main objective of this document was to present consensus statements on optimizing the use of rituximab in India for patients with RA. It is envisaged that this consensus statements would help guide the good clinical practice in this regard not only in India but also would be a useful framework for rheumatologists in other Asian countries too.


  Methods Top


Expert panel

The nominal group technique, which is also known as the expert panel; a well-validated group process involving problem identification, solution generation, and decision-making, was employed with some modifications. Facilitators (ANM and SKM, two of the senior most rheumatologists of the country with over 55 years of experience) invited 12 rheumatologists (experience ranging from 9 to 37 years) from across the country. All panel members were required to disclose any potential intellectual or commercial conflicts of interest before taking up their positions. Funding of this academic exercise was through an unrestricted educational grant, with the sponsor having no role in the development of this consensus.

Process

A preframed list of questions by the facilitators regarding optimal usage of rituximab in India was presented and debated at the initial meeting. Expert panel deliberated with their own experience-based inputs and identified additional areas in need of a consensus. With this final set of questions, expert panel then tasked two members (KT and VR) to conduct a review (vide infra) of the relevant literature. Collected evidence was subsequently presented to the expert panel for review and discussion and expert inputs by all members, and based on these discussions, the same two members (KT and VR) produced draft wordings for the summary of evidence and accompanying statements under several specific subheading. The quality of evidence supporting each statement was evaluated using the evidence-assessment frameworks prescribed by the Grading of Recommendations, Assessment, Development, and Evaluations system.[8] These draft summaries of evidence and consensus statements were then presented to the expert panel for further discussion, voting, and revision. For the voting, though a threshold of 75% was required for approval of each statement, all statements were approved unanimously, i.e. with a 100% agreement. These meetings were held both conventionally and virtually.

Broader consultative process and final steps

As the next step, in a broader consultative process, the facilitators approached 18 more rheumatologists (experience ranging from 7 to 50 years) across India. This group also did not have any conflict of interest relevant for this exercise. In four different groups (in meetings held virtually), they discussed aforementioned draft summaries of evidence and consensus statements and voted to approve them with similar 75% threshold. The present final consensus document was then prepared which was once again discussed by the expert panel and unanimously approved, i.e. with a 100% agreement. The resultant present document has 28 consensus statements related to the following seven areas of rituximab therapy in RA, namely, indication, contraindication, pretreatment screening, treatment schedule, evaluation of response, safety, and research agenda for future. In this document, summary of relevant evidence is presented under aforementioned seven distinct subheadings and the consensus statements are presented in [Table 1].
Table 1: Consensus statements on the usage of rituximab for the management of rheumatoid arthritis in India

Click here to view


Search strategy

Literature search covered Medline, Google Scholar, Scopus, and Web of Science databases and included articles published in English between January 2000 to April 2020 using the following keywords: arthritis, rheumatoid arthritis, inflammatory arthritis, anti-rheumatic agents, disease modifying anti-rheumatic drugs, rituximab, B-cell depletion therapy, biological, biosimilars, safety, toxicity. In addition, a supplementary literature search was performed for articles published in the “Indian Journal of Rheumatology” from 2001 to 2020. After removing the duplications, remaining articles underwent detailed appraisal and data related to use of rituximab in RA with respect to indications, prior medications used, presence of comorbidities, pretreatment screening, dosing, evaluation of response, and safety was extracted. Literature of all types were considered; however, studies reporting pharmacokinetics and pharmacodynamics of rituximab and those reporting animal studies were excluded, so were case reports.


  Results Top


A. Indications for Rituximab

Severity of rheumatoid arthritis

Rituximab was approved by the US FDA in 2006 for the treatment of moderate-to-severe RA, refractory to DMARDs, and/or anti-tumor necrosis factor (TNF) therapy.[9] Most of the clinical trials of rituximab in RA have included patients with moderate-to-severe RA. No trials have included patients with mild RA. Indian studies too have included patients with moderate-to-severe disease activity.[7],[10]

