Rituximab Infusion Research Articles

Txagorrapid: Ultrarapid infusion in 30 minutes of the biosimilar of rituximab truxima—A cohort study.

e13638 Background: Rituximab (anti-CD20 Ab) is the cornerstone of the treatment of non-Hodgkin B lymphomas. Infusion-related reactions (IRR) are the most common adverse effects. To reduce them, intravenous premedication with antihistamine and acetaminophen is administered prior to rituximab. If no IRR after first infusion, subsequent infusions time takes 3-6 hours. Many centers use the rapid 90-minute infusion (off-label). Since 2017 subcutaneous rituximab formulation is available, that takes 5 minutes of administration. Nevertheless, in order to reduce cost, due to approval of biosimilars, some health providers continue using intravenous rituximab. On the other hand, with COVID pandemic, an effort to reduce visits and day-care hospitals stays has been made. In the current situation, it would be convenient to reduce day-care stay and the nursing care burden. We wanted to evaluate the safety of an ultrarapid infusion of biosimilar rituximab in a total time of 30 minutes by analyzing IRR and adverse events (AE). Methods: Since November 2021, 3 cohorts of ultrafast infusion have been studied as follows: One cohort (Cohort 1) with intravenous premedication with dexchlorpheniramine and acetaminophen, followed by rituximab infusion over 1 hour, and 2 cohorts with rituximab infusion over 30 minutes: Cohort 2: with intravenous premedication, and cohort 3 with oral premedication. IRR and adverse events have been independently reviewed and graded using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (November 27, 2017). Results: 34 patients have been included receiving 48 rituximab infusions (16 infusions in each cohort). Median age was 64 years old (range: 51-91). Diagnostic of NHL were as follows: large b cell: 10; follicular: 13; marginal: 7; mantle cell: 1, Waldeström: 1; Ritcher transformation: 2. Rituximab infusion was in monotherapy (21), and in combination (27) with: bendamustine: 9, CHOP: 17, GEMOX: 1. Considering safety, no IRR has been observed in cohort 1 (1 hour infusion), and 1 IRR grade II in cohort 3 (30 minutes, oral premedication). Other AE were: hypertension grade I and hypotension grade I, both in cohort 2. Conclusions: Ultrarapid rituximab infusion is safe. Oral premedication is feasibly allowing a total infusion time of 30 minutes. This infusion rate alleviates day-care burden saving between 75-90% of time in each rituximab infusion, reduce day-care stay and is comfortable for the patients. Clinical trial information: NCT05191225.

The impact of pembrolizumab on patients with pre-existing autoimmune diseases.

2660 Background: Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape across a range of solid and hematologic malignancies. With the mechanistic activation of the adaptive immune response and known unique development of immune-related adverse effects (irAE), there is a theoretical risk of causing detrimental effects on patients with pre-existing autoimmune diseases (AID). However, this patient population was excluded from many clinical trials, and there is limited and conflicting retrospective data speculating upon the impacts of using ICI therapy in patients with AID. This study aims to report the impact of pembrolizumab in patients with AID. Methods: Patients who received pembrolizumab for treatment of any type of cancer between 1/1/2017-8/1/2021 were retrospectively reviewed, and patients with AID (rheumatologic or non-rheumatologic) were identified. Data including age, gender, race, ECOG, and primary cancer diagnosis were collected. AID was characterized by type, activity (symptomatic vs. asymptomatic at ICI initiation), and immunosuppressive treatment (IST) use. Outcomes included flare of AID, irAE, and ICI discontinuation. Results: Out of 810 patients, 12 with pre-existing AID were found and being treated for non-small cell lung cancer (NSCLC) (58% N=7), renal cell carcinoma (RCC) (16.6% N=2), colorectal cancer (CRC) (8% N=1), head and neck cancer (8% N=1), and cervical cancer (8% N=1). Around 67% of these patients were females with a median age of 65 years (50-77). Median ECOG was 1 (0-2). 9 patients (75%) had rheumatologic disease (5 rheumatoid arthritis (RA), 1 systemic lupus erythematosus (SLE), 2 psoriatic arthritis, and 1 systemic sclerosis (SS)). 3 patients (25%) had non-rheumatologic AID (1 multiple sclerosis (MS), 1 autoimmune hepatitis, and 1 Evan’s syndrome). All patients were asymptomatic prior to initiation of therapy. At the time of ICI initiation, 11 patients (92%) were on therapy, including steroids, methotrexate, and other IST. Due to concern for severe flare, pembrolizumab was discontinued in 3 (25%) MS, RA, and SS patients treated for RCC, CRC, and NSCLC, respectively. 3 patients (25%) developed irAE unrelated to their AID (pneumonitis, dermatitis, arthritis, gastritis) and received steroids. 4 patients (33.3%) had documented flares while on pembrolizumab requiring escalation of their ongoing therapy, and 1 NSCLC patient had a severe exacerbation of SS requiring cyclophosphamide and rituximab infusions. Conclusions: This analysis adds to the limited available literature that patients with an AID and on IST appear to have minimal AID-associated flares requiring intervention and tolerate pembrolizumab with a similar rate of irAE compared to patients without AID. Additional larger studies are needed to assess the efficacy of treatment in this population.

INCREASED RISK OF MECHANICAL VENTILATION AND DEATH IN PATIENTS WITH COVID-19 RECENTLY TREATED WITH RITUXIMAB

TYPE: Late Breaking Abstract TOPIC: Chest Infections PURPOSE: To determine if recent rituximab treatment causes worse outcomes for patients with COVID-19 infection. We specifically evaluated mechanical ventilation and mortality as primary outcomes. METHODS: We used TriNetX, a global research network with anonymized medical information of 86 million patients in 65 large healthcare organizations. We created two patient cohorts: one consisting of patients positive for COVID-19 infection, with the second consisting of COVID-19-infected patients who had received rituximab infusion in the previous 3 months. The cohorts were then balanded for age, gender, race and ethnicity and evaluated for the outcome of “dependence on respirator” via International Classification of Disease (ICD)-10 code Z99.1. RESULTS: Patients who had received rituximab within 3 months of COVID-19 positivity were 3.63 times more likely to require treatment with a ventilator (RR 3.63, CI (2.374,5.55)). See figure 1. Figure 1. Percentage of patients requiring a ventilator Mortality was 2.67 times more likely in recently-treated rituximab patients as well (CI 1.744,4,095), P = 0.0065. CONCLUSIONS: Treatment with Rituximab in the 3 months prior to COVID-19 infection is associated with a significantly increased risk of requiring a ventilator and increased mortality. CLINICAL IMPLICATIONS: Patients requiring rituximab treatment should take every precaution to avoid exposure to COVID-19, as they are at increased risk of requiring a ventilator and experiencing a poor outcome. DISCLOSURE: Nothing to declare. KEYWORD: rituximab

AB1514 AN UNUSUAL ASSOCIATION BETWEEN THROMBOTIC THROMBOCYTOPENIC PURPURA AND PRIMARY ANTIPHOSPHOLIPID SYNDROME

BackgroundThrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic haemolytic anemia, consumption thrombocytopenia and organ injury, particularly kidney failure and neurological manifestation1.Two forms are distinguished: the hereditary one, caused by a deficit of the metalloprotease ADAMTS13, and the idiopathic one characterized by the presence of antibodies directed against ADAMTS13. The second one is the most common. There are various subgroups of acquired TTP associated with HIV infection, sepsis, pregnancy, autoimmune disease, disseminated malignancies and drugs. Antiphospholipid syndrome (APS) is a clinical immunological condition characterized by thromboembolic events, repetead miscarriages or stillbirth and thrombocytopenia; it can be a primary disorder or due to connective tissue disease, in particular systemic lupus erythematosus2.ObjectivesWe describe a case of TTP associated with a primary APS. The real clinical challenge lies in the differential diagnosis between TTP and anti-phospholipid antibody syndrome.MethodsA 37-year-old man presented to the emergency department for short-term episodes of anesthesia of the right upper limb and face with spontaneous resolution. In his past medical history, he suffered of antiphospholipid syndrome treated with warfarin. Upon admission, blood tests revealed severe thrombocytopenia, haemolytic anemia with schistocytes on peripheral blood smear, low thrombin time and prolongation in the prothrombin time. Neurological symptoms were assessed by electroencephalogram and CT brain, resulted negative, while a brain MRI revealed acute-subacute ischemic stroke. Based on these findings we suspected a diagnosis of TTP, subsequently confirmed by reduced activity of ADAMTS-13 with borderline ADAMTS-13 inhibitory antibodies. Immunological testing confirmed positivity of antiphospholipid antibodies and antinuclear antibodies.ResultsAccording to the last guidelines3 about management of acute episode of TTP, immediate therapy with high-dose corticosteroids (prednisone 1 mg/kg) and plasmapheresis was started and then we added infusion of rituximab (375 mg/m2/week for 4 times). Efficacy of treatment was evaluated by weekly dosage of ADAMTS13 activity, with a gradual rise in values (3 → 78%) and improvement in symptoms and laboratory examination. After persistent remission, we gradually reduced steroid therapy. Few months later, in February 2021, patient developed a bilateral comunitary pneumonia, that required hospitalization, oxygen - therapy (also with C-PAP) and endovenous antibiotics. After two weeks patient was discharged from hospital in good clinical health and he was subjected to periodic outpatients visits. Disease activity was in remission, so steroid therapy was reduced and recently we added hydroxychloroquine for APS. Some days ago patient developed covid – 19 infection, despite vaccination, and he was treated with monoclonal antibodies, with good clinical response.ConclusionWe have described a rare clinical case of TTP, despite concomitant warfarin treatment for primary anti-phospholipid syndrome. A careful follow-up of these medical conditions is recommended for patient’s fragility and for the risk of related serious clinical complications.

