Rituximab Therapy Research Articles

Rituximab in the Treatment of LRP4-Antibody-Positive Myasthenia Gravis: A Case Report

Antibodies against LRP4 were found in 2-4% of patients with myasthenia gravis (MG). LRP4-antibody-positive (LRP4+) MG presents with more severe disease with bulbar involvement. No standard treatment guideline has been established for this subtype. We identified a LRP4+MG patient with severe symptoms including bulbar dysfunction that were refractory to standard therapy. Rituximab was started due to treatment failure with standard therapy. At the time of initiation of rituximab, patient was on plasmapheresis every 1-2 weeks. Her work and quality of life were greatly compromised. Six weeks after initiating rituximab therapy, remarkable improvements in dyspnea, dysphagia, ptosis, and proximal limb muscle strength were reported without adverse events. Improvements in 3 standardized Myasthenia Gravis scoring systems were observed. The maintenance plasmapheresis was discontinued and pyridostigmine dose decreased by 50% because of sufficient symptom control. Stable improvement was achieved with rituximab maintenance therapy spaced 5 months apart. Our case demonstrates rapid onset of efficacy of rituximab in patient with refractory LRP4+MG. This response and the proposed mechanism of action of LPR4-Ab suggest that the efficacy of rituximab in LRP4+MG may parallel that in MuSK+MG. Further exploration of this treatment option is warranted.

Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis

Postmarketing data on outcomes of avacopan use in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) are lacking. We performed a multicenter retrospective analysis of 92 patients with newly diagnosed or relapsing AAV who received therapy with avacopan. The coprimary outcome measures were clinical remission at 26 and 52 weeks. We use descriptive statistics and univariate logistic regression to assess outcomes and predictors of remission, respectively. Of the 92 patients, 23% (n = 21) had a baseline estimated glomerular filtration rate (eGFR)< 15 ml/min per 1.73 m2 and 10% on kidney replacement therapy at baseline. Among those with kidney involvement, mean (SD) enrollment eGFR was 33 (27) ml/min per 1.73 m2 with a mean (SD) change of+12 (25) and+20 (23) ml/min per 1.73 m2 at weeks 26 and 52, respectively. In addition to avacopan, 47% of patients received combination therapy of rituximab and low-dose cyclophosphamide, and 14% of patients received plasma exchange (PLEX). After induction, the median (interquartile range [IQR]) time to start avacopan was 3.6 (2.1-7.7) weeks, and the median time to discontinue prednisone after starting avacopan was 5.6 (3.3-9.5) weeks. Clinical remission was achieved in 90% of patients at week 26 and 84% of patients at week 52. Of the patients, 20% stopped avacopan due to adverse events, with the most common being elevated serum aminotransferases (4.3%). A high rate of remission and an acceptable safety profile were observed with the use of avacopan in the treatment of AAV in this postmarketing analysis, including the populations excluded from the ADVOCATE trial.

Sensitive B-cell receptor repertoire analysis shows repopulation correlates with clinical response to rituximab in rheumatoid arthritis

BackgroundAlthough B-cell depleting therapy in rheumatoid arthritis (RA) is clearly effective, response is variable and does not correlate with B cell depletion itself.MethodsThe B-cell receptor (BCR) repertoire was prospectively analyzed in peripheral blood samples of twenty-eight RA patients undergoing rituximab therapy. Timepoints of achieved BCR-depletion and -repopulation were defined based on the percentage of unmutated BCRs in the repertoire. The predictive value of early BCR-depletion (within one-month post-treatment) and early BCR-repopulation (within 6 months post-treatment) on clinical response was assessed.ResultsWe observed changes in the peripheral blood BCR repertoire after rituximab treatment, i.e., increased clonal expansion, decreased clonal diversification and increased mutation load which persisted up to 12 months after treatment, but started to revert at month 6. Early BCR depletion was not associated with early clinical response but late depleters did show early response. Patients with early repopulation with unmutated BCRs showed a significant decrease in disease activity in the interval 6 to 12 months. Development of anti-drug antibodies non-significantly correlated with more BCR repopulation.ConclusionOur findings indicate that rather than BCR-depletion it is repopulation with unmutated BCRs, possibly from naïve B cells, which induces remission. This suggests that (pre-existing) differences in B-cell turnover between patients explain the interindividual differences in early clinical effect.