Use of prior medications

Rituximab was originally approved by the FDA for treatment of RA patients who are TNF inhibitor (TNF-i) failures. However, clinical trials have shown rituximab to be effective in patients who are DMARD naïve,[11] DMARD failures,[12],[13],[14] and TNF-i failures[15],[16] [Table 2]. The DANCER trial enrolled 465 patients with active long-standing RA refractory to DMARDs, who were randomized to receive placebo, rituximab (two doses of 500 mg), or rituximab (two doses of 1000 mg) along with methotrexate (MTX).[12] This trial demonstrated that both dosages of rituximab in conjunction with MTX were very effective in a significantly high proportion of patients with active RA.
Table 2: Pivotal clinical trials of rituximab in rheumatoid arthritis

Click here to view


The IMAGE trial has highlighted that targeted B cell depletion by the combination of rituximab and MTX is effective and well tolerated for treating MTX-naïve RA.[11] Likewise, the MIRROR trial demonstrated improved therapeutic outcomes with rituximab in patients with RA and an inadequate response to DMARDs, regardless of the earlier anti-TNF treatment.[13] The phase III trial, namely SERENE, also established the efficacy of rituximab plus MTX in patients with active RA, who had an inadequate response to MTX and were naïve to previous biologics.[14] Furthermore, randomized double-blind trials such as SUNRISE and REFLEX have shown positive results with the use of rituximab therapy in cases of inadequate responses to TNF-i.[15],[16] Real-life data also indicate that switching to rituximab is more efficacious than switching to another TNF-i in individuals who has had inadequate response to TNF-i.[17],[18]

In the Indian setting, biosimilar rituximab was found to be effective in biological naïve patients with inadequate response to MTX in several clinical studies.[10],[18],[19] A prospective study evaluating efficacy of rituximab in biological-naïve patients with active RA reported prolonged benefits in a majority of the cohort.[19] Similarly, a placebo-controlled study which enrolled biological-naive RA patients demonstrated a significantly diminished disease activity score (DAS) in the rituximab group, compared to the control group (MTX plus placebo).[20] Another study reported the real-world experience for the biosimilar rituximab in patients who failed at least two conventional synthetic DMARDs including MTX.[10] In another study, good efficacy of rituximab in patients with refractory RA who had failed combination DMARDs and infliximab was noted.[21]

Presence of comorbidities and infections

The risk of infections and serious infections with rituximab in RA has been reported to be 43.8% and 4.6%, respectively.[22] There is no increased risk of infections with rituximab as compared to MTX and other TNF-i.[22] Clinical data suggest that rituximab is generally well tolerated over multiple courses, and the risk of serious infections does not increase by the treatment course, or overall time of exposure to rituximab.[23] There were no reports of active tuberculosis (TB) in any of the randomized controlled trials (RCTs) of rituximab in RA, and rituximab was well tolerated in those with a past history of active TB.[24] In the oncologic setting, rituximab has been reported to cause reactivation of hepatitis B in individuals who were hepatitis B surface antigen (HBsAg) positive and even in those who were HBsAg negative and anti-HBc positive. Reactivation of hepatitis C is unclear though there are few case reports in the oncology literature. The evidence in rheumatologic conditions is insufficient and contradictory.[25] Progressive multifocal leukoencephalopathy (PML) has been reported in patients with RA treated with rituximab; but in low numbers.[26]

Rituximab has also shown promise in extra-articular manifestations such as interstitial lung disease, scleritis, and vasculitis.[4],[27],[28],[29] In addition, postmarketing reports have been reassuring that rituximab is generally safe for the heart, with no evidence of significant cardiovascular adverse effects with its use.[30] However, it is worth noting that majority of the clinical trials of rituximab in RA have excluded patients with uncontrolled cardiac disease because of the associated risk with severe infusion reactions.[4] There are few reports establishing rituximab's safety in patients with chronic renal failure, without the need for dose reductions.[31] In cases of strong antinuclear antibody positivity, rituximab appears to be well tolerated.[32]

Seropositivity

Rituximab appears to have better efficacy in seropositive patients compared to seronegative patients.[4] Several randomized trials and patient registries have indicated that rituximab is more efficacious in those who have positive RF and/or anti-citrullinated peptide antibodies.[4] According to the REFLEX trial, fewer RF-negative patients achieved ACR20 response as compared to RF-positive patients.[16] On the contrary, a small Indian study demonstrated that seronegativity did not influence the efficacy of a biosimilar rituximab in a cohort of biologic naïve patients with active RA.[33]

