Trial Of Rituximab Research Articles

Six-year follow-up of participants in two clinical trials of rituximab or cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

In this six-year follow-up study, we used patient-reported outcome measures (PROMs) to compare values at baseline, at 18 months, and at six-year follow up from the CycloME and the RituxME trials. Based on the hypothesis that ME/CFS in a subgroup of patients is a variant of an autoimmune disease, we performed two clinical trials between 2014 and 2017. The RituxME trial was a randomized, double-blind and placebo-controlled phase III trial of 151 patients, assessing the B-cell depleting antibody rituximab. The CycloME trial was an open-label phase II trial of 40 patients using intravenous cyclophosphamide. Here we report six-year follow-up from both trials, using the Short Form 36 Physical Function (SF-36 PF) and DePaul short form (DSQ-SF) questionnaires. Of the patients available after six years, 75.7% of RituxME and 94.4% of CycloME patients participated. In the RituxME rituximab group, the mean SF-36 PF scores were 32.9 at baseline, 42.4 at 18 months and 45.5 at six years. In the placebo group, the mean SF-36 PF scores were 32.3 at baseline, 45.5 at 18 months and 43.1 at six years. In the CycloME trial, mean SF-36 PF increased from 35.4 at baseline to 54.4 at 18 months, and 56.7 at six years. At six-year follow-up, 44.1% of cyclophosphamide-, 27.6% of rituximab- and 20.4% of placebo-treated patients had an SF-36 PF ≥ 70, and further, 17.6%, 8.6% and 7.4% of the corresponding patient groups had an SF-36 PF ≥ 90, which is within normal range. In terms of worsening at six years, 5.9% of cyclophosphamide-treated, 10.3% of rituximab-, and 14.8% of placebo-treated patients had a drop in SF-36 PF of 20 points or more from baseline. There were no serious unexpected adverse reactions. After six years, 44.1% of the cyclophosphamide group scored an SF-36 PF of at least 70, and 17.6% of at least 90, suggesting that cyclophosphamide in a subgroup may modulate the disease course in a beneficial way. However, cyclophosphamide carries toxicity concerns and should not be used for ME/CFS patients outside clinical trials. Rather, these data should encourage efforts to better understand the disease mechanisms and to search for targeted and less toxic immune modulatory treatment for this patient group.

B-cells in pulmonary arterial hypertension: friend, foe or bystander?

There is an unmet need for new therapeutic strategies that target alternative pathways to improve the prognosis of patients with pulmonary arterial hypertension (PAH). As immunity has been involved in the development and progression of vascular lesions in PAH, we review the potential contribution of B-cells in its pathogenesis and evaluate the relevance of B-cell-targeted therapies. Circulating B-cell homeostasis is altered in PAH patients, with total B-cell lymphopenia, abnormal subset distribution (expansion of naïve and antibody-secreting cells, reduction of memory B-cells) and chronic activation. B-cells are recruited to the lungs through local chemokine secretion, and activated by several mechanisms: 1) interaction with lung vascular autoantigens through cognate B-cell receptors; 2) costimulatory signals provided by T follicular helper cells (interleukin (IL)-21), type 2 T helper cells and mast cells (IL-4, IL-6 and IL-13); and 3) increased survival signals provided by B-cell activating factor pathways. This activity results in the formation of germinal centres within perivascular tertiary lymphoid organs and in the local production of pathogenic autoantibodies that target the pulmonary vasculature and vascular stabilisation factors (including angiotensin-II/endothelin-1 receptors and bone morphogenetic protein receptors). B-cells also mediate their effects through enhanced production of pro-inflammatory cytokines, reduced anti-inflammatory properties by regulatory B-cells, immunoglobulin (Ig)G-induced complement activation, and IgE-induced mast cell activation. Precision-medicine approaches targeting B-cell immunity are a promising direction for select PAH conditions, as suggested by the efficacy of anti-CD20 therapy in experimental models and a trial of rituximab in systemic sclerosis-associated PAH.

Fragility of randomised controlled trials for systemic lupus erythematosus and lupus nephritis therapies

ObjectiveWe aimed to evaluate the robustness of phase III randomised controlled trials (RCTs) for SLE and lupus nephritis (LN) using the fragility index (FI), the reverse FI (RFI) and the...

Can efficacy and safety data from clinical trials of rituximab in RA be extrapolated? Insights from 1984 patients from the AIR-PR Registry.

