INTRODUCTION — Rituximab is a monoclonal antibody (mAb) that targets the CD20 antigen; it depletes B cells and is used as a therapeutic biologic agent in rheumatoid arthritis (RA), as well as other autoimmune disorders and lymphoproliferative disorders.
Among interventions for RA, rituximab is considered a biologic disease-modifying antirheumatic drug (DMARD) because it can decrease the signs and symptoms of disease and reduce the progression of joint injury. The activation of the immune system induced by rituximab to deplete B cells, together with its immunogenicity and immunosuppressive properties, are largely responsible for its adverse effects, including infusion reactions, reduced immunoglobulin levels, and increased risk of certain infections.
The mechanism of action, administration, dosing, and adverse effects of rituximab are presented here. The relative role and efficacy of rituximab for the treatment of RA are described in detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)
MECHANISM OF ACTION — Rituximab is an immunoglobulin G1 (IgG1) monoclonal antibody (mAb), which targets CD20, a protein expressed on the surface of most B cells, and is thought to act primarily by depleting CD20-positive B cells. It is a chimeric antibody, composed of both mouse and human portions. B cell depletion also appears to have long-acting effects on immune cell function. (See 'B cell depletion' below and 'Reduction in signs and symptoms of RA' below.)
●Fc receptor gamma-mediated antibody-dependent cytotoxicity and phagocytosis
●Complement-mediated cell lysis
●B cell apoptosis
It is uncertain which of these mechanisms is most important in the depletion of B cells in patients with rheumatoid arthritis (RA), although data suggest that Fc receptor gamma-mediated antibody-dependent cytotoxicity and antibody-dependent phagocytosis are the principal mechanisms. It is possible that the relative importance of some of the mechanisms of depletion induced by rituximab differs depending upon the tissue location of the B cells and their maturation and activation status.
Lymphocytes of the B cell lineage undergo an orderly developmental process that includes the B cell-specific surface expression of CD20, beginning at the pre-B cell stage in the bone marrow. Expression of CD20 on the cell surface is then lost as B cells differentiate into plasma cells. (See "Normal B and T lymphocyte development".)
Absent CD20 protein expression on the surface of plasma cells accounts for resistance of these long-lived antibody-producing cells to rituximab. As a consequence of plasma cell resistance, overall immunoglobulin levels usually remain within the normal range, despite profound B cell lymphopenia that persists for months following a single course of treatment. However, hypogammaglobulinemia can occur in a minority of patients. (See 'Hypogammaglobulinemia and infection' below.)
The absence of CD20 expression in stem cells and earlier B cell precursors in the bone marrow allows repopulation of the peripheral blood and other tissues. Once rituximab is cleared from the body, the early B cell emigrants from the bone marrow migrate to the secondary lymphoid tissue and reconstitute the B cell repertoire.
Reduction in signs and symptoms of RA — The exact mechanism(s) by which rituximab results in reduced disease activity in RA is not known. B cell targeted therapy for RA was developed with the objective of removing B cell clones responsible for the production of pathogenic autoantibodies. A specific objective was to induce sustained remission from short-term B cell depletion, based upon the hypothesis that autoantibodies could not only produce tissue pathology but might be expected to drive their own production through a vicious cycle . Although sustained remission has yet to be achieved, B cell depletion therapy has been found to have a major beneficial impact on RA in the short term.
Antigen presentation by B cells and cytokine-mediated interactions with stromal and accessory cells could also potentially activate autoreactive T cells, although there is some doubt as to whether this possibility is consistent with the behavior of synovial T cells in RA [3,4]. B cells are very efficient at presenting soluble antigen that has been bound by their antigen receptor (surface immunoglobulin) during the acquisition of T cell help.
Clarification of the roles of B cells in RA is crucial to future developments in B cell-targeted therapy and optimization of this strategy. If the main role of B cells is to activate autoreactive pathogenic T cell clones through antigen presentation, patients may require continuous B cell depletion for their disease to remain under control. On the other hand, if autoantibodies play a key role in propagation of the disease, then achieving sustained remissions from short periods of depletion seems a much more realistic prospect. Exploration of more potent depleting regimens and specific approaches for blocking signals involved in B cell proliferation and differentiation may potentially increase efficacy and, in particular, duration of clinical response.
There are data that levels of autoantibodies, with the potential for roles in disease pathophysiology, are proportionally more affected by B cell depletion than total immunoglobulin levels, suggesting that these autoantibodies are produced at least in part by short-lived plasma cells. Examples of this include both rheumatoid factor (RF) in RA [5,6], antineutrophil cytoplasmic antibodies (ANCA) in ANCA-associated vasculitis [7-9], and other autoantibodies in other disorders [7-10].
One study has also suggested that treatment with rituximab may also result indirectly in substantial but reversible depletion of CD4+ T cells during the months following rituximab administration . The relevance of these findings is supported by the observation that a lack of CD4+ T cell depletion was associated with an inadequate clinical responsive to rituximab therapy but requires further confirmation.
CONTRAINDICATIONS — Several conditions pose absolute or relative contraindications to rituximab:
●Hypersensitivity to the active substance or to murine proteins or any of the excipients – In the absence of another effective treatment option, we obtain consultation with an allergist for consideration of retreatment with a desensitization protocol.
●Active, severe infection.
●Patients in a severely immunocompromised state.
●Severe heart failure or severe, uncontrolled cardiac disease – In patients who lack other effective treatment options, we hospitalize the patient for treatment and give the infusion slowly with very close monitoring for both the first and second dose of the cycle because of the increased risk of adverse outcomes if an infusion reaction occurs in such an already compromised patient. (See 'Premedication' below and 'Infusion reactions' below and 'Management' below.)
Other conditions that may require discontinuation of ongoing therapy are described separately. (See 'Complications requiring treatment discontinuation' below and 'Adverse effects' below.)
IMMUNIZATIONS AND BASELINE STUDIES
Immunization and response to vaccines — Patients should receive appropriate immunizations, depending upon their prior immunization history, preferably several weeks prior to administration of rituximab. In patients in whom vaccination is indicated (eg, for seasonal influenza, pneumococcal, and hepatitis B vaccines), we prefer to immunize patients at least four weeks before the administration of rituximab  because responses to inactivated viral or bacterial vaccines may be impaired following rituximab therapy. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Vaccine efficacy and immunogenicity'.)