BCD020 rituximab bioanalog compared to standard treatment in juvenile systemic lupus erythematosus: The data of 12 months case-control study.

Systemic lupus erythematosus (SLE) is the most frequent and serious systemic connective tissue disease. Nowadays there is no clear guidance on its treatment in childhood. There are a lot of negative effects of standard-of-care treatment (SOCT), including steroid toxicity. Rituximab (RTX) is the biological B-lymphocyte-depleting agent suggested as a basic therapy in pediatric SLE. To compare the benefits of RTX above SOCT. The data from case histories of 79 children from the Saint-Petersburg State Pediatric Medical University from 2012 to 2022 years, were analyzed. The diagnosis of SLE was established with SLICC criteria. We compared the outcomes of treatment of SLE in children treated with and without RTX. Laboratory data, doses of glucocorticosteroids, disease activity measured with SELENA-SLEDAI, and organ damage were assessed at the time of initiation of therapy and one year later. Patients, treated with RTX initially had a higher degree of disease activity with prevalence of central nervous system and kidney involvement, compared to patients with SOCT. One year later the disease characteristics became similar between groups with a more marked reduction of disease activity (SELENA-SLEDAI activity index) in the children who received RTX [-19 points (17; 23) since baseline] compared to children with SOCT [-10 (5; 15.5) points since baseline, P = 0.001], the number of patients with active lupus nephritis, and daily proteinuria. During RTX therapy, infectious diseases had three patients; one patient developed a bi-cytopenia. RTX can be considered as the option in the treatment of severe forms of SLE, due to its ability to arrest disease activity compared to SOCT.

Comparing Clinical Outcomes of Steroid-Sparing Therapy With Rituximab Versus Rituximab Alone in Pemphigus.

Previous clinical trials have demonstrated that rituximab therapy combined with conventional steroid-sparing therapy (SST) has increased rates of disease control for mucous membrane pemphigoid compared with rituximab alone. However, limited data is available regarding the role of SST with rituximab therapy in pemphigus. This study aimed to examine clinical outcomes in pemphigus patients treated with rituximab with SST versus without the addition of SST. A retrospective chart review was performed for adult pemphigus patients in the Southeastern US at Emory between January 1, 2011, and December 31, 2021. Primary outcomes, including time to remission, time to prednisone dose of 10 mg or less, time to cessation of prednisone therapy, and time to relapse after a rituximab cycle, were compared between patients on SST and patients without SST.&nbsp; Results: Following rituximab therapy, there was no difference in time to remission, time to prednisone dose of 10 mg or less, time to cessation of prednisone therapy, or time to relapse for patients with or without SST. Our study is limited by its retrospective decline, setting at a single academic center, and inclusion of a high proportion of patients with moderate disease. The use of SST with rituximab dosing did not improve clinical outcomes related to time to remission, reduction in prednisone dosing, or relapse. These data provide further evidence for the use of rituximab in the majority of pemphigus patients without the need for SST. J Drugs Dermatol. 2024;23(3):e97-e99&nbsp; &nbsp; doi:10.36849/JDD.7949e.

An Acute Infection due to Hepatitis E in the Context of a Patient with Rituximab and Methotrexate Therapy.

