Rituximab In Autoimmune Diseases Research Articles

Real-life drug retention rate and safety of rituximab when treating rheumatic diseases: a single-centre Swiss retrospective cohort study

BackgroundIn Switzerland, rituximab (RTX) is licenced for the treatment of rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) but is frequently used off-label to treat other auto-immune diseases (AID), especially connective tissue diseases (CTD). We aimed to characterise the use of RTX in AID in a real-life Swiss setting and compare RTX retention rates and safety outcomes between patients treated for RA, CTD and AAV.MethodsA retrospective cohort study of patients who started RTX in the Rheumatology Department for RA or AID. The RTX retention rate was analysed using Kaplan–Meier survival curves. Occurrences of serious adverse events (SAE), low IgG levels and anti-drug antibodies (ADA) were reported.ResultsTwo hundred three patients were treated with RTX: 51.7% had RA, 29.6% CTD, 9.9% vasculitis and 8.9% other AIDs. The total observation time was 665 patient-years. RTX retention probability at 2 years (95%CI) was similar for RA and CTD 0.65 (0.55 to 0.73), 0.60 (0.47 to 0.72) and lower for vasculitis 0.25 (0.09 to 0.45). Survival curves for RTX retention matched closely (p = 0.97) between RA and CTD patients but were lower for patients with vasculitis due to a higher percentage of induced remission. Patients with vasculitis (95%) and CTD (75%) had a higher rate of concomitant glucocorticoid use than RA (60%). Moderate to severe hypogammaglobulinaemia was observed more frequently in patients with vasculitis (35%) than with RA (13%) or CTD (9%) and was associated with an increased risk of presenting a first infectious SAE (HR 2.01, 95% CI 1.04 to 3.91). The incidence rate of SAE was 23.3 SAE/100 patient-years (36% were infectious). When searched, ADAs were observed in 18% of the patients and were detected in 63% of infusions-related SAE. 10 patients died during RTX treatment and up to 12 months after the last RTX infusion, 50% from infection.ConclusionRTX retention rates are similar for patients with RA and CTD but lower for those with vasculitis due to more frequent remission. Patients treated with RTX for vasculitis present more SAE and infectious SAE than patients with RA and CTD, potentially due to a higher use of concomitant glucocorticoids and the occurrence of hypogammaglobulinaemia.

P167 Overcoming rituximab resistance in autoimmune disease: back to basics

Abstract Background/Aims Previous research into B cell biomarkers of poor response to the anti-CD20 drug rituximab in autoimmune disease relates to insufficient B cell depletion. Expansion of memory B cell (MBC) subsets were also associated with poorer response. We investigated whether the relative expression of the target antigen CD20 on B cell subpopulations could also contribute to drug resistance. Methods Peripheral blood samples from 6 rituximab naïve (RTX-N) patients with autoimmune rheumatic diseases (active systemic lupus erythematosus and rheumatoid arthritis), 6 patients previously treated with rituximab (RTX-T), and 6 healthy controls (HC) were obtained. B cell subpopulations were defined using the relative expression of IgD and CD27 using flow cytometry. Results Patients in the RTX-N group had significantly higher frequency of CD19+CD20- B cells (median=25.9% of total B cells, compared to 1.26% in HC), p = 0.0022. CD19+CD20-B cells were predominantly switched MBC (IgD-CD27+) and double negative (IgDCD27-) MBC cells. All patients in the RTX-T group (median 22 months post-rituximab) had detectable CD19+CD20- B cells (median=52.25% of total B cells), of which the majority were switched MBC (median=4.54%, range 0.23-74%) and DN B cells (median=53.5%, range 11.6-98.1%). Collectively, we noted that the frequency of CD19+CD20- B cells in peripheral circulation was higher in RTX-T>RTX-N>HC. Conclusion Our preliminary results have identified greater frequency of CD19+CD20- population of B cells in peripheral blood of patients with autoimmune disease, particularly after treatment with rituximab, suggesting that they evade rituximab. These are predominantly of the switched MBC and DN B cell subpopulations. Given the potential of these cells to contribute to disease activity in autoimmune disease, alternative strategies targeting CD19 may help overcome rituximab resistance. Disclosure K. Shah: Grants/research support; Roche Glycart. C. Klein: Corporate appointments; Roche Glycart. Shareholder/stock ownership; Roche. G. Cambridge: None. D. Sen: None. M. Castelino: None. A. Akbar: None. D.A. Isenberg: None. M. Leandro: None. V.R. Reddy: Grants/research support; Roche Glycart, BRC UCLH.