To investigate whether the efficacy and safety data from drug-registration trials can be extrapolated to real-life RA patients receiving RTX. The 'AutoImmunity and Rituximab' (AIR-PR) registry is a French multicentre, prospective cohort of RA patients treated with RTX in a real-life setting. We compared treatment responses at 12 months and serious adverse events (AEs) between eligible and non-eligible patients, by retrieving the eligibility criteria of the three rituximab-registration trials. We determined critical eligibility criteria and modelled the benefit-risk ratio according to the number of fulfilled critical eligibility criteria. Among 1984 RA patients, only 9-12% fulfilled all eligibility criteria. Non-eligible patients had fewer EULAR responses at 12 months (40.3% vs 46.9%, P = 0.044). Critical inclusion criteria included swollen joints count ≥4, tender joints count ≥4, CRP ≥15 mg/l and RF positivity. Critical exclusion criteria were age >80 years, RA-associated systemic diseases, ACR functional class IV, DMARD other than MTX and prednisone >10 mg/day. Only 20.8% fulfilled those critical eligibility criteria. During the first year, serious AEs occurred for 182 (9.2%) patients (70.3% serious infections) and patients with ≥1 critical exclusion criterion were at higher risk (hazard ratio 3.03; 95% CI 2.25-4.06; for ≥3 criteria vs 0). The incremental risk-benefit ratio decreased with the number of unmet critical inclusion criteria and of fulfilled exclusion criteria. Few real-life RA patients were eligible for the drug-registration trials. Non-eligible patients had lower chance of response, and higher risk of serious AEs. Efficacy and safety data obtained from those trials may not be generalizable to RA patients receiving RTX in real-world clinical practice.

Autologous CD19-Targeted Chimeric Antigen Receptor (CAR)T-Cells as the Future of Systemic Lupus Erythematosus Treatment.

Systemic lupus erythematosus (SLE) is a chronic autoimmune illness with an unclear etiology and a range of clinical manifestations. The therapeutic results of current conventional treatments are frequently unsatisfactory. Many B-cell-directed immunotherapies have recently been discovered, as B cells play a key role in the pathogenesis of SLE. However, large-scale rituximab trials found that the antibody against CD20 was no better than a placebo. Autologous CAR T-cell therapy has garnered considerable interest and is considered a potential treatment option for SLE. CD19+CD20- B cells are thought to play an essential role in the onset and progression of SLE. CD19-targeted CAR T-cells destroy B cells without requiring an accessory cell type, thereby decreasing B cells more efficiently. Preclinical trials of CAR T-cells in mice have shown promising results against SLE. The review aimed to shed light on autologous CD19-targeted CAR T-cells as a potential treatment for SLE.

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

Gastric dysmotility and gastrointestinal symptoms in myalgic encephalomyelitis/chronic fatigue syndrome

Background Gastrointestinal symptoms are common in ME/CFS, but there is a knowledge gap in the literature concerning gastrointestinal motility features and detailed symptom description. Objective In this study, we aimed to characterize gastric motility and gastric symptoms in response to a liquid meal. Methods We included 20 patients with ME/CFS with abdominal complaints who were recruited to a double-blind randomized placebo-controlled trial of Rituximab. The patients of this sub study were examined with an ultrasound drink test, and gastrointestinal symptoms were evaluated using the Rome III questionnaire and Irritable Bowel Syndrome Symptom Severity Scale (IBS-SSS) questionnaire. Results We found that patients commonly reported fullness/bloating (75%), abdominal pain (45%) and nausea (35%). Ultrasound measurements revealed lower proximal measurements of the stomach after a meal (p < 0.01) and larger fasting antral area (p = 0.019) compared to healthy controls. The patients had a stronger symptomatic response to the liquid meal compared to healthy controls regarding epigastric pain, discomfort and nausea (p < 0.05). Ninety percent of the patients reported bowel movement frequencies within the normal range but scored high on bowel habit dissatisfaction and life disruption. Conclusion The patients presented with fullness/bloating, nausea and epigastric pain, showed signs of impaired gastric accommodation and visceral hypersensitivity, showing that the gastrointestinal symptoms of ME/CFS patients are similar to functional dyspepsia. Key summary Gastrointestinal symptoms are common in ME/CFS, but there is a knowledge gap in the literature concerning gastrointestinal motility features and detailed symptom description. • In this study, patients with ME/CFS had signs of impaired gastric accommodation after a liquid meal. • Out of 20 patients, 15 patients reported fullness/bloating, 9 reported abdominal pain, and 7 reported nausea. The patients showed signs of visceral hypersensitivity on a drink test. • Our findings suggest that patients with ME/CFS share many similarities with patients with Functional Dyspepsia. The findings were not typical for Irritable Bowel Syndrome.