POS0145 CLINICAL RESPONSE TO RITUXIMAB IS ASSOCIATED WITH PREVENTION OF B-CELL DRIVEN SALIVARY GLAND INFLAMMATION AND EPITHELIAL RESTORATION AS REVEALED BY MOLECULAR PATHOLOGY: RESULTS FROM THE TRACTISS TRIAL IN PRIMARY SJOGREN’S SYNDROME

BackgroundThe TRial for Anti-B-Cell Therapy In patients with pSS (TRACTISS) is the largest multi-centre, placebo-controlled, phase-III trial with the administration of 2 cycles of Rituximab (RTX) or placebo at week 0 and 24, with trial clinical endpoints at week 48. Despite the primary endpoints (30% reduction in fatigue or oral dryness) were not met, RTX treated patients showed an improvement in secondary endpoints, such as unstimulated whole salivary flow (UWSF), and salivary gland (SG) total ultrasound score1,2. Additionally, recent post-hoc analysis of TRACTISS using novel CRESS composite endpoints3, highlighted a significantly increased response rate in the RTX vs placebo arm.ObjectivesTo perform the first longitudinal analysis of matched transcriptomic and histological data of SG biopsies of pSS patients treated with RTX vs placebo at 3 time points, over 48 weeks, from the TRACTISS cohort, in order to identify mechanisms of response/resistance to B cell depletion.Methods29 pSS patients randomised to RTX or placebo arm consented for labial SG biopsies at week 0, 16 and 48. Patients received two 1000mg cycles of RTX or placebo at week 0 and 24. SG focus score, inflammatory aggregate area fraction, B-cells (CD20+), T-cells (CD3+), follicular dendritic cells (FDCs) (CD21+) and plasma cells (CD138+) density were assessed using quantitative digital image analysis. RNA sequencing with deconvolution and pathway analysis was performed to identify genes signatures and consensus gene modules as biomarkers of disease evolution and response/resistance to therapy.ResultsPlacebo-treated SGs showed worsening of SG inflammation highlighted by the increment of aggregate size, B-cell density, development of new FDC networks, and a higher ectopic GC prevalence over 48 weeks, compared to RTX-treated patients. No difference in focus score, total T-cell and plasma cell infiltration was observed. RTX downregulated genes involved in immune cell recruitment and inflammatory aggregate organisation (e.g. CXCL13, CCR7 and PDCD1). Gene signature-based analysis of 35 immune cell types using XCell highlighted how RTX blocked class-switched and memory-B-cells accumulation in SGs over 48 weeks. Pathway analyses confirmed the downregulation of leukocyte migration, MHC-II antigen presentation, and T-cell co-stimulation immunological pathways, such as the CD40 receptor complex pathway. Among RTX-treated patients, only CRESS-responders demonstrated prevention of worsening B cell-driven molecular pathology signatures over time and a significant improvement in UWSF, in parallel with the upregulation of molecular pathways associated to SG restoration of the glandular epithelium. None of the above effects were observed at week 16 after the first RTX cycle.ConclusionTwo RTX infusions repeated at week 24 exerted beneficial effects on labial SG inflammatory infiltration in pSS by downregulating genes involved in immune cell recruitment, activation and organisation in ectopic GCs. Conversely, all the above parameters showed significant evolution in placebo treated patients over 48 weeks demonstrating progression of SG immunopathology. Clinical responders to RTX based on CRESS response criteria were characterised by preservation of exocrine function which appear driven by SG epithelial restoration.

Factors Associated With Serological Response to SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis Treated With Rituximab

B-cell-depleting monoclonal antibodies are widely used for treatment of multiple sclerosis but are associated with an impaired response to vaccines. To identify factors associated with a favorable vaccine response to tozinameran. This prospective cohort study was conducted in a specialized multiple sclerosis clinic at a university hospital from January 21 to December 1, 2021. Of 75 patients evaluated for participation who received a diagnosis of multiple sclerosis with planned or ongoing treatment with rituximab, 69 were included in the study, and data from 67 were analyzed. Sex, age, number of previous rituximab infusions, accumulated dose of rituximab, previous COVID-19 infection, time since last rituximab treatment, CD19+ B-cell count before vaccination, CD4+ T-cell count, and CD8+ T-cell count were considered potential factors associated with the main outcome. Serological vaccine responses were measured by quantitation of anti-spike immunoglobulin G (IgG) antibodies, anti-receptor-binding domain (RBD) IgG antibodies, and their neutralizing capacities. Cellular responses to spike protein-derived SARS-CoV-2 peptide pools were assessed by counting interferon gamma spot-forming units in a FluoroSpot assay. Among 60 patients with ongoing rituximab treatment (49 women [82%]; mean (SD) age, 43 [10] years), the median (range) disease duration was 9 (1-29) years, and the median (range) dose of rituximab was 2750 (500-10 000) mg during a median (range) time of 2.8 (0.5-8.3) years. The median (range) follow-up from the first vaccination dose was 7.3 (4.3-10.0) months. Vaccine responses were determined before vaccination with tozinameran and 6 weeks after vaccination. By using established cutoff values for anti-spike IgG (264 binding antibody units/mL) and anti-RBD IgG (506 binding antibody units/mL), the proportion of patients with a positive response increased with the number of B cells, which was the only factor associated with these outcomes. A cutoff for the B-cell count of at least 40/μL was associated with an optimal serological response. At this cutoff, 26 of 29 patients (90%) had positive test results for anti-spike IgG and 21 of 29 patients (72%) for anti-RBD IgG, and 27 of 29 patients (93%) developed antibodies with greater than 90% inhibition of angiotensin-converting enzyme 2. No factor associated with the cellular response was identified. Depending on the peptide pool, 21 of 25 patients (84%) to 22 of 25 patients (88%) developed a T-cell response with interferon gamma production at the B-cell count cutoff of at least 40/μL. This cohort study found that for an optimal vaccine response from tozinameran, rituximab-treated patients with multiple sclerosis may be vaccinated as soon as possible, with rituximab treatment delayed until B-cell counts have reached at least 40/μL. An additional vaccination with tozinameran should be considered at that point.