In patients who have already received rituximab, vaccine responses may be blunted until B cell recovery occurs (ie, 6 to 12 months). Timing of immunization should be individualized in such patients. Thus, vaccines could be given and responses then assessed, or vaccination could be postponed until B cells have recovered, depending upon risk and the time until the expected initiation of B cell repopulation. In the case of seasonal influenza vaccine, we instruct patients to have the vaccine as soon as it is available as it is difficult to predict what will be the best timing, particularly in patients on repeated courses of treatment. The safety and efficacy of immunization in patients who will or have received rituximab, the effect of rituximab upon vaccine responses, and an overview of immunization in patients with rheumatic disease are discussed in detail separately. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab' and "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
Pretreatment testing — We obtain the following testing at baseline, prior to starting rituximab:
●Serologic testing for hepatitis B (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [anti-HBs], and hepatitis B core antibody [anti-HBc]), hepatitis C, and human immunodeficiency virus (HIV). (See 'Opportunistic infections and viral reactivation' below.)
●Baseline levels of serum immunoglobulins (including IgM, IgG, and IgA). (See 'Hypogammaglobulinemia and infection' below.)
●Serum protein electrophoresis.
●Chest radiograph (if not obtained within the prior six months).
ADMINISTRATION AND DOSING
•Chlorpheniramine (10 mg administered intravenously)
•Acetaminophen (1000 mg taken orally)
•Methylprednisolone (100 mg administered intravenously)
Modifications in the premedication regimen may be needed based upon individual patient characteristics.
●Holding antihypertensives – Because of the frequency of mild to moderate hypotension occurring in the setting of rituximab infusions, patients should be instructed not to take their antihypertensive medications the morning of the rituximab infusion unless necessary. In addition, the infusion can be administered with the patient reclining or supine.
Initial dose — We administer rituximab as a dose of 1000 mg, given twice, two weeks apart, by intravenous infusion. However, some trials and cohort studies have suggested that a lower dose, either 500 mg given twice two weeks apart or 1000 mg given once, may also be effective; and expert opinion differs regarding the most appropriate dose for initial therapy. Responsiveness to rituximab correlates with the degree of B cell depletion at either of these doses [13,14]. The approach to dosing in rheumatoid arthritis (RA) thus usually differs from the approach to treatment for lymphoproliferative disorders, for which the drug is often administered once weekly for four weeks or as part of each treatment cycle in combination with chemotherapy.
In patients with RA, rituximab infusions are typically given to those who are already receiving weekly methotrexate, but can be given as monotherapy or together with leflunomide or other conventional standard disease-modifying antirheumatic drugs (DMARDs) in patients in whom methotrexate is contraindicated. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Rituximab'.)
Infusion rate — To prevent infusion reactions, we start slowly and gradually increase the rate of administration during the infusion period. The first infusion is begun at a rate of 50 mg/hour. If no evidence of hypersensitivity or other reaction is evident, the rate may be increased by 50 mg/hour every 30 minutes to a maximum of 400 mg/hour. If the initial infusion is well tolerated, we start the subsequent infusion(s) of the same cycle at a rate of 100 mg/hour, and the rate can be increased by 100 mg/hour every 30 minutes to a maximum of 400 mg/hour if there is no evidence of hypersensitivity. Some centers use a more rapid infusion protocol described by the manufacturer if the first has been well tolerated without an infusion reaction. (See 'Infusion reactions' below and 'Prevention' below and 'Management' below.)
Management of infusion reactions — Most mild infusion reactions occurring during a treatment can be managed by temporarily stopping the rituximab infusion, waiting for symptoms to completely subside, and restarting the infusion at one-half of the initial rate. An additional dose of acetaminophen (625 mg orally) and diphenhydramine (50 mg orally) is typically given at the time of the reaction. If symptoms do not recur, the infusion may be increased by 50 mg/hour to the maximal rate of 400 mg/hour.
Additional treatment, including saline infusion, inhaled bronchodilators, intramuscular epinephrine, and parenteral glucocorticoids may be required in the event of a more serious reaction with bronchospasm, hypotension, or other signs and symptoms suggestive of anaphylaxis. The emergency management of anaphylaxis in adults is detailed in the table (table 1). Although severe anaphylactic reactions and severe bronchospasm are rare, appropriate medications to treat anaphylaxis should be available at the patient's bedside during the entire rituximab infusion to respond to infusion reactions. Recognition and management of infusion reactions to rituximab and of anaphylaxis are discussed in more detail elsewhere. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab' and "Anaphylaxis: Emergency treatment".)
In our experience, close monitoring of the patient during the infusion, as recommended by the manufacturer, and adjustment of the dose, if symptoms or signs suggesting an infusion reaction occur, allow completion of the treatment in the great majority of patients. In patients with a previous history of infusion reactions, we give the infusion slowly with close monitoring of symptoms.
Treatment with rituximab should be discontinued in patients in whom there is concern of a recurrent severe infusion reaction, and in patients in whom the infusion reaction has features suggesting it is due to hypersensitivity (including type III, serum sickness type of reactions) and is not exclusively a cytokine release syndrome that can be managed by slowing down the infusion.
Alternative dosing approaches
Low-dose regimens — The data comparing relatively lower and standard (often termed "high") dose regimens are illustrated by the following:
●Evidence comparing the benefits of low- and high-dose rituximab in combination with methotrexate was analyzed in a 2014 systematic review and meta-analysis of reports up to June 2012 . Six randomized trials and two cohort studies met inclusion criteria, and four of the randomized trials, including a total of 1308 patients, were included in the meta-analysis of efficacy outcomes. The majority of the patients included in these trials had not previously been treated with tumor necrosis factor (TNF) inhibitors. The meta-analysis found no statistically significant difference between low-dose (500 mg given twice) and high-dose (1000 mg given twice) treatments at 24 and 48 weeks in most of the composite measures of disease activity (eg, American College of Rheumatology criteria for 20 percent improvement in disease activity [ACR20], ACR50, ACR70, and Disease Activity Score in 28 joints [DAS28]), or in patient-reported outcomes (eg, improvement in Health Assessment Questionnaire scores).
