anti-B Cell Therapy Research Articles

Resident memory B cells are enriched in chronic rhinosinusitis with nasal polyps

BackgroundChronic rhinosinusitis with nasal polyps (CRSwNPs) is a chronic nasal and sinonasal inflammatory disease. Recently, resident memory B cells (BRMs) have been identified in the lungs, although not in the sinonasal mucosa. ObjectiveTo characterize memory B cell phenotypes with regards to patients with CRSwNPs and to identify BRMs in both normal sinonosal mucosa and CRSwNPs. MethodsCD19+ B cells were isolated from patients with CRSwNPs and analyzed using flow cytometry and immunohistochemistry. ResultsAlthough BRMs were found in the normal sinonasal mucosa, their numbers and frequencies tended to be limited. These findings were confirmed based on immunohistochemical analyses indicating an upregulation of CD69/CD45RB in tissue sections from CRSwNPs, although not in normal sinonasal mucosa. Accordingly, BRMs were established to be enriched in the nasal polyps isolated from patients with CRSwNPs. ConclusionOur findings in this study reveal that BRMs can be detected in normal sinonasal mucosa, although are significantly enriched in nasal polyps derived from patients with CRSwNP. These findings can contribute to gaining a more comprehensive understanding of the immune reactions associated with CRSwNP and facilitate the identification of potential therapeutic targets, such as anti-B cell therapy.

Parenteral anti-B cell therapy for multiple sclerosis: From origins to the creation of the Russian drug divosilimab

Parenteral anti-B cell therapy for multiple sclerosis: From origins to the creation of the Russian drug divosilimab

Autoimmune Nodopathy: When to Suspect and How to Treat?

Autoimmune nodopathy (AN) is a rare condition marked by autoantibodies that target specific proteins located within the node of Ranvier or paranodes. This disorder is distinctly different from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), with AN patients displaying unique clinical symptoms that include acute or subacute onset, primarily distal muscle weakness, sensory ataxia, tremors, and a significant increase in cerebrospinal fluid protein levels. Certain antibodies are linked to specific clinical manifestations; for instance, anti-contactin-1 neuropathy is often accompanied by nephrotic syndrome, whereas anti-pan-neurofascin neuropathy resembles fulminant Guillain-Barre syndrome. In contrast to CIDP patients, who usually experience substantial improvement with intravenous immunoglobulin (IVIG), those with AN may see poor or merely temporary benefits from IVIG therapy. Nonetheless, treatment with the anti-B cell therapy, rituximab, has shown promising results. These findings underscore the critical need for accurate identification of AN's clinical indicators, swift diagnosis of affected individuals, and the application of more effective, targeted treatments for this specific condition.

Autoimmune Nodopathy: When to Suspect and How to Treat?

Autoimmune nodopathy (AN) is a rare condition marked by autoantibodies that target specific proteins located within the node of Ranvier or paranodes. This disorder is distinctly different from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), with AN patients displaying unique clinical symptoms that include acute or subacute onset, primarily distal muscle weakness, sensory ataxia, tremors, and a significant increase in cerebrospinal fluid protein levels. Certain antibodies are linked to specific clinical manifestations; for instance, anti-contactin-1 neuropathy is often accompanied by nephrotic syndrome, whereas anti-pan-neurofascin neuropathy resembles fulminant Guillain-Barre syndrome. In contrast to CIDP patients, who usually experience substantial improvement with intravenous immunoglobulin (IVIG), those with AN may see poor or merely temporary benefits from IVIG therapy. Nonetheless, treatment with the anti-B cell therapy, rituximab, has shown promising results. These findings underscore the critical need for accurate identification of AN's clinical indicators, swift diagnosis of affected individuals, and the application of more effective, targeted treatments for this specific condition.

Abstract PO5-20-12: A Case of Bilateral Breast Cancer in a patient on Ocrelizumab