Comparative Effectiveness of Fostamatinib Vs. Rituximab in Refractory Chronic Immune Thrombocytopenia: A Network Meta-Analysis

Introduction Immune thrombocytopenia (ITP) is an autoimmune condition characterised by platelet destruction and insufficient platelet production. The American Society of Hematology ITP guidelines recommend rituximab, splenectomy, and thrombopoietin receptor agonists (TPO-RAs) as primary treatment options in patients with chronic ITP (Neunert C, et al. 2019). Fostamatinib, a spleen tyrosine kinase inhibitor, is approved for the treatment of chronic ITP in patients who have had an insufficient response to a previous treatment (FDA 2018, EMA 2020). Recent real-world evidence suggests that fostamatinib is used after a previous TPO-RA line (Hughes DM, et al. 2021). The objective of this network meta-analysis (NMA) was to estimate the relative efficacy of fostamatinib compared with current standard treatments after TPO-RAs in patients with refractory chronic ITP for overall platelet response. Methods A systematic literature review was conducted in 2019 and updated in July 2021. Six identified studies informed the NMA, including 2 placebo-controlled trials of fostamatinib (Bussel J, et al. 2018), 2 placebo-controlled trials of rituximab (Arnold DM, et al. 2012, Ghanima W, et al. 2015), 1 randomised trial of 3 rituximab regimens (Zwaginga JJ, et al. 2015) and 1 non-randomised study of 2 rituximab regimens (Zaja F, et al. 2012) (Figure 1). No studies assessing additional comparators of interest were found that could inform the NMA. The outcome of interest was overall platelet response, however definitions varied across studies in terms of platelet count thresholds and assessment time points, and several analyses were therefore performed to investigate sensitivity in variation in outcome definition. Analysis 1 used the published definitions for each study. Analysis 2 used an alternative standardised definition (platelet count >30,000/µL by week 4) for the fostamatinib trials, and the published definitions for each of the remaining studies. Analysis 3 used the alternative standardised definition for all studies and was restricted to those with results available: Bussel 2018 and Ghanima 2015. Possible treatment effect modifiers were evaluated by 8 British haematologists via a Delphi panel. None were identified and it was assumed that the differing baseline characteristics between studies did not have a significant impact on the outcome of interest. Random-effect models were employed in the analyses. The Odds Ratio (OR) for outcome occurrence of each treatment compared to fostamatinib together with the 95% credible intervals (CrI), 95% prediction intervals (PrI), median rank and probability of being the best treatment were estimated and are displayed in forest plots for each analysis. ORs<1 indicate reduced response relative to fostamatinib. All analyses were performed following the guidance of the National Institute for Health and Care Excellence Decision Support Unit and were implemented with WinBUGS and R. Results In analysis 1, pairwise comparisons indicated that fostamatinib was statistically significantly more effective than placebo and all rituximab regimens with ORs for comparators vs. fostamatinib ranging from 0.11 to 0.20 (Figure 2A). In analysis 2, fostamatinib was associated with improved response vs. placebo and all rituximab regimens (OR range 0.14 - 0.25) but statistical significance was only reached vs. placebo and rituximab 4 x 100 mg/week (Figure 2B). In analysis 3, pairwise comparisons suggested increased efficacy of fostamatinib relative to placebo and rituximab 4 x 375 mg/m2/week with ORs of 0.25 and 0.34, respectively. However, OR was only statistically significant vs. placebo (Figure 2C). The probability of fostamatinib being the most effective treatment ranged 0.91 - 0.97 across analyses; median rank for fostamatinib was 1 in all analyses (Figure 2). The between study standard deviations indicated moderate heterogeneity in treatment effects between studies. Conclusions The results from all analyses indicate that fostamatinib was associated with improved overall platelet response relative to rituximab at all regimens evaluated (4 x 375 mg/m2/week, 2/4 x 375 mg/m2/week, 2 x 750 mg/m2/week, 4 x 100 mg/week), and placebo. The use of rituximab offered no additional benefit with regards to achieving a platelet response than being on placebo. Fostamatinib may be a better alternative than rituximab to increase platelet counts in patients with refractory chronic ITP. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Smart Start: Rituximab, Lenalidomide, and Ibrutinib in Patients With Newly Diagnosed Large B-Cell Lymphoma.

Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades. Both preclinical models and clinical data suggest the combination of lenalidomide and ibrutinib may have synergy in DLBCL, particularly in the non-germinal center B-cell-like subset. We enrolled 60 patients with newly diagnosed non-germinal center B-cell-like DLBCL in this investigator-initiated, single-arm phase II trial of rituximab, lenalidomide, and ibrutinib (RLI) with the sequential addition of chemotherapy (ClinicalTrials.gov identifier: NCT02636322). Patients were treated with rituximab 375 mg/m2 intravenous once on day 1, lenalidomide 25 mg once per day on days 1-10, and ibrutinib 560 mg once daily continuously of each 21-day cycle (RLI). After two cycles, standard chemotherapy was added to RLI for six additional cycles. The primary end points were overall response rate (ORR) after two cycles of RLI alone and complete response rate after completion of RLI with chemotherapy. In evaluable samples, circulating tumor DNA and DLBCL90 assays were performed. The median age was 63.5 years (range, 29-83 years) with 28% age 70 years or older. The revised international prognostic index identified 42% as high risk, and 62% were double expressor of MYC and BCL2 protein. The ORR after two cycles of RLI was 86.2%, and the complete response rate at the end of RLI-chemotherapy was 94.5%. With a median follow-up of 31 months, the progression-free survival and overall survival were at 91.3% and 96.6% at 2 years, respectively. Smart Start is the first study, to our knowledge, to treat newly diagnosed DLBCL with a targeted therapy combination before chemotherapy. RLI produced a high ORR, and RLI with chemotherapy resulted in durable responses. This establishes the potential for developing biologically driven and noncytotoxic first-line therapies for DLBCL.

Treating Autoimmune-Related Interstitial Lung Disease With B Cell Depletion.

Autoimmune rheumatic diseases may affect vital organs with lung involvement being severe and difficult to treat manifestation. Systemic sclerosis (SSc) commonly affects the lung in the form of interstitial lung disease (ILD). ILD may be also seen in patients with rheumatoid arthritis (RA), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), inflammatory myositis (IM), antisynthetase syndrome (AS), and the ANCA-associated vasculitides (AAV). Rituximab (RTX) is an anti-CD20 B lymphocyte depleting mAb, often administered in the treatment of autoimmune rheumatic diseases. Although RTX is an off-label treatment for CTD–ILD, there are numerous reports providing data that is effective in improving both pulmonary function tests (PFTs) and chest computed tomography findings consistent with ILD. There are retrospective uncontrolled studies that assess RTX as a treatment of ILD in autoimmune diseases. These studies, apart from one, do not include patients with AAV-ILD. In SSc-ILD, in particular, there are both controlled and uncontrolled studies displaying encouraging results following B cell depletion. In addition, a number of retrospective uncontrolled studies and fewer prospective studies evaluate RTX in connective tissue diseases CTD–ILD. Although RTX is an approved treatment for AAV there are scarce only data focusing on patients with AAV-ILD specifically. The results of a handful of studies comparing treatment of CTD-ILD with RTX to treatment with other agents are in favor of RTX. Results from large, still ongoing controlled trials are awaited to ascertain RTX effects in ILD encountered in autoimmune rheumatic diseases. We review herein the results of the different RTX trials in patients with autoimmune disease–associated with ILD. Despite the heterogeneity of these studies, RTX may be considered an alternative and safe but still off-label treatment for patients with refractory CTD–ILD.