B. Contraindications for Rituximab Therapy

The contraindications to rituximab include hypersensitivity to murine proteins, hypogammaglobulinemia, serious active infections such as serious bacterial infections, active TB, active viral hepatitis B and C, severe congestive heart failure, and pregnancy.[4] Rituximab should be avoided or considered cautiously in patients with existing hypogammaglobulinemia. Patients who are HBsAg and/or anti-HBc positive should considered for prophylaxis before rituximab therapy in conjunction with a hepatologist to minimize aforementioned risk of reactivation. As the evidence regarding hepatitis C reactivation with rituximab remains unclear, the expert panel felt that it is best to avoid it in those who are hepatitis C virus (HCV) positive. If the clinical scenario necessitates rituximab, it would be best to start concomitant antiviral therapy under appropriate specialist supervision. Rituximab should be discontinued at conception and avoided during pregnancy.[34],[35] The expert panel noted that consensus has emerged that it could be used during lactation and also during pregnancy if severe life- or organ-threatening maternal disease so warrants, but such scenarios would be unlikely to occur in the context of RA.[35]

C. Pretreatment Screening

History and clinical assessment

Before initiating rituximab, a thorough history including allergies, medical comorbidities, past infections, and vaccinations must be elicited.[34] Further, complete physical examination and appropriate patient screening are mandatory.[4],[34] Most importantly, when selecting the appropriate biologic therapy for their RA patients, clinicians must take into consideration the risk factors, particularly associated with specific infections such as TB, intracellular bacterial infections, reactivation of chronic viral infections, and HIV.[24] Since rituximab is contraindicated during pregnancy, this also must be excluded.[34]

Viral serologies

Before initiating treatment with rituximab, hepatitis B serology should be assessed by HBsAg and anti-HBc tests.[24] and patient should be screed for HCV. HIV screening before administration of rituximab is necessary in patients with risk factors.[24] However, whether rituximab can be given to stable HIV-positive patients with acceptable (>200/ml) CD4 cell counts remains unclear.[36]

Screening for tuberculosis

Screening for the presence of latent TB is not essential before commencing rituximab as the risk of reactivation of TB directly related to rixuibmab appears very unlikely.[4],[37] However, the panel felt that TB being endemic in this country, it is advisable to screen for active TB. Screening must comprise a detailed history of prior TB, antituberculous treatment received, treatment compliance, and chest X-ray.[37] A few panelists felt that screening for latent TB including tuberculin skin test/interferon gamma release assay before rituximab therapy may be considered; however, no consensus could be achieved on this point.

Immunoglobulin G levels

Baseline immunoglobulin (Ig) levels must be evaluated before rituximab is administered, because depleted IgG, IgM, and IgA levels have been observed after repeated rituximab courses.[34] Screening for baseline total serum IgG level (not its subcomponents) is recommended before commencement of rituximab therapy, since low baseline IgG levels predispose to risk of serious infections.[8],[34]

Vaccination

The immunogenicity to influenza and pneumococcal vaccines may be decreased in patients on rituximab, especially when they are given within 4–8 weeks after rituximab administration.[38],[39] The effect on HBV and other vaccines is not known. As the immunogenicity of the vaccines may be affected, it is best to administer vaccines such as pneumococcal, influenza, hepatitis B virus, and human papillomavirus vaccines at least 4 weeks before starting rituximab therapy. Expert panel noted that this is an arbitrary interval with no studies addressing this aspect directly.