Abstract Background: Ocrelizumab is an anti-CD20 B cell depleting monoclonal antibodies that was FDA approved in 2017 for Relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis based on two large phase III trials (OPERA I and ORATORIO)1. In these trials, patients being treated with Ocrelizumab developed more malignancies compared to placebo. Among these cancers, breast cancer was prominent occurring in about 0.5-0.8% of the patients in the Ocrelizumab group as opposed to 0% in the placebo group. Here we present a case of bilateral breast cancer in a patient with Multiple Sclerosis (MS) treated with Ocrelizumab. Case Presentation A 66-year-old woman with a long-standing history of relapsing-remitting multiple sclerosis (MS) presented to us with concerns of bilateral masses on a screening mammogram. She was diagnosed with MS 30 years prior to presentation and was initially treated with multiple immunomodulators. However, she had progression of disease and was started on Ocrelizumab two years prior to presentation. She was up to date with her screening mammograms which had been unrevealing till now. Family history was significant for breast cancer in her grandmother in her 70s. Her annual mammogram screening showed bilateral irregular masses. A subsequent right breast ultrasound showed three breast masses(1cm, 0.5cm and 0.5cm respectively) and her left breast showed a 0.5 cm mass. Biopsy from the right breast showed invasive ductal and lobular carcinoma(ER+, PR+, HER2-) and that from the left breast showed invasive lobular carcinoma(ER+, PR+, HER2-).She underwent bilateral mastectomies and sentinel lymph node biopsies. The surgical margins and lymph nodes were negative for malignancy hence radiation was not warranted. Genetic testing revealed one pathogenic variant in MSH3 but was negative for BRCA1 and 2. Since her Oncotype dx score was low, adjuvant chemotherapy was not offered. She was started on aromatase inhibitor and her Ocrelizumab was permanently discontinued. Discussion Ocrelizumab is one of the immunomodulator drugs for MS with a probable mechanism being B-cell depletion. The mechanism of how it causes breast cancer is unknown. However, suggested theory is that B cell inhibitors can increase the risk of breast cancer by inhibiting the potentially protective role of the B cells. The B cells are thought to play a role in the tumor micro-environments as antigen presenting cells and activators of natural killer and cytolytic T cells targeted toward lysis of tumors. Also, B cell presence, specifically CD20 B cells, is linked to a better prognosis in breast cancer. One study has also pointed out the importance of timing of anti-b cell therapy in relation to cancer morbidity. Treatment of mice with Anti-CD20 therapy prior to tumor challenge did not result in cancer metastasis. Whereas post tumor challenge, there was increased tumor cell survival and metastasis. Our patient although had a family history of breast cancer, did not have a genetic mutation that could have contributed to her breast cancer. Her breast cancer developed after her therapy with Ocrelizumab hence raising suspicion for causation. With rise in the use of immunosuppressive therapies, further data is needed to delineate pathogenesis. Women with MS have lower all-cause survival after breast cancer diagnosis than women without MS. Hence it is important to identify any risk factors or therapies that might be associated with increased risk of cancer. Citation Format: Kriti Mehra, Mohamad Hejazi. A Case of Bilateral Breast Cancer in a patient on Ocrelizumab [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-12.

Abstract 6409: A multiparametric flow cytometry assay to monitor regeneration of B-cells following anti B-cell therapy in cancer and autoimmune patients

Abstract Purpose Functional dysregulation of B-cells leads to a variety of autoimmune disorders and blood cancers. Multiple B-cell depleting therapies (e.g., BTK inhibitors, antibodies or CAR-Ts) are currently in active clinical trial investigation. Following therapeutic elimination of pathogenic B-cells, it is critical to monitor the productive regeneration of fully functional B-cells as they mediate innate and adaptive immune responses. To this end, we developed a multiparametric flow cytometry assay for exquisite monitoring of early stages of B cell development, maturation, and antibody production to correlate it with treatment outcomes and determine if continuous depletion of B-cells is necessary to maintain clinical benefits for patients. Study Design We designed a high throughput 12-parameter flow cytometry panel incorporating primary differentiation markers namely, CD45, CD3, CD38, CD10, CD27, CD19, CD20, IgD, Lambda & Kappa Light Chains required for identification of different developmental stages of B-cells in peripheral blood using an in vitro diagnostic grade flow cytometry system (BD FACSLyric). The optimized method underwent robust fit-for-purpose analytical validation per CLSI H62 guidelines with emphasis on establishing assay sensitivity, specificity, and reproducibility across experimental days, operators, and instruments. Results We were able to reliably identify different stages of B-cell development, namely, Naïve (CD19+CD20+IgD+CD27-), Unswitched/Marginal (CD19+CD20+IgD+CD27+), Memory (CD19+CD20+IgD-CD27+), Transitional (CD19+CD20+IgD+CD27-CD10+), Antibody Secreting Cells (CD19+CD20-IgD-CD27+CD38hi) as well as clonality (CD19+CD20+Lambda+ or Kappa+). The lower limit of quantitation was determined to be around 60 events, based upon analysis of 90 data points with good reproducibility (CV range: 0-11.7%) across experimental days, operators and instruments demonstrating sensitive detection and robust performance. Conclusion In summary, we have developed and validated a 12-parameter flow cytometry assay focusing on monitoring the regeneration of different subsets of B-cells in various B-cell malignancies (Non-Hodgkin’s Lymphoma, B CLL) and autoimmune disorders (Multiple Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus). The high reproducibility/robustness of the assay demonstrates its suitability for use in clinical trials as a valuable tool for safety monitoring and disease evaluation enabling development of novel therapeutic agents. Citation Format: Amit Kumar Mehta, Ruby Tandon, Anil Pahuja, Jane Gao, Kevin Nguyen, Naveen Dakappagari, Zeni Alfonso. A multiparametric flow cytometry assay to monitor regeneration of B-cells following anti B-cell therapy in cancer and autoimmune patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6409.

