Version July 2025
INTRODUCTION —
Rituximab is a monoclonal antibody (mAb) that targets the CD20 antigen. Rituximab depletes B cells and is commonly used for the treatment of multiple rheumatic diseases, including rheumatoid arthritis (RA), granulomatosis with polyangiitis, microscopic polyangiitis, systemic lupus erythematosus, Sjögren's disease, IgG4-related disease, idiopathic inflammatory myopathy, and others.
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.
Rituximab's 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 specific rheumatic diseases are described in detail separately:
●(See "Treatment and prognosis of IgG4-related disease", section on 'Rituximab or inebilizumab'.)
MECHANISM OF ACTION —
Rituximab is an immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets CD20, a protein expressed on the surface of most B cells. It is a chimeric antibody, composed of both mouse variable regions, which carry the amino acid sequences with specificity for CD20 and human constant regions, which are responsible for its functional properties.
Rituximab 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 'B-cell depletion' below and 'Rituximab and rheumatic disease' below.)
B-cell depletion
●Mechanism of action – Rituximab causes B-cell depletion through one or more of several antibody-dependent mechanisms, including the following [1]:
•Fc receptor gamma-mediated antibody-dependent cytotoxicity and phagocytosis
•Complement-mediated cell lysis
•Growth arrest
•B-cell apoptosis
It is uncertain which of these mechanisms is most important in the depletion of B cells in patients with rheumatologic disease, although data suggest that Fc receptor gamma-mediated antibody-dependent cytotoxicity and antibody-dependent phagocytosis are the principal mechanisms.
The relative importance of some of the mechanisms of B-cell depletion induced by rituximab differs depending upon the tissue location of the B cells and their maturation and activation status.
●Anti-CD20 antibody resistance – 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-mediated depletion. As a consequence of plasma cell resistance, overall immunoglobulin levels usually remain within the normal range following one course of rituximab treatment, despite profound B-cell lymphopenia that persists for months following a single course of treatment. However, clinically significant hypogammaglobulinemia can occur in a minority of patients, especially in those receiving long-term rituximab therapy over many years. (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 naïve B cells in the peripheral blood and other tissues. Once rituximab is cleared from the body, the naive B cells migrate to the secondary lymphoid tissue and reconstitute the B-cell repertoire.
Rituximab and rheumatic disease — The exact mechanism(s) by which rituximab results in reduced disease activity when used for the treatment of rheumatic diseases is not known. The two most explored mechanisms are mentioned below.
●Autoantibody production – B-cell targeted therapy was developed with the objective of removing B-cell clones responsible for the production of pathogenic autoantibodies. For rheumatoid arthritis (RA), investigators hypothesized that autoantibodies self-propagate, and short-term B-cell depletion might be adequate to induce sustained remission [2].
There are studies indicating that serum levels of autoantibodies 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 (that are not renewed following the depletion of the B-cell precursors). Examples of this phenomenon include rheumatoid factor (RF) in RA [3,4], antineutrophil cytoplasmic antibodies (ANCA) in ANCA-associated vasculitis [5-7], and other autoantibodies in other disorders [5-8].
●Autoreactive B cells – Antigen presentation by B cells and cytokine-mediated interactions with stromal and accessory cells could also potentially activate autoreactive T cells. B cells are efficient at presenting soluble antigen that has been bound by their antigen receptor (ie, surface immunoglobulin) during the acquisition of T-cell help.
There is some doubt as to whether this hypothesis is consistent with the behavior of synovial T cells in RA if antigen presentation by B cells to autoreactive T cells occurred locally and was essential to disease perpetuation [9,10]. However, this mechanism may be more important for other rheumatic diseases.
Clarification of the role of B cells in specific rheumatic diseases is crucial to optimize the use of rituximab. For example:
●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.
●If autoantibodies play a key role in propagation of the disease, short periods of B-cell depletion should be adequate to achieve sustained remission, although autoreactive B cells may redevelop over time. Optimization of B-cell depletion would therefore aim at increasing the depth of B-cell depletion and/or targeting both B cells and plasma cells if relevant autoantibodies are produced by long-lived plasma cells.
CONTRAINDICATIONS
●Absolute contraindications – The only absolute contraindication to rituximab is hypersensitivity to any of the components of the formulation. In such patients, we would try another anti-CD20 antibody (eg, obinutuzumab, ocrelizumab). In some cases, an allergist may be able to desensitize the patient, although the process is complex and time-consuming (see "Rapid drug desensitization for immediate hypersensitivity reactions", section on 'Technical aspects of desensitization'). However, in our local experience, the use of a desensitization protocol was very rarely effective at allowing the patient to tolerate the rituximab infusion and was then associated with a shorter duration of peripheral blood B-cell depletion, reflecting the presence of anti-rituximab antibodies (HACAs) and the more rapid clearance of the drug.