FC066: Circulating Anti-Rituximab Antibodies Do Not Affect Response to Rituximab in Steroid-Dependent Nephrotic Syndrome

Abstract BACKGROUND AND AIMS Previous studies reported that the chimeric anti-CD20 monoclonal rituximab may lead to the production of anti-rituximab antibodies (Anti-RTX-Abs), due to the chimeric nature, impairing the efficacy of further infusions. In the context of glomerulonephritis, recent findings have described that the incidence of anti-RTX-Abs development may affect the efficacy of rituximab in paediatric steroid dependent nephrotic syndrome (SDNS) [Fujinaga et al. Pediatr Nephrol. 2020 Oct; 35(10): 2003–2008] and in membranous nephropathy [Boyer-Suavet et al. Front Immunol. 2020 Jan 13; 10: 3069]. The improved patient outcomes and cost-effectiveness have led to the development of a new generation of fully human anti-B cell agents in haematological and autoimmune diseases [Klomjit et al. Am J Kidney Dis. 2020 Dec; 76(6): 883–888]. Therefore, elucidating the role of Anti-RTX-Abs with the aim to develop personalized therapies is mandatory. In a randomized clinical trial, we compared the efficacy of fully humanized anti-CD20 antibody ofatumumab versus rituximab in children and young adults with SDNS [Ravani et al. JASN Oct 2021, 32 (10) 2652–2663]. METHOD We randomized 140 subjects to single infusion of rituximab or ofatumumab. Follow-up was of 24 months. We measured anti-rituximab IgG antibodies (LISA- TRACKER, Theradiag© Croissy Beaubourg, France) at the enrollment in 64/140 (46%) patients who previously received rituximab, regardless of the randomization arm, and at 6 months in 54/70 of the patients in the rituximab arm. (Fig. 1) Median time of last rituximab treatment was 36 months (13–54) before enrollment. RESULTS Anti-RTX-Abs were detected in none of the patients receiving more than or equal to one rituximab infusion before enrollment. At 6 months, Anti-RTX-Abs are detected in 14/54 patients (26%) who received rituximab (Fig. 2A). Patients developing anti-RTX-Abs or not had similar characteristics at enrollment. At T6, anti-RTX-Abs was not statistically different comparing who received rituximab before enrollment and who did not (Fig. 2B). Of the 54 patients treated with rituximab, 35 (65%) relapsed in 12 months of follow-up. Incidence of patients with anti-RTX-Abs at T6 was not statistically different comparing who experienced relapse with who did not (Fig. 2C). Time to relapse is reported in Fig. 2D. According to the protocol study, the 35 relapsing received a further infusion of rituximab. In this subgroup, incidence of patients with anti-RTX-Abs at T6 was not statistically different comparing who experienced further relapses with who did not (Fig. 2E). Both patients with and without anti-RTX-Abs had similar levels of total B-cell counts before rituximab therapy and at month 6 and 12 thereafter, showing similar B-cell reconstitution (Fig. 2F). We found similar percentages for memory B-cells comparing patients with and without Anti-RTX-Abs at enrollment, at month 6 and at month 12 of follow-up (Fig. 2G). CONCLUSION We evaluated the impact of Anti-RTX-Abs in a prospective study considering a large cohort of SDNS patients who received additional rituximab in case of relapse after a single infusion (375 mg/m2). According to the literature, we reported the development of Anti-RTX-Abs after a single infusion, which seems to persist for limited time. However, in contrast to previous findings, the development of Anti-RTX-Abs does not represent an unfavourable factor, which may limit the efficacy and the safety of further infusions. The prospective design of our study, in contrast to previous ones, represents one of the major strength of the present work. Moreover, Anti-RTX-Abs did not affect total and memory B-cell reconstitution following rituximab treatment.

Acquired hemophilia A in the setting of dual anticoagulation therapy and lupus anticoagulant: a case report

BackgroundAcquired hemophilia A is a disorder caused by autoantibodies against coagulation factor VIII that may present with severe bleeding. We report a rare case of acquired hemophilia A presenting with coexisting lupus anticoagulant.Case presentationAn 81-year-old Caucasian female presented with large ecchymoses over the torso and extremities in the setting of an enoxaparin bridge to warfarin. Anticoagulation was held, but she continued to develop bruises with significant anemia and prolonged coagulation studies that failed to correct with mixing. Workup revealed factor VIII activity < 1% and a positive lupus anticoagulant. Initial testing for a factor VIII inhibitor was confounded by the presence of lupus anticoagulant, requiring a chromogenic Bethesda assay to confirm the presence of the inhibitor, establishing the diagnosis of acquired hemophilia A. The patient was initially treated with oral prednisone 80 mg daily and factor VIII inhibitor bypassing activity 25 units/kg twice daily before transitioning to susoctocog alfa 50 units/kg twice daily after placement of a tunneled line for outpatient rituximab infusions. On discharge, the patient’s ecchymoses were resolving and factor VIII levels improved. Following completion of rituximab therapy, the patient’s factor VIII activity normalized and factor VIII inhibitor was suppressed.ConclusionsDiagnosis of acquired hemophilia A can be confounded by other causes of abnormal coagulation studies and may require specialized testing, such as a chromogenic Bethesda assay, to confirm the presence of a factor VIII inhibitor.