Colitis Due to Anti-B Cell Therapy: A Clinical Reality

Colitis Due to Anti-B Cell Therapy: A Clinical Reality

Extended interval dosing of ocrelizumab modifies the repopulation of B cells without altering the clinical efficacy in multiple sclerosis

BackgroundRecent studies suggest that extended interval dosing of ocrelizumab, an anti-B cell therapy, does not affect its clinical effectiveness in most patients with multiple sclerosis (MS). However, it remains to be established whether certain B cell subsets are differentially repopulated after different dosing intervals and whether these subsets relate to clinical efficacy.MethodsWe performed high-dimensional single-cell characterization of the peripheral immune landscape of patients with MS after standard (SID; n = 43) or extended interval dosing (EID; n = 37) of ocrelizumab and in non-ocrelizumab-treated (control group, CG; n = 28) patients with MS, using mass cytometry by time of flight (CyTOF).ResultsThe first B cells that repopulate after both ocrelizumab dosing schemes were immature, transitional and regulatory CD1d+ CD5+ B cells. In addition, we observed a higher percentage of transitional, naïve and regulatory B cells after EID in comparison with SID, but not of memory B cells or plasmablasts. The majority of repopulated B cell subsets showed an increased migratory phenotype, characterized by higher expression of CD49d, CD11a, CD54 and CD162. Interestingly, after EID, repopulated B cells expressed increased CD20 levels compared to B cells in CG and after SID, which was associated with a delayed repopulation of B cells after a subsequent ocrelizumab infusion. Finally, the number of/changes in B cell subsets after both dosing schemes did not correlate with any relapses nor progression of the disease.ConclusionsTaken together, our data highlight that extending the dosing interval of ocrelizumab does not lead to increased repopulation of effector B cells. We show that the increase of CD20 expression on B cell subsets in EID might lead to longer depletion or less repopulation of B cells after the next infusion of ocrelizumab. Lastly, even though extending the ocrelizumab interval dosing alters B cell repopulation, it does not affect the clinical efficacy of ocrelizumab in our cohort of patients with MS.

The use of “Acellbia” – a biosimilar of rituximab in systemic sclerosis

Introduction. The possibilities of modern therapy for systemic sclerosis (SSc) remains limited, since most of the used drugs do not have a diseasemodifying effect. This encourages the study of new approaches that potentially affect the fundamental pathological processes underlying the disease. One example is anti-B cell therapy, in particular rituximab (RTX). Until now RTX do not have a registration for the treatment of SSc, but there is a large positive experience of its use, which is reflected in recent meta-analyses and clinical recommendations. Complicated and expensive methods for obtaining genetically engineered biological preparations have contributed to the emergence of more accessible biosimilars, one of which is the RTX biosimilar, Acellbia (Biocad, Russian Federation). The “biosimilar” versions of RTX might reduce the cost of therapy and increase patients accessibility to this treatment option. The RTX biosimilar Acellbia (ACB) has received approval in Russian Federation in 2014 for all indications held by reference RTX (including rheumatoid arthritis and ANCA-associated vasculitis).The aim of this study was to investigate the efficacy and safety of Acellbia in patients with systemic sclerosis.Material and methods. Our prospective uncontrolled study included 20 patients (14 women) aged 50±14 years, with a disease duration of 3.5±2.7 years. Indications for the prescribing of ACB were high disease activity and the presence of risk factors for progression. All patients had radiological signs of interstitial lung disease, 13 (65%) were positive for antibodies to topoisomerase 1. None of the patients had previously been treated with biological therapy. All patients received glucocorticoids in low doses and 15 (75%) patients were not on concomitant immunosuppressants during the study. ACB was administered in doses of 2 g (two doses of 1 g with a weekly interval) at inclusion of the study and after 6–8 months according to the same scheme, cumulative dose – 4 g. An assessment of basic measurements was obtained at baseline (Point 0), before the second course (after 7.2±1.7 mo, Point 1) and at the end of follow-up (13.4±1.6 mo, Point 2). The results are presented in the form of mean values and standard deviations.Results. There was a positive effect on the main manifestations of the disease, which accompanied by stable depletion of CD19+ B lymphocytes in the peripheral blood. At the intermediate assessment (between points 0–1), no significant changes were observed, with the exception of the skin score. At the end of the study, most of the parameters showed a significant improvement between points 0–2. The activity of the disease (EScSG-AI) decreased, and the skin score decreased from 12.8±11 to 6.2±5.6 (p=0.002). The forced vital capacity (% of predicted) increased from 89±18.2 to 98.26±16.13% (p=0.0002), and the diffusion capacity of the lungs (% of predicted) increased from 56.8±15.7 to 61.9±17.2% (p<0.019). A significant decrease in CRP, antitopoisomerase-1 antibodies, as well as IgG (from 12.6±2.6 to 10.2±2.2 g/l) was noted. Repopulation to normal level of B lymphocytes did not occur in any case, and complete depletion of B lymphocytes at the end of the study was maintained in 83% of patients (15 of 18). The quality of life questionnaire SHAQ improved (p=0.0001), and the average dose of prednisolone was reduced from 11.0±2.7 to 9.4±2.3 mg/day (p=0.03). Positive changes according to HRCT was evident in 9 (45%) patients due to a decrease in ground glass opacity. The frequency and spectrum of adverse events (AEs) corresponded to those already known for RTX. Of the 20 patients who received 2 courses of ACB, two withdrew from the evaluation at Point 2 due to pregnancy (1) and lung cancer (1). A total of 11 (55%) AEs were reported in 9 (45%) patients, most of them were classified as mild. Infectious complications developed in 7 (35%) patients: respiratory infections of the upper respiratory tract (4), positivity in the TB skin test (2), otitis (1), cystitis (1) and cholecystitis (1). One patient developed calf vein thrombosis and lung cancer was diagnosed in one case.Conclusion. Our data suggest that Acellbia could be used for the treatment of SSc. A short-term, prospective, uncontrolled study showed good efficacy and acceptable safety of the ACB biosimilar in SSc. A significant decrease of skin fibrosis and improvement of lung functions have been proven. The clinical effect of ACB manifested by the 6th month from the start of therapy and reached its maximum one year after its initiation. Due to the positive efficacy of ACB, it can be prescribed for the patients with SSc with ineffectiveness and/or intolerance to immunosuppressants, and could be considered as a first-line therapy. Our data should be confirmed by the results of controlled clinical trials.

