Rituximab is a monoclonal antibody that depletes B cells from the circulation. It was originally used to treat lymphoma but is increasingly used for the treatment of autoimmune diseases.
Rituximab was found to be effective in randomised controlled trials for rheumatoid arthritis, granulomatosis with polyangiitis and other antineutrophil cytoplasmic antibody-associated vasculitides. However, evidence of efficacy is very limited for many other autoimmune conditions.
Before starting rituximab, it is important to check the patient’s baseline immunoglobulins and immunisation status. Patients should also be screened for latent infections and other contraindications.
Rituximab was first developed for the treatment of non-Hodgkin lymphoma, and is also used in chronic lymphocytic leukaemia. It is increasingly being prescribed for the treatment of autoimmune diseases. While we know that rituximab works by removing B lymphocytes from the circulation, exactly how this leads to clinical improvement in many of the conditions that rituximab is used to treat is still to be determined.
Mechanism of action
Rituximab is a chimeric monoclonal antibody that binds to the CD20 surface marker expressed on B cells. This includes precursor B cells (pre-B cells) and mature and memory B cells.1 Following antibody binding, B cells die by a number of mechanisms including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis.2 Although the loss of B cells from the circulation is transient (usually for about six months), the duration of depletion can be highly variable among individuals.
Rituximab was developed to remove malignant, clonal B cells expressing CD20 in conditions such as lymphoma. Empirically, it makes sense to use it to remove malignant B-cell clones but how does it work in diseases where the B cells are not malignant?While rituximab decreases concentrations of antibodies that are pathogenic (or presumed pathogenic), levels of other protective antibodies are maintained, such as those to tetanus toxoid.1 Rituximab does not reduce plasma cells, which secrete antibodies, because they do not express CD20. Instead, the efficacy of rituximab in autoimmune disease is thought to be due to the decrease in the rate of new plasma cell synthesis (as CD20+ B cells are a required intermediary) or to the disruption of another role of B cells in the immune system, such as the role of B cells as antigen-presenting cells to T cells.
Indications for use
In Australia, rituximab is available on the Pharmaceutical Benefits Scheme (PBS) for a number of different types of non-Hodgkin lymphoma and for CD20+ chronic lymphocytic leukemia. It has been shown to be effective in rheumatoid arthritis3-5 and is subsidised for severe disease.
Evidence from randomised controlled studies has also shown benefit in granulomatosis with polyangiitis and other antineutrophil cytoplasmic antibody (ANCA)- associated vasculitides.6-8 This led to the approval of rituximab by the Therapeutic Goods Administration in 2013 for ANCA-associated vasculitis. In January 2016, rituximab was added to the PBS for induction of remission (and for re-induction of remission) for granulomatosis with polyangiitis and microscopic polyangiitis, two forms of ANCA-positive vasculitis.
A six-month survey in Australian hospitals, published in 2013, found more than 300 instances of ‘off-label’ use of rituximab.9 It was prescribed in over 50 conditions, including autoimmune conditions listed in the Table.10-17 For most of these conditions, there is only evidence from case reports and case series. For others, randomised controlled studies failed to show benefit for rituximab, or contradictory case studies exist.9 Randomised controlled studies of systemic lupus erythematosus failed to show a benefit for rituximab despite promising earlier reports. The addition of rituximab to standard immunosuppressive therapy did not show a difference in the outcomes for non-renal and renal lupus erythematosus10,11 but this may have been due to problems with study design such as the choice of treatment regimen and study outcome measures. In particular, in the study of lupus nephritis, rituximab reduced the need for rescue medication with cyclophosphamide, despite not showing an overall benefit.10
A recent randomised controlled trial in immune thrombocytopenia failed to show a difference between rituximab and placebo in the primary outcome measure, despite promising data from case studies.17
|Condition||Evidence of benefit (if any)|
Systemic lupus erythematosus (non-renal and renal)
Case reports and case series including meta-analysis of case series showed benefit 12
Blistering diseases of the skin, such as pemphigus and cicatricial pemphigoid
Neurological diseases such as myasthenia gravis and neuromyelitis optica
Randomised controlled trial failed to show benefit 17 despite promising data from case studies
Patients with acute or chronic infections should not be treated with rituximab and it is also contraindicated in severe congestive heart failure (New York Heart Association Class IV). Known hypersensitivity to rituximab or other mouse-derived proteins is also a relative contraindication, and rituximab should not be given in pregnancy.1
Dosing and administration
The optimal dose of rituximab is poorly defined because of limited studies exploring dose response for many conditions. Rituximab is used in hospitals as it is given as an intravenous infusion, although a subcutaneous formulation is also being evaluated. There are two different intravenous dosing strategies – 375 mg/m2 weekly for four weeks (lymphoma protocol) and 1000 mg fortnightly (independent of body weight) for two doses (rheumatoid arthritis protocol). For some conditions and in some hospitals, the fortnightly strategy is modified to a low-dose strategy which involves two 500 mg doses given 1–2 weeks apart.18
Infusion-related reactions to rituximab are common (30% with the first infusion). Premedication with paracetamol and corticosteroid (usually 100 mg of hydrocortisone) is used to minimise these.1
As immunisation responses are compromised after treatment with rituximab,28 it is recommended that any required immunisations are given before treatment.1 Current guidelines recommend pneumococcus and influenza vaccination for patients with autoimmune disease, and hepatitis A and B vaccinations in at-risk groups.29 A four-week gap between vaccination with non-live vaccines and commencement of rituximab is recommended, but the optimal interval is an area of ongoing research.1
Live vaccines are contraindicated in those who have had treatment with rituximab or are being considered for it.