Immunogenicity of the BNT162b2 Vaccine in Patients Undergoing Maintenance Hemodialysis Is Associated with Medical Conditions

Background and Objectives: Patients undergoing maintenance hemodialysis have an attenuated immune response to vaccination. The aim of our study was to determine the predictive factors for humoral response to vaccination with the BNT162b2 mRNA vaccine (Pfizer-BioNTech) in patients on maintenance hemodialysis. Design, Setting, Participants, and Measurements: In this retrospective, single-center study, we included patients on maintenance hemodialysis already vaccinated with two doses of the BNT162b2 vaccine (Pfizer-BioNTech) and with a post-vaccination serological follow-up. Results: 252 patients were included for study with a mean age of 71.9 (±14.4) years. Twelve patients (4.7%) were under immunosuppressive therapy (calcineurin inhibitors: n = 4; chemotherapy for myeloma: n = 3; last infusion of rituximab over the previous 4 years: n = 2; abatacept: n = 2; adalimumab n = 1). Three of these patients were under immunosuppressive therapy for nonrenal solid organ transplantation. Multivariate analysis identified immunosuppressive therapy (OR 4.73 [1.38–16.17], p = 0.013) and lower baseline albumin levels (OR 1.23 [1.09–1.38], p < 0.001) as independent predictive factors of nonresponse to vaccination. Older age (β = −0.59 ± 0.21, p = 0.006) and immunosuppressive therapy (β = 40.33 ± 13.33, p = 0.003) were significantly associated with lower humoral response to vaccination. Conclusions: Approximately 90% of patients under maintenance hemodialysis developed specific antibodies to the BNT162b2 mRNA vaccine. Immunosuppressive therapy, malnutrition, and older age were associated with a higher risk of nonseroconversion or lower humoral response to mRNA-based vaccination against SARS-CoV-2. We strongly recommend serological monitoring after vaccination to determine booster timing, especially for patients with malnutrition or on immunosuppressive therapy.

Effect of mycophenolate mofetil dose on antibody response following initial SARS-CoV-2 vaccination in patients with systemic sclerosis.

Effect of mycophenolate mofetil dose on antibody response following initial SARS-CoV-2 vaccination in patients with systemic sclerosis.

P006 Rituximab biosimilar switching shows non-inferior outcomes in routine clinical practice

Abstract Background/Aims Biosimilar biologic therapy has been widely implemented in recent years. However, little data exists outwith clinical trials to confirm patient response to therapy and any safety signal following switch from originator products or between biosimilars. This study reviewed all rheumatoid arthritis patients prescribed biosimilar rituximab in a ‘real world' clinical practice setting to a certain clinical response following switching. Methods Retrospective review of clinical data from medical record was undertaken across three hospital sites in the UK. Patients were identified from biologic database and infusion facility records. Basic demographics were collected. The current biosimilar brand of rituximab, previous brands including originator were also collected and previous record of biologic and steroid therapy. The DAS-28 ESR was recorded pre- and post-biosimilar switch along with any note of infusion reactions. Results The database screening of 925 patients on biologic therapy identified 64 patients with rheumatoid arthritis taking rituximab biosimilar therapy. 48 female and 16 male patients with mean disease duration of 7.7 years were identified. 78% of patients were seropositive and all were on 6-monthly pulse infusions of 1g rituximab, 2 weeks apart. 34 (52%) patients were also taking methotrexate, (mean dose of 15mg/wk). Nine patients (14%) were taking concurrent oral prednisolone. Mean current DAS-28 ESR was 3.23. At biosimilar initiation DAS-28 was 4.00 (19% fall, non-significant). There were 14 adverse events, of which 11 were infusion-related reactions, six of which were for truxima, the remainder were with mabthera and rixathon. No anaphylaxis was recorded, although one patient had a hypersensitivity reaction. 38 (59%) patients had rituximab as first biologic. Conclusion This ‘real-life’ clinical review found similar clinical efficacy of rituximab biosimilar to originator product based on the DAS-28 ESR score. There were no notable safety or infusion differences. Disclosure J. Bilan: None. X. Chew: None. M.E. Perry: Honoraria; Lilly, Celltrion, Gilead, Abbvie, Biogen, Jaansen.