Efficacy and Safety of Rituximab in Autoimmune Disease-Associated Interstitial Lung Disease: A Prospective Cohort Study.

Objectives: To analyze the efficacy and safety of rituximab (RTX) in connective tissue disease associated with interstitial lung disease (CTD-ILD). Methods: We performed a multicenter, prospective, observational study of patients with CTD-ILD receiving rituximab between 2015 and 2020. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline, at 12 months, and at the end of follow-up. The main outcome measure at the end of follow-up was forced vital capacity (FVC) > 10% or diffusing capacity of the lungs for carbon monoxide (DLCO) > 15% and radiological progression or death. We recorded clinical characteristics, time to initiation of RTX, concomitant treatment, infections, and hospitalization. A Cox regression analysis was performed to identify factors associated with worsening ILD. Results: We included 37 patients with CTD-ILD treated with RTX for a median (IQR) of 38.2 (17.7–69.0) months. At the end of the follow-up, disease had improved or stabilized in 23 patients (62.1%) and worsened in seven (18.9%); seven patients (18.9%) died. No significant decline was observed in median FVC (72.2 vs. 70.8; p = 0.530) or DLCO (55.9 vs. 52.2; p = 0.100). The multivariate analysis showed the independent predictors for worsening of CTD-ILD to be baseline DLCO (OR (95% CI), 0.904 (0.8–0.9); p = 0.015), time to initiation of RTX (1.01 (1.001–1.02); p = 0.029), and mycophenolate (0.202 (0.04–0.8); p = 0.034). Only 28 of the 37 patients (75.6%) were still undergoing treatment with RTX: two patients (5.4%) stopped treatment due to adverse events and seven patients (18.9%) died owing to progression of ILD and superinfection. Conclusion: Lung function improved or stabilized in more than half of patients with CTD-ILD treated with RTX. Early treatment and combination with mycophenolate could reduce the risk of progression of ILD.

Clinical features and prognosis of pneumocystis pneumonia in patients treated with rituximab for autoimmune diseases

Objective: To determine the clinical features and outcomes of pneumocystic pneumonia (PCP) in patients treated with rituximab for autoimmune diseases. Methods: PCP patients with autoimmune diseases as underlying diseases from January 2009 to April 2019 in Peking University First Hospital (male 67 cases, female 35 cases, age 17-79) were retrospectively reviewed. Patients were grouped as rituximab group and non-rituximab group based on the fact if they were treated with rituximab before the onset of PCP. Demographic data, clinical features, and outcomes of the two groups were analyzed. Results: There were 102 cases altogether, and 7 patients were treated with rituximab before the onset of PCP. Patients in rituximab group were relatively younger than that in non-rituximab group [(32.0±18.7) vs (52.4±14.9) years, P=0.010]. Patients in rituximab group had more CD3(+), CD4(+), CD8(+)T lymphocytes in peripheral blood samples than that in non-rituximab group [(1 306±596) vs (546±439)/μl, (674±401) vs (243±232)/μl, (616±249) vs (282±256)/μl, respectively, all P<0.01]. However, the B lymphocyte count and plasma level of IgG and IgM were significantly lower in rituximab group than that in non-rituximab group [0 (0, 0.2) vs 72 (50.0, 124.4)/μl, 4.0 (2.6, 5.8) vs 9.4 (5.3, 12.0) g/L, 0.3 (0.2, 1.0) vs 1.1 (0.6, 1.8) g/L, respectively, all P<0.05]. The incidence of Cytomegalovirus (CMV) pneumonia was significantly lower in rituximab group (0/7 and 57/95, P=0.007). Other demographic data, the use of corticosteroids, the incidence of severe PCP, mechanical ventilation, intubation, pneumothorax and mediastinal emphysema complications, as well as hospital mortality and length of stay in hospital in the two groups were comparable. Conclusions: In patients treated with rituximab for autoimmune diseases, the number of B lymphocytes in peripheral blood and the plasma level of immunoglobulins but not CD3(+), CD4(+), and CD8(+)T lymphocyte counts may play an important role in the pathogenesis of PCP. These patients are not vulnerable to be complicated with CMV pneumonia.