Rituximab for the Treatment of Primary Membranous Nephropathy

&#x0D; Membranous nephropathy is an autoimmune disease and one of the most common causes of nephrotic syndrome in adults. The incidence of membranous nephropathy is 1.2 in 100,000 persons per year worldwide. Approximately 80% of patients with membranous nephropathy have a classification of primary (or idiopathic) membranous nephropathy. The treatment goal of patients with primary membranous nephropathy is to induce remission. Current treatment options include calcineurin inhibitors (cyclosporine and tacrolimus), cyclophosphamide, and rituximab.&#x0D; Rituximab is not approved for the indication of primary membranous nephropathy in Canada. This review aimed to evaluate the evidence on the use of rituximab compared to cyclophosphamide, tacrolimus, and cyclosporine in adult patients with primary membranous nephropathy.&#x0D; A systematic review of the efficacy and safety of rituximab versus cyclosporine, tacrolimus, or cyclophosphamide was conducted with 18 included randomized controlled trials. A network meta-analysis of 11 of the 18 included randomized controlled trials was uninformative due to the small number of studies, the heterogeneity in the studies, and unreliable point estimates and wide credible intervals obtained with the network meta-analysis.&#x0D; Due to the uninformative nature of the network meta-analysis, a narrative analysis was conducted of the head-to-head trials of rituximab. Two randomized controlled trials showed no evidence of a difference between rituximab and cyclophosphamide, whereas rituximab resulted in a better response rate (complete remission and the composite outcome of partial or complete remission) at 24 months compared with cyclosporine. There were no head-to-head trials comparing rituximab with tacrolimus.&#x0D; Given the small network of studies, the heterogeneity in the included studies, and the limited information provided by the network meta-analysis and the pairwise comparisons of the MENTOR and RI-CYCLO trials, CADTH was unable to conduct an informative economic evaluation. Further, in addition to the clinical evidence gaps, there were also issues identifying information to inform key parameters to address the policy question of interest to decision-makers. Given the limitations associated with the clinical evidence and absence of evidence to inform key model parameters, an economic evaluation would not be able to quantify all relevant incremental costs and effects of using rituximab over the currently used alternatives.&#x0D;

Development and preliminary validation of the Sjögren’s Tool for Assessing Response (STAR): a consensual composite score for assessing treatment effect in primary Sjögren’s syndrome

ObjectiveTo develop a composite responder index in primary Sjögren’s syndrome (pSS): the Sjögren’s Tool for Assessing Response (STAR).MethodsTo develop STAR, the NECESSITY (New clinical endpoints in primary Sjögren’s syndrome: an...

The lessebo effect in randomized controlled trials of rituximab in patients with rheumatoid arthritis: ameta-analysis.

The goal of this study was to assess the impact of negative expectations associated with receiving aplacebo (the lessebo effect) on efficacy outcomes in randomized clinical trials (RCTs) of rituximab in patients with rheumatoid arthritis (RA). We performed ameta-analysis on the American College of Rheumatology 20%, 50%, and 70% (ACR20, 50, 70) response rates in the placebo and active (biosimilar)-controlled groups (reference-pbo and reference-bs) of rituximab showing an insufficient response to methotrexate or tumor necrosis factor. We evaluated the difference in ACR20, 50, 70response rates between the two groups (reference-bs vs. reference-pbo). Nine RCTs included atotal of 2734 patients with RA. The pooled incidence of ACR20 response rate in the placebo- and active-controlled groups of the rituximab RCTs for RA was 53.1% (95% confidence interval [CI] 49.9-56.3%) and 75.0% (95% CI 71.2-78.4%), respectively. The difference in the ACR20 response rate between the placebo- and active-controlled groups was -20.9% (95% CI -26.9 to 61.9%, p < 0.001). The pooled incidence of ACR50 response rate in the placebo- and active-controlled groups of the rituximab RCTs for RA was 29.0% (95% CI 26.2-32.0%) and 47.4% (95% CI 43.2-51.6%), respectively. The ACR50 response rates were significantly higher in the active-controlled groups than in the placebo-controlled groups (-18.4%; 95% CI -18.4 to -13.4%, p < 0.001). The difference in the ACR70 response rate between the placebo- and active-controlled groups was -14.9% (95% CI -22.2 to -7.6%, p < 0.001). The ACR20, 50, 70response rates were significantly higher in the active-controlled groups than in the placebo-controlled group. This study shows that the use of aplacebo can be associated with aclinically significant reduction in the magnitude of change of the ACR20, 50, 70response rates in rituximab RCTs for RA. The lessebo effect has potential implications for the development of new treatments and appraisal of current treatment options for RA.

Relapsed Refractory Acquired Thrombotic Thrombocytopenic Purpura (aTTP) Following COVID-19 Vaccination

Introduction:Acquired thrombotic thrombocytopenic purpura (aTTP) due to an acquired deficiency in the enzyme ADAMTS13 leads to ultra-large von Willebrand multimers, thrombocytopenia and microangiopathic hemolytic anemia. Complications include microvascular and macrovascular thrombosis. We present an unusual case of a patient with a history of refractory aTTP who experienced relapsed aTTP following COVID-19 vaccine.Case Description:A 57-year-old African-American male with a history of refractory aTTP experienced a relapse following 3 years of remission after receiving COVID-19 vaccination. The patient was initially diagnosed with aTTP in 2016, after presenting with symptoms of dark urine, mild headaches and transient episodes of aphasia and paresthesia. Due to symptoms and persistently low ADAMTS13 levels, he required prolonged and extensive treatment including over 5 weeks of daily therapeutic plasma exchange (TPE), followed by gradual reduction in frequency of TPE sessions, as well as trials of rituximab, eculizumab, steroids, mycophenolate mofetil and bortezomib. Ultimately, he achieved remission after 9 months of intermittent TPE, 3 months of weekly bortezomib 1 mg/m 2, mycophenolate mofetil up-titrated to 1,750 mg twice daily, and then slowly tapered off over a 2-year period. The patient was doing well for 3 years without manifestations of aTTP (2 years off all therapeutics), until he developed a petechial rash 7 weeks after receiving the second dose of the Moderna COVID-19 vaccine. He was found to have acute thrombocytopenia with platelets of 38 x 10 9/L (normal range 135-317 x 109/L), from a baseline of 200-300 x 10 9/L. He was referred to the emergency department, where additional labs were notable for mildly elevated LDH of 508 U/L (normal range 122-222 U/L), hemoglobin of 12.4 g/dL (normal range 13.2-16.6 g/dL), creatinine at baseline, and peripheral blood smear showing 1-3 schistocytes per high-powered field. ADAMTS13 activity level was t <5% (normal >/= 70%), with positive ADAMTS13 inhibitor screen and titer of 1.5 (normal <0.4), consistent with relapsed aTTP.The patient was admitted to the hospital, and initiated on daily TPE, with steroids and diphenhydramine prior to each TPE session. He quickly improved with TPE alone , but given his history of refractory aTTP, he was discharged on weekly rituximab for 4 weeks and caplacizumab 11 mg daily for 30 days. His platelets remained stable within the upper limit of normal during his 30 day course of caplacizumab. However, 3 weeks after completion of caplacizumab, he had an acute drop in his platelets to 23 x 10 9/L. His ADAMTS13 level was again found to be <5%, and inhibitor level was the highest that it had ever been at 11.4. He was again hospitalized and underwent 8 sessions of daily TPE, as well as re-initiation of caplacizumab, mycophenolate mofetil 500 mg bid (with increasing taper), and a prednisone taper. Intravenous Cyclophosphamide 750 mg/m 2 was also added every 3 weeks. With this regimen, patient's platelet count normalized and remain stable, and his ADAMTS13 activity level has reached 52-59%.Discussion:Cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) have been described as a complication following vaccination with formulations containing replication-defective adenoviral vectors (AstraZeneca-Oxford and Johnson&Johnson COVID-19 vaccines)(Arepally and Ortel 2021, Simpson, Shi et al. 2021). VITT and aTTP are both immune-mediated, however, VITT is distinct and pathogenically linked to autoimmune heparin-induced thrombocytopenia (HIT), given the presence of anti-platelet factor 4 antibodies in these patients, whereas aTTP is due to reduction in ADAMTS13 level, secondary to an antibody inhibitor of ADAMTS13 (Arepally and Ortel 2021). Recently, cases have been reported of de novo aTTP developing shortly after COVID-19 vaccination with all available vaccines, except the Moderna (mRNA-1273) vaccine (Al-Ahmad, Al-Rasheed et al. 2021, de Bruijn, Maes et al. 2021, Maayan, Kirgner et al. 2021, Ruhe, Schnetzke et al. 2021, Waqar, Khan et al. 2021, Yocum and Simon 2021). Additionally, cases of relapsed aTTP have been described following only the BNT162B2 (Pfizer-BioNTech) vaccine (Maayan, Kirgner et al. 2021, Sissa, Al-Khaffaf et al. 2021). This is the first case, to our knowledge, reported in the literature of aTTP following vaccination with Moderna's mRNA-1273 vaccine. DisclosuresNo relevant conflicts of interest to declare.

Rituximab Is Preferable to Cyclophosphamide for Treatment of Membranous Nephropathy: CON.