Trends that did not achieve statistical significance but favored high-dose rituximab were found for the ACR70 at 24 weeks, the ACR50 and DAS28 at 48 weeks, and early withdrawal due to lack of efficacy. Nevertheless, noninferiority criteria for low-dose rituximab were met for the ACR20, ACR50, and DAS28 at 24 and at 48 weeks. The incidence of remission at 48 weeks favored the high-dose regimen. Serious adverse events did not differ significantly between the two doses.
●As an example of the trials included in the meta-analysis above, the Dose-ranging Assessment International Clinical Evaluation of Rituximab in RA (DANCER) trial compared a regimen of rituximab 1000 mg given twice with a lower dose (500 mg given twice) in 465 patients with RA refractory to methotrexate alone . There was no difference between the two groups in the proportion of patients who achieved an ACR20 response (54 and 55 percent). However, the 1000 mg regimen was associated with significant increases in the proportion of patients achieving an ACR70 response (20 versus 13 percent) or a European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) "good" response (28 versus 14 percent). The use of oral glucocorticoids during the first two weeks of therapy (as used in the two other trials) did not influence efficacy results at 24 weeks.
●A subsequent observational cohort study of patients in national registries, which analyzed data from 2625 patients treated with rituximab using two doses of 1000 mg and 248 patients treated with two doses of 500 mg, described comparable improvements in DAS28 scores and EULAR response rates in the two groups at six months following the first course of rituximab treatment .
Lower doses of rituximab may also be effective for the retreatment of patients who have responded to usual initial therapy (see 'Retreatment of responders' below), while limited data suggest that initial therapy with a higher-dose regimen may be beneficial in patients with incomplete B cell depletion following the first infusion. (See 'Treatment implications of B cell depletion and repopulation' below.)
Treatment implications of B cell depletion and repopulation — We do not routinely recommend measuring the extent of B cell depletion and repletion in clinical practice; however, studies of B cell kinetics and retreatment strategies have been a valuable research tool and can offer insight in individuals not responding adequately to therapy. Within two to four weeks after rituximab infusion, B cell numbers in peripheral blood, when measured by standard techniques, fall to unmeasurable levels in most patients and remain low for 6 to 12 months (or longer in some patients) [6,18]. However, when more sensitive techniques are used to identify remaining B cells, incomplete B cell depletion with rituximab appears to be more common than initially appreciated and associated with reduced efficacy.
We do not wait until patients repopulate again to retreat because of the increased risk of flare by that approach. B cell repopulation usually starts within six to nine months after treatment. In the author's experience, approximately two-thirds of patients flare as soon as the B cells start repopulating. One-third flare only a variable time later. There is a lack of agreement regarding whether CD19 counts to assess kinetics are needed clinically and to what extent they should guide practice in RA. (See 'Retreatment of responders' below.)
The frequency and consequences of incomplete B cell depletion were illustrated by a study of 60 RA patients treated with rituximab (two infusions of 1 g each given two weeks apart) in which the degree of B cell depletion was assessed by use of a high-sensitivity minimal residual disease (MRD) flow cytometry technique used to evaluate patients with leukemia . Complete B cell depletion was defined as levels below 0.1 cells/microL using the MRD protocol and 5 cells/microL by conventional cytometry. More patients with residual B cells were identified after the first and second infusion by the MRD technique than conventional techniques (63 versus 6 percent and 18 versus 6 percent, respectively). After the first infusion, moderate to good clinical responses (by EULAR criteria) were identified more often in patients with complete compared with partial B cell depletion with the MRD technique (87 versus 59 percent at 3 months and 59 versus 21 percent at 12 months). Patients who only attained complete B cell depletion after the second infusion had outcomes similar to those in patients who never achieved complete B cell depletion.
Relapse of active RA may coincide with recovery of B cells in peripheral blood or occur at a variable time after such recovery. It is usually associated with rising autoantibody levels. This was illustrated in a report of 22 patients treated with a variety of rituximab-based regimens. Clinical relapses were preceded by resolution of B cell lymphopenia and rising serum levels of rheumatoid factor (RF; IgM and IgA subtypes) and anti-cyclic citrullinated peptide (anti-CCP) antibodies .
A proof-of-concept trial involving 25 patients with RA suggested that higher initial doses of rituximab (administration of a 1000 mg dose after four weeks, in addition to the usual doses of 1000 mg at baseline and two weeks later) may be beneficial in patients whose peripheral blood B cell depletion was incomplete following the first infusion, based upon findings on high-sensitivity flow cytometry .
B cell depletion in bone marrow, synovial tissue, and lymph node biopsies has been evaluated in RA patients treated with rituximab. In general, B cell depletion was often incomplete and variable. The ability of rituximab to deplete synovial B cells appears in small series to be more variable than the effect on peripheral blood B cells [21,22]. The clinical significance of this effect is uncertain.
In patients with RA treated with rituximab, depletion in lymph node biopsies was shown to be incomplete, and the majority of persistent B cells were IgD- memory B cells (IgD-CD27+ or IgD-CD27-) . Histology showed persistence of follicular structures and plasma cells in the lymph nodes. Similar to initial lymph node biopsies in patients treated for lymphoma, there was variability in the extent of depletion achieved between different patients. This variability and also the different susceptibility of the B cell subsets to depletion with rituximab could not be explained by differences on level of cellular surface expression of CD20, complement inhibitors (CD55 and CD59), or receptors for B cell activating factor (BAFF)/April (survival factors). The frequency of early-activated T cells decreased, but the frequency of late-activated T cells did not, and total levels of interleukin (IL)-21 messenger ribonucleic acid (mRNA; as a reflection of follicular T cell activity) remained high. No correlations were found with clinical response, but the study included just 14 patients, and only 3 patients did not respond to treatment with rituximab.