This report presents the influence of immunosuppression by new rheumatological therapies on hepatitis E virus infection in a 54-year-old male patient with an anti-synthetase syndrome and treatment with methotrexate and rituximab. The patient arrived at the Emergency Department with epigastric pain, vomiting and dark urine. Initial examination revealed signs of inflammation and hepatic dysfunction. Subsequent laboratory tests and imaging confirmed acute hepatitis E infection in the context of recent initiation of rituximab therapy. Despite initial suspicion of pancreatitis, subsequent investigations ruled out pancreatic involvement. Treatment with ribavirin, along with supportive measures, led to significant clinical improvement with resolution of jaundice, ascites, and oedema. This case underscores the importance of considering hepatitis E in patients with autoimmune conditions, especially when initiating immunosuppressive therapies, a situation that is not well described in scientific literature and is increasingly common, necessitating proper recognition. Suspect hepatitis E virus infection in the presence of persistent liver failure of unknown cause.Recognise immunosuppression as a cause of increased risk of hepatitis E infection.Take into account the repercussions of immunosuppressive therapy such as rituximab regarding hepatitis E infections in immunocompromised patients.

Neuroleptic Intolerance and Residual Mutism in a Young Woman with Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis

We report a case of anti-NMDAR encephalitis and residual mutism in a 23-year-old woman who presented with neuroleptic intolerance. Admission to our department for investigation of her abnormal behavior revealed cerebrospinal fluid (CSF) positivity for anti-NMDAR antibodies, and the patient underwent immunotherapy. However, generalized tonic seizures developed, requiring mechanical ventilation in the intensive care unit. Antipsychotic drugs were also administered for involuntary movements and insomnia. Thereafter, a malignant syndrome of severe hyperCKemia (Max: 191,120 IU/L) and shock developed, requiring resuscitation and three sessions of hemodialysis. Subsequent rituximab therapy led to improvement, except for mutism, which had newly developed during resuscitation. Seven months after initial admission, the patient was discharged with independent gait. However, her mutism still persists. Temporary mutism has been reported to occur in this type of encephalitis, albeit rarely. The fact that remission was not observed in this case may have been due to cerebellar infarction occurring during resuscitation, but the true cause remains unclear. Malignant syndrome or rhabdomyolysis, as seen in this patient, has also sometimes been reported in this form of encephalitis when antipsychotic agents, especially dopamine receptor blockers, have been administered. Therefore, such agents should be administered with caution in patients with anti-NMDAR encephalitis. (Received August 17, 2023; Accepted October 24, 2023; Published March 1, 2024).

VARICELLA-ZOSTER VIRUS INFECTION IN A PATIENT 12 DAYS POST RITUXIMAB: UNUSUAL CO-PRESENTATION OF SHINGLES AND CHICKENPOX

Rituximab, an anti CD20 monoclonal antibody, is used in the management of lymphoproliferative and autoimmune conditions such as pemphigus. As an immunosuppressor, it exposes patients to an increased risk of infection. Two cases of varicella-zoster virus infection post Rituximab were been reported in literature. The coexistence of chickenpox (primary infection) and shingles (reactivation of latent infection) in the same patient has never been reported in the literature, especially after rituximab treatment. Herein we present the first case of association of these 2 manifestations in a patient 12 days after rituximab therapy for pemphigus.

Paraproteinemia‐associated neuropathy with or without anti‐myelin‐associated glycoprotein antibody

AbstractParaproteinemia‐associated neuropathy (PAN) develops with paraproteinemia and is mainly caused by the monoclonal proliferation of mature B cells, especially monoclonal gammopathy of undetermined significance (MGUS). PAN tends to increase with age, and in a super‐aging society, its frequency is expected to increase. Among paraproteinemias, the immunoglobulin (Ig)G type is most common, but the frequency of PAN is reported to be higher for the IgM type. IgG/IgA‐type PAN includes MGUS, plasma cell myeloma, and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome. IgM‐type PAN includes anti‐myelin‐associated glycoprotein antibody‐associated neuropathy, chronic ataxic neuropathy with IgM antibody that recognizes disialosyl ganglioside and IgM‐type PAN without anti‐nerve antibodies. Light chain‐type PAN includes immunoglobulin‐related amyloidosis. PAN has the characteristics of a blood disease, as well as an immune‐mediated disease, and is treated by immunotherapy. As an example, anti‐myelin‐associated glycoprotein antibody‐associated neuropathy is treated with rituximab, plasmapheresis and intravenous immunoglobulin therapy, but their effectiveness has not been established. As novel treatments, lenalidomide, Bruton tyrosine kinase inhibitors, B‐cell lymphoma 2 inhibitors and mimetic human natural killer‐1 epitope polymers have been investigated. By analyzing the human natural killer‐1‐related sugar chain structure as an antigen, the selective removal of pathological antibodies might be a new therapeutic target.