Experience with Tixagevimab and Cilgavimab (Evusheld) in 86 rheumatic patients undergoing anti-B cell therapy with rituximab

The problem of prevention of coronavirus disease 2019 (COVID-19) in patients with immune-mediated inflammatory rheumatic diseases (IMRD) remains highly relevant. The presence of IRD is associated with a high risk of disease and severe course of COVID-19 during immunosuppressive treatment, primarily anti-B cell therapy with rituximab (RTX), and a low level of post-vaccination response in such patients. A new strategy for the prevention and treatment of COVID-19 are virus-neutralizing monoclonal antibodies to coronavirus; currently, combined long-acting monoclonal antibodies tixagevimab and cilgavimab (Evusheld) are registered for prevention in the world and the Russian Federation. . Tixagevimab and cilgavimab (TC) show neutralizing activity against SARS-CoV-2, including the Omicron strain, primarily its variants BA.4, BA.5, BA.2.75 ("Centaur").Objective – to evaluate the efficacy and safety of TC for pre-exposure prophylaxis of COVID-19 in rheumatic patients receiving RTX, based on a prospective observational study.Materials and methods. The main group included 86 patients with various IMRD receiving RTX: 50 of them had ANCA-associated systemic vasculitis (AAV), 15 – rheumatoid arthritis, 9 – Sjogren’s syndrome (SS), 4 – IgG4-related disease, 3 – systemic lupus erythematosus (SLE), 3 – dermatomyositis (DM), 2 – systemic scleroderma (SSD). Median age was 59 (19–82) years; male : female ratio – 1:1,8. From March 26 to August 30 2022, patients received a single intramuscular injection of TC in a total dose of 300 mg, mainly after RTX (in 52% of cases, in 28% on the next day after RTX). The control group included 42 patients with AAV (median age – 45 (35–71) years; male : female ratio – 1:1), also treated with RTX, who did not receive pre-exposure prophylaxis of TC. The duration of observation was 7 months, until November 1 2022. At this time, 98% of confirmed cases of coronavirus in the Russian Federation were Omicron. A telephone and/or online survey of patient has been conducted to detect cases of COVID-19 and adverse reactions.Results. In the TC group, confirmed coronavirus infection have been detected in 17 (20%) patients (AAV – 10, SS – 3, SSD – 2, SLE – 1, DM – 1), with fever in 7 (8%), only in one case hospitalization was required (lung damage was not detected in computed tomography), in two cases, according to CT mild lung damage (CT 1–2), there were no deaths. Good TC’s tolerability was noted, signs not associated with COVID-19 or progression of IMRD after administration of TC were observed in 8 (9%) patients (GPA – 3 MPA – 1, RA – 2, SLE – 1, IgG4-related disease – 1), adverse reactions definitely associated with the use of TC were not found. The most serious event not associated with coronavirus infection was the progression of polyneuropathy in a patient with RA. In the control group, 3 (7%) patients were diagnosed with COVID-19, one with severe lung injury (CT 3, pulmonary embolism) and death.Conclusions. The data of clinical studies and our own clinical experience evidence the effectiveness of the use of a combination of long-acting monoclonal antibodies TC (Evusheld), registered for indications for pre-exposure prophylaxis and treatment of COVID-19. Patients with IMRD treated with RTX have a favorable safety profile of TC. The introduction of virus-neutralizing monoclonal antibodies, a new drug class for the prevention and treatment of infectious diseases, opens significant prospects for improving the prognosis of patients with IRD.

A comprehensive analysis of coagulopathy during anti-B cell maturation antigen chimeric antigen receptor-T therapy in multiple myeloma, a retrospective study based on LEGEND-2.