RETREATMENT — The timing of retreatment with rituximab depends upon the patient's response to therapy:
●We typically retreat patients six months after the first course of rituximab if disease is still active (as evidenced by persistence of inflammatory symptoms, swollen joints, and/or raised serum C-reactive protein [CRP]) . Patients may need more than one course of treatment to achieve their maximum response.
●The package insert for rituximab that is based upon the US Food and Drug Administration (FDA) approval states that retreatment may be "based on clinical evaluation but not sooner than every 16 weeks." Therefore, shorter retreatment intervals (eg, every four or five months) may be appropriate when indicated clinically. In Europe, regulatory restrictions only allow retreatment at six months or after, so funding to use it earlier is limited.
●In patients who respond very well to the first course of rituximab and go into remission or acceptable low disease activity, we wait to see how long the response lasts and retreat at first signs of flare.
●We usually offer retreatment as a preventive measure to prevent relapse/flare based upon the duration of the individual patient response to the previous rituximab cycles. Such retreatment is usually scheduled approximately one month prior to when the disease would be expected to flare or relapse based upon the duration of the patient's previous response to rituximab . Some patients who have responded well to therapy for at least two years will tolerate an increase in the dosing interval.
Retreatment of responders — Data that illustrate the evidence supporting the efficacy and safety of retreating patients who initially respond to rituximab therapy with usual or lower doses are shown below:
●The efficacy and safety of repeated infusions of rituximab have been assessed in the extension phase of three double-blind-trials cited above (including Randomized Evaluation of Long-Term Efficacy of Rituximab in RA [REFLEX] and Dose-ranging Assessment International Clinical Evaluation of Rituximab in RA [DANCER]) that involved a total of 1039 patients; of these, 570, 191, and 40 patients received two, three, or four courses of therapy, respectively . Patients eligible for repeat treatment with rituximab had a swollen/tender joint count (SJC/TJC) of eight or more and had relapsed at ≥16 weeks (or 24 weeks in REFLEX) after the previous course. The criteria for repeat treatment were at least 20 percent reductions in both the SJC and TJC at any visit more than 16 weeks after initial therapy. Among such patients, the administration of repeat rituximab (rather than some other approach) was at the discretion of the clinician.
American College of Rheumatology criteria for 20 percent improvement in disease activity (ACR20), 50, and 70 responses, as well as Disease Activity Score in 28 joints (DAS28) scores, were similar after the first and subsequent courses, as were adverse events other than infusion reactions, which were most often seen during the first three months. The authors concluded that patients treated with repeated courses of rituximab have sustained clinical responses with no new adverse events.
●In a pooled retrospective analysis of data from randomized trials and their extension phases, comparison of retreatment to target (repeated rituximab courses from 24 weeks after previous course if DAS28 of ≥2.6) with retreatment per demand (at clinician's discretion, but both TJC and SJC ≥8) showed better responses in patients retreated to target [26,27]. No significant differences in the incidence of serious adverse events were noted between the two different groups.
●Pooled safety data from a six-year follow-up of the rituximab trials included a total of 2578 patients who received multiple treatment courses; of these, 1890, 1043, 425, and 133 patients received at least two, three, four, or five courses without an increase in total adverse events, serious adverse events, or overall infection rates . Similar findings were seen in subsequent analyses of the pooled trial data [29,30]; the final long-term safety report involved 3595 patients who had received up to 20 courses of therapy over 11 years, with 1246 of the patients followed for over five years . Clinically significant hypogammaglobulinemia occurred in a very small number of patients in this large cohort of trials patients. (See 'Hypogammaglobulinemia and infection' below.)
●Retreatment may also be effective using a lower dose of rituximab than the dose used for the initial set of infusions. Retreatment with low-dose rituximab (one infusion of 1000 mg) was noninferior to high-dose rituximab (two infusions of 1000 mg, two weeks apart) in an open-label trial, the SMART study, in which 143 patients who had previously responded to a first course of high-dose rituximab were randomly assigned to retreatment after 24 weeks with either a high- or a low-dose of the drug . Prior to the initial treatment with rituximab, all patients had been refractory to or intolerant of at least one tumor necrosis factor (TNF) antagonist. The overall safety profile of the two dosing regimens was also similar.
The majority of patients started on rituximab remained on this treatment after four years of therapy, as illustrated by an analysis of 1629 patients with RA started on this agent in the British Society for Rheumatology Biologics Registry, in which 60 percent of the cohort had remained on rituximab after four years . The median follow-up was 4.5 years (interquartile range 3.6 to 5.4). The most common reason for discontinuation was ineffectiveness, which was reported in 46 percent of the patients who discontinued treatment with the drug. Rheumatoid factor (RF) negativity was associated with discontinuation of treatment.
Retreatment of initial nonresponders — Patients with some improvement in disease activity but who do not achieve adequate benefit (assessed, for example, by European Alliance of Associations for Rheumatology [EULAR] response criteria) may benefit from a second cycle of therapy after six months. Some patients need at least two courses of rituximab to achieve an adequate response to treatment. We distinguish between patients who do not show any response to rituximab (as assessed by inflammatory symptoms, joint counts, and serum CRP levels) and patients who show some response but do not fulfill DAS28 response criteria . A second cycle of rituximab treatment can be considered in the latter group of patients at six months, particularly if they are seropositive and other treatment options are not available or not preferred (see "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Rituximab'). Whether this group of patients would benefit from a second course of treatment earlier than six months is not known. The range of evidence includes the following:
●A small observational study of 30 patients found that a lack of a response to an initial course of treatment predicted that retreatment would also be ineffective. Patients with recurrent or persistent active disease, as defined by the EULAR response criteria, were treated with up to three courses of rituximab at intervals of at least six months, regardless of whether they responded to the first course of therapy . Of the 24 patients who qualified for retreatment, seven did not respond to the initial course of treatment, and these patients remained generally nonresponsive to subsequent treatment courses. By contrast, the 17 initial responders experienced responses to further treatment similar to those that followed the first course.
However, in subsequent studies, retreatment of patients who did not respond by EULAR criteria to a first cycle of rituximab was associated with a response by the same criteria in several of the patients to a second course of treatment administered usually after week 24.