P073 Patient with rheumatoid arthritis on regular rituximab infusions with severe COVID-19 pneumonitis despite both vaccinations

Background/AimsCoronavirus Disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). International mass vaccination schemes are implemented to control the disease and reduce mortality. The data on serological immune response among rheumatology patients receiving immunosuppressive therapy following SARS-CoV-2 vaccines is very sparse. We present a case of a rheumatoid arthritis patient receiving rituximab (RTX) who developed fatal nosocomial COVID-19 infection despite receiving SARS-CoV-2 vaccine.MethodsA 71-year-old Caucasian male with longstanding seropositive rheumatoid arthritis, interstitial lung disease with bullous emphysema, paraproteinemia, osteoporosis, anxiety, and depression. His treatment included hydroxychloroquine, sulfasalazine, oral prednisolone (2-5 mg), and RTX every 6 months. He received his last cycle of RTX almost 8 weeks before vaccination. This gentleman received two doses of COVID-19 mRNA Vaccine (BioNTech-Pfizer) eleven weeks apart. Nine weeks after the second vaccination he was admitted with supraventricular tachycardia and heart failure. This admission coincided with a COVID-19 outbreak in the ward. Eight patients and one staff member tested (PCR) positive during regular ward screening. All patients were initially asymptomatic, and six of them were fully vaccinated. He was allowed to go home with advice to self-isolate for 10 days. Two days after discharge, he presented to the emergency department with shortness of breath, lethargy, and cough. The diagnosis was COVID-19 pneumonitis and pre-renal acute kidney injury. He received supplemental oxygen, dexamethasone, and intravenous co-amoxiclav. Unfortunately, he died from COVID-19 pneumonitis on his sixth day of admission. Our patient was the only one among the nine SARS-CoV-2 positive individuals who developed symptomatic disease.ResultsIt is known that RTX along with other immune modulatory drugs reduce the response to some vaccines such as the seasonal flu vaccine, and it is expected that the same effect could be seen after COVID-19 vaccination. Octave study is evaluating immune responses in patients with a range of chronic rheumatic conditions on specific immunomodulatory and biologic treatments. This has shown the response to vaccine was dependent on the disease cohort, with 90% of those with RTX-treated antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and 54% of those with inflammatory arthritis responding less well than the baseline for healthy subjects. There is no evidence to suggest how long after RTX a patient should delay vaccination with a COVID-19 vaccine, but published consensus suggests 4-8 weeks.ConclusionMore studies are needed to assess the response to SARS-COV-2 vaccines among immunocompromised patients and the need for a third vaccine dose if antibodies level were low. The first approved monoclonal antibody treatment—Ronapreve™ for treating and preventing acute covid-19 in adults, is a promising drug for poor vaccine responders who develop COVID-19 infection. This case also highlights the importance of infection control within hospital setting.Disclosure N. Abdullah: None. A. Kinder: None. D. Jenkins: None. V. Patel: None.

Humoral response to coronavirus disease-19 vaccines is dependent on dosage and timing of rituximab in patients with rheumatoid arthritis.

ObjectivesHumoral response to vaccines in RA patients treated with rituximab (RTX) in standard dosages (≥1000 mg) is decreased. Ultra-low dosages (500 or 200 mg) may have better response. Also, timing after latest RTX infusion may be an important variable. We aimed to investigate the influence of RTX dosage and timing on response to COVID-19 vaccination in RA patients.MethodsA single-centre observational study (n = 196) investigated the humoral response, measured by total Ig anti-COVID-19 assay (positive response ≥1.1), 2–6 weeks after complete COVID-19 vaccination. A multivariable logistic regression model was built to study the effect of RTX dosage and time between latest rituximab and vaccination on response, adjusting for age and methotrexate use.ResultsAfter two-dose vaccination, the response rate was significantly better for patients receiving 200 mg (n = 31, 45%) rituximab compared with 1000 mg (n = 98, 26%; odds ratio 3.07, 95% CI 1.14–8.27) and for each additional month between latest rituximab and vaccination (OR 1.67, 1.39–2.01).ConclusionBoth increased time between latest rituximab infusion and complete vaccination, and 200 mg as latest dose were associated with a better response to COVID-19 vaccination and should be considered when trying to increase vaccine response after rituximab in RA patients.Trial registrationNetherlands Trial Register, https://www.trialregister.nl/, NL9342.

Non HCV-Related Mixed Cryoglobulinemic Vasculitis With Biopsy-Proven Renal Involvement: The Effects of Rituximab.