This is an Early Access article. Please select the PDF button, above, to view it. Be sure to also read the PRO: 10.34067/KID.0001842021 and the COMMENTARY: 10.34067/KID.0002492021

Rituximab for eradicating inhibitors in people with acquired haemophilia A.

Acquired haemophilia A is a rare bleeding disorder caused by the development of specific autoantibodies against coagulation factor VIII. Standard treatment, usually steroids alone, or in combination with cyclophosphamide, aims to stop acute bleeds by using haemostatic agents to promote clotting. Rituximab may be an alternative approach to the treatment of acquired haemophilia by eradicating FVIII autoantibodies. This is an update of a previously published Cochrane Review. To assess the efficacy and adverse effects of rituximab for treating people with acquired haemophilia A. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's trials registers, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings (January 2021). We also undertook searches of CENTRAL, MEDLINE and online trial registries (January 2021). Randomised and quasi-randomised controlled trials of rituximab for people with acquired haemophilia A, with no restrictions on gender, age or ethnicity. No trials matching the selection criteria were eligible for inclusion. No trials matching the selection criteria were eligible for inclusion. We found no randomised clinical trials of rituximab for acquired haemophilia A. Thus, we are not able to draw any conclusions or make any recommendations on rituximab for eradicating inhibitors in people with acquired haemophilia A based on the highest quality evidence. Given that undertaking randomised controlled trials in this field is a complex task, we suggest that, while planning such trials, clinicians treating the disease continue to base their choices on alternative, lower-quality sources of evidence. In a future update of this review, we plan to appraise and incorporate eligible randomised controlled trials, as well as other high-quality, non-randomised studies.

Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS): development and validation of a novel outcome measure.

Recent randomised controlled trials (RCTs) in primary Sjögren's syndrome used the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) as their primary endpoint. Given the heterogeneous and complex nature of primary Sjögren's syndrome, it might be more appropriate to also assess other clinically relevant disease features. We aimed to develop a novel composite endpoint for assessing treatment efficacy in patients with primary Sjögren's syndrome: the Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS). A multidisciplinary expert team selected clinically relevant items and candidate measurements for inclusion in the composite score. For each measurement, cutoff points for response to treatment were chosen based on expert opinion, previously published data on minimal clinically important improvements, and trial data, primarily the week-24 data of the single-centre ASAP-III trial of abatacept versus placebo. CRESS was validated using data from three independent RCTs: one trial of rituximab (TRACTISS), one of abatacept (multinational trial), and one of tocilizumab (ETAP). We calculated the number and percentage of patients who were responders in the separate CRESS items, and the percentage of responders based on the total CRESS at the primary endpoint visits (week 48 for TRACTISS, week 24 for the other two trials). Patients with fewer than three items available for evaluating CRESS response were imputed as non-responders. Based on expert opinion, five complementary items were selected to assess response: (1) systemic disease activity by Clinical ESSDAI (less than 5 points); (2) patient-reported symptoms by EULAR Sjögren's Syndrome Patient Reported Index, assessed by a decrease of at least 1 point or at least 15% from baseline; (3) tear gland item by Schirmer's test and ocular staining score, assessed by an increase of at least 5 mm or decrease of at least 2 points, respectively, in patients with abnormal Schirmer's test or ocular staining score findings at baseline, or, in patients with normal baseline values, assessed by no change to abnormal for both; (4) salivary gland item, assessed by unstimulated whole saliva secretion (increase of at least 25%) and salivary gland ultrasonography (decrease of at least 25%); and (5) serology, assessed by rheumatoid factor (decrease of at least 25%) and IgG (decrease of at least 10%). Total CRESS response is defined as response on at least three of five items. Post-hoc assessment of phase 3 trial data showed that CRESS response rates at the primary endpoint visits were 60% (24 of 40) for abatacept versus 18% (seven of 39) for placebo (p<0·0001) in ASAP-III, 49% (33 of 67) for rituximab versus 30% (20 of 66) for placebo (p=0·026) in the TRACTISS trial, 45% (41 of 92) for abatacept versus 32% (30 of 95) for placebo (p=0·067) in the multinational abatacept trial, and 18% (10 of 55) for tocilizumab versus 24% (13 of 55) for placebo (p=0·48) in the ETAP trial. The CRESS is a feasible, well-balanced, composite endpoint for use in trials of primary Sjögren's syndrome. As a next step, the CRESS will require validation in a prospective RCT. None. For the Dutch translation of the abstract see Supplementary Materials section.