Systematic review of rituximab for autoimmune diseases: a potential alternative to intravenous immune globulin.

The anti-CD20 monoclonal antibody rituximab has immune-modulatory effects similar to intravenous immunoglobulin (IVIG). We performed a systematic review and meta-analysis to determine the efficacy and safety of rituximab in autoimmune diseases that are also treated with IVIG. The most common indications for immune modulation with IVIG, as identified from a 2012 regional audit in Canada, were chronic inflammatory demyelinating polyneuropathy (CIDP), immune thrombocytopenia (ITP), myasthenia gravis, multifocal motor neuropathy, Guillain-Barré syndrome, systemic lupus erythematosus (SLE), Sjogren's syndrome, and pemphigus vulgaris. We searched MEDLINE, EMBASE, and the Cochrane Library until July 2016 for studies evaluating rituximab in each of these conditions. The primary outcome in our meta-analysis was clinical response at 6 months as defined by disease-specific criteria in randomized trials. We also calculated pooled proportions of responders within disease types from observational studies. Ninety-five rituximab studies were identified: 86 were observational studies in patients with ITP (n = 1746), SLE (n = 1047), pemphigus vulgaris (n = 564), Sjogren's syndrome (n = 138), myasthenia gravis (n = 66), and CIDP (n = 31) and nine were randomized controlled trials (n = 992) in patients with ITP, SLE, and Sjogren's syndrome that compared rituximab with placebo plus standard of care. Among randomized trials, response rates were higher with rituximab (relative risk, 1.38; 95% confidence interval [CI], 1.05-1.83). The pooled proportion of rituximab responses ranged from 94% (95% CI, 88%-98%) for pemphigus vulgaris to 48% (95% CI, 30%-66%) for CIDP. Rituximab was generally well tolerated in observational studies although in the randomized trials, adverse events were more common in the rituximab group. Rituximab is an immune-modulating agent with biologic activity across many autoimmune conditions. Our data support the use of comparative trials with broad eligibility criteria to evaluate rituximab as an alternative to IVIG in autoimmune diseases.

Off-label use of rituximab in autoimmune disease in the Top End of the Northern Territory, 2008-2016.

Rituximab, an anti-CD20 B-cell depleting monoclonal antibody, is increasingly prescribed off-label for a range of autoimmune diseases. There has not previously been an audit of off-label rituximab use in the Northern Territory, where the majority of patients are Aboriginal. To evaluate retrospectively off-label rituximab use in autoimmune diseases in the Top End of the Northern Territory. We performed a retrospective audit of 8 years of off-label rituximab use at the Royal Darwin Hospital, the sole tertiary referral centre for the Darwin, Katherine and East Arnhem regions. Electronic and paper records were reviewed for demographic information, diagnosis/indication for rituximab, doses, previous/concomitant immunosuppression, clinical outcomes and specific adverse events. Rituximab was prescribed off-label to 66 patients for 24 autoimmune diseases. The majority of patients (62.1%) were Aboriginal and 60.6% female. The most common indications were refractory/relapsing disease despite standard therapies (68.7%) or severe disease with rituximab incorporated into an induction immunosuppressive regimen (19.4%). Systemic lupus erythematosus was the underlying diagnosis in 28.8% of cases. A clinically significant response was demonstrated in 74.2% of cases overall. There were 18 clinically significant infections; however, 13 were in patients receiving concurrent immunosuppressive therapy. There was a total of nine deaths from any cause. Rituximab has been used off-label for a range of autoimmune diseases in this population with a high proportion of Aboriginal patients successfully and safely in the majority of cases.

Rituximab in myasthenia gravis: a "to be or not to be" inhibitor of T cell function.

In recent years, rituximab (RTX), a monoclonal antibody that binds the B lymphocyte membrane protein CD20, has been increasingly used for the treatment of autoimmune diseases, with the rationale of destroying pathogenic B lymphocytes and decreasing autoantibody formation. Surprisingly, RTX has also proven effective in predominantly T cell-mediated diseases, raising the question whether additional mechanisms may play roles in determining the therapeutic response. Here, we review the current literature on the effects of RTX in autoimmune diseases, with special emphasis on myasthenia gravis (MG). To elicit a complete and effective immune response, B and T lymphocytes cooperate in a loop in which they affect each other. Disruption of this cross talk has profound effects on the immune system. RTX is likely to affect the whole spectrum of B cell function, including antigen presentation, cytokine production, and T cell stimulation. In addition, as a small subset of T lymphocytes expresses CD20, its direct targeting by RTX may contribute to the therapeutic effect. Owing to its distinctive immune characteristics, MG proved to be a useful model to investigate the multifaceted implications of B cell depletion.

Low pre-treatment B-cell counts are not a risk factor of infection in patients treated with rituximab for autoimmune diseases: An observational study

ObjectivesRituximab (RTX) is increasingly used in patients with refractory rheumatoid arthritis (RA) and other severe autoimmune diseases (AID). In practice, many clinicians are reluctant to prescribe RTX in patients with low B-cell counts because of the presumed risk of infection. The aim of this study was therefore to investigate whether B-cell counts before treatment or retreatment with RTX predict the occurrence of infections. MethodsObservational, single-centre study of 161 patients treated with RTX for RA and other AID at a tertiary hospital. CD19+ B-cell counts were assessed by flow cytometry and multivariate statistical analysis adjusted for various potential predictors was performed. ResultsThe rate of severe infection was 5.9/100 patient-years in RA patients and 24.9 in non-RA AID (P<0.001). Low B-cell counts at the time of RTX infusion were not associated with subsequent severe (HR=0.55, P=0.60) or overall infection (HR=0.85, P=0.58). Significant pre-treatment predictors of severe infection were a diagnosis other than RA (HR=4.68, P<0.001), immunoglobulin (Ig) G levels <7g/L (HR=2.36, P=0.01), age (HR=1.03, P=0.01), and diabetes (HR=3.61, P=0.01). ConclusionsLow B-cell counts before RTX infusion did not predict subsequent infections in this population treated with RTX for RA and other AID, therefore not supporting the practice of pre-treatment assessment of B-cells. Nevertheless, a higher risk of severe infection was confirmed for low pre-treatment IgG levels, older age, diabetes, and AID other than RA.

B Cell Therapies, Approved and Emerging: a Review of Infectious Risk and Prevention During Use.

The development of B cell-targeted biologics represents a major advance in the treatment of autoimmune rheumatic diseases. As with other immunosuppressive agents, risk of infection is a key clinical concern. This review summarises safety data from 15years of experience of rituximab in autoimmune diseases with a particular focus on opportunistic infection and class-specific complications and infection risk. Rarely, cases of progressive multifocal leucoencephalopathy in rituximab-treated patients (5/100 000) have accumulated over time although no proven causal association has yet been shown. With repeat cycles of therapy, hypogammaglobulinaemia has been observed in a larger proportion of patients and is associated with increased risk of serious infections. The infection profile of the newer B cell-targeted agent, belimumab, in patients with active systemic lupus erythematosus is also discussed. Data from registries are needed to extend insights further and also to evaluate for any impact with the difference in mode of action of belimumab and infection risk in this population.

DI-012 Rituximab efficacy in the treatment of autoimmune diseases

Background The treatment of rare autoimmune diseases presents for patients the additional problem of limited therapeutic options, which are usually reduced to corticosteroids and immunosuppressants. The use of rituximab could be an effective alternative. Purpose To determine the efficacy of treatment with rituximab in autoimmune diseases. Material and methods Retrospective observational study of patients with autoimmune diseases who were treated with rituximab between January 2008–March 2014. Data was collected from electronic prescription records. Diagnosis, reason for prescribing, previous and concomitant treatments, dose, recurrence and treatment outcome were collected as study variables. Results 11 patients (36% male), mean age 47 years were analysed. The diseases were lupus erythematosus (36%) autoimmune thrombocytopenia (9%) and a miscellaneous group: vasculitis, pemphigus, scleroderma, cryoglobulinaemia, Sjogren’s syndrome, antiphospholipid syndrome (55%). The reason for using rituximab was: treatment failure with pre-treatments in 81% of cases or first choice in the remaining 19%. 81% of administrations followed the pattern 375 mg/m²/week for 4 weeks while 19% followed the pattern of 1,000 mg on days 1 and 15 of each cycle. With respect to previous treatment, 81% of patients had received high doses of corticosteroids, 54% corticosteroids with immunosuppressant; 1 patient was on prior treatment with intravenous immunoglobulin. Rituximab was administered concomitantly with corticosteroids for the majority of patients (91%). Treatment efficacy was assessed according to the response as: complete response (27%), partial response (54%) and no response (18%). Of the 11 patients studied, 6 (54%) received only one cycle of rituximab, 3 (27%) currently remain in treatment and 2 patients (18%) died due to progression of their disease. Conclusion Although its efficacy is variable, rituximab may be a valid therapeutic option in autoimmune diseases. Randomised controlled studies are necessary to ensure the various indications of rituximab. Reference 1. Rosman Z, Shoenfeld Y, Zandman-Goddard G. Biologic therapy for autoimmune diseases: an update. BMC Medicine 2013;11:88 Reference No conflict of interest.

AB0376 The efficacy of rituximab treatment for thrombotic thrombocytopenic purpura complicated with connective tissue disease

BackgroundRituximab has been used widely and established the key role for B-cell lymphoma treatment. Rituximab is a chimeric monoclonal antibody bound to the CD20 antigen present on the surface of...

Indications of Rituximab in autoimmune diseases

B cell targeted therapies are becoming widespread for the treatment of multiple autoimmune diseases including conditions such as Rheumatoid Arthritis, Multiple Sclerosis and Type ! diabetes typically considered as T cell mediated. This interest stems from the convergence of tremendous progress in understanding the multiple effector and regulatory roles played by B cells in regulating autoimmunity as well as in the promising results reported for B cell depletion in an ever expanding number of autoimmune diseases. This review will review current knowledge of Rituximab-induced B cell depletion in diseases where this therapy is either well established or represents a promising therapeutic avenue with potential to uncover important disease mechanisms.

Treatment of retinal vasculitis in Behçet's disease with rituximab

Behçet's disease (BD) is more common in eastern than western countries. Physicians have frequently encountered problems in its treatment, especially eye involvement. Recurrent oral and genital aphthous ulcerations are the hallmarks of Behçet's disease but other organs can be involved and ocular disease is one of the most disabling manifestations. Up to now, there are some problems in treatment of the retinal vasculitis due to Behçet's disease. We reported one patient, with visual loss due to retinal vasculitis that was resistant to prednisolone and azathioprine. Our patient was treated successfully with rituximab and his remission was sustained for 24 months of follow-up. Rituximab is a chimeric monoclonal antibody that acts against the specific B cell antigen, CD20. The recent success of rituximab in autoimmune diseases, which is considered to be T cell-mediated, indicates that B cells must have a much broader role in the pathogenesis of autoimmune diseases than generally appreciated.

Rituximab off-label use for immune diseases: assessing adverse events in a single-centre drug-utilization survey

Rituximab is an anti-CD20 autoantibody approved for rheumatoid arthritis. It induces deep and prolonged depletion of CD20-bearing lymphocytes. Rituximab is increasingly used off-label for autoimmune diseases (AIDs) in immunocompromised patients (ICP), whereas its safety is not well documented in this setting. We assessed off-label rituximab use in AIDs through a drug-utilization survey in Toulouse University Hospital (2834 beds) from January 2004 to December 2005. Patients who had received at least one rituximab infusion for AIDs were identified from the pharmacy department database. We used the World Health Organization definition for serious adverse events (SAEs) [1]. Patients taking >20 mg day−1 prednisone and/or an immunosuppressive drug at the time of first rituximab infusion were considered immunocompromised. All patients were followed 1 year after the first rituximab infusion. Thirty-seven patients (18 women), mean age 51.7 years (95% confidence interval ±17.6) were included in the study. Median disease duration was 87 months (range 1–396). Diagnostic groups were: autoimmune cytopenia (n = 19), autoimmune coagulation disorder (n = 5), cryoglobulinaemia (n = 7), Wegener's granulomatosis (n = 3), pemphigus (n = 2) and lupus erythematosus (n = 1). The mean daily corticosteroid dosage at the time of rituximab first infusion was 35.2 mg day−1 (median 30; range 0–60). There was 30 ICPs (81.1 ± 12.6%); 75.7% (±13.8) of the patients received a complete cycle of four 375 mg kg−1 day−1 infusions. Eight then had maintenance therapy. We estimated that the complete remission rate after rituximab was 20/37 (54 ± 16.1%) according to criteria used in major international publications. One patient had a partial response. Rituximab was the main contributor to complete remission in 14 patients (37.8 ± 15.6) who had no intensification of other therapies. Among 20 complete responders, three were treated again because of relapse between 12 and 13 months after the first infusion. SAEs occurred in 14/37 patients (37.8 ± 15.6%) (Table 1), including death in six with uncontrolled disease. Seven (18.9 ± 12.6%) had serious infections, of whom two had pneumocystosis. Six of these seven patients were immunocompromised and another had undergone splenectomy 3 months earlier. The estimated incidence rate of infectious SAEs was 20.7 (±14.5) per 100 patient-years in ICPs. Table 1 Serious adverse events (SAE) among 37 patients treated by Rituximab for AIDs To our knowledge, this is the first report of a systematic hospital-based safety survey of rituximab off-label utilization for AIDs. Incidence of SAE, especially infectious, was much higher than in another study including adult patients with various AIDs [2]. In this retrospective study, 1/3 of patients had rheumatoid arthritis, some had a short follow-up, and patients were included on a voluntary basis by their attending physician. We cannot exactly determine the contribution of rituximab to infectious SAEs, as SAEs occur in about 13.5 per 100 years in patients receiving chronic immunosuppressive therapy for various AIDs [3]. Given a large confidence interval, this may not be very different from the 20.7 (±14.5) per 100 years infection rate we have found. However, hypogammaglobulinaemia occurring in some patients [4], loss of IgM-only producing memory B cells that are crucial for defence against bacteria [5], alteration of antigen-presenting cell function due to B-cell depletion [6] and the possibility of delayed neutropenia [7] may worsen susceptibility to infection in previously immunocompromised patients exposed to rituximab. In conclusion, in this study SAEs were frequent among patients treated off-label by rituximab for AIDs. The infection rate was perhaps abnormally high. Benefit-to-risk ratio of rituximab off-label use for immune diseases in real life should be further systematically assessed.

Drug Insight: the mechanism of action of rituximab in autoimmune disease—the immune complex decoy hypothesis

Inflammatory responses to cell-associated or tissue-associated immune complexes are key elements in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and immune thrombocytopenic purpura. Effector cells, such as monocytes, macrophages and neutrophils, bind immune complexes in a process mediated by Fcgamma receptors, and these cells then initiate inflammatory reactions that lead to tissue destruction. Rituximab is an anti-CD20 monoclonal antibody that suppresses inflammation effectively in autoimmune diseases. It was initially approved by the FDA for the treatment of B-cell lymphomas and later for rheumatoid arthritis refractory to anti-tumor necrosis factor therapies. Rituximab is hypothesized to suppress disease injury in autoimmune diseases by promoting rapid and long-term elimination of circulating and possibly lymphoid-tissue-associated B cells. We suggest, however, that a different mechanism may underlie much of the therapeutic action of rituximab in autoimmune diseases: binding of tens of thousands of rituximab-IgG molecules to B cells generates decoy sacrificial cellular immune complexes that efficiently attract and bind Fcgamma receptor-expressing effector cells, which diminishes recruitment of these effector cells at sites of immune complex deposition and, therefore, reduces inflammation and tissue damage.