Chimeric antigen receptor (CAR)-reprogrammed T cell therapy is a novel and powerful treatment against hematological malignancies. Cytokine release syndrome (CRS) and other potentially life-threatening toxicities are known side effects which need appropriate management and supportive care. Coagulopathy is a common and severe CAR-T-related adverse event, while a comprehensive profile of coagulopathy in patients with multiple myeloma (MM) undergoing CAR-T cell therapy has not been reported. Therefore, we performed a comprehensive analysis of coagulopathy in 51 patients with r/r MM given anti-B cell maturation antigenCAR-T cell therapy. We found that 49% of patients had coagulation disorders, and 29% of patients experienced disseminated intravascular coagulation (DIC). Severe CRS, abnormal liver function and higher tumor burden were risk factors for the CAR-T-related coagulopathy. We found that the serum IL-6 level and alanine aminotransferase level were potential indicators for CAR-T-related DIC. Furthermore, we found that coagulation disorders occurred within 1month after CAR-T cell infusion, mainly between days 10 and 13, which was 2-5days later than the beginning of CRS and simultaneous with the beginning of abnormal liver function and the peak of CRS. In addition, although patients with coagulation dysfunction had a trend for better outcomes and prognosis, no statistical significance was found. In conclusion, our research provided a comprehensive understanding of CAR-T-related coagulopathy in MM. Upon timely and standardized treatment, coagulopathy was manageable in most cases.

P146 Pragmatic Biologic Tapering Combining Clinical and Ultrasound Assessment in Patients with Rheumatoid Arthritis in Routine Clinical Practice - Predictors of Failure from a Regional Centre in UK

Abstract Background/Aims Tapering biologic therapies in patients with rheumatoid arthritis (RA) is evolving. Our primary objective was to combine clinical and ultrasound assessment in selecting patients with RA for tapering biologic therapies. The secondary objectives were to identify predictors for failure and cost savings. Methods RA patients on biologics in sustained clinical remission (defined as DAS 28 < 2.6) in the previous year and imaging remission (defined as Power Doppler US of small joints of hands not significant) were included. The patients were seen in a multidisciplinary clinic with an advanced pharmacy practitioner between April 2019 and March 2022. They were advised to lengthen the interval of their biologics gradually and were followed quarterly till September 2022. Failure was defined as reverting to previous regime at any point during follow up. Independent predictors of failure were identified with Cox multiple regression analysis SPSS v29.0 (IBM 2022). Results Biologics were tapered in 184 patients including 129 on anti-cytokine therapy (abatacept 13, adalimumab 35, certolizumab 31, etanercept 18, golimumab 8, infliximab 4, tocilizumab 20) and 55 on rituximab. The mean age of the cohort was 63.8±11.7 years and there were 72.3% females. The mean duration of RA was 15.2 ± 7.9 years and baseline DAS28 before taper was 1.93±1.04 years. Concomitant DMARDs were used in 53.8%. Anti-cytokine therapy:Over 287.9 patient-years follow up (mean follow up duration: 26.8 ± 14.1 months), taper failure occurred in 36 (27.9%) patients in a mean time of 12.0 ± 8.1 months. There was no statistically significant difference in failure rate between different agents. A 50% dose reduction could be achieved in 65 (50.4%) patients with the mean time to achieve it of 10.4 ±9.1 months. Thirteen (10.1%) patients stopped biologics completely. Current smoking [HR:3.67 95%CI:1.50-9.00, p:0.04] and higher DAS28 at initiation of taper [HR:1.93 95%CI:1.11-3.36, p:0.020] were predictive of taper failure. All but 3 of the 36 patients who failed taper, responded on reverting to their previous treatment regime. Anti B-cell therapy:The 55 patients on Rituximab were tapered to a lower dose or had their interval lengthened. Over 98.6 patient-years follow up (mean follow up: 21.5 ± 11.3 months). Mean dose reduction achieved was 62.2 ± 19.9 %. Mean interval between RTX infusions was 12.9 ± 6.4 months. We have managed to save nearly £800,000 over the 3 years with tapering of biologics in this cohort of RA patients compared to the standard dose. Conclusion Successful tapering of biologic therapies in patients with rheumatoid arthritis is feasible and safe in majority of patients who are in clinical and imaging remission. Current smoking and baseline high DAS28 predicted taper failure for anti-cytokine biologics. This can be safely managed by reverting to the original dosing in most patients. Disclosure H. Muhammed VK: None. A. Yau: None. G. Hirsch: None. T. Sheeran: None. S. Venkatachalam: None.

