Rituximab in rheumatoid arthritis

Daien Cl, Fabre S, Rittore C, Soler S, Daien V, Tejedor G et al (2012) TGF betal polymorphisms are candidate predictors of the clinical response to rituximab in rheumatoid arthritis. Joint Bone Spine 79 471-475... 

Quartuccio L, Fabris M, Pontarini E, Salvin S, Zabotti A, Benucci M et al (2013) The 158W Fcgamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis results of an Italian multicentre study. Ann Rheum Dis 73(4) 716-721... 

FCGR3A genotype on the therapeutic response to rituximab in rheumatoid arthritis an observational cohort study. BMJ Open 2(5) pii e001524... 

Szodoray P, Alex P, Dandapani V, Nakken B, Pesina J, et al, Apoptotic effect of rituximab on peripheral blood B cells in rheumatoid arthritis. Scand J Immunol 2004 60 209-18. 

Fabris M, Quartuccio L, Lombardi S, Saracco M, Atzeni F, Carletto A (2012) The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis. Autoimmun Rev 11 315-320... 

Ng C M, Bruno R, Combs D, et al. (2005). Population pharmacokinetics of rituximab (anti-CD20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial. Clin. Pharmacol. 45 792-801. 

Infection risk The risk of infections and serious infections with rituximab may be similar to that with the TNT antagonists. To date, there have been no reports from trials of an increased risk of tuberculosis or opportunistic infections with rituximab [162 ]. Some investigators have reported an increase in Pneumocystis jirovecii pneumonia, and increased number of infections has been documented in patients treated with maintenance rituximab for low-grade lymphoma and in patients with concomitant severe immunodeficiency, whether caused by HIV or immunosuppressive agents [152 ]. In rheumatoid arthritis, the susceptibility factors for severe infections include chronic lung and/or cardiac disease, extra-articular involvement, and low IgG before rituximab treatment [163 ]. After kidney transplantation, the off-label use of rituximab is associated with a high risk of infectious disease and death related to infectious disease [164 ]. 

Bingham 3rd CO, Looney RJ, Deodhar A, Halsey N, Greenwald M, Codding C, Trzaskoma B, Martin F, Agarwal S, Kelman A. Immunization responses in rheumatoid arthritis patients treated with rituximab results from a controlled clinical trial. Arthritis Rheum 2010 62(1) 64-74. 

Skin - psoriasis in rheumatoid arthritis patients Psoriasis has been reported with rituximab therapy. A nationwide registry set up by the French Society of Rheumatology to collect data on patients was examined to assess the rates of new-onset and flare of pre-existing psoriasis in patients taking rituximab for rheumatoid arthritis. Incidence rates were 1.04/1000 person-years for new-onset psoriasis and 2.6/1000 person-years for flare. Rechallenges of two new-onset and two flare cases were not followed by recurrence or exacerbation of psoriasis. Although the number of cases observed were fairly small (1927), the findings do not support a causative role for rituximab in the promotion of psoriasis in rheumatoid arthritis patients [194 ]. 

In addihon to treahng tumors, and because depleting B cells in humans with rituximab has been found to be safe, Rituxan is now in clinical trials and has shown efficacy for a number of autoimmune disorders. These include rheumatoid arthritis, idiopathic thrombocytopenia purpura (ITP, a platelet-depletion disorder), and lupus. It is expected that depleting B cells with rituximab will be approved in a nononcology indication within several years. 

Examples of antibodies in the market include trastuzumab (anti-HER2 monoclonal antibody), rituximab, natalizumab (x4-integiin antibody), abciximab, infiximab (targets TNF-a in Crohn s disease and rheumatoid arthritis), alemtuzumab, adalimumab (TNF-a antibody for the treatment of rheumatoid arthritis) and efalizumab (anti-CDlla monoclonal antibody for the treatment of psoriasis)Rituximab is a mouse/human chimeric anti-CD20 monoclonal antibody used for the treatment of various l)unphoid malignancies. As CE)20 antigen is found on the surface of... 

Rituximab has shown benefit in the treatment of rheumatoid arthritis refractory to anti-TNF agents. It has been approved for the treatment of active rheumatoid arthritis when combined with methotrexate. 

Rituximab is indicated for the treatment of moderately to severely active rheumatoid arthritis in combination with methotrexate in patients with an inadequate response to one or more TNF- antagonists. 

Keystone E et al Improvement in patient-reported outcomes in a rituximab trial in patients with severe rheumatoid arthritis refractory to antitumor necrosis factor therapy. Arthritis Rheum 2008 59 785. [PMID 18512710]... 

Edwards J, Szczepanski L, Szechinski J, Filipowicz-Sosnowaska A, et al. 2004. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. NEJM. 350 2572-2581. 