●In a small study, retreatment of 25 of 38 nonresponders to a first cycle of rituximab therapy led to a response by EULAR criteria in 72 percent (18 of 25) six months after a second cycle of rituximab . Second cycles of rituximab were administered at least six months after the first cycle, at a time when B cell counts were lower than baseline. All patients were positive for RF, anti-cyclic citrullinated peptide (anti-CCP) antibodies, or both. When first-cycle nonresponders were compared with first-cycle responders, nonresponders had higher circulating levels of plasmablasts at baseline and were less likely to have reached complete depletion, as assessed by high-sensitivity flow cytometry (CD19 count less than 0.0001 x 109/L, ie, below 0.1 cells/microL), following the first rituximab infusion (12 versus 88 percent). Retreatment of nonresponders was associated with a higher number of patients achieving complete depletion (38 versus 12 percent).
●In the pooled retrospective analysis of data from randomized trials and their extension phases referred to above, up to 60 percent of patients who had not responded by EULAR criteria six months after a first course of rituximab achieved a response six months after receiving a second course .
MONITORING — Patients treated with rituximab should be monitored both by the same approach as in other patients with rheumatoid arthritis (RA) and with additional attention to the specific risks associated with this agent. Patients with RA should be seen on a regular basis for such clinical and laboratory assessment of their disease and for screening for drug toxicities, as described in detail separately. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Assessment and monitoring'.)
In addition to routine clinical and laboratory assessments (eg, complete blood counts [CBCs], inflammatory markers [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)], liver chemistries, and measurement of renal function), patients receiving rituximab should receive the following evaluation and testing:
●Particular attention to symptoms or signs of opportunistic and other infections and of reactivation of viral disease or other adverse effects. (See 'Opportunistic infections and viral reactivation' below and 'Others' below.)
●CBC and differential white count, with particular attention to the absolute neutrophil count, four to six weeks after treatment and at any time up to one year following rituximab infusions in the presence of a severe infection or unusual severe mouth ulcers or mucositis. (See 'Late-onset neutropenia' below.)
●Serum immunoglobulin levels (total, IgG, IgM, and IgA) should be obtained at least before each retreatment and if a patient develops a serious infection or repeated infections. (See 'Serum immunoglobulins and rheumatoid factor' below and 'Hypogammaglobulinemia and infection' below.)
DURATION OF THERAPY — In patients who tolerate rituximab and continue to respond to therapy, we continue treatment. The author's experience includes use of up to 19 cycles of treatment as of early 2019. In patients whose disease has been well controlled for two years or more with ongoing regular (preventive) retreatment, we sometimes increase the interval between the cycles of rituximab but have had mixed results, so do this with particular caution and limit it to patients under very good control on a stable medical regimen. Some patients no longer need the rituximab infusions at the time previously scheduled, while others continue to flare with the same interval if not retreated. In the author's experience, all patients go on to flare eventually after drug discontinuation, although the length of time before flare can be very prolonged in the occasional patient.
Complications requiring treatment discontinuation — Complications that may require drug discontinuation are discussed in more detail elsewhere in this topic review. These include:
●Serum IgG less than 5 g/L. (See 'Hypogammaglobulinemia and infection' below.)
●Development of progressive multifocal leukoencephalopathy (PML). (See 'Opportunistic infections and viral reactivation' below.)
Infusion reactions — One of the most predictable side effects of rituximab is a constellation of symptoms/signs that occurs within the initial 30 to 120 minutes of the first exposure. Infusion reactions are more likely during the first infusion, occurring in up to 20 to 30 percent of patients with rheumatoid arthritis (RA) treated with rituximab . The most common symptoms are headache, fever, chills, sweats, skin rash, dyspnea, mild hypotension, nausea, rhinitis, pruritus, asthenia, back pain, and a mild sensation of tongue and throat swelling (angioedema). Bronchospasm and/or severe hypotension are present in less than 10 percent of cases, and less than 5 percent of reactions are severe (grade 3 or 4) or suggestive of anaphylaxis.
Certain signs and symptoms are highly suggestive of anaphylaxis, such as urticaria, repetitive cough, wheeze, and throat tightness/change in voice; and their presence should be specifically sought when evaluating a patient with an infusion reaction. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Anaphylaxis'.)
The incidence of serious infusion reactions in patients with RA treated with rituximab has been analyzed in patients who are part of the French Registry, Autoimmunity in Rheumatoid Arthritis (started in 2005; data collection March 2015) . Serious infusion reactions were classified as an occurrence during or within 24 hours of a rituximab infusion and requiring discontinuation of treatment. The incidence of serious infusion reactions to rituximab was 2.8 percent or 0.7 out of 100 patient-years; 56 out of 1986 patients. Median follow-up was 5.9 years (interquartile range 3.7 to 7.1). A severe anaphylactic reaction occurred in 2 out of 56 patients during the fourth cycle. No fatal infusion reactions occurred and all resolved with discontinuation of the infusion and appropriate treatment with antihistamines and/or glucocorticoids.
The majority of these standard infusion reactions (SIRs) are thought to be related to an antibody-antigen interaction between rituximab (the antibody) and CD20 (the antigen) on lymphocytes, resulting in cytokine release from B cells. In most patients, the reaction complex is mild, is brief, lacks more specific symptoms to suggest anaphylaxis, and resolves completely when drug infusion is withheld.
Prevention — Attempts to identify patients who are likely to develop infusion reactions have not been successful; thus, we premedicate patients before their rituximab infusions routinely as a preventive measure and very gradually increase the infusion rate while monitoring for evidence of hypersensitivity when administering the drug. (See 'Premedication' above and 'Drug administration' above.)
In one review of patients who had a serious infusion reaction to rituximab in a large French Registry, less than one-third of patients (16 out of 56 patients, 28 percent) had had at least one previous milder infusion reaction to rituximab (19 previous reactions in 16 patients; 3 during the same cycle, 12 during the previous cycle, and 4 at least 2 cycles before) .
Premedication with antihistamines and acetaminophen, with or without a glucocorticoid, can help prevent and/or reduce the severity of infusion reactions, particularly SIRs (see 'Premedication' above). By contrast, anaphylaxis is generally not prevented by premedication, although the severity of the reaction may be reduced in some cases. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Prophylaxis of infusion reactions'.)
These premedication regimens have been empirically derived rather than established through randomized trials. Furthermore, they are not completely protective, even for SIRs. Therefore, despite the use of premedication, patients must be monitored closely during and immediately following all infusions. In our experience, close monitoring of the patient during the infusion, as recommended by the manufacturer, and adjustment of the dose, if symptoms or signs suggesting an infusion reaction occur, allow completion of the treatment in the great majority of patients.
Premedication protocols have largely been derived from the experience in patients treated with rituximab for malignancy. A standard premedication regimen in patients with RA is acetaminophen (1000 mg orally), chlorpheniramine (10 mg intravenously) or diphenhydramine (50 mg orally), and methylprednisolone (100 mg) given at least 30 minutes before the first and second infusion of rituximab in each treatment cycle. Modifications in the premedication regimen may be needed based upon individual patient characteristics. Additionally, at some institutions, routine premedication also includes an H2-receptor blocker (eg, famotidine), but we have not found this necessary in our experience. In patients with a previous history of infusion reactions, we give the infusion slowly with close monitoring of symptoms.
The efficacy of pretreatment with H1- and H2-antihistamines has not been assessed in patients receiving rituximab for RA. The benefit of glucocorticoids was addressed in the placebo-controlled Dose-ranging Assessment International Clinical Evaluation of Rituximab in RA (DANCER) trial . A single dose of methylprednisolone (100 mg) given 30 minutes before beginning the rituximab infusion reduced the frequency and intensity of first infusion-associated events; oral glucocorticoids (ie, 60 mg daily on days 2 to 7 and 30 mg daily on days 8 to 14) conferred no additional benefit.
Management — The management of infusion reactions is described above. (See 'Management of infusion reactions' above.)
Effects on B cells, antibodies, and risk of infection
Serum immunoglobulins and rheumatoid factor — Measuring rheumatoid factor (RF) at baseline to document seropositivity is useful, but there is no suggestion that serial measurements of RF serum levels are useful to guide retreatment decisions. Mean immunoglobulin levels decrease in patients who have received a single course of rituximab, but only a small proportion of such patients have levels that are below the lower limit of normal [5,6,18]; RF levels are reduced by a greater proportion than are serum immunoglobulin levels by rituximab treatment. As an example, in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) trial, the mean RF level fell by 40 to 50 percent and remained depressed for up to 24 weeks in patients receiving both rituximab and methotrexate compared with those receiving placebo and methotrexate . Subnormal IgM levels were noted in 5.5 percent of patients treated with rituximab plus methotrexate versus 1.9 percent of patients treated with methotrexate and placebo, while none of the controls and less than 1 percent of patients treated with rituximab had depressed IgA or IgG levels. Repeated courses of rituximab may lead to further, usually modest, reduction in serum IgG and IgA levels, but IgM may be reduced to a greater degree . These effects are discussed in more detail below. (See 'Hypogammaglobulinemia and infection' below.)
Hypogammaglobulinemia and infection — Immunoglobulin levels should be measured before treatment and whenever retreatment is being considered (see 'Pretreatment testing' above). They should also be measured if the patient develops any serious or recurrent infections. We exercise particular caution when considering initial treatment or a repeat course of rituximab in the presence of low IgG, particularly if less than 500 mg/dL (5 g/L), or in the presence of other risk factors for repeated or serious infections, such as older age and glucocorticoid use.
In patients with severe or recurrent infections, rituximab therapy may require discontinuation, depending upon an individualized assessment of risk that should include a review of immunoglobulin levels, including IgG, IgM, and IgA; the specific infection and clinical risk and comorbidities; other risk factors for infection (eg, glucocorticoids, advanced age) and their potential for correction or reduction; available treatment options if rituximab is discontinued; and the degree to which rituximab is likely to have contributed to the occurrence of the infection(s). The utility of determining IgG subclass levels in guiding retreatment decisions is not known; thus, we do not measure these levels in routine clinical practice.
We generally will switch from rituximab to a different agent if IgG drops below 5 g/L. However, in a patient with serum IgG below 5 g/L, who has had no infections and in whom no other reasonable treatment options are available, we would consider continuing rituximab while monitoring for infections (including monitoring for the presence of bronchiectasis or its worsening), based upon an individualized risk assessment, as described above for patients with severe or recurrent infection.
We consider replacement immunoglobulin treatment if patients have low IgG (with or without low IgM or IgA) and recurrent infections that are not prevented by prophylactic antibiotics. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab' and "Overview of intravenous immune globulin (IVIG) therapy".)
In patients with hypogammaglobulinemia who discontinue rituximab, we monitor immunoglobulin levels every 6 to 12 months until normalization.
Total immunoglobulin levels following one course of therapy with rituximab usually remain within the normal range, but repeated courses of therapy are associated with an increasing risk of hypogammaglobulinemia [18,25,28,36]. A 2009 meta-analysis of three trials including 1143 patients with RA found no increase in serious infections associated with use of rituximab with or without methotrexate compared with methotrexate plus placebo , but other studies have found that repeated courses of rituximab may be associated with a higher rate of serious infections .
In one report, among 19 patients referred to a clinical immunology department for persistent, symptomatic hypogammaglobulinemia, there were four patients with RA and two patients with systemic lupus erythematosus (SLE). Two of the RA patients had hypogammaglobulinemia before starting treatment with rituximab. Five of these patients needed treatment with IVIG (three RA and two SLE) . The risk of serious infections in patients treated with rituximab increases with age [28,39], but it is not known to what extent this is a drug effect or a reflection of a higher baseline risk of infection in older adults.
These points were best illustrated in a pooled analysis of 2578 patients who received rituximab together with methotrexate in clinical trials for RA, some of whom received rituximab for up to five cycles over six years :
●Levels of IgM, IgG, and IgA below the lower limits of normal occurred at any point during follow-up in 23, 5, and less than 1 percent of patients, respectively.
●The proportion of patients with low IgM six months after each course of treatment increased successively from 10 percent after the first course to 40 percent after the fifth. Low IgM levels were not associated with serious infection.