Prevalence and clinical profiles of anti-myelin-associated glycoprotein neuropathy in Japan: A nationwide survey study of 133 patients.

The aim of this study was to determine the prevalence of anti-myelin-associated glycoprotein (MAG) neuropathy and the current status of such patients in Japan. We conducted a nationwide survey in 2021 using established epidemiological methods. Questionnaires were sent to all neurology and pediatric neurology departments throughout Japan to identify patients with anti-MAG neuropathy. An initial questionnaire was used to determine the number of patients, with a second one used to collect detailed clinical information. The estimated number of patients with anti-MAG neuropathy was 353, with a prevalence of 0.28 per 100,000 and an incidence of 0.05 per 100,000. The detailed clinical profiles of 133 patients were available. The median (range) age of onset was 67 (30-87) years, with a prominent peak in the age range 66-70 years, and the male-to-female ratio was 3.6. Most patients had distal sensory-predominant polyneuropathy, and neuropathic pain (50%), or sensory ataxia (42%), while 18% had Waldenström's macroglobulinemia or multiple myeloma. Intravenous immunoglobulin was the most frequently used treatment (65%), but the response rate was <50%, whereas rituximab was given in 32% of patients, and 64% of these showed improvement. At the last visit, 27% of patients could not walk independently. This study on anti-MAG neuropathy provides updated insights into the epidemiology of this disease, clinical profiles, and treatment approaches in Japan. Rituximab therapy, used for only one-third of the patients, demonstrated efficacy. During the final visit, a quarter of the patients were unable to walk independently. Further studies are warranted to determine the optimal management of this rare and intractable disorder.

Фолликулярная лимфома 1–3А цитологического типа с наличием или отсутствием t(14;18)(q32;q21): прогноз, выбор противоопухолевой терапии и ее результаты