●Relative contraindications
•Active severe infection
•Severe heart failure or severe, uncontrolled cardiac disease – In these patients, we consider hospitalizing the patient for treatment if necessary and giving the rituximab 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 with less organ function reserve.
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 — In patients who require immunizations (eg, for seasonal influenza, pneumococcal, and hepatitis B vaccines), we vaccinate patients at least four weeks before the administration of rituximab, when feasible [11].
When this is not feasible, we individualize the timing of immunization, taking into account the risk of infection and the timing of B-cell recovery (typically 6 to 12 months following rituximab):
●Influenza – 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 receiving repeated courses of rituximab.
●Other vaccinations including COVID-19 – For other vaccinations, options include delaying vaccination until B-cell repopulation or revaccinating patients who do not have an increase in the relevant antibody titer following initial vaccination.
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 "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.)
●Chest radiograph (if not obtained within the prior six months).
ADMINISTRATION AND DOSING
Precautions
●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.
Premedication
●Regimen – To prevent infusion reactions, we premedicate patients 30 minutes before each infusion of rituximab in each treatment cycle with (see 'Infusion reactions' below):
•Diphenhydramine (25 to 50 mg administered intravenously or orally) or chlorpheniramine (10 mg administered intravenously)
•Acetaminophen (650 to 1000 mg taken orally)
•Methylprednisolone (80 to 125 mg administered intravenously)
Another antihistamine may be used in place of diphenhydramine or chlorpheniramine.
Additionally, at some institutions, routine premedication also includes an H2-receptor blocker (eg, famotidine), but we have not found this necessary in our experience.
Modifications in the premedication regimen may be needed based upon their response to prior rituximab infusions.
●Efficacy – Premedication with antihistamines and acetaminophen, with or without a glucocorticoid, can reduce the incidence of mild but not severe infusion reactions. In particular, premedication does not prevent anaphylaxis and may not prevent all mild infusion reactions, although it may reduce their severity.
The efficacy of pretreatment with H1 and H2 antihistamines has not been assessed in patients receiving rituximab for rheumatoid arthritis (RA).
The benefit of glucocorticoids was addressed in the placebo-controlled Dose-ranging Assessment International Clinical Evaluation of Rituximab in RA (DANCER) trial [12]. A single dose of methylprednisolone (100 mg) given 30 minutes before beginning the rituximab infusion reduced the frequency (29 versus 37 percent) and intensity of first infusion-associated events among patients receiving two doses of rituximab 1 g administered 2 weeks apart; oral glucocorticoids (ie, 60 mg daily on days 2 to 7 and 30 mg daily on days 8 to 14) conferred no additional benefit.
The use of premedications with monoclonal antibodies such as rituximab is discussed elsewhere. (See "Infusion-related reactions to monoclonal antibodies for cancer therapy", section on 'Prophylaxis of infusion reactions'.)
Initial dose — For most indications, we administer rituximab as a dose of 1000 mg, given twice, two weeks apart, by intravenous infusion. Rituximab may be given as monotherapy. For patients already treated with a conventional standard disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate, the csDMARD may be continued until the patient achieves clinical remission.
However, expert opinion differs regarding the most appropriate dose for initial therapy. Alternate strategies may be used for the following diseases:
●ANCA-associated vasculitis – For patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (eg, granulomatosis with polyangiitis, microscopic polyangiitis), rituximab may also be administered at 375 mg/m2 weekly for four weeks. Some clinicians feel that the higher dose may lead to better outcomes among patients with ANCA-associated vasculitis, although this has not been demonstrated in clinical trials. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Rituximab-based regimen'.)
●Rheumatoid arthritis – For patients with RA, 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; response to rituximab in RA correlates with the degree of B-cell depletion at either of these doses [13,14]. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Rituximab'.)
Not all patients will require retreatment with rituximab, even following the return of circulating peripheral B cells. These issues are discussed in the relevant treatment topics.
Infusion rate — To prevent infusion reactions, we start slowly and gradually increase the rate of administration during the infusion period.
●Initial infusion – 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.
●Subsequent infusions – 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. However, in patients with a previous history of infusion reactions, we give the infusion slowly with close monitoring of symptoms. (See 'Infusion reactions' below.)
Subsequent doses
●General considerations – 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) [4,15].
Across rheumatologic diseases, relapse is more common among patients treated with rituximab following B-cell repopulation. However, the decision to retreat patients following B-cell repopulation must be individualized, accounting for the patient's preferences, the likelihood of relapse, and the potential for irreversible damage due to disease flare.
Anecdotally, some patients will enter prolonged remission following a single course of rituximab, even after B-cell repopulation. In a retrospective study of 126 patients with RA receiving remission maintenance therapy with rituximab (on average, 14 infusions over a period of 76 months), patients who achieved persistent, complete B-cell depletion did not have a better clinical response (as measured by the DAS28-CRP) than patients who did not maintain complete B-cell depletion [16].