●The proportion of patients with low IgG six months after each course of treatment remained stable, varying from 3 to 6 percent. Sustained low IgG levels were present for at least one year in 32 patients (1 percent), of whom 5 developed very low IgG levels (less than 300 mg/dL [3 g/L]).
●Serious infections occurred in 6 of 32 patients with sustained low IgG; however, given the low number of these patients, this was not statistically significant. Older age was an independent predictor of both serious infection and sustained low IgG levels.
Prior subgroup analyses of smaller numbers of patients had not revealed an increased risk of infections with low IgM or IgG, although individual patients with hypogammaglobulinemia associated with repeated courses of rituximab therapy and repeated infectious episodes had been observed [18,25,36].
In another study, among 4479 patients receiving rituximab (including 1241 with rheumatic disease), hypogammaglobulinemia worsened with rituximab use in the minority in whom it was measured, and was associated with increased risk of serious infections and mortality . However, severe infection rates were not increased significantly following treatment in the rheumatic disease subgroup, although like the study group as a whole and the other subgroups (cancer, hematologic disease, and common variable immunodeficiency), increased risk of mortality in the rheumatic disease patients was associated with the occurrence of serious infections in the six months prior to and following the first rituximab infusion (hazard ratio [HR] 4.06, 95% CI 2.91-5.68 and HR 7.06, 95% CI 5.07-9.84); male sex and age were also associated with increased mortality risk (HR 1.42, 95% CI 1.05-1.93 and HR 1.03, 95% CI 1.02-1.04).
Opportunistic infections and viral reactivation — No increase in the incidence of opportunistic infections was apparent in clinical trials for RA. However, among patients with RA and other rheumatic diseases, rituximab has been associated in case reports with severe Pneumocystis carinii (P. jirovecii) infection , cryptococcal meningitis , cytomegalovirus colitis , and PML [44-47]. We generally avoid the use of rituximab in patients with a chronic active viral infection (eg, hepatitis B or C, HIV).
A report on the risk of opportunistic infections in patients with RA treated with biologics from the British Society for Rheumatology Biologics Registry included 5072 patients treated with rituximab with a mean follow-up of three years and a total of 17,154 years of follow-up . Twenty-five out of 5072 patients treated with rituximab had an opportunistic infection, with P. jirovecii pneumonia the most common in 9 out of 25 patients, followed by herpes zoster in 7 out of 25 patients. No cases of PML were reported. When different biologic treatments were compared, the risk of P. jirovecii pneumonia was higher with rituximab compared with tumor necrosis factor (TNF) inhibitors, while the risk of tuberculosis was lower (only two documented cases) .
At least six patients have been reported with PML in association with rituximab treatment for RA, for an estimated incidence of less than 1 in 20,000 to less than 1 in 25,000 [47,49]. Most patients had received other immunosuppressive drugs, sometimes concurrently; two had a history of malignancy and prior chemotherapy, radiotherapy or both; and several were lymphopenic . However, one had early RA, naïve to methotrexate or other disease-modifying antirheumatic drugs (DMARDs) . We would consider the diagnosis of PML in any patient treated with rituximab who develops new neurologic manifestations, although these events are very rare and PML is more strongly associated with deficient cellular immunity. The evaluation and management of such patients is described in detail elsewhere. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'.)
Rituximab therapy carries a risk of hepatitis B reactivation among patients positive for hepatitis B surface antigen (HBsAg) or for hepatitis B core antibody (anti-HBc) [50,51]. All patients should be screened for HBsAg and anti-HBc prior to starting treatment (see 'Pretreatment testing' above). Patients with evidence of prior hepatitis B infection should be monitored for clinical and laboratory signs of reactivation during therapy and for several months after completion of therapy. Rituximab should be discontinued in patients with hepatitis reactivation. This is discussed in more detail separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
Reactivation of hepatitis B infection has been reported in patients with RA, but is rare in such patients [49,52]. Reports are more common among rituximab-treated patients with lymphoma or other malignancies . A retrospective study in a rheumatology center in Taiwan, where hepatitis B is endemic, reviewed findings in 54 patients with RA treated with rituximab from 2000 to 2015 . Forty-four (81.5 percent) had serologic evidence of previously resolved hepatitis B, ie, were anti-HBc positive and HBsAg negative. Four patients experienced reactivation of hepatitis B with an incidence of 9.1 percent. Reactivation occurred a mean of 25 months±4.6 months after the first rituximab cycle (range 17 to 32 months). No information on hepatitis B surface antibody (anti-HBs) status was given in the report. All cases had a good outcome with discontinuing rituximab and antiviral treatment. The authors reviewed the literature and found only three other cases.
SARS-CoV-2 — Data from observational studies have suggested that patients on rituximab, including patients with RA, with coronavirus disease 2019 (COVID-19; the disease caused by severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) are at increased risk of more severe disease and of worse outcomes. The risk of more severe infection associated with COVID-19 as well as other specific management considerations, including pre-exposure prophylaxis, are discussed elsewhere. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'Risks associated with rheumatologic disease therapies' and "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'Pre-exposure prophylaxis in selected patients'.)
In addition, patients on rituximab or other anti-CD20 B cell-depleting therapies are also known to be at increased risk of poor humoral response to vaccines. The use of COVID-19 vaccines in patients receiving rituximab for rheumatologic disease is described separately. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)
Other adverse effects
Human antichimeric antibodies — The prevalence of human antichimeric antibodies (HACA) to rituximab in patients with RA and SLE treated with this agent is higher than that previously noted in patients treated for lymphoma . As an example, in the dose-ranging study previously cited , HACA were detectable in 0.7 percent, 4.2 percent, and 2.7 percent of those receiving placebo, low-dose rituximab, and high-dose rituximab, respectively, compared with 0.6 percent in a group of patients treated for relapsed lymphoma . In the REFLEX trial, 4.3 percent of patients treated with methotrexate, glucocorticoids, and rituximab had detectable HACA at the end of 24 weeks .
