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Background: Long noncoding RNAs (lncRNAs) are implicated in the initiation and progression of diffuse large B-cell lymphoma (DLBCL). Small nucleolar RNA host gene 20 (SNHG20) has been recognized as a critical lncRNA in multiple human cancers. However, the role of SNHG20 and its underlying mechanism in DLBCL are still unclear. Methods: The expression levels of SNHG20, c-MYC, β-catenin, and ubiquitin-specific peptidase 14 (USP14) were measured by reverse transcription-quantitative polymerase chain reaction (RT‒qPCR) and immunoblotting. Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EdU) incorporation, and flow cytometry assays were used to assess the proliferation and apoptosis of DLBCL cells. The transcriptional regulation of SNHG20 by c-MYC was confirmed by a luciferase reporter assay and RNA immunoprecipitation. The interaction between USP14 and β-catenin was demonstrated using coimmunoprecipitation. A subcutaneous xenograft model was constructed to determine the role of SNHG20 in vivo. Results: In the present study, we found that SNHG20 expression was upregulated in DLBCL cell lines and tissues compared to their normal counterparts. SNHG20 knockdown prominently reduced the proliferation and induced the apoptosis of U2932 and OCI-LY3 cells. However, SNHG20 overexpression increased the proliferation and apoptosis resistance of DLBCL cells. Mechanistically, the expression of SNHG20 was positively regulated by c-MYC in DLBCL cells. C-MYC directly bound to the promoter of SNHG20 to activate its transcription. SNHG20 was expressed mainly in the cytosol in DLBCL cells. SNHG20 silencing did not impact USP14 expression but markedly decreased the level of β-catenin, the substrate of USP14, in DLBCL cells. USP14 overexpression increased the β-catenin level, and this increase was attenuated by SNHG20 knockdown. Treatment with the proteasome inhibitor MG132 abolished SNHG20 knockdown-induced β-catenin downregulation. Moreover, SNHG20 silencing reduced the half-life but increased the ubiquitination of β-catenin in DLBCL cells. SNHG20 knockdown weakened the interaction between both endogenous and exogenous USP14 and β-catenin. In turn, SNHG20 overexpression increased the c-MYC level, and this increase was attenuated by β-catenin knockdown. Importantly, β-catenin knockdown attenuated the SNHG20-mediated increase in DLBCL cell proliferation in vitro and tumour growth in vivo. Conclusions: Taken together, our results suggested that c-MYC-activated SNHG20 accelerated the proliferation and increased the apoptosis resistance of DLBCL cells via USP14-mediated deubiquitination of β-catenin. The c-MYC/SNHG20 positive feedback loop may be a new target for anti-DLBCL treatment. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionWe report three cases of occlusive vasculitis following intravitreal rituximab therapy for biopsy-proven primary vitreoretinal lymphoma (PVRL), one of which was following an injection of the biosimilar Riabni (rituximab-arrx, AmGen) and two of which were following an injection of Rituxan (rituximab, Genentech).Case series.Three cases of occlusive vasculitis confirmed with fluorescein angiography are reported 5 days, 8 days, and 3.5 weeks following intravitreal injection of rituximab. The initial vision was poor (20/500, 20/150, and light perception), but vision recovered to baseline in two cases, and remained poor in the case of combined artery and vein occlusion.Occlusive vasculitis is a rarely reported but potential complication of intravitreal rituximab therapy in patients who have been previously treated with the agent and may have delayed onset. A low threshold for fluorescein angiography as a diagnostic test for post-injection vision loss and prompt treatment with topical and/or oral steroids should be considered. [ABSTRACT FROM AUTHOR]

Summary: The bendamustine–rituximab (BR) schedule is an efficient first‐line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression‐free (PFS) and overall survival (OS). With a median follow‐up of 76.1 months (95% confidence interval [CI] 69.9–80.6), 5‐year outcome is still excellent at 66.63% (95% CI 56.09–79.17) for PFS and 80.01% (95% CI 70.82–90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99–27.64) at 66 months. Relapsed patients who received ibrutinib as second‐line clearly benefited from this schedule. This confirms current recommendations suggesting BR long‐term efficacy as first‐line option in WM. [ABSTRACT FROM AUTHOR]

AbstractLenalidomide (LEN) and rituximab (RTX) have independently improved progression-free survival (PFS) in CLL, leading to interest in use of LEN + RTX (R2) following induction chemoimmunotherapy. Patients with previously untreated CLL received bendamustine + RTX (BR) for 6 cycles, then 24 cycles of R2. LEN dosing was 5–10 mg daily; RTX was given odd cycles (12 doses). The primary endpoint is PFS; secondary endpoints are response and overall survival. Thirty-six patients enrolled, median age 64.5 years. Twenty-nine received R2; 12 completed a full course R2 (33.3%), 5 completed R2 with premature discontinuation of LEN. Dose reductions/holds were most often for neutropenia. Complete response was achieved in 33.3%. After median >4 years follow-up, 2-year and 3-year PFS were 86.1% and 69.4%. Five-year overall survival was 92.3%. R2 maintenance may improve PFS after BR induction, and a lower dose of 5 mg/day and ≤1 year of R2 may be most tolerable (NCT00974233). [ABSTRACT FROM AUTHOR]

Key Clinical Message: We should consider IgG4‐related disease (IGRD) as one of the potential causes of constrictive pericarditis. In patients with constrictive pericarditis due to IGRD, the combination of surgical treatment and immunosuppressive therapy may be an effective strategy. [ABSTRACT FROM AUTHOR]

Polatuzumab vedotin is a CD79b‐directed antibody–drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R‐CHP) as first‐line treatment of diffuse large B‐cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure–response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful relationship between cycle 6 (C6) antibody‐conjugated (acMMAE)/unconjugated MMAE area under the concentration–time curve (AUC) or maximum concentration, and weight, sex, ethnicity, region, mild or moderate renal impