Rituximab Therapy In Patients Research Articles

Can quantitative monitoring of B cells evaluate the efficacy of Rituximab in primary CNS demyelinating disorders?

Abstract Introduction: Rituximab (RTX), initially approved for various blood cancers, is additionally used for the management of primary central nervous system (CNS) demyelinating disorders. This study aimed to quantify the % of B cells following RTX therapy in patients with primary CNS demyelinating disorders, so as to establish a correlation, if any, between the degree of B-cell depletion and clinical response(s). Materials and Methods: A prospective, observational study was conducted from February 2020 to August 2021 in 15 adults diagnosed with primary CNS demyelinating disorders. The % of B cells was quantified in terms of CD20 by flow cytometry, and clinical evaluation was by Expanded Disability Status Scale (EDSS) scores. Following the first dose of RTX, the %CD20 counts were measured 2 and 24 weeks later; subsequently, depending on the %CD20, RTX was administered. Accordingly, patients were divided into Group 1 (n = 7, %CD20 ≥ 1.5) and Group 2 (n = 8, %CD20 < 1.5) and followed up on the basis of CD counts till the completion of the study or until they were lost to follow-up. Safety was evaluated by recording of treatment-emergent adverse drug reactions (ADR). Results: In patients with CNS demyelinating disorders (n = 15), their median (interquartile range [IQR]) %CD20 and EDSS at baseline was 9.8 (5.6–18.8)% and 8.0 (7.5–8.0)%, respectively. In Group 1 (n = 7, %CD20 ≥ 1.5), there was a gradual decrease of %CD20 and EDSS, whereas in Group 2 (n = 8, %CD20 < 1.5), despite withholding RTX, patients remained asymptomatic, and their %CD20 remained <1.5 and EDSS showed a gradual decrease. 87% of patients experienced at least one ADR, the median (IQR) of ADRs per patient was 3 (0–3), and all 31 ADRs were infusion-related, with 100% recovery. Conclusion: RTX was relatively safe to use in these disorders, and monitoring its efficacy was adequately achieved using EDSS, with no additional benefits accrued by measuring %CD20 counts.

Association between functional FCGR3A F158V and FCGR2A R131H polymorphisms and responsiveness to rituximab in patients with autoimmune diseases: a meta-analysis.

To investigate the association between the functional Fc gamma receptor 3 A (FCGR3A) V158F and FCGR2A R131H polymorphisms and rituximab therapy in patients with autoimmune diseases. We searched the Medline, Embase, and Cochrane databases for relevant articles. We conducted a meta-analysis of the association between FCGR3A V158F and FCGR2A R131H polymorphisms and responsiveness to rituximab in patients with autoimmune diseases. Eleven studies, consisting of 661 responders and 267 non-responders for FCGR3A V158F polymorphism and 156 responders and 89 non-responders for FCGR2A R131H polymorphism, were included. The meta-analysis revealed a significant association between the FCGR3A V allele and responsiveness to rituximab (odds ratio [OR] = 1.600, 95% confidence interval [CI] = 1.268-2.018, P < 0.001). Furthermore, associations were found using the dominant and homozygous contrast models. Subgroup analysis showed an association between the FCGR3A V allele and responsiveness to rituximab in European, RA, ITP, small (<50) and large (≥50) groups, and short- (≤6 months) and long-term follow-up periods (≥6 months). These associations were also found in recessive, dominant or homozygous contrast models. Meta-analysis revealed no association between the FCGR2A R allele and responsiveness to rituximab (OR = 1.243, 95% CI = 0.825-1.873, P = 0.229). We demonstrated that the FCGR3A F158V polymorphism is associated with better responsiveness to rituximab therapy in patients with autoimmune diseases, indicating that individuals carrying the FCGR3A V allele will likely respond better to rituximab. However, FCGR2A R131H polymorphism was not associated with better response to rituximab.

The experience of rituximab therapy in patients with juvenile systemic lupus erythematosus: the preliminary results of two-center cohort study

Systemic lupus erythematosus is an immunopathological disease which is characterized by a poor prognosis. Biologics applied in the disease treatment allow reducing the corticosteroid toxicity and controlling the disease.Purpose. To evaluate the efficacy and safety of rituximab therapy in children with systemic lupus erythematosus.Material and methods. The retrospective study included data of 48 patients with systemic lupus erythematosus treated with rituximab. Systemic lupus erythematosus was diagnosed based on the SLICC classification criteria. Patients were assessed at baseline disease status, at the time of rituximab initiation and follow-up. The indications for the rituximab were: lupus nephritis, CNS involvement, and hematological involvement resistant to the standard therapy, and in cases of severe corticosteroid toxicity.Results. During rituximab therapy the significant decrease of the SELENA–SLEDAI activity index was observed. There was a significant decrease of the level of antibodies against dsDNA, normalization of the levels of hemoglobin, ESR, complement C4. The proportion of patients with cytopenia decreased up to their complete absence in patients receiving therapy for three years. The number of patients with active lupus nephritis decreased from 16 at the time of rituximab initiation to 1 after 3 years of therapy. Significant dynamics of proteinuria and hematuria was noted, except for 1 patient. The daily dose of corticosteroids was reduced by 90% from baseline in patients treated for 3 years. Serious adverse events included three deaths in patients with high systemic lupus erythematosus activity with uncontrolled macrophage activation syndrome associated with infections. Various infectious complications, hypogammaglobulinemia, which required replacement therapy with intravenous immunoglobulin, were also recorded.Conclusion. Rituximab can be considered as an option for the treatment of severe forms of systemic lupus erythematosus which are resistant to standard therapy. Further studies are required to evaluate efficacy and safety.

Breakthrough SARS-CoV-2 infections and prediction of moderate-to-severe outcomes during rituximab therapy in patients with rheumatic and musculoskeletal diseases in the UK: a single-centre cohort study.

Concerns have been raised regarding the reduced immunogenicity of vaccines against COVID-19 in patients with autoimmune diseases treated with rituximab. However, the incidence and severity of breakthrough infections in unbiased samples of patients with specific rheumatic and musculoskeletal diseases are largely unknown. We aimed to assess the incidence of breakthrough SARS-CoV-2 infection, compare rates of moderate-to-severe COVID-19 with any severe infection event, and evaluate predictors of moderate-to-severe COVID-19 outcomes in patients treated with rituximab. We did a retrospective cohort study in all rituximab-treated patients with rheumatic and musculoskeletal diseases in a single centre in Leeds, UK between March 1, 2020 (the index date), and April 1, 2022. Adults aged 18 years and older, who fulfilled classification criteria for established rheumatic and musculoskeletal diseases, and received therapy with at least one rituximab infusion between Sept 1, 2019 (6 months before the pandemic in the UK), and April 1, 2022, were eligible for inclusion in the study. SARS-CoV-2 infection was defined by antigen test or PCR. COVID-19 outcomes were categorised as mild (from ambulatory to hospitalised but not requiring oxygen support) or moderate-to-severe (hospitalised and requiring oxygen support or death). The primary outcome was breakthrough COVID-19 infection, which was defined as an infection occurring 14 days or more after the second vaccine dose. Predictors of moderate-to-severe COVID-19 outcomes were analysed using Cox regression proportional hazards. Of the 1280 patients who were treated with at least one cycle of rituximab since Jan 1, 2002, 485 (38%) remained on rituximab therapy on April 1, 2022. Of these patients, 400 fulfilled all inclusion criteria and were included in our final analysis. The mean age at the index date was 58·9 years (SD 14·6), 288 (72%) of 400 patients were female and 112 (28%) were male, 333 (83%) were White, and 110 (28%) had two or more comorbidities. 272 (68%) of 400 patients had rheumatoid arthritis, 48 (12%) had systemic lupus erythematosus, 48 (12%) had anti-neutrophil cytoplasmic antibody-associated vasculitis, and 46 (12%) had other rheumatic and musculoskeletal diseases. During the study, 798 rituximab cycles were administered. Of the 398 (>99%) of 400 patients with vaccine data, 372 (93%) were fully vaccinated. Over the 774·6 patient-years of follow-up, there was an incremental increase in all SARS-CoV-2 severity types over the three pandemic phases (wild-type or alpha, delta, and omicron), but most infections were mild. The rates of moderate-to-severe COVID-19 were broadly similar across these three variant phases. Of 370 patients who were fully vaccinated and with complete data, 110 (30%) had all severity type breakthrough COVID-19, 16 (4%) had moderate-to-severe breakthrough COVID-19, and one (<1%) died. In the post-vaccination phase (after Dec 18, 2020), the incidence rates of all severity type and moderate-to-severe COVID-19 were substantially lower in those who were fully vaccinated compared with unvaccinated or partially vaccinated individuals (22·83 per 100 person-years [95% CI 18·94-27·52] in those who were fully vaccinated vs 89·46 per 100 person-years [52·98-151·05] in those who were partially vaccinated or unvaccinated for infections of all severities, and 3·32 per 100 person-years [2·03-5·42] in those who were fully vaccinated vs 25·56 per 100 person-years [9·59-68·10] in those who were partially vaccinated or unvaccinated for moderate-to-severe infections). The rate of moderate-to-severe COVID-19 was broadly similar to other severe infection events in this cohort (5·68 per 100 person-years [95% CI 4·22-7·63]). In multivariable Cox regression analysis, factors associated with an increased risk of moderate-to-severe COVID-19 were the number of comorbidities (hazard ratio 1·46 [95% CI 1·13-1·89]; p=0·0037) and hypogammaglobulinaemia (defined by a pre-rituximab IgG concentration of <6 g/L; 3·22 [1·27-8·19]; p=0·014). This risk was reduced with each vaccine dose received (0·49 [0·37-0·65]; p<0·0001). Other factors, including concomitant prednisolone use, rituximab-associated factors (eg, rituximab dose and time to vaccination since last rituximab dose), and vaccine-associated factors (eg, vaccine type and peripheral B-cell depletion) were not predictive of moderate-to-severe COVID-19 outcomes. This study presented detailed analyses of rituximab-treated patients during various phases of the COVID-19 pandemic. In later stages of the pandemic, the SARS-CoV-2 breakthrough infection rate was high but severe COVID-19 rates were similar to any severe infection event rate in patients who were vaccinated. The risk-benefit ratio might still favour rituximab in vaccinated patients with severe rheumatic and musculoskeletal diseases who have few other treatment options. Increased vigilance is needed in the presence of comorbidities and hypogammaglobulinaemia for all infection types. Wellcome Trust and Eli Lilly.

Outcome of rituximab therapy in patients with systemic lupus erythematosus

Purpose: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs. Rituximab (RTX) is an anti-CD20 monoclonal antibody that is an approved treatment for various autoimmune diseases. However, no randomized controlled trial (RCT) has proved the benefit of RTX for patients with lupus nephritis (LN). We conducted a retrospective study to evaluate the effectiveness of RTX as an immunosuppressive treatment for SLE and LN. Methods: Subjects were selected by reviewing medical records from January 2004 to July 2020 in the rheumatology departments of two hospitals in Saudi Arabia. Patients were included if they were >16 years of age with a diagnosis of SLE that fulfilled the 2019 European League Against Rheumatism and the American College of Rheumatology criteria and had received RTX for SLE. Clinical and laboratory data, SLE disease activity index (SLEDAI) score and adverse events before and 3, 6, and 12 months after starting RTX were collected. Statistical analysis was conducted comparing median baseline values with those at various times after starting RTX. Results: 40 patients with SLE were included in the study. The indications for RTX were arthritis (37.5%) and LN (32.5%), with LN varying in severity. Over the 12 months from starting RTX, there were significant improvements in SLEDAI score, and anti-dsDNA antibody, C3, and C4 levels (P<0.001, P=0.048, P<0.001, and P=0.005, respectively). Steroid dose was also significantly reduced (P<0.001) post-RTX. Meanwhile, serum creatinine at 6 and 12 months did not differ significantly from the baseline. Proteinuria in patients receiving RTX for LN showed a significant reduction from median baseline value to that at 12 months (P=0.028). Conclusions: RTX effectively controlled multiple manifestations of SLE in a Saudi population and exhibited a steroid-sparing effect in this population. Larger RCTs should be conducted to determine the patients that could benefit from such treatment.

Evaluation of Rituximab for Induction and Maintenance Therapy in Patients 75 Years and Older With Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Older patients are underrepresented in studies of rituximab for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Little is known about outcomes and adverse events associated with the use of rituximab therapy among patients 75 years and older with ANCA-associated vasculitis. To examine outcomes and adverse events associated with the use of rituximab therapy in patients 75 years and older with ANCA-associated vasculitis, specifically granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). This multicenter cohort study involved 93 patients 75 years and older with ANCA-associated vasculitis from 36 university and nonuniversity hospitals in France. Data were obtained from the French Vasculitis Study Group database between January 1, 2000, and July 1, 2018, and a call for observation sent to French Vasculitis Study Group members on June 6, 2019. Data analysis was performed from November 15 to December 31, 2021. Inclusion criteria included a diagnosis of GPA or MPA according to European Medicines Agency classification criteria and receipt of treatment with rituximab after age 75 years. Patients were excluded if they were missing relevant clinical or biological data. Data on race and ethnicity were not reported because inclusion of this information was not authorized by the ethics committee. At least 1 infusion of rituximab as induction or maintenance therapy. Occurrence of remission, relapse, drug discontinuation, death, and serious infections (including types of serious infections). Of 238 patients screened, 93 were included (median [IQR] age, 79.4 [76.7-83.1] years; 51 women [54.8%]); 52 patients (55.9%) had a diagnosis of GPA, and 41 (44.1%) had a diagnosis of MPA. Thirty patients (32.3%) received rituximab as induction therapy in combination with high-dose glucocorticoid regimens, 27 (29.0%) received rituximab as maintenance therapy, and 36 (38.7%) received rituximab as both induction and maintenance therapy. The median (IQR) follow-up was 2.3 (1.1-4.0) years. Among 66 patients who received rituximab as induction therapy, 57 (86.4%) achieved remission, and 2 (3.0%) experienced relapses. The incidence of serious infection was significantly higher when rituximab was used as induction therapy vs maintenance therapy (46.6 [95% CI, 24.8-79.7] per 100 patient-years vs 8.4 [95% CI, 3.8-15.9] per 100 patient-years; P = .004). Most infections (12 of 22 [54.5%]) were gram-negative bacterial infections. The incidence of death was 19.7 (95% CI, 7.2-42.9) per 100 patient-years among those who received rituximab as induction therapy and 5.3 (95% CI, 1.9-11.6) per 100 patient-years among those who received rituximab as maintenance therapy. In this cohort study, rituximab therapy was associated with achievement and maintenance of remission in most patients 75 years and older with ANCA-associated vasculitis. The incidence of serious infections and death was high when rituximab was used as induction therapy in combination with high-dose glucocorticoid regimens but not when rituximab was used as maintenance therapy. Efforts might focus on reducing serious infections during the first months of therapy.

The efficacy and safety of rituximab therapy in patients with juvenile systemic lupus erythematosus

The efficacy and safety of rituximab therapy in patients with juvenile systemic lupus erythematosus

DECREASE OF ANTI-TOPOISOMERASE-1 ANTIBODY IN PATIENTS WITH INTERSTITIAL LUNG DISEASE, ASSOCIATED WITH SYSTEMIC SCLEROSIS, AS A PREDICTOR OF BETTER RESPONSE ON RITUXIMAB THERAPY

TOPIC: Diffuse Lung Disease TYPE: Original Investigations PURPOSE: To compare clinical parameters and B-lymphocytes (B-lymph) level in systemic sclerosis (SSc) patients depending on the decrease of anti-topoisomerase-1 antibody (a-Topo-1) during rituximab (RTX) therapy with prospective long-term follow-up. METHODS: This study included 63 patients with SSc. The mean follow-up period was 26,3±10,7 months. The mean age was 47 years (18-66), female-53 patients (84%), the diffuse cutaneous subset of the disease had 39 patients (62%). Symptoms of the interstitial lung disease (ILD) were observed in 60 patients (95%). The mean disease duration was 6,03±4,9 years. The cumulative mean dose of RTX was 2,9±1,1 grams. All patients received prednisolone at a dose of 11,1±4,4 mg, immunosuppressants at inclusion received 43% of them. All patients were positive for a-Topo-1. Patients were divided into 2 groups depending on the changes of a-Topo-1 on RTX therapy: group 1 (n=32) – patients with decrease in a-Topo-1 and group 2 (n=31) – patients with stable level of a-Topo-1. Patients of the compared groups did not differ in the main demographic and clinical parameters, except disease subset: there was 47% of patients with diffuse cutaneous subset in group 1 and 80% of them in group 2. The results are presented in the form of mean values and changes in parameters (delta(Δ) - difference between the baseline parameter and follow up point). RESULTS: Considering the entire cohort, an improvement of almost all outcome parameters was found. In group 1 there was ΔActivity score (EScSG-AI)=1,93; ΔRodnan skin score (mRSS)=5,33; ΔB-lymph (absolute count)=0,222; Δforced vital capacity % predicted (FVC)=11,9; Δdiffusion capacity for carbon monoxide % predicted (DLCO)=3,2; cumulative mean dose of RTX=3,3±1,2 mg. In group 2 there was ΔActivity score (EScSG-AI)=1,84; ΔmRSS=4,68; ΔB-lymph=0,223; ΔFVC=5,75; ΔDLCO=2,73; cumulative mean dose of RTX=2,7±0,9 mg. When groups were analyzed separately, we observed a significantly higher increase of FVC (p=0,03) and DLCO (p=0,02) in group 1. In group 1 the a-Тopo-1 level decreased from 174,2±50,1 to 148,1±66,1 units/ml (p=0,0009). There was a moderate negative statistically significant correlation between the a-Topo-1 and cumulative mean dose of RTX (r=-0,298, p=0,017). A moderate negative statistically significant correlation was found between the a-Topo-1 and FVC (r=-0,322, p=0,009). CONCLUSIONS: In our study, the a-Topo-1 level significantly decreased during RTX therapy. The decrease of a-Topo-1 level correlated with the cumulative mean dose of RTX and an increase of FVC, and was accompanied by a decrease of mRSS, disease activity index and an increase of DLCO. There was a greater increase of FVC and DLCO in the group of patients with a decrease of a-Topo-1. CLINICAL IMPLICATIONS: Therefore, decrease of a-Topo-1 could be considered as a predictor of a better response on RTX therapy in patients with ILD associated with SSc. DISCLOSURES: No relevant relationships by Lidia Ananyeva, source=Web Response No relevant relationships by Oxana Desinova, source=Web Response No relevant relationships by Liudmila Garzanova, source=Web Response No relevant relationships by Olga Koneva, source=Web Response No relevant relationships by Olga Ovsynnikova, source=Web Response No relevant relationships by Rushana Shayakhmetova, source=Web Response No relevant relationships by Mayya Starovoytova, source=Web Response

Efficacy and safety of rituximab therapy in patients with autoimmune neurological disorders

Efficacy and safety of rituximab therapy in patients with autoimmune neurological disorders

Efficacy and safety of rituximab in autoimmune pancreatitis type 1: our experiences and systematic review of the literature

Introduction Autoimmune pancreatitis (AIP) is a special form of pancreatitis that responds well to glucocorticoid (GC) treatment. Relapses of AIP are common. The anti-CD20 antibody rituximab (RTX) has shown promising results in GC refractory cases, but long-term data are scarce. The study aims to determine the clinical and imaging response to RTX and summarize the existing data on RTX therapy in patients with AIP type 1 in the literature. Patients and methods Retrospective analysis of electronic medical records was conducted. Additionally, we conducted a systematic review of the literature concerning RTX use in AIP type 1. Results Twelve (11.7%) of 103 patients with AIP type 1 were treated with RTX during the study period: eight (66.7%) achieved complete and four (33.3%) partial remission. RTX was discontinued in one patient who developed fever and reactivation of latent tuberculosis. None of the remaining 11 patients relapsed during a median follow-up of 17 months. No significant differences were detected in baseline clinical characteristics or history of relapse between the patients who obtained complete and partial remission. Altogether, eight studies with 110 AIP type-1 patients treated with RTX were analyzed. Adverse effects ranged from 11–43% and the relapse-free period during follow-up (range 2–173 months) ranged from 38–94%. Conclusions Our results confirm that RTX is efficacious in the treatment of AIP type 1 by inducing remission and preventing relapse. In addition, there are few adverse effects of the treatment.

OP0129 BELIMUMAB AFTER RITUXIMAB SIGNIFICANTLY REDUCED IGG ANTI-DSDNA ANTIBODY LEVELS AND PROLONGED TIME TO SEVERE FLARE IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Background:B cell depletion with rituximab, an anti-CD20 mAb, has shown efficacy for systemic lupus erythematosus (SLE) in open-label studies but failed to meet primary endpoints in two randomised, placebo controlled trials. Rituximab increases BAFF levels which has been associated with subsequent lupus flares. We hypothesised that high BAFF levels after rituximab limit its effectiveness in SLE and that the anti-BAFF monoclonal antibody belimumab given immediately after rituximab could be a valuable therapeutic strategy.Objectives:To assess the safety and obtain preliminary evidence for efficacy of belimumab following rituximab therapy in patients with SLE.Methods:BEAT-LUPUS (Belimumab after B cell depletion in SLE) is a 52-week phase IIb, randomised, double-blind, placebo-controlled clinical trial investigating the safety and efficacy of intravenous belimumab after B cell depletion therapy (rituximab). The maximum permissible prednisolone dose throughout the trial was 20mg/day with encouragement to reduce by 50% from baseline by 6 months. The primary outcome measure was log IgG anti-dsDNA antibody serum levels at 52 weeks measured by ELISA. A linear regression ANCOVA model was fitted to evaluate the difference in 52-week anti-dsDNA levels between treatment arms adjusting for anti-dsDNA value at screening (before rituximab) and randomisation (4-8 weeks after the 1st infusion of rituximab), CD19 &gt; or &lt; 0.01x109/l at randomisation, and renal involvement at screen. Secondary outcomes included measures of disease activity and incidence of adverse events. B cell (CD19) counts were measured by flow cytometry. Intention to treat analysis was adopted. Full ethical and regulatory approval was obtained. A comprehensive description of the protocol and statistical analysis plan is available(1,2).Results:52 patients with active SLE received rituximab (2 infusions, 2 weeks apart) and then randomised to receive either belimumab (n=26) or placebo (n=26) 4-8 weeks after their 1st dose of rituximab. 32 patients completed trial treatment protocol (belimumab or placebo) through to 52 weeks, withdrawals were equally split between belimumab and placebo. There was a significant reduction in IgG anti-dsDNA antibody levels in patients treated with belimumab compared to placebo at 52 weeks (p&lt;0.001, Figure 1); 43 patients were included in the intention to treat analysis at 52 weeks.Figure 1.Serum IgG anti-dsDNA antibody levels (geometric means with 95% confidence intervals) in patients treated with rituximab, then randomised to belimumab or placebo at 1st trial infusion. An intention to treat linear regression ANCOVA model was fitted to evaluate the difference in 52-week anti-dsDNA between belimumab or placebo adjusting for baseline values and stratification factors. N= patient numbers who provided serum samples at time indicated.Kaplan-Meier curves demonstrated that belimumab reduced the risk of severe flare (BILAG A flare) compared to placebo (hazard ratio 0.27, 95% confidence interval 0.07-0.97, unadjusted log-rank p=0.03). There were 10 and 3 severe flares in the placebo and belimumab group respectively. There was no difference in cumulative steroid dose over the course of the trial between belimumab and placebo.Belimumab did not increase the incidence of infections, serious or total adverse events, nor withdrawals due to adverse events compared to placebo. Belimumab significantly suppressed B cell repopulation at 52 weeks compared to placebo (p=0.001), but not total serum IgG.Conclusion:This placebo controlled double blind trial met its primary endpoint, a significant reduction in IgG anti-dsDNA antibody levels, and demonstrated that belimumab prolongs the time to severe flare compared to placebo. These results suggest that belimumab after rituximab is a safe and effective treatment for patients with SLE and supports further development of this combination as a novel therapeutic strategy.

Efficacy and safety of rituximab therapy in patients with systemic sclerosis disease (SSc): systematic review and meta-analysis.

The clinical benefits of rituximab in systemic sclerosis (SSc) are still contentious. The present meta-analysis aimed to systematically assess rituximab's safety and efficacy profile in SSc patients. A systematic online query was performed in PubMed, Scopus, Web of Science, and Embase. The studies on the application of rituximab for patients with SSc were reviewed comprehensively for over two years. In terms of efficacy profile, mRSS, MS, LVEF, sPAP, FVC, DLCO, TLC, FEV, DAS, severity activity, HAQ-DI and SF36 were assessed for organ involvement and quality of life. The level of biological and immunological markers was also evaluated in SSc patients treated with RTX. In total, 24 studies met the criteria. Although they did not have a high quality, they were free from heterogeneity and publication bias. The pooled results revealed a long-term improvement in mRSS and MS. HAQ-DI was improved to 0.78 after 12 months, and DAS was significantly reduced to 0.33, 0.23, and 0.24 following 6, 12, and 24 months of treatment, respectively (p = 0.00 for both parameters). The rest of the parameters remained stable over time in patients with SSc. The pooled analysis of these patients demonstrated that the induction of death, cancer, infection, and infusion were 9, 5, 18 and 10%, respectively. Based on the pooled results of this meta-analysis, rituximab improves skin score and disease indices and stabilizes organ involvement in SSc patients. Rituximab seems to possess reasonable safety, similar to previous data from other autoimmune diseases.

Intravenous rituximab therapy for active Graves' ophthalmopathy: a meta-analysis.

The successful treatment of Graves' ophthalmopathy (GO) remains a challenge, while the efficacy of rituximab (RTX) is at present controversial. The aim of this meta-analysis was to investigate the potential impact of intravenous RTX therapy in patients with GO. We performed a search in the PubMed, Embase, and Web of Science databases for relevant studies published before July 2020. The primary outcome was the change of clinical activity score (CAS), and secondary outcomes were the change of proptosis and TSH receptor antibodies (TRAb). A meta-analysis was conducted to calculate the standard mean difference (SMD) for these outcomes by using fixed- or random-effect models. Analysis of outcomes in 152 patients collected from 12 published articles was conducted. Compared to baseline value, CAS was significantly decreased at 1, 6, 12, and >12 months after RTX treatment. For proptosis, the results revealed no significant decrease at 1-3, 6, and ≥12 months. Moreover, the pooled analysis employed in this meta-analysis showed no significant difference of TRAb at 1 month, but significant declines were observed at 6 and ≥12 months. Our results strongly suggest that intravenous RTX treatment has an acute and long-lasting beneficial effect on decreasing both CAS and TRAb. The study also indicates that the effect of RTX on proptosis is limited. There is evidently a need to investigate the mechanism behind RTX ineffectiveness on proptosis and explore other therapeutic regimens for the reduction of proptosis.

A Follow-Up Study of a European IgG4-Related Disease Cohort Treated with Rituximab.

Objectives: IgG4-related disease (IgG4-RD) is a chronic fibro-inflammatory disorder affecting virtually any organ. Type 1 autoimmune (type 1 AIP) is its pancreatic manifestation. To date, steroids are considered the first-line pancreatitis treatment. The CD20-binding antibody rituximab (RTX) appears a promising steroid-sparing therapy, although long-term data are lacking. We aimed to bridge this gap with a cohort of IgG4-RD patients treated with RTX and to assess the potential value of the Responder Index (RI) as a discriminatory score for disease activity. Methods: We retrospectively evaluated 46 patients from a tertiary referral centre who were diagnosed with IgG4-RD and/or type 1 AIP according to the International Consensus Diagnostic Criteria or Unifying-AIP criteria between June 2006 and August 2019. Results: Patients resembled previous cohorts in terms of characteristics, diagnosis, and therapeutic response. Thirteen of the 46 patients with IgG4-RD/type 1 AIP were treated with RTX pulse therapy due to relapse, adverse reactions to steroids, or high-risk constellations predicting a severe course of disease with multi-organ involvement. Median follow-up after diagnosis was 52 months for all subjects, and 71 months in IgG4-RD patients treated with RTX. While patients in the RTX group showed no significant response to an initial steroid pulse, clinical activity as measured by the RI significantly decreased in the short-term after RTX induction. Within 16 months, 61% of patients relapsed in the RTX group but responded well to re-induction. Clinical and laboratory parameters improved equally in response to RTX. Conclusion: RTX therapy in patients with IgG4-RD is an effective and safe treatment to induce treatment response and possible long-term remission. Repeated RTX administration after 6–9 months may be of value in reducing the risk of relapse. The RI appears to be a reasonable index to assess disease activity and to identify patients with IgG4-related disease who may benefit from B-cell-depleting therapy.

Rituximab in practice: Clinical evaluation of patients with pemphigus after rituximab administration.

Pemphigus Vulgaris (PV) is a rare autoimmune blistering disease, which mainly causes mucosal and/or cutaneous lesions. In June 2018, FDA approved Rituximab (RTX)-a B-cell depleting agent-for the management of patients with moderate-to-severe pemphigus. Although the majority of patients respond well to this drug, some do not reach complete remission with a single cycle of RTX. In this review, following an overview of RTX and its clinical outcomes, we have focused on the possible outcomes after RTX therapy in patients with PV. The response is defined into four main categories; complete responders, partial responders, nonresponders, and paradoxical reactions, based on three possibilities of reaching the consolidation phase after 3 months, reaching remission until 6 months, and the ability of corticosteroid tapering in 6 months after RTX administration. Concerning the safety of RTX, three categories of infusion reactions, short and long-term side effects are discussed. Additionally, we have suggested approaches for the evaluation of clinical and serological responses at different critical time-points, including 1, 2, 3, and 6 months after RTX administration. Finally, available markers to predict the response to RTX and research gaps in the field of RTX therapy have been summarized.

Intravenous Rituximab Therapy for Active Graves’ Ophthalmopathy: A Meta-Analysis

Objective: The successful treatment of GO remains a challenge, and the efficacy of rituximab (RTX) remains debated. The aim of this meta-analysis is to investigate the potential impact of intravenous RTX therapy in patients with GO. Methods: We performed a search in PubMed, Embase and Web of Science for relevant studies published before July, 2020. The primary outcome was the change of CAS, and secondary outcomes were the change of proptosis and TRAb. A meta-analysis was conducted to calculated standard mean difference for these outcomes by using fixed- or random-effects model. Results:12 eligible articles were finally included. Compared with baseline value, CAS was significantly decreased at 1, 2, 3,6, and at least 12 month after RTX treatment. And for proptosis, the results revealed no significantly decrease at 1-3 month and 6 month, but there was a significant decrease at last visit. Similarly, pooled analysis showed no significant difference of TRAb at 1 month, but a significant decline was observed at 6 month and last visit. Conclusion: The acute and long-lasting beneficial effect of intravenous RTX for GO patients was confirmed in our meta-analysis. But, a significant improvement of proptosis was only found at last visit. The mechanism of the late reduction of proptosis remained to be elucidated.

Lessons for rituximab therapy in patients with rheumatoid arthritis.

B-cell depletion therapy is an effective option for the treatment of rheumatoid arthritis but often does not result in complete B-cell depletion. Complete B-cell depletion after rituximab treatment is associated with clinical response, and this outcome leads to long-term maintenance of therapy. Low pretreatment plasmablast counts, concomitant treatment with disease-modifying antirheumatic drugs, no smoking exposure, the presence of anticitrullinated protein antibodies or rheumatoid factor, and a low interferon signature are all predictive of complete B-cell depletion and clinical response. Half of patients who initially show complete B-cell depletion and clinical response after rituximab treatment eventually lose responsiveness with further infusions. However three-quarters of these patients regain this outcome in their following treatment cycle, suggesting that loss of response is reversible and that patients can still benefit from rituximab retreatment. The efficacy of reduced doses of rituximab is being investigated, but preliminary results suggest that these strategies are best used for maintenance therapy, particularly in patients who suffer adverse events or who are at a high risk of infection. Infusion-related reactions are the most common adverse events associated with rituximab treatment, and monitoring of IgG concentrations is crucial, as low concentrations are correlated with an increased risk of infection.

Serious Infectious Complications After Rituximab Therapy in Patients With Autoimmunity: Is This the Final Word?

Serious Infectious Complications After Rituximab Therapy in Patients With Autoimmunity: Is This the Final Word?

Post-rituximab immunoglobulin M (IgM) hypogammaglobulinemia.

Rituximab is a B cell depleting monoclonal antibody that targets the B cell-specific cell surface antigen CD20 and is currently used to treat several autoimmune diseases. The elimination of mature CD20-positive B lymphocytes committed to differentiate into autoantibody-producing plasma cells is considered to be the major effect of rituximab, that makes it a beneficial biological agent in treating autoimmune diseases. Hypogammaglobulinemia has been reported after rituximab therapy in patients with lymphoma and rheumatoid arthritis. Similar data are scarce for other autoimmune diseases. Low immunoglobulin G (IgG) or hypogammaglobulinemia has attracted the most attention because of its significant role in protective immunity. However, the incidence and clinical implications of low immunoglobulin M (IgM) or hypogammaglobulinemia have not been studied in detail. This review will focus on the frequency and the clinical concerns of low IgM levels that result as a consequence of the administration of rituximab. The etiopathogenic mechanisms underlying post-rituximab IgM hypogammaglobulinemia and its implications are presented. The long-term consequences, if any, are not known or documented. Multiple factors may be involved in whether IgG or IgM decreases secondary to rituximab therapy. It is possible that the autoimmune disease itself may be one of the important factors. The dose, frequency and number of infusions appear to be important variables. Post-rituximab therapy immunoglobulin levels return to normal. During this process. IgM levels take a longer time to return to normal levels when compared to IgG or other immunoglobulins. IgM deficiency persists after B cell repopulation to normal levels has occurred. Laboratory animals and humans deficient in IgM can have multiple infections. Specific pharmacologic agents or biologic therapy that address and resolve IgM deficiency are currently unavailable. If the clinical situation so warrants, then prophylactic antibiotics may be indicated and perhaps helpful. Research in this iatrogenic phenomenon will provide a better understanding of not only the biology of IgM, but also the factor(s) that control its production and regulation, besides its influence if any, on rituximab therapy.

Опыт применения биоаналога генно-инженерного биологического препарата у больных ревматоидным артритом в реальной клинической практике

The article presents the data of the Moscow Unified Arthritis Register (MUAR) and the results of rituximab therapy in patients with rheumatoid arthritis (RA).Aim: to evaluate the efficacy and safety of switching from the original rituximab (MabThera®) to its biosimilar (Acellbia®) in patients with RA in real clinical practice.Patients and Methods: patients with RA, included in MUAR register, were evaluated with an assessment of therapy efficacy and safety with the original rituximab (MabThera®), as well as after switching to the rituximab biosimilar (Acellbia®). A standard examination was performed to determine the number of swollen and tender joints, erythrocyte sedimentation rate, and C-reactive protein. Treatment efficacy was assessed using the DAS28 composite index, HAQ-DI (Health Assessment Questionnaire Disability Index) and RAPID-3 (Routine Assessment of Patient Index Data 3). In terms of safety, adverse events were recorded based on patient reports.Results: switching therapy regimen of 46 patients with RA from the original rituximab to the biosimilar was not accompanied by a decrease in the treatment efficacy. There was statistically significant increase in the proportion of the patients with low disease activity (DAS28&lt;3.2) from 39.1% to 52.2% and remission (DAS28&lt;2.6) from 17.4% to 23.9%, respectively. Further positive dynamics of HAQ-DI and RAPID-3 indices were noted. According to the authors, the increase in the frequency of a positive response to the treatment was associated with the duration of rituximab use in general. The frequency of adverse events during therapy with the original rituximab and its biosimilar was comparable: 9.22 and 10.9 per 100 patient years respectively.Conclusion: there were no significant differences between the original rituximab and its biosimilar. The results of switching therapy regimen of patients with RA from the original rituximab (MabThera®) to its biosimilar (Acellbia®), observed in real clinical practice, confirm their therapeutic equivalence.KEYWORDS: rheumatoid arthritis, rituximab, biosimilar, real clinical practice.FOR CITATION: Zhilyaev E.V., Koltsova E.N., Shmidt E.I. et al. Experience of using a genetically engineered biological drug biosimilar in patients with rheumatoid arthritis in real clinical practice. Russian Medical Inquiry. 2020;4(8):492–497. DOI: 10.32364/2587-6821-2020-4-8-492-497.