Aim. To determine the prognostic value of t(14;18)(q32;q21) in follicular lymphoma (FL) of grades 1–3А, to assess the chemotherapy efficacy in “t(14;18)+ FL” and “t(14;18)– FL” patients, and to analyze the cases of ineffective therapy.&#x0D; Materials &amp; Methods. The retrospective/prospective study carried out at the National Research Center for Hematology in the period of 2001–2022 enrolled 362 patients with newly diagnosed FL of grades 1–3А. Their risk stratification was based on predictive models FLIPI and PPI3 (Personalized Predictive Index[1]). The patients were 30–81 years of age (median 52 years). There were 225 women and 137 men. They received the following regimens: R-B (n = 80), R-CHOP (n = 189), R-CHOP (4 cycles) + R-DHAP (2 cycles) (n = 28), and R-CHOP (4 cycles) + R-DHAP (2 cycles) + auto-HSCT in the first-line therapy (n = 65). For 2 years, maintenance rituximab therapy was administered to all the enrolled patients, whichever drug chemotherapy they received. Standard cytogenetic analysis and FISH were carried out in 265/362 (73 %) patients.&#x0D; Results. Patients were divided into two comparable groups: “t(14;18)+ FL” (n = 196) and “t(14;18)– FL” (n = 69). Patients without cytogenetics/FISH (n = 97) were excluded from the analysis. In patients without t(14;18), poor prognostic factors, such as grade 3А (p = 0.003) and Ki-67 &gt; 35 % (p = 0.001), were identified significantly more often, and also high PPI3 risk was reported (p = 0.008). No differences (p = 0.84) were detected during FLIPI risk stratification of patients. Bone marrow lesions were observed significantly more often in “t(14;18)+ FL” compared to “t(14;18)– FL” (p = 0.002). The chemotherapy outcomes, such as 2-year EFS and OS, appeared to be considerably worse in “t(14;18)– FL” compared to “t(14;18)+ FL” patients.&#x0D; Conclusion. The group of FL patients with t(14;18) appeared to be most numerous and more prognostically favorable. Immunochemotherapy regimens R-B and R-CHOP are more justified in the first-line therapy of FL with low PPI3 risk. Therapy outcomes were comparable in efficacy. In intermediate and high PPI3 risk FL patients with t(14;18), the most effective first-line therapy was the one with consistent administration of R-CHOP, R-DHAP, and auto-HSCT. Based on the results of this study, FL of grades 1–3А without t(14;18) can well be considered to be a prognostically unfavorable variant of this malignant lymphoid tumor. The rate of early relapses/progression after the standard immunochemotherapy (R-B and R-CHOP), according to our data, is 60 %. In patients with newly diagnosed FL who received consistent administration of R-CHOP, R-DHAP, and auto-HSCT in the first-line therapy, this rate drops to 30 %. Our results clearly indicate the need for new FL treatment approaches.

Rituximab Resistance in Glomerular Diseases: A GlomCon Mini Review

Resistance to rituximab B-cell depletion therapy is a clinically pertinent adverse sequela, which can have significant implications for the treatment of immune-mediated glomerular diseases. The true incidence of rituximab resistance remains unknown, however, it is an increasingly recognized treatment complication. Resistance typically presents with suboptimal treatment response, rapid B-cell reconstitution, and a relapsing disease course. While the diverse mechanisms resulting in rituximab resistance are ongoing topics of research, both primary and secondary mechanisms have been identified as key catalysts.The emergence of human anti-chimeric antibodies (HACA) is a major cause of secondary resistance to rituximab therapy and typically appears following repeated drug exposure. Frequently, HACA develop in the setting of underlying autoimmune disease and contribute to poor B-cell depletion, reduced rituximab therapeutic efficacy, and enhanced drug clearance.The clinical challenge of rituximab resistance necessitates heightened awareness among clinicians. Screening for HACA should be considered in individuals with poor clinical response to rituximab, more rapid B-cell reconstitution, and relapsing disease. Detection of HACA may guide treatment alterations, including addition of further immunosuppressive therapy and transitioning to a humanized B-cell depleting monoclonal antibody.