COVID-19 in a patient with granulomatosis with polyangiitis: Management tactics

Patients with ANCA-associated vasculitis (AAV) cause extreme alertness during the coronavirus disease 2019 (COVID-19) pandemic, associated with many factors: the initial damage to the respiratory system (upper respiratory tract, lungs) and kidneys, immunosuppressive treatments, difficult prognosis of COVID-19 with the risk of AAV exacerbation. We present a clinical case of а moderate COVID-19 in a patient with granulomatosis with polyangiitis, who received anti-B cell therapy with rituximab (RTX) for a long time. Coronavirus pneumonia developed one year after RTX, while B-lymphocyte depletion persisted. In order to achieve an adequate antiviral immune response and prevent hyperinflammation, treatment was carried out with antiviral drugs, anticoagulants, convalescent plasma, human normal immunoglobulin, and interleukin-6 antagonist tocilizumab. Possible predictors of severe COVID-19 in patients with AAV are discussed.

Imaging CD19+ B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model using Positron Emission Tomography.

Multiple sclerosis (MS) is the most common demyelinating central nervous system (CNS) disease affecting young adults, often resulting in neurological deficits and disability as the disease progresses. B lymphocytes play a complex and critical role in MS pathology and are the target of several therapeutics in clinical trials. Currently, there is no way to accurately select patients for specific anti-B cell therapies or to non-invasively quantify the effects of these treatments on B cell load in the CNS and peripheral organs. Positron emission tomography (PET) imaging has enormous potential to provide highly specific, quantitative information regarding the in vivo spatiotemporal distribution and burden of B cells in living subjects. This paper reports methods to synthesize and employ a PET tracer specific for human CD19+ B cells in a well-established B cell-driven mouse model of MS, experimental autoimmune encephalomyelitis (EAE), which is induced with human recombinant myelin oligodendrocyte glycoprotein 1-125. Described here are optimized techniques to detect and quantify CD19+ B cells in the brain and spinal cord using in vivo PET imaging. Additionally, this paper reports streamlined methods for ex vivo gamma counting of disease-relevant organs, including bone marrow, spinal cord, and spleen, together with high-resolution autoradiography of CD19 tracer binding in CNS tissues.

Booster and Btki Interruption Improve Response to Sars-Cov-2 Vaccine in Patients with CLL

Introduction: Patients with chronic lymphocytic leukemia (CLL) have inadequate responses to vaccination, including SARS-CoV-2 mRNA vaccines. Treatment with anti-B cell therapies, such as anti-CD20 monoclonal antibodies (mAb) and Bruton's tyrosine kinase inhibitors (BTKi), further suppress the antibody (Ab) response to vaccines. We investigated whether BTKi interruption around the time of a booster injection could enhance vaccine response. Methods: A single-institution retrospective cohort study of patients with CLL was conducted at the National Institutes of Health from 2020-2022. Treatment naïve (TN) patients as well as those receiving treatment with a BTKi or venetoclax (VEN) were included. Patients who received IVIG, anti-SARS-CoV-2 mAb, or convalescent plasma within three months of vaccination were excluded. Anti-spike Ab titers were measured after completion of the primary series (2 doses of Pfizer-BioNTech/Moderna vaccines or 1 dose of Janssen vaccine) and the first booster. Ab titers were measured using the Roche Elecsys® immunoassay and categorized as no response (<0.8 U/mL), weak response (0.8-50 U/mL), or strong response (>50 U/mL). Ultra-deep TCRβ sequencing (Adaptive Biotechnologies) was performed before and after the primary series to identify and track spike-specific clonotypes. A T-cell vaccine response was defined as significant expansion of ≥1 spike-specific clonotype. Results: We studied Ab response in 86 patients (54 on BTKi, 14 on VEN, and 18 TN). The median age was 68.0 (range 66-69) and 97.7% of patients received mRNA vaccine. After the primary series, seroconversion (anti-spike Ab ≥0.8 U/mL) was detected in 53% of BTKi-treated patients, 57% of patients on single-agent VEN, and 67% of TN patients. After booster, anti-spike Ab was detected in 87% of BTKi-treated patients, 50% of patients on single-agent VEN, and 83% of TN patients. No patients who received anti-CD20 mAb within 12 months of vaccination (in combination with VEN) responded to the primary series or booster. All patients with seroconversion post primary series also had detectable anti-spike Ab post booster. Anti-spike Ab increased after booster in 90% of patients who responded to the primary series. Of the patients who did not respond to the primary series, 57% seroconverted post booster. Seroconversion was associated with higher serum IgM after the primary series (median 37g/L (IQR 24-63) vs. 26g/L (IQR 9-37), p=0.02) as well as higher serum IgG (median 848g/L (IQR 620-920) vs. 611g/L (IQR 395-782), p=0.02). Patients with detectable anti-spike Ab after booster had higher IgM (median 35g/L (IQR 22-65) vs. 9g/L (IQR 5-437), p=0.04) as well as higher IgA (median 88g/L (IQR 65-112) vs. 41g/L (IQR14-84), p=0.01). Of patients on BTKi, 21/40 (52%) had seroconversion after the primary series, albeit with mostly weak responses (62%). After booster, 34/40 (85%) had detectable anti-spike Ab. Of BTKi-treated patients with a weak response to the primary series, 10/13 (77%) mounted a strong response to booster. Twelve patients interrupted BTKi for a median of 21 days (range 8-22) around the time of booster. Patients who interrupted BTKi had higher anti-spike Ab (median 7,149 U/mL, IQR 1109-19900) than those who continued therapy (median 1,198 U/mL, IQR 2.05-2985, p=0.02). Three patients experienced lymph node pain and swelling during BTKi interruption and resumed BTKi earlier than intended. Longitudinal analysis of Ab titers post-booster among BTKi patients demonstrated a decline in anti-spike Ab of 0.45% per day, which denotes a 50% decline in 111 days. No difference in the rate of decline was observed between patients who interrupted BTKi and those who continued BTKi. T-cell response to the primary series was observed in 7/15 (47%) of BTKi-treated patients. No significant difference in T-cell response was found between patients on ibrutinib and those on acalabrutinib (p=0.6). T-cell response after the primary series was not predictive of Ab response post-booster (p=0.3). Conclusion: Increasing anti-spike Ab with subsequent vaccinations support additional boosters in patients with CLL. BTKi interruption at the time of vaccination results in a more robust Ab response.