As it is assumed that a protective response to tetanus toxoid booster vaccination may not occur after rituximab treatment, for a tetanus-prone wound, passive immunisation with tetanus antibodies is advised for 24 weeks after rituximab treatment.29 However if the patient is persistently B-cell lymphopenic, passive immunisation may need to be considered even after this time.
Monitoring and re-treatment
Patients are usually found to have depleted B cells after one dose of rituximab. This is confirmed by checking B- and T-cell lymphocyte subsets through a different surface marker – CD19 – to ensure that rituximab is not just blocking access to the surface marker for the detection antibody. Most clinicians would also follow the titre of the pathogenic (or presumed pathogenic) antibody specific for the disease that is being treated.
The optimum timing and safety and efficacy of any re-treatment with rituximab is still an area of active research.1 This is reflected in current variable practices, which include patients starting re-treatment:
- when their B cells return before any disease manifestations
- after B cells return and symptoms develop
- after a certain number of months even if there are no detectable B cells in the blood.
Rituximab is being used more widely for the treatment of autoimmune diseases, in many cases as an off-label drug. It works by transiently depleting B cells from the circulation. While it is used increasingly for autoimmune disease, with case studies and case series describing efficacy, for most conditions there have been no randomised controlled studies. Patients need to be appropriately screened before the use of rituximab, and monitored for adverse effects, particularly infection.
Conflict of interest: none declared
- Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dörner T, et al.; Rituximab Consensus Expert Committee. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2011;70:909-20.
- Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 2003;22:7359-68.
- Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al.; REFLEX Trial Group. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793-806.
- Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, et al.; DANCER Study Group. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390-400.
- Peterfy C, Emery P, Tak PP, Ostergaard M, DiCarlo J, Otsa K, et al. MRI assessment of suppression of structural damage in patients with rheumatoid arthritis receiving rituximab: results from the randomised, placebo-controlled, double-blind RA-SCORE study. Ann Rheum Dis 2016;75:170-7.
- Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al.; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363:221-32.
- Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, et al.; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363:211-20.
- Walters G, Willis NS, Craig JC. Interventions for renal vasculitis in adults. Cochrane Database Syst Rev 2015:CD003232.
- .O’Connor K, Liddle C. Prospective data collection of off-label use of rituximab in Australian public hospitals. Intern Med J 2013;43:863-70.
- Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, et al.; LUNAR Investigator Group. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012;64:1215-26.
- Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62:222-33.
- Erkan D, Aguiar CL, Andrade D, Cohen H, Cuadrado MJ, Danowski A, et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev 2014;13:685-96.
- Le Roux-Villet C, Prost-Squarcioni C, Alexandre M, Caux F, Pascal F, Doan S, et al. Rituximab for patients with refractory mucous membrane pemphigoid. Arch Dermatol 2011;147:843-9.
- Wang HH, Liu CW, Li YC, Huang YC. Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. Acta Derm Venereol 2015;95:928-32.
- Iorio R, Damato V, Alboini PE, Evoli A. Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. J Neurol 2015;262:1115-9.
- Collongues N, Brassat D, Maillart E, Labauge P, Ouallet JC, Carra-Dalliere C, et al.; OFSEP and CFSEP. Efficacy of rituximab in refractory neuromyelitis optica. Mult Scler 2016;22:955-9.
- Ghanima W, Khelif A, Waage A, Michel M, Tjønnfjord GE, Romdhan NB, et al.; RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015;385:1653-61.
- Chay J, Donovan P, Cummins L, Kubler P, Pillans P. Experience with low-dose rituximab in off-label indications at two tertiary hospitals. Intern Med J 2013;43:871-82.
- Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis. Arthritis Rheum 2007;56:3896-908.
- Roberts DM, Jones RB, Smith RM, Alberici F, Kumaratne DS, Burns S, et al. Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease. J Autoimmun 2015;57:60-5.
- Tony HP, Burmester G, Schulze-Koops H, Grunke M, Henes J, Kötter I, et al.; GRAID investigators. Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID). Arthritis Res Ther 2011;13:R75.
- Gottenberg JE, Ravaud P, Bardin T, Cacoub P, Cantagrel A, Combe B, et al.; AutoImmunity and Rituximab registry and French Society of Rheumatology. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 2010;62:2625-32.
- Salmon JH, Cacoub P, Combe B, Sibilia J, Pallot-Prades B, Fain O, et al. Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the AutoImmunity and Rituximab registry. RMD Open 2015;1:e000034.
- Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy in patients with rheumatic diseases: are patients with systemic lupus erythematosus at particular risk? Autoimmun Rev 2008;8:144-6.
- Hoofnagle JH. Reactivation of hepatitis B. Hepatology 2009;49 Suppl S5:S156-65.
- Martin-Garrido I, Carmona EM, Specks U, Limper AH. Pneumocystis pneumonia in patients treated with rituximab. Chest 2013;144:258-65.
- Jiang XQ, Fang L, Mei XD, Wang XJ, Bao MH. Pneumocystis jiroveci pneumonia in patients with non-Hodgkin’s lymphoma after Rituximab-containing regimen: two cases of report and literature review. J Thorac Dis 2013;5:E162-6.
- Eisenberg RA, Jawad AF, Boyer J, Maurer K, McDonald K, Prak ET, et al. Rituximab-treated patients have a poor response to influenza vaccination. J Clin Immunol 2013;33:388-96.
- van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF, Dougados M, et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 2011;70:414-22.