●Dosing interval – When rituximab is used as a preventative measure to prevent disease relapse, rituximab is often redosed at six-month intervals. In some patients, a shorter retreatment interval (eg, every four or five months) may be used if there is evidence of early disease relapse. However, in the United States and Europe, payor restrictions may prevent the use of shorter intervals.
In patients who have remained in remission for at least two years, we may consider increasing the interval, balancing the risks of relapse against the risks of ongoing B-cell depletion.
●Duration of therapy – In patients who tolerate rituximab and continue to respond to therapy, we continue treatment.
INFUSION REACTIONS
Precautions
●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.
●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.
●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 'Infusion rate' above.)
Frequency
Mild 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 [4]. The incidence of infusion reactions among patients with other rheumatic diseases is unclear.
Severe infusion reactions — 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) [17]. Serious infusion reactions were classified as an occurrence during or within 24 hours of a rituximab infusion and requiring discontinuation of treatment. Severe infusion reactions to rituximab occurred in 56 of 1986 patients (2.8 percent) or 0.7 per 100 patient-years. 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.
Small studies imply that severe infusion reactions are rare when rituximab is used for the treatment of other rheumatologic diseases [18,19].
Clinical features
Mild infusion reactions — The majority of these standard infusion reactions 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.
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).
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.
Severe infusion reactions — Severe infusion reactions are rare and include anaphylaxis and severe bronchospasm.
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 monoclonal antibodies for cancer therapy", section on 'Anaphylaxis'.)
Management — The management of both mild and severe infusion reactions is discussed elsewhere. (See "Infusion-related reactions to monoclonal antibodies for cancer therapy", section on 'Rituximab' and "Anaphylaxis: Emergency treatment".)
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 kidney 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. If IgG levels below normal range but above 5g/L and there is no history of severe or recurrent infections, we usually continue rituximab with monitoring. If IgG levels fall below 5 g/L and/or patients develop serious or repeated infections, we consider switching to other therapies and referring/consulting with clinical immunology colleagues. (See 'Rheumatoid factor in patients with rheumatoid arthritis' below and 'Hypogammaglobulinemia and infection' below.)
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. For example, incomplete B-cell depletion with rituximab appears to be more common than initially appreciated and may be associated with reduced efficacy in some patients.
ADVERSE EFFECTS
Complications requiring treatment discontinuation — Complications that may require drug discontinuation are discussed in more detail elsewhere in this topic review. These include:
●Severe or recurrent infusion reactions (see 'Infusion reactions' above)
●Serum IgG less than 5 g/L (see 'Hypogammaglobulinemia and infection' below)
●Severe or recurrent infections, depending upon an individualized assessment of risk (see 'Hypogammaglobulinemia and infection' below and 'Opportunistic infections and viral reactivation' below)
●Development of progressive multifocal leukoencephalopathy (PML) (see 'Opportunistic infections and viral reactivation' below)
Effects on B cells, antibodies, and risk of infection
Rheumatoid factor in patients with rheumatoid arthritis — For patients with rheumatoid arthritis (RA), measuring rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) antibodies 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.
Rituximab therapy reduces RF levels more than serum immunoglobulin levels. 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 [15]. 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 [20].
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.
●Epidemiology – 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 [3,4,15]. However, repeated courses of therapy are associated with an increasing risk of hypogammaglobulinemia [15,20-22]. Hypogammaglobulinemia is associated with increased risk of infection and infection-related mortality, although this has not been conclusively demonstrated in patients receiving rituximab for rheumatic disease.
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 [20]:
•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 five 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.
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 [23]. 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).
●Management – When other therapeutic options exist, we avoid using 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 and glucocorticoid use.
•Severe or recurrent infections – 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.
•Hypogammaglobulinemia – 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.
In patients with hypogammaglobulinemia who discontinue rituximab, we monitor immunoglobulin levels every 6 to 12 months until normalization. It is important to document the presence of hypogammaglobulinemia in the patient's problem list so that colleagues are aware in case patient presents with serious or recurrent infections and there is need to assess its possible contribution and any need for specific management.
•Parenteral immunoglobulin therapy – 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".)
Opportunistic infections and viral reactivation — We avoid the use of rituximab in patients with a chronic active viral infection (eg, hepatitis B or C, HIV).
●Epidemiology – 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 [24]. Twenty-five out of 5072 patients treated with rituximab had an opportunistic infection, with Pneumocystis 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 (ie, only two documented cases) [24].
●Progressive multifocal leukoencephalopathy – 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 [25,26]. 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 [25]. However, one had early RA, naïve to methotrexate or other disease-modifying antirheumatic drugs (DMARDs) [25]. The incidence of PML among patients receiving rituximab for the treatment of other rheumatic diseases is unknown.