D. Treatment Schedule

First cycle

Appropriate dosing

The approved dose of rituximab is 1000 mg × 2 with a 2-week interval per treatment course.[40],[41] Nevertheless, evidence suggests that a lower dose of 500 mg × 2 is also effective.[40],[41] Various clinical trials such as DANCER, SERENE, and IMAGE have shown that both doses of 2 × 1000 mg and 2 × 500 mg significantly improved clinical outcomes in patients with RA.[11],[12],[14] There were no clinically relevant differences between the two dosing regimens in population-based studies too.[42] Similarly, studies from India have also reported the efficacy of 1000 mg of rituximab.[7],[10] However, it has been observed that the higher dose was more effective in retarding radiographic damage in comparison to the lower dose.[4] The efficacy of ultra-low–dose rituximab has not been established except in a few case reports.[43] Trial designs for evaluating the same however have been proposed.[44]

Administration of premedication

Routine premedication with antihistamines and antipyretics along with titrated infusion helps in decreasing the chances of hypersensitivity reactions in patients being treated with rituximab.[45] In the DANCER trial, 100 mg of intravenous methylprednisolone was administered as a premedication before rituximab infusion.[12] It reduced the frequency and severity of the initial infusion-associated reactions, without contributing to the primary clinical end point.[12] Paracetamol, hydrocortisone, diphenhydramine, and other antihistamines have also been routinely administered before rituximab infusions.[34],[45]

Co-medications

Rituximab should be combined with MTX for better efficacy.[40] Apart from the use of rituximab along with MTX, certain observational studies have described its use with other DMARDs. The GERINIS trial demonstrated that rituximab in combination with leflunomide might be an alternative therapy for patients who are intolerant to MTX.[46] A randomized study evaluated the use of rituximab with patients on concomitant etanercept or adalimumab and MTX.[47] An increased number of infections with the former combination was observed, but with no additional efficacy.[47] One of the earliest trials of rituximab in patients with active RA despite MTX treatment demonstrated that its efficacy was only slightly less when combined with cyclophosphamide than with MTX.[48]

Infusion schedule

For the first infusion, the recommended initial rate for infusion is 50 mg/h; after the first 30 min, it can be escalated in 50 mg/h increments every 30 min, to a maximum of 400 mg/h. For subsequent infusions, rituximab can be infused at an initial rate of 100 mg/h and increased by 100 mg/h increments at 30 min intervals, to a maximum of 400 mg/h. Based on this, in standard practice, rituximab infusion takes 4.25 h for the first infusion and 3.25 h for the second and subsequent infusions.[49] Longer infusion times and frequent infusion rate changes are problematic and may also add to infusion costs linked to duration of hospital stay.[4] In the RATE-RA trial, it was noted that rituximab could be administered at a faster infusion rate at the second and subsequent infusions without increasing the rate/severity of infusion-related reactions (IRRs).[49]

Necessity of hospital setup

The possibility of potentially serious adverse effects with the use of rituximab (monotherapy or combination therapy) requires rheumatologists, intensivists, and hematologists to be familiar with the drug.[50] Expert panel felt that it is therefore best to administer rituximab in a setting with critical care facility.

Re-treatment

Several RCTs, conducted in MTX-inadequate responders and MTX-naive patients, established that the clinical efficacy of reduced doses of rituximab (500 mg × 2) during retreatment was similar to that of standard doses with respect to reduced disease activity.[51] Results from SERENE, IMAGE, and MIRROR trials have established that reduced doses of rituximab used after the first course of rituximab had similar clinical efficacy to the standard dose.[11],[13],[14] In a French national-wide prospective observational study, reduced doses of rituximab (1000 mg × 1) for retreatment not only did not alter of the drug at 5 years in patients with RA but also enabled a 39% total dose reduction and a lesser rate of serious infections.[51] Similarly, the SMART study demonstrated that in RA patients who had achieved a EULAR response after the first course of rituximab at the standard dose of 1000 mg × 2, retreatment with a reduced dose of 1000 mg × 1 was not inferior to a 1000 mg × 2 regimen.[52]

On-demand versus fixed retreatment

Generally, patients are retreated either based on treat-to-target or on-demand when disease activity increases (flares) and not at fixed intervals.[44] However, it has been shown that fixed interval rituximab retreatment significantly improves DAS28 for RA, compared to on-flare retreatment after both first and second retreatments.[53],[54] On the contrary, another study has reported that over a year of follow-up, fixed retreatment and on-demand retreatment with rituximab had similar efficacy as measured by the ACR response, EULAR response, change in DAS28 results, health assessment questionnaire scores, and radiographic progression.[55] Expert panel noted that till date, though the best retreatment strategy has not been established, either fixed 6-month interval retreatment or disease activity-guided treat-to-target retreatment appears to be the optimal approach.