In the countries where HCV infection is still endemic, about 90% of subjects with mixed cryoglobulinemia had previously been infected with HCV and about 80% are RNA positive. Remarkable results in severe HCV-related cryoglobulinemic vasculitis have been obtained with Rituximab. Details of the clinical characteristics and effective treatment of non HCV-related cryogloulinemic syndromes are presently lacking. This paper reports on a prospective single-Center open study aimed at evaluating the clinical presentation and effects of Rituximab administered alone in patients with severe non HCV-related cryoglobulinemic syndrome. The study group included 11 patients followed for at least 6 months. Three patients had type I cryoglobulinemia, 6 had type II and the remaining 2 patients had type III. Mean cryocrit was 2.5%. Four out of 11 patients had symptomatic sicca complex with anti-SSA (Ro)/anti SSB (La) antibodies. All 11 patients presented with biopsy-proven renal involvement, 4 out of 11 with leukocytoclastic vasculitis, and 8 with involvement of the peripheral nervous system. Renal biopsy revealed diffuse membranoproliferative glomerulonephritis (MPGN) in 9 out of 11 patients. Extracapillary proliferation and necrosis of the glomerular tuft was observed in 1 of these 9 cases. Interstitial nephritis together with mesangial expansion and capillary immune deposits were observed in 1 patient. Prevalent interstitial fibrosis and glomerular sclerosis were detected in the remaining case. Patients underwent treatment with rituximab alone. After 6 months we observed a remarkable improvement in the necrotizing skin ulcers and a substantial amelioration of the electrophysiological parameters of motor and sensory peripheral neuropathy. Improvement in both renal function (from 2.8 to 1.4 mg/dl, p < 0.001) and proteinuria (from 4.2 g/24 to 0.4 g/24 h, p < 0.001) was found in 10 out of 11 patients, while 1 could not be fully treated because of a severe infusion reaction and sudden development of anti-Rituximab antibodies. Good renal response was confirmed at the end of follow-up (38.4 months). Three patients had a relapse at 6, 12, and 48 months, respectively. In our cohort the administration of 4 once-weekly infusions of Rituximab followed by 2 more infusions after 1 and 2 months proved to be effective in the management of these rare patients.

B Cell Reconstitution Is Strongly Associated With COVID-19 Vaccine Responsiveness in Rheumatic Disease Patients Who Received Treatment With Rituximab.

To assess the association of a detectable antibody response to COVID-19 vaccination with factors including B cell depletion in patients who received treatment with rituximab (RTX). We conducted a retrospective review of the charts of adult patients who received treatment with RTX and completed messenger RNA vaccination for SARS-CoV-2. The primary outcome measure was the presence or absence and strength of the serologic antibody response to vaccination. Comparisons between those with and those without a detectable serologic response were calculated using t-tests, Fisher's exact test, and Wilcoxon's rank sum test. The relationship between the serologic response to COVID-19 vaccination and B cell reconstitution status was assessed using negative predictive values and positive predictive values with data reported as percentages with 95% confidence intervals (95% CIs). In 56 patients being treated with RTX, a significant difference in terms of the level of B cell reconstitution was observed in those with a positive serologic response compared to those with a negative serologic response to vaccination (proportion of B cells reconstituted among total lymphocytes, median 2% [interquartile range (IQR) 0.13-10%] versus median 0% [IQR 0-0%]; P < 0.001).There was also a significant difference in the time since the last RTX infusion between patients with a positive serologic response compared to those with a negative serologic response to vaccination (median time since last infusion 594 days [IQR 262-1,163] versus median 138 days [IQR 68-197]; P < 0.001). There was no serologic response to COVID-19 vaccination after the last exposure to RTX in 13% of patients (3 of 24) at >12 months after last exposure, 55% of patients (6 of 11) at 6-12 months after last exposure, and 86% of patients (18 of 21) at <6 months after last exposure. B cell reconstitution and a longer time since a patient's last exposure to RTX are associated with a positive serologic response to the COVID-19 vaccine. Strategies for maximizing vaccine responsiveness in patients who receive treatment with RTX should incorporate assessment of B cell reconstitution.

Evaluation of Serious Infection in Pediatric Patients with Low Immunoglobulin Levels Receiving Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis.

IntroductionThe aim of this work was to assess the impact of prolonged low immunoglobulin (IgG or IgM) serum concentrations on the potential cumulative serious infection (SI) risk in pediatric patients following rituximab treatment for granulomatosis with polyangiitis or microscopic polyangiitis (GPA/MPA) in PePRS.MethodsPatients aged ≥ 2 to < 18 years received four weekly intravenous rituximab infusions of 375 mg/m2 and concomitant glucocorticoid taper. After 6 months, patients could receive further rituximab and/or other immunosuppressants per investigator discretion. Immunoglobulin levels and SIs were assessed throughout the 4.5-year observation period. Prolonged low IgG or IgM was defined as below the lower limit of normal age-specific reference range for ≥ 4 months.ResultsA total of 25 patients were included, of whom 19 (76%) had GPA and six (24%) had MPA; 18 (72%) had newly diagnosed disease and seven (28%) had relapsing disease. All 25 patients completed the rituximab induction regimen; 24 completed ≥ 18 months of follow-up. At month 18, eighteen patients (72%) had prolonged low IgG; 19 (76%), prolonged low IgM; and 15 (60%), both. Seven patients (28%) had nine SIs; one occurred during or after prolonged low IgG only, two during or after prolonged low IgM only, and six during or after concurrent prolonged low IgG and IgM. No patients died or discontinued the study due to SI. All patients had complete and sustained peripheral B-cell depletion for ≥ 6 months.ConclusionsThe majority of pediatric patients who received rituximab for GPA/MPA with prolonged low immunoglobulin levels did not experience SIs. In patients with SIs, these events were manageable, and the number of SIs did not increase over time or with multiple rituximab treatments. These observations are consistent with the rituximab safety profile in adults with GPA/MPA.Trial registrationClinicalTrials.gov identifier, NCT01750697.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00433-0.