Past, Present, and Future in Dermatomyositis Therapeutics.

This review highlights current and emerging pharmacologic therapies for the treatment of dermatomyositis (DM). Current clinical evidence, in addition to recently published and ongoing clinical trials for various drugs in development, are summarized in this review. There has been significant progress in the research and development of potential treatments in DM. The FDA recently approved Octagam® 10% Immune Globulin Intravenous (IVIg) for the treatment of DM. Several drug targets are being explored as viable therapeutic options in phase 2 and phase 3 clinical trials; at the forefront of these are JAK inhibitors (tofacitinib and baricitinib) and T-cell co-stimulation blockers (i.e. abatacept). In addition, clinical trials are currently under way for therapeutics targeting novel molecular pathways, including immunoproteasome inhibitors, anti-B cell therapy, anti-interferon drugs, complement inhibitors, and phosphodiesterase-4 inhibitors. With the large number of clinical trials, multiple novel therapeutics in development, and improved classification and outcome measures, the treatment landscape for DM will continue to rapidly evolve in the coming years as more options become available.

Late-onset neutropenia induced by anti-B cell therapy with rituximab in patients with ANCA-associated systemic vasculitis

In the last decade, anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (SV) has been treated with the anti-B-cell drug, rituximab (RTM) both for induction and maintenance therapy. One of the problems of the treatment with RTM in patients with ANCA-SV is the risk of late-onset neutropenia (LON), mechanisms of development of which have not been studied enough yet.Objective: to evaluate the incidence and outcomes of LON in patients with ANCA-SV treated with RTM. Patients and methods. A retrospective analysis of the register of 140 patients with ANCA-SV who received RTM treatment at the V.A. Nasonova Research Institute of Rheumatology from 2009 to 2021 years. The median duration of RTM treatment was 49 (6–121) months, the median of the total RTM dose was 3.5 (0.5–9.5) grams. The duration of follow-up exceeded 6 months after the first administration of RTM.Results and discussion. LON was detected in 16 (11.4%) patients, of which 6 suffered from Wegener's granulomatosis with polyangiitis (GPA), 4 – microscopic polyangiitis (MPA), 4 – Churg-Strauss eosinophilic granulomatosis with polyangiitis (EGPA) and 2 – undifferentiated ANCA-SV. In 8 (50%) out of 16 patients, LON developed within 2 months after the 1st course of RTM, in the remaining 8 patients, on average, after 10 (4– 15.5) months. A lethal outcome was documented in 5 (31.2%) of 16 cases of LON (1 with MPA, 3 with GPA, and 1 with EGPA) on average 2 (1.5–9) months after the 1st course of RTM, at the same time, in 4 patients LON was complicated by pneumonia, including 2 with septic shock, in another 1 case LON was combined with the development of acute myocardial infarction and progression of chronic renal failure. Overall mortality among 140 patients with ANCA-SV treated with RTM was 11.4%, while in cases with a fatal outcome, the frequency of LON reached 31.2%.Conclusion. Thus, LON induced by RTM is a common (11%) and clinically significant consequence of B-cell depletion in patients with ANCA-SV, in every 5th case it is complicated by serious infections (including sepsis in 13%) and accounts for a significant proportion in the structure of lethal outcomes (31.2%).Patients treated with RTM require careful monitoring of absolute neutrophil count both during the first months after initiation of anti-B-cell therapy and thereafter. In the combined administration of RTM with cytotoxic drugs (primarily cyclophosphamide) in patients with ANCA-SV, it is necessary to consider the risk of LON developing, secondary immunodeficiency, and infectious complications. During the coronavirus pandemic, one should remember that treatment with interleukin 6 inhibitors used in severe COVID-19 can also be accompanied by neutropenia and requires careful dynamic monitoring of the absolute number of neutrophils in patients with ANCA-SV treated with RTM. It is necessary to inform both patients and physicians of the risk of LON development during the treatment of RTM in ANCA-SV and other rheumatic diseases.