Long-term Follow-up and Correlative Analysis of Two Phase II Trials of Rituximab and Lenalidomide Followed by Continuous Lenalidomide in Untreated and Relapsed/Refractory Indolent Lymphoma.

Rituximab and lenalidomide are effective for previously untreated and relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). However, long-term survival and predictive biomarkers are not well described. We conducted two phase II open-label trials involving 60 patients with previously untreated and R/R advanced-stage iNHL. Patients received lenalidomide and rituximab induction followed by continuous lenalidomide until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Correlative studies included plasma cytokine monitoring, flow cytometry of peripheral blood mononuclear cells (PBMC; days 0, 15, 30, and 60), and RNA sequencing (RNA-seq) of pretreatment tumor biopsies. At a median follow-up of 63 months for previously untreated and 100 months for R/R, ORR was 82% for both. The 11 R/R patients who achieved complete remission remained in continuous remission for 16 to 141 months, thereafter. Median overall survival (OS) was not reached in the previously untreated and was 140 months (95% confidence interval, 53.4-140) in the R/R group. A mixed-effects linear regression model identified significant associations between Granzyme B+ (GranB+) CD8+ T cells and long-term complete response (LTCR; P = 5.3e-4). Furthermore, prior to start of therapy, treatment response could be predicted by B-cell and GranB+ CD8+ T-cell levels (% total lymphocytes). Rituximab plus lenalidomide followed by continuous lenalidomide is effective with manageable toxicity in patients with previously untreated and R/R iNHL. This regimen produces durable remissions, even in heavily pretreated patients, with some lasting greater than 10 years. GranB+ CD8+ T cells, B cells, and plasma IFNγ allowed prediction of LTCR but need validation in larger trials.

Advances in Membranous Nephropathy.

Membranous nephropathy (MN) is a rare auto-immune disease where the glomerulus is targeted by circulating auto-antibodies mostly against podocyte antigens, which results in the formation of electron-dense immune complexes, activation of complement and massive proteinuria. MN is the most common cause of nephrotic syndrome in adults leading to severe thrombotic complications and kidney failure. This review is focused on the recent therapeutic and pathophysiological advances that occurred in the last two years. For a long time, we were lacking a head-to-head comparison between cyclophosphamide considered as the gold standard therapy and other medications, notably rituximab. Substantial progress has been achieved owing to three randomized controlled trials. MENTOR (Membranous Nephropathy Trial of Rituximab) and STARMEN (Sequential Therapy with Tacrolimus and Rituximab in Primary Membranous Nephropathy) conclusively established that calcineurin inhibitor-based regimens are slower to result in an immunologic response than rituximab or cyclophosphamide, achieve fewer complete clinical remissions, and are less likely to maintainremission. Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO) suggested that competition between cyclophosphamide and rituximab remains open. Given the technological leap combining laser microdissection of glomeruli and mass spectrometry of solubilized digested proteins, four “new antigens” were discovered including NELL-1 and Semaphorin 3B in so-called primary MN, and exostosins 1 and 2 and NCAM 1 in lupus MN. NELL-1 is associated with about 8% of primary MN and is characterized by segmental immune deposits and frequent association with cancer (30%). Semaphorin 3B-associated MN usually occurs in children, often below the age of two years, where it is the main antigen, representing about 16% of non-lupus MN in childhood. Exostosins 1/2 and NCAM 1 are associated with 30% and 6% of lupus MN, respectively. Exostosins 1/2 (EXT1/2) staining is associated with a low rate of end-stage kidney disease (ESKD) even in mixed classes III/IV+V. These findings already lead to revisiting the diagnostic and therapeutic algorithms toward more personalized medicine.

Estimating the susceptibility to SARS-CoV-2 infection with rituximab use for pemphigus vulgaris

The occurrence of the COVID-19 pandemic has raised new uncertainties for dermatologists and their patients, importantly concerning initiation and continuation of immunosuppressants for dermatological conditions at this time. We review two phase III trials of rituximab, a chimeric CD20 monoclonal antibody, used for the treatment of pemphigus vulgaris. Without specific data studying rituximab use and susceptibility of SARS-CoV-2, we hope to utilize available data in order to assist clinician decision making for rituximab in the context of the pandemic.