A166 STEROID-REFRACTORY ILEITIS FOLLOWING RITUXIMAB THERAPY: A CASE REPORT AND LITERATURE REVIEW

Abstract Background Rituximab, an anti-CD20 monoclonal antibody commonly used in treatment of hematologic and rheumatologic disease is generally well-tolerated from a gastrointestinal perspective however rare reported side effects include diarrhea and enterocolitis. Aims We describe a case of steroid-refractory ileitis presenting in a woman with follicular lymphoma post Rituximab therapy. Methods A case report and literature review were performed. Results A 73-year-old woman presented with a 4-week history of fevers, bloody diarrhea and abdominal pain. She had a known history of stage IV follicular lymphoma treated with six cycles of Bendamustine and Rituximab followed by four doses of maintenance Rituximab, with the last dose ending 4 weeks prior to her presentation. On examination, she had multiple peri-anal round ulcers. An abdominal CT revealed circumferential mural thickening involving the distal terminal ileum. On colonoscopy, there were multiple discrete ulcers and nodularity in the terminal ileum. Pathology showed evidence of chronic active ileitis with no signs of malignancy, lymphoproliferative disorders, or granulomas. AFB smear and cultures were negative. She was given IV steroids for 1 week and then placed on a Prednisone taper scheduled to finish in 9 weeks. 4 weeks later she presented again with fevers and abdominal pain. Inflammatory markers were elevated, and a repeat CT abdomen showed ongoing multifocal ileitis. She was put back on IV steroids and monitored. She continued to have persistent abdominal pain and fevers, and then underwent a repeat colonoscopy after 9 days of IV steroids which showed an interval increase in the size of her ileal ulcers. Pathology showed granulation tissue and reactive changes with no evidence of malignancy, lymphoma, granulomas, inclusion bodies or other viral cytopathic effects. Repeat AFB smear was negative. CMV PCR in blood was negative. She was assessed for Behcet’s disease (BD) given her peri-anal ulcers however she lacked other findings needed to fulfill the diagnostic criteria for BD. Steroids were continued with plans to initiate biological therapy. A review of literature revealed rare reports of rituximab-associated ileocolitis and development of de novo inflammatory bowel disease post rituximab therapy. Among patients who received Rituximab and underwent Colonoscopy, 4% had evidence of colitis. Rituximab-associated colitis appears to be usually mild presenting with diarrhea and requiring supportive care only, but in rare cases can lead to fulminant colitis and bowel perforation. Conclusions Rituximab-associated enterocolitis remains an under-reported entity and can lead to significant morbidity and treatment-associated challenges requiring prolonged courses of steroids and considerations for biological therapies. Important differentials to consider include malignancy, lymphoma, Tuberculosis, Bechet’s disease, and CMV enterocolitis. Ulcer in terminal ileum and ileocecal valve - Pre steroids (Left), Post steroids (Right) Funding Agencies None

Efficacy of rituximab therapy for 10 patients suffering from systemic lupus erythematosus with intestinal involvement

We retrospectively analyzed therapy efficacy and the adverse reactions of 10 patients suffering from systemic lupus erythematosus (SLE) with intestinal involvement treated with rituximab (RTX). Patients were hospitalized in the Department of Rheumatology and Immunology of the First Medical Center of PLA General Hospital from January 2015 to January 2023. Among the 10 patients, two were men and eight were women. The age of the cohort was (41.9±8.8) years. The age at disease onset was (28.8±9.2) years. The total course of the SLE diagnosis was(109.6±59.9) months. The course of the diagnosis of SLE with intestinal involvement was (89.3±50.2) months. The time from the appearance of intestinal symptoms to the diagnosis of SLE with intestinal involvement was 1.5 (1.0,8.0) months. The time from the diagnosis of SLE with intestinal involvement to RTX use was 13.0 (1.0,46.3) months. Follow-up duration after application of RTX treatment was (55.3±28.4) months. There were five cases of abdominal pain, four cases of abdominal distension, nine cases of diarrhea, three cases of nervous-system involvement, nine cases of lupus nephritis, and seven cases of serositis. All 10 patients underwent computed tomography and radiology of the abdomen. Eight patients had intestinal-wall edema, seven suffered intestinal dilation, four had target signs, three suffered congestion of mesenteric blood vessels, eight had increased mesenteric-fat density, and six had false intestinal obstruction. All 10 patients showed a low level of complement C3 (250-750 mg/L). Nine cases showed a low level of complement C4 (10-90 mg/L). The SLE disease activity index 2000 (SLEDAI-2K) at baseline in 10 patients was 20.5 (17.8, 30.0). After receiving RTX (0.5 g: day 1, day 14, or 375 mg/m2: day 1, day 14) induction treatment, the intestinal symptoms of 10 cases were relieved completely. Four patients had adverse reactions, of which three received a high-dose glucocorticoid combined with RTX treatment simultaneously. Adverse reactions manifested mainly as a reduced level of IgG and infection with herpes simplex virus in one case, reduced level of IgG and lung infection in one patient, lung infection in one case, and reduced IgG level in one patient. RTX may an efficacious treatment strategy for patients suffering from refractory SLE with intestinal involvement.

Pneumocystis jirovecii Pneumonia Prophylaxis in Patients with ANCA Vasculitis on Rituximab Maintenance Therapy.

Although an increased risk of Pneumocystis jirovecii pneumonia (PJP) has been reported in adults receiving rituximab for induction therapy, current evidence is lacking on the utility of PJP prophylaxis in ANCA-associated vasculitis (AAV) patients on maintenance rituximab therapy. The purpose of this study was to compare the incidence of PJP pneumonia and the outcomes of AAV patients with and without PJP prophylaxis. We performed an observational, single-center, retrospective study examining patients with AAV in clinical remission and on rituximab maintenance therapy. We divided the patients into two groups: those with and without PJP prophylaxis. We explored factors associated with PJP prophylaxis use. We additionally looked at several outcomes, including PJP infections, infections requiring hospitalizations, end-stage kidney disease (ESKD), and death. Data were analyzed using T test, Fisher's exact test, univariate, and multivariate logistic regression as appropriate. A total of 129 patients with mean follow-up time of 7.2 (5.4) years were included: 44% received PJP prophylaxis and 56% of patients did not. There were no PJP infections in the entire cohort. Lung involvement was associated with increased odds of prescribing PJP prophylaxis (OR: 4.09 [95% CI: 1.8-9.82]). PJP prophylaxis did not decrease infection rates requiring hospitalizations, ESKD, or death. Glucocorticoid use, however, was associated with increased rates of infections requiring hospitalizations (OR: 5.54 [95% CI: 2.01-15.4]) and death (OR: 4.67 [95% CI: 1.36-15.71]) even after adjustment for age, gender, and use of PJP prophylaxis. Regardless of the use of PJP prophylaxis during the maintenance phase of AAV management, PJP pneumonia was not observed. AAV patients with lung involvement were more likely to be on PJP prophylaxis.

Using real-world data to inform dosing strategies of rituximab for pediatric patients with frequent-relapsing or steroid-dependent nephrotic syndrome: a prospective pharmacokinetic-pharmacodynamic study.

Objectives: Rituximab is frequently used off-label for the treatment of frequent-relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). However, the optimal dosing schedules remain undetermined. The objective of this study was to establish a population pharmacokinetic-pharmacodynamic (PK-PD) model in pediatric patients with FRNS/SDNS, and to investigate dosing regimens that provide adequate suppression of B lymphocytes. Methods: A prospective, open-label, single-center study was conducted in Nephrology Department at Children's Hospital of Fudan University, and a two-compartment PK model of rituximab in pediatric FRNS/SDNS has been developed previously by our group. CD19+ lymphocyte count profiles were obtained from these patients. The presence of anti-rituximab antibodies was assessed prior to medication in children who had previously received rituximab or during follow-up at the last sampling point for PK analysis. PK-PD analyses were performed to describe the changes of CD19+ lymphocytes, with rituximab assumed to increase their death rate. Monte Carlo simulation was conducted to evaluate different dosing regimens. Results: In total, 102 measurements of CD19+ lymphocyte counts were available for PK-PD analysis. No detectable levels of anti-rituximab antibodies were observed during the PK follow-up period. A turnover model with saturable stimulatory action of rituximab on the removal of lymphocytes best characterized the relationship between rituximab concentration and CD19+ lymphocyte counts, where the Emax and EC50 were estimated to be 99.6*106/L and 5.87μg/mL, respectively. Simulations indicated that a single infusion of 750mg/m2 and 2 infusions of 375mg/m2 both yielded a 10-week suppression of CD19+ lymphocytes. Conclusion: This study represents a first attempt to quantitatively describe the PK-PD relationship of rituximab in pediatric patients with FRNS/SDNS, and provide a potential pathway for future precision dosing strategy for rituximab therapy. Further clinical studies are warranted to evaluate the efficacy and safety of different dosing schemes.

Small intestinal perforation manifesting as post-transplant lymphoproliferative disorder occurring 23 years after living lung transplantation: a case report

A Japanese female patient underwent a living lung transplant at age 29 and has been on immunomodulatory drug therapy since then. At age 52, she presented with sudden hematochezia. Despite abdominal computed tomography scan, esophagogastroduodenoscopy, and colonoscopy, no definitive source of bleeding was identified. Considering the possibility of small bowel bleeding, video capsule endoscopy was performed, which revealed a suspected ulcerative lesion in the jejunum. Subsequent per-oral double-balloon endoscopy confirmed the presence of an ulcerative lesion in the jejunum. A potential pathological diagnosis of post-transplant lymphoproliferative disorder (PTLD) was considered based on endoscopic biopsy specimens from the jejunal lesion. However, before the pathologic biopsy results were available, the patient experienced small intestinal perforation, necessitating emergency partial resection. Pathologic examination revealed a dense proliferation of medium-to-large atypical lymphocytes with neutrophilic infiltration in the perforated area of the small intestinal wall. Immunostaining showed lymphoid cells positive for CD20 but negative for CD3. Epstein-Barr virus (EBV) -encoded RNA was detected by in situ hybridization, and Ki-67 staining demonstrated a higher percentage of positive cells. Consequently, an EBV-positive diffuse large B-cell lymphoma, developed as PTLD, was diagnosed. Complete remission was achieved with a reduced immunomodulatory drug dosage and rituximab therapy. She has been alive for 8 months postoperatively without recurrence. This case suggests that PTLD should be considered in assessing patients presenting with abdominal symptoms following organ transplantation.

Risk of severe infection associated with immunoglobulin deficiency under rituximab therapy in immune-mediated inflammatory disease

ObjectivesWe evaluated the risk of severe infection in patients with immune-mediated inflammatory disease (IMID) treated with RTX and with Ig deficiency.MethodsThis was an observational, retrospective single-centre study of patients undergoing...

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

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

Rituximab treatment for refractory and moderate-to-severe pemphigus patients in the pandemic era: A single-center retrospective study

Abstract Background: The management of refractory pemphigus in the pandemic conditions is challenging. There are limited data comparing the safety of rituximab and other immunosuppressive therapies during the COVID-19 pandemic. Objectives: We evaluated the safety and efficacy of rituximab and conventional treatments in patients with pemphigus who received treatment during the COVID-19 pandemic period. Methods: The patients with pemphigus treated with immunosuppressive treatments in a university hospital between September 2020 and May 2023 were retrospectively evaluated. All patients initially received conventional treatments. Fifteen of them who were refractory to prior treatments or could not use prednisolone due to adverse effects received rituximab. Eighteen patients were treated with only conventional treatments. Results: Thirty-three patients with a mean age of 50 ± 15 years were included in the study. Twenty-two of the patients (66.7%) were female. The baseline mean pemphigus disease area index (PDAI) score of the patients was 37 ± 34 (range: 4–168). The mean follow-up time was 13.8 ± 6.8 months. The mean PDAI scores were significantly lower after treatment in both rituximab and conventional treatment groups (P: 0.001, P &lt; 0.001; respectively). In the rituximab group, the monthly mean prednisolone dose was statistically reduced after rituximab treatment compared to before treatment (P &lt; 0.001). There was no statistically significant difference in the relative odds of COVID-19 positivity or death between the groups (3.06 (95% [confidence interval (CI): 0.68–13.79]; 0.57 [95% CI: 0.05–7.00], respectively). Of 11 patients diagnosed with COVID-19, one patient (1/7, 14.3%) in the rituximab group and two patients (2/4, 50%) in the conventional treatment group died from SARS-CoV-2. Conclusion: We observed that rituximab treatment was effective and safe for treatment-resistant moderate-to-severe pemphigus patients during the COVID-19 pandemic.