AB0606 Health-related quality of life in patients with rituximab-induced remission of ANCA-associated vasculitis: registry-based cohort studies

BackgroundSurvival rate in ANCA-associated vasculitis (AAV) has significantly improved due to anti-B cell therapy with rituximab (RTX). The main issue now appears to be the management of comorbidities and the improvement of quality of life.ObjectivesBased on a prospective analysis of the single centre registry of AAV patients (pts) treated with RTX, to study the impact of sustained remission on health-related quality of life using Short-Form 36 (SF-36).MethodsHealth-related quality of life was assessed in 70 AAV pts: 35 (50%) with granulomatosis with polyangiitis (GPA), 24 (34.3%) - microscopic polyangiitis (MPA) and 11 (15,7%) - eosinophilic granulomatosis with polyangiitis (EGPA). The mean age was 49,7 ± 15,7 years, 53% women. The median total dose of RTX was 4.3± 2,5 g. As a rule, a reduced dose of RTX 500 mg was used for repeated courses. Mean duration of RTX therapy 46.8 ± 29.4 months. Remission of AAV was defined as a Birmingham Vasculitis Activity Score = 0 regardless of prednisone treatment or dosage. All pts were in remission.ResultsIn 70 patients the average indicators of physical functioning: MPA 62.5 (47.5, 78.8), GPA 75 (55, 92.5), EGPA 60 (45, 77.5); social functioning: MPA 25 (0, 56.3), GPA 50 (25, 100), EGPA 50 (12.5, 62.5), physical health component: MPA 41.6 (31.5, 44.8), GPA 43.7 (36.7, 52.5), EGPA 38.7 (33.8, 45). There were no significant differences between men and women within the GPA, MPA, and EGPA groups. There were also no differences between different age groups. When comparing the EGPA group with GPA or MPA, no significant differences were found. At the same time, in patients with MPA, the indicators of physical functioning (p=0.015, w= 3.92) and the physical component of health (p=0.012, w 4.026) were significantly lower than in patients with GPA.ConclusionRTX maintenance allows to achieve a good quality of life in AAV pts. SF-36 summary measures were significantly higher in GPA pts compared with MPA. Further research is required to analyze the effect of AAV phenotype and complications on health-related quality of life.

On the issue of post COVID-19 condition in patients with rheumatic diseases

Actual problems of rheumatology include the possibility of developing a wide range of long-term consequences of COVID-19, so-called post-COVID syndrome (PCS). The results of our own research are presented, during which among 45 patients over 18 years with rheumatic diseases (RD) PCS was detected in 20% cases: 6 of them had ANCAassociated vasculitis (AAV) and one each for rheumatoid arthritis, juvenile arthritis and osteoarthritis. In AAV cases PCS was more severe and varied than in other RD: lung lesions according to computed tomography (up to the damage 75% of the lung parenchyma), skin an d nervous (Guillain–Barré syndrome) lesions, myalgias, arthralgias were present. In most patients PCS ended in recovery, sudden death occurred only in the patient with AAV. The frequency of RD’s relapses in patients with PCS was 9%. Relapses were not noted in AAV, against the background of anti-B cell therapy with rituximab. Our own results and literature data indicate that patients with RD after COVID-19 need careful continuous monitoring to detect long-term complications of coronavirus infection and early diagnosis of relapses of the underlying disease.

Controversies about immunoglobulin replacement therapy in HSCT recipients with hypogammaglobulinemia.

The efficacy of immunoglobulin replacement therapy (IgRT) has been demonstrated for primary immune deficiency diseases and hematological malignancies such as chronic lymphocytic leukemia (CLL) or multiple myeloma with hypogammaglobulinemia. Clinical development of anti-B cell therapies including a monoclonal antibody, bispecific antibody, or chimeric antigen receptor T-cell therapy which could result in severe hypogammaglobulinemia accelerates the argument of prophylactic use of IgRT. Clinical guidelines for CLL describe immunoglobulin administration in patients with a low IgG who have experienced a severe/repeated bacterial infection. The utility in hematopoietic stem-cell transplantation (HSCT) remains unknown. Although an early randomized trial demonstrated that IgRT decreased infection risk and transplant-related mortality after HSCT, subsequent clinical trials could not validate the benefit. Consequently, a meta-analysis did not show the benefit of IgRT in HSCT. Most of the available data derives from matched-related HSCT using myeloablative regimen, and the impact in haploidentical and cord blood transplantation, or reduced-intensity HSCT remains unknown. One crucial issue is that no studies exist for patients with only hypogammaglobulinemia after HSCT. Other challenges are heterogeneous patient characteristics, or immunoglobulin formulation, dosage, schedule, route and duration of IgRT. Without evidence in HSCT, it would be reasonable to follow the guidelines for other diseases with hypogammaglobulinemia.