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'.)
●Hepatitis B reactivation – 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) [27]. 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 greater detail separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
Reactivation of hepatitis B infection is rare among patients receiving rituximab for the treatment of rheumatologic diseases [26,28]. Reports are more common among rituximab-treated patients with lymphoma or other malignancies [26]. 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 [29]. 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.
●Other infectious complications – Among patients with RA and other rheumatic diseases, rituximab has been also been associated in case reports with severe P. jirovecii infection [30], cryptococcal meningitis [31], and cytomegalovirus colitis [32]. P. jirovecii prophylaxis therapy should be considered, particularly in patients with lung or kidney involvement or on concomitant high-dose steroids [33].
SARS-CoV-2
●Clinical outcomes – Data from observational studies have suggested that rituximab is associated with an increased risk of more severe disease and of worse outcomes from coronavirus disease 2019 (COVID-19; the disease caused by severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]). Patients on rituximab are also at risk of poor viral clearance and ongoing or recurrent clinical infectious manifestations.
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'.)
●Vaccination response – Patients receiving anti-CD20 B cell-depleting therapies such as rituximab 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
●Epidemiology – The prevalence of human antichimeric antibodies (HACA) to rituximab in patients with RA and systemic lupus erythematosus treated with this agent is higher than that previously noted in patients treated for lymphoma [34]. As an example, in the dose-ranging study previously cited [12], HACA were detectable in 0.7, 4.2, 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 [35]. In the REFLEX trial, 4.3 percent of patients treated with methotrexate, glucocorticoids, and rituximab had detectable HACA at the end of 24 weeks [15].
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).
●Clinical significance – 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 [36]:
•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 systemic lupus erythematosus and has been reported in the literature in one case [37].
Late-onset neutropenia — Late onset of neutropenia is well recognized as a complication of rituximab therapy in patients treated for lymphoid malignancy. However, late-onset neutropenia is a sporadic complication of rituximab and does not preclude future use in a given patient.
●Epidemiology – Late-onset neutropenia is less frequent in patients with RA and other autoimmune diseases than in patients with lymphoma [38,39].
•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 [38].
•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 [39]. 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.
●Timing – It is typically seen several months after drug administration and can be associated with a higher incidence of infections. We have also seen a small number of cases of early-onset (within one month) neutropenia in addition to late-onset neutropenia.
●Management – Although most cases are mild, some may develop neutropenic fever requiring admission for treatment with granulocyte-colony stimulating factor and antibiotics. (See "Management of the adult with non-chemotherapy-induced neutropenia".)
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 [40,41]. Additionally, cases of organizing pneumonia in patients treated with rituximab have been described, one of whom was treated for RA [42]. (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) [43,44].
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
●Mechanism of action – 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.)
●Contraindications – The only absolute contraindication to rituximab is a history of hypersensitivity to the drug or components of its formulation. We also avoid using it in patients with active infection or decompensated heart failure. (See 'Contraindications' above.)
●Pre-treatment considerations
•Immunizations – Patients should receive appropriate immunizations, depending upon their prior immunization history, at least several weeks prior to administration of rituximab, whenever possible. One exception is seasonal influenza vaccination, which should be administered as soon as it is available. (See 'Immunization and response to vaccines' above.)
•Baseline testing – 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 'Pretreatment testing' above.)
●Premedications – Premedication may reduce the incidence and/or the severity of infusion reactions. Thirty minutes prior to each infusion, we administer a combination of acetaminophen (650 to 1000 mg once orally); diphenhydramine (25 to 50 mg, orally or intravenously) or chlorpheniramine (10 mg); and methylprednisolone (80 to 125 mg intravenously). We also hold antihypertensive medications prior to the infusion. (See 'Premedication' above and 'Infusion reactions' above.)
●Dosing – For most rheumatic indications, rituximab is initially administered as two doses of rituximab (1000 mg) given intravenously, two weeks apart. Rituximab infusions may be combined with conventional synthetic disease-modifying antirheumatic drugs (csDMARD), such as methotrexate (See 'Initial dose' above.)
●Subsequent dosing – Rituximab is often redosed in six-month intervals to maintain remission. However, this varies broadly depending on the specific diagnosis, the patient's history of response, and other considerations. (See 'Subsequent doses' above.)
●Infusion reactions – 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 depends on the severity of the reaction:
•Mild infusion reactions – 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.)
•Severe infusion reactions – 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.)
●Monitoring – We obtain serum immunoglobulin levels (total, IgG, IgM, and IgA) before each retreatment and if a patient develops a serious infection or repeated infections. If IgG levels fall below 5 g/L and/or patients develop serious or repeated infections, we consider switching to other therapies. We do not routinely recommend measuring the extent of B-cell depletion and repletion in clinical practice (See 'Monitoring' above.)
●Adverse events - 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.)