Interchangeability of biologics

Repeated switching between biosimilars and their reference (innovator) products has a potential theoretical risk of patients developing immunogenicity.[56] A randomized trial has reported noninferiority of an infliximab biosimilar to the originator;[57] however, for rituximab, there are no such studies available. Currently, therefore, there are significant evidence gaps about the safety and efficacy of switching between rituximab innovator and their biosimilars. Interchangeability between the originator and biosimilar rituximab is hence not recommended. Appropriate clinical trials and pharmacovigilance studies with long-term follow-ups of multiple switches appear necessary.[58]

E. Evaluation of Response

Time for assessment of response

In majority of the patients, a clinical response is generally seen by 16 weeks after the first infusion; thus, 16 weeks is an appropriate time period for assessment.[12],[16],[48] Trials such as SERENE, MIRROR, and DANCER have demonstrated that typical clinical responses from rituximab were usually seen 3–4 months after the initial infusions.[12],[13],[14] The administration of concomitant corticosteroids might deliver a very early but transient effect.[4] The duration of effect is rather variable, due to which predicting the optimal timing for retreatment is challenging.

Clinical response

Rituximab in RA improves pain, function, and other symptoms; reduces disease activity; and reduces joint damage as visible on X-ray.[59] ACR and EULAR responses are important criteria for assessing the effect of rituximab on disease activity.[34] Radiographic assessments are also used for evaluating clinical responses after rituximab therapy.[16] The REFLEX trial depicted radiographic benefit with rituximab versus placebo at 1 year.[16] Among the rituximab-treated patients, 87% who did not have radiological progression at 1 year continued to have no progression at 2 years. Further, several studies from India reported significant reduction in DAS28 levels from baseline, which was consistent with landmark studies.[7],[10],[19]

Predictive factors

Biomarkers and genetic markers (serum interleukin 33, circulating miR-125b, 1H-nuclear magnetic resonance, and ultra-high-pressure liquid chromatography mass spectrometry) have been hypothesized to affect the clinical response to rituximab.[4] Various predictors such as ESR, C-reactive protein level, and serologic status for RF and anti-citrullinated cyclic peptide are used currently.[60] Markers of B cell activation, such as IgG, have been shown to correlate with disease activity in patients with early RA.[61] CD19 + B lymphocyte repopulation precedes clinical RA relapse and allows its prediction 4 months in advance.[61] Thus, monitoring depletion of CD19 + B lymphocytes after administering rituximab might help in anticipating clinical RA relapse ≤4 months after their reappearance.[62] This approach can be relevant for follow-ups for controlling the disease properly but not recommended in the routine clinical setting.[61]

G. Safety of Rituximab

General

Rituximab has a reasonable safety profile but seems to be associated with a small risk of serious infections, which generally reduce and are stabilized over time and after following repeat courses.[4] It is usually well tolerated with the most common adverse effects being mild, IRRs, which manifest as fever, chills, headache, weakness, nausea, pruritus, and rash.[8] Other side effects reported were upper respiratory infections, nasopharyngitis, urinary tract infections, bronchitis, sinusitis, diarrhea, and gastroenteritis.[4] Rituximab can also cause hypogammaglobulinemia.[4]

Infusion reactions

Infusion reactions occur in around 25% of RA patients following the first dose of rituximab, despite premedication with glucocorticoids.[12],[27] The incidence of these reactions decreases with succeeding doses and is generally mild to moderate in severity. These reactions might need additional interventions such as paracetamol, antihistamines, bronchodilators, and further doses of glucocorticoids. Severe infusion reactions resulting in drug withdrawal are rare (<1%). Various Indian studies have also highlighted the safety profile of rituximab therapy in RA with minimum infusion reactions [Table 3].[7],[10],[19],[20],[21]
Table 3: Indian studies of rituximab therapy in rheumatoid arthritis

Click here to view


Infections

Potential reactivation of hepatitis B and C reactivation is a concern as discussed earlier. However, there are only few isolated cases of reactivation of hepatitis B and C have been reported with rituximab therapy in patients with RA.[34] Further, opportunistic infections are rarely seen.[4]