A 55-year-old man with chronic lymphocytic leukemia and rheumatoid arthritis took methotrexate for 4 years and developed a B cell non-Hodgkin s lymphoma in the shoulder and axillary lymph nodes he had Epstein-Barr viral antigens in the serum. After radiation and chemotherapy had failed, complete remission was achieved with a combination of rituximab and EPOCH (etoposide -I- prednisone -I- vincristine -I-cyclophosphamide + doxorubicin). 

Stewart M, Malkovska V, Krishnan J, Lessin L, Barth W. Lymphoma in a patient with rheumatoid arthritis receiving methotrexate treatment successful treatment with rituximab. Ann Rheum Dis 2001 60(9) 892-3. 

Fabris M, Quartuccio L, Vital E, Pontarini E, Salvin S, Fabro C et al (2013) The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers. Arthritis Rheum 65 88-97... 

Ruyssen-Witrand A, Rouanet S, Combe B, Dougados M, Le Loet X, Sibilia J et al (2012) Fcgamma receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab. Ann Rheum Dis 71 875-877... 

Sarsour K, Greenberg J, Johnston JA, Nelson DR, O Brien LA, Oddoux C et al (2013) The role of the FcGRIIIa polymorphism in modifying the association between treatment and outcome in patients with rheumatoid arthritis treated with rituximab versus TNF-alpha antagonist therapies. Clin Exp Rheumatol 31 189-194... 

Rituximab is a monoclonal antibody that destroys B lymphocytes. It was previously licensed only for the treatment of particular types of leukaemia (see Chapter 10). Since November 2006, rituximab has been licensed for treatment of refractory rheumatoid arthritis, where other treatments, including anti TNF-a have failed to produce an adequate response. NICE guidelines were produced in 2007. 

Rituximab is a sterile, clear, colorless, preservative-free, liquid concentrate formulated for IV administration. It has changed the treatment of rheumatoid arthritis by showing that targeted B-cell therapy in combination with methotrexate can reduce signs and symptoms of rheumatoid arthritis in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. Although... 

B cells once were considered to be one of the main contributing factors in the pathogenesis of rheumatoid arthritis, recent evidence has shown that T cells, dendritic cells, and macrophages also were involved. Rituximab has rekindled Interest in B cells, highlighting their important role in perpetuating the inflammatory process and showing how they may interact with other cell types and contribute to joint inflammation. 

Although originally approved for use in people with non-Hodgkin s lymphoma, rituximab was approved for rheumatoid arthritis in 2006. 

In 2002, rituximab became the number one, brand name, cancer therapeutic in the world. It is an important component of the current curative combination for aggressive NHL (R + CHOP). In the future, rituximab may become a part of other curative treatment regimens for hematologic malignancies and will also find utility in the treatment of major diseases such as rheumatoid arthritis and other autoimmune disorders. 

Observational studies In a pooled analysis of data from patients with rheumatoid arthritis treated with rituximab in combination with methotrexate safety analyses were based on 5013 patient-years of rituximab exposure [146 ]. The most frequent adverse event was infusion-related reactions, which occurred in 25% of patients during the first infusion under 1% of infusion-related reactions were considered serious. The overall serious infection rate was 4.31 per 100 patient-years. Infections and serious infections remained stable over time across five courses. Compared with other patients with rheumatoid arthritis and with the general US population, there was no increased risk of malignancy. 

Recall responses to the T ceU-dependent protein antigen tetanus toxoid as well as delayed-type hypersensitivity responses were preserved in rituximab-treated patients with rheumatoid arthritis 24 weeks after treatment responses to neoantigen (keyhole limpet hemocyanin) and T ceU-independent responses to pneumococcal vaccine were reduced, but many patients were able to mount responses [160 ]. These data suggest that polysaccharide and primary immunizations should be administered before rituximab infusions in order to maximize responses. 

In a retrospective analysis of 10 patients with rheumatoid arthritis treated with a combination of rituximab and leflunomide 20 mg/ day orally, leflunomide had to be reduced to 10 mg/day in two patients because of newly diagnosed arterial hypertension and a rise in liver enzymes and had to be stopped in two others after 3 and 6 months because of rises in liver enzymes with gastrointestinal intolerance and aphthous ulcers [62 ]. 

Fleischmann RM. Progressive multifocal leukoencephalopathy following rituximab treatment in a patient with rheumatoid arthritis. Arthritis Rheum 2009 60 3225-8. 

Immunologic Rituximab is a frequent cause of infusion reactions, usually classified as cytokine release syndrome. Whether these reactions are in fact so-called cytokine release syndrome or true type I hypersensitivity responses is not always clear. In an investigation of immxme responses to the mAb in a rheumatoid arthritis patient who experienced two infusion reactions, the patient proved skin test-positive to the mAb and IgE anti-rituximab antibodies were found in the serum. The findings of rituximab-specific IgE antibodies and Th2 cells suggested type I hypersensitivity may be involved in at least some rituximab infusion reactions [195 ]. 

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