The greater incidence of HACA formation in patients with RA may relate to the higher doses of rituximab used in lymphoma treatment regimens or to the autoimmune nature of RA and a higher tendency to develop anti-drug antibodies. For B cell lymphomas, the approved dosing regimen is 375 mg/m2 weekly times four doses. In addition, patients with lymphoma typically receive more potent immunosuppressive agents (eg, cyclophosphamide).
The clinical significance of HACA development in patients with RA is not clear. However, experience with other chimeric agents, and with rituximab in other diseases, suggests the following possible consequences of HACA formation :
●Increase in the risk of infusion reactions. This has been observed with a different chimeric monoclonal antibody (mAb), infliximab. (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors".)
●Decrease in the therapeutic efficacy caused by enhanced clearance of the therapeutic agent. This phenomenon has been noted by some observers in patients with SLE and has been reported in the literature in one case .
Late-onset neutropenia — Late onset of neutropenia, typically seen several months after drug administration, can occur in rituximab-treated patients with RA and other rheumatic disorders and is associated with a higher incidence of infections; it is well recognized as a complication of rituximab therapy in patients treated for lymphoid malignancy, but is less frequent in patients with RA and other autoimmune diseases than in patients with lymphoma [58,59].
As an example, in a cohort of patients treated with rituximab in Sweden for various rheumatic diseases, late-onset neutropenia (40 to 362 days following rituximab administration, with a median of 102 days) was found in 3 percent of patients with RA in association with marked B cell depletion .
In another study involving 1975 patients with RA, with median follow-up of 14.4 months after the last regimen of rituximab, 25 patients (1.3 percent, 0.6 per 100 patient-years) were identified with neutropenia without another cause . Neutropenia occurred in the RA patients after a median period of 4.5 months after the last infusion, and similar results were seen in patients with other autoimmune diseases. We have also seen a small number of cases of early-onset (within one month), in addition to late-onset, neutropenia. Although most were mild, a few were severe and required admission for treatment with granulocyte-colony stimulating factor and antibiotics. Drug-induced neutropenia and other adverse effects of rituximab are discussed in more detail elsewhere. (See "Drug-induced neutropenia and agranulocytosis", section on 'Rituximab'.)
Others — Other less common adverse effects associated with rituximab include serious mucocutaneous reactions (Stevens-Johnson syndrome, vesiculobullous dermatitis, and toxic epidermal necrolysis). These rare adverse effects usually present 1 to 13 weeks after therapy. Serum sickness (delayed type III hypersensitivity) reactions have been reported following rituximab therapy in rare cases [60,61]. Additionally, cases of organizing pneumonia in patients treated with rituximab have been described, one of whom was treated for RA . (See "Drug eruptions" and "Serum sickness and serum sickness-like reactions" and "Drug-induced lung disease in rheumatoid arthritis".)
PREGNANCY AND LACTATION — Reproductive health concerns related to the use of rituximab are described separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Rituximab'.)
RITUXIMAB BIOSIMILARS — Biosimilars to rituximab are commercially available in some countries and have been found similar to the originator rituximab in efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and safety in a series of randomized trials in patients with rheumatoid arthritis (RA) [63,64]. (See "Overview of biologic agents in the rheumatic diseases", section on 'Biosimilars for biologic agents'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)
SUMMARY AND RECOMMENDATIONS
●Rituximab is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody (mAb), which targets CD20, a protein on most B cells, and is thought to act primarily by depleting CD20-positive B cells. B cell depletion also appears to have long-acting effects on immune cell function. (See 'Mechanism of action' above.)
●Patients should receive appropriate immunizations, depending upon their prior immunization history, at least several weeks prior to administration of rituximab. Before starting rituximab, baseline testing should include serologic testing for hepatitis B (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [anti-HBs], hepatitis B core antibody [anti-HBc]), hepatitis C, and HIV; measurement of serum immunoglobulin levels (including IgM, IgG, and IgA); serum protein electrophoresis; and a chest radiograph. (See 'Immunization and response to vaccines' above and 'Pretreatment testing' above.)
●Premedication may reduce the incidence and/or the severity of infusion reactions. We use a combination of acetaminophen (1000 mg once orally), and chlorpheniramine (10 mg) and methylprednisolone (100 mg) intravenously 30 minutes prior to each infusion. We also hold antihypertensive medications prior to the infusion. (See 'Premedication' above and 'Infusion reactions' above.)
●For patients with rheumatoid arthritis (RA), each cycle of therapy typically consists of two doses of rituximab (1000 mg) given intravenously, two weeks apart. Rituximab infusions are typically given to those who are already receiving weekly methotrexate. (See 'Initial dose' above.)
●We typically retreat patients six months after the first course of rituximab if disease is still active, although retreatment at intervals as short as four months may be appropriate in some patients. Patients may need more than one course of treatment to achieve their maximum response. For patients who go into remission with one cycle of rituximab, we wait and retreat at first signs of disease flare. We retreat to prevent relapse/flare based upon the duration of the individual patient response to the previous rituximab cycles, usually approximately one month prior to when the disease would be expected to flare or relapse based upon the duration of the patient's previous response to rituximab. (See 'Retreatment' above.)
●Potential adverse effects include infusion reactions, hypogammaglobulinemia, infection, reactivation of hepatitis B, and neutropenia. Immunoglobulin levels should be monitored prior to each infusion cycle. (See 'Infusion reactions' above and 'Hypogammaglobulinemia and infection' above and 'Opportunistic infections and viral reactivation' above and 'Other adverse effects' above and 'Monitoring' above.)
●Infusion reactions to rituximab are common, particularly with the first infusion, and may represent a response to cytokines released during B cell depletion. Management of infusion reactions in patients with RA is analogous to that in patients with malignant B cell disorders:
•Most reactions occurring during a treatment can be managed by temporarily stopping the rituximab infusion, waiting for symptoms to completely subside, and restarting the infusion at one-half of the initial rate. (See 'Management' above.)
•Saline solution for infusion, bronchodilators for inhalation, epinephrine for intramuscular injection, and glucocorticoids (eg, methylprednisolone 100 mg) for intravenous administration may be required in the event of a serious hypersensitivity reaction with bronchospasm and/or hypotension. These agents should be available at the bedside throughout the infusion. (See 'Infusion reactions' above.)
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