In the IMAGE trial, serious infections were reported more frequently with MTX alone than with either doses in the rituximab group.[11] The DANCER and REFLEX trials concluded that the rate of serious infections (excluding opportunistic infections and TB) was statistically higher for the group of patients receiving two doses of 1000 mg rituximab than in the placebo groups.[12],[16] In contrast, a meta-analysis of three rituximab RCTs did not confirm an increase in the rate of serious infections with rituximab compared with the placebo.[34]

There is no evidence to suggest reactivation of TB with rituximab therapy in RA patients.[34] The rate of herpes zoster infections (0.98 events per 100 patient-years) with rituximab was similar to that reported for other RA populations.[23] Likewise, the rates of vascular events and malignancies were not higher than the general RA population.[34] The overall incidence rate of malignancies was stable over multiple rituximab courses, and no identifiable pattern of malignancies was observed.[23] Cases of PML have been reported in patients with RA following use of rituximab.[3]

A comprehensive review of 9.5-year follow-up data of a global clinical trial program assessing the long-term safety of rituximab in RA showed that rituximab was generally well tolerated over time and over multiple courses.[61] Its safety profile is consistent with published data and clinical trial experience involving patients with moderate-to-severe RA.[61] The conclusions specified that there was no evidence of an increased safety risk or increased reporting rates of any type of adverse event with prolonged exposure to rituximab during 9.5 years of observation.[61]

H. Unmet Needs and Future Research Agenda

Evidence for therapy with biological agents such as rituximab in RA in India is insufficient, and hence, there is a need for more robust studies. Efficacy and safety particularly in the long term of rituximab biosimilars and their interchangeability with the originator/other biosimilars are to be evaluated. Efficacy in seronegative RA patients and RA with extra-articular manifestations requires more studies. The retreatment dosages and dosing interval during long-term treatment with rituximab have not been established, and therefore, this needs to be included in a future research agenda. Biomarkers which can be used in routine clinical practice to establish response are to be sought for. The appropriate timing for vaccines before and during rituximab administration needs further study.


  Conclusion Top


This consensus document developed by a panel of experienced rheumatologists paves the way for optimal usage of rituximab for appropriate treatment of RA in India. Based on several global and Indian clinical studies, rituximab appears to be an effective and reasonably well-tolerated biological DMARD in the management of RA. In patients with RA who show an inadequate response or intolerance to MTX or TNF-i, rituximab is an effective alternative biologic. Availability of more evidence would clarify uncertainties regarding optimal dosing and retreatment schedule of rituximab as well as its use in seronegative patients. In conclusion, this expert panel sincerely believes that the present 28 consensus statements related to the following seven areas of rituximab therapy in RA, namely, indication, contraindication, pretreatment screening, treatment schedule, evaluation of response, safety, and research agenda for future would be helpful for not only to the rheumatologists in India but also other countries.

Acknowledgments

  1. We would like to thank following rheumatologists for taking part in the consultative process, Dr. Amit Dua, Dr. Abraham Mohan, Dr. Aniruddha Tembe, Dr. Anish Aggarwal, Dr. Benzeeta Pinto, Dr. C. P. Rajendran, Dr. Dantis Emmanuel, Dr. Deonis Xess, Dr. Manish Dugar, Dr. Parasar Ghosh, Dr Raj Kiran Dudam, Dr. Rohini Samant, Dr. S. Nagaraj, Dr. Satbir Kaur, Dr. Shashank Akerkar, Dr. Sonal Mehra, Dr. Sourabh Malviya and Dr. Vineeta Shobha.
  2. The expert panel wishes to acknowledge an unrestricted educational grant from Dr. Reddy's Laboratories Limited for the development of these consensus statements.
  3. We would like to convey our sincere thanks to Dr. Sujeet Narayan Chargulla and Mr. Subhrajit Paul of Dr. Reddy's Laboratories Limited for providing logistical support in organizing the meetings for this work.
  4. We would like to acknowledge Scientimed Solutions Pvt. Ltd. for their assistance in developing this manuscript.


Financial support and sponsorship

Unrestricted education grant from the Dr. Reddy's Laboratories Limited, India, supported the work.

Conflicts of interest

There are no conflicts of interest.



 
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