Early rituximab treatment is associated with increased and sustained remission in pemphigus patients: A retrospective cohort of 99 patients.

Rituximab is the front-line therapy for pemphigus disease. Although very effective, relapse rates are high. We assessed factors associated with disease remission and early relapse following the first rituximab cycle. A single center, retrospective cohort study of patients with pemphigus treated with rituximab (1000 mg0, 14 days) at the Autoimmune Bullous Disease Clinic of the Division of Dermatology in Rabin Medical Center, Israel, between January 1, 1995 and March 31, 2020. The cohort included 99 patients with a median follow-up of 37 months (range 12-155). After a single rituximab cycle, 74 patients (75%) achieved remission. Increased time to rituximab was associated with decreased remission rates (OR, 0.98 per month; 95% CI, 0.97-0.998). Of patients in remission with sufficient follow-up, 15/69 (22%) experienced an early relapse (≤12 months from remission). Prolonged time to rituximab and increased baseline disease severity, were associated with early relapse (OR, 1.02 per month; 95% CI, 1.001-1.04; OR, 1.04 per point; 95% CI, 1.01-1.08, accordingly). Initiating rituximab early following diagnosis is recommended. Maintenance rituximab infusions, especially for patients with severe baseline disease, should be further investigated.

Co-Infection of COVID-19 and Pneumocystosis Following Rituximab Infusion—A Case Report

Immunocompromised patients with respiratory viral infections are at increased risk of fungal superinfections, including Pneumocystosis. Within the scope of the COVID-19 pandemic, Pneumocystis jirovecii co-infections are being increasingly reported. Differential diagnosis often creates a dilemma, due to multiple overlapping clinical and radiographic features. Awareness of fungal co-infections in the context of the COVID-19 pandemic is crucial to initiate prophylactic measures, especially in high-risk individuals. We report the second case of Pneumocystis jirovecii pneumonia and COVID-19 co-infection in a renal transplant recipient in Poland.

Impact of electronic interventions on guideline concordant ordering of rituximab infusion rate.

Rituximab carries a boxed warning for severe or fatal infusion reactions; most occurring with the initial infusion. Prior studies established that if the initial rituximab infusion is tolerated, subsequent infusions can be given safely over 90 min. The University of Chicago Medicine (UCM) did not have a standardized method to document infusion reactions for outpatient chemotherapy patients, making it challenging for providers to know a patients' eligibility for rapid infusion. This quality improvement project focused on a series of interventions to improve documentation and electronic ordering of rituximab. A flowsheet for nurses to record patients' tolerance of chemotherapy infusions was created within the electronic health record (EHR). Following results of flowsheet impact, a second intervention was implemented to modify ordering of rituximab. The primary endpoint was the incidence of guideline concordant rate ordering of rituximab. Secondary endpoints included the incidence of accurate chair time scheduling pre- and post-interventions and nursing compliance with flowsheet documentation. Prior to flowsheet implementation, 85% of patients were infused at the guideline concordant rate, compared to 79% post-implementation. Prior to modification of rituximab ordering in the EHR, 85% of patients were infused at the guideline concordant rate, compared to 87% after implementation. Complete nursing documentation was done 89% of the time when the flowsheet was utilized, compared to 11% pre-interventions. No difference in primary or secondary endpoints was found following our interventions. However, the infusion documentation flowsheet, when used, provided more complete reaction data compared to when it was not used.

Rituximab related non-infectious lung injury complicating treatment of severe TTP in pregnancy – literature review and case-report

Background: Thrombotic thrombocytopenic purpura (TTP) in pregnancy is a rare but potentially life-threatening condition. Management of severe, refractory TTP during pregnancy is challenging and includes multidisciplinary approach. The prognosis of cases with a variety of hematological and autoimmune diseases, including TTP has changed profoundly after the rituximab therapy was introduced into clinical practice. However, adverse pregnancy outcomes associated with biological agents should be kept in mind and the decision to treat should be weighed by measurement of potential risks vs benefits. Case report: We reported the first documented case of noninfectious lung toxicity in pregnancy related to rituximab use for TTP treatment. 26 y/o patient at 23 weeks gestation initially presented to ED secondary to numbness, headache, and slurred speech with negative brain imaging. Her laboratory findings revealed severe deficiency of platelets, hemoglobin and ADAMT13 activity. She underwent multiple therapeutic interventions including plasmapheresis, intravenous immunoglobulins (IVIG), prednisone, and eventually required more often hospitalizations. Ultimately, the decision was made to proceed with rituximab therapy. After the third infusion of rituximab, she developed non-infectious lung injury without evidence of SARS-CoV-2 or other infections, pulmonary edema, or pulmonary embolism. The maternal condition worsened acutely resulting in significant desaturation that required intubation and eventual emergent premature delivery at 31-weeks’ gestation via C-section. Conclusion: Rituximab therapy for TTP management in pregnancy may be associated with significant adverse maternal-fetal outcomes. Risks and benefits of treatment should be discussed with each patient and during multidisciplinary communications. Physicians should maintain high index of suspicion for non-infectious lung injury associated with rituximab treatment in order to be able to diagnose this complication early and start treatment to avoid severe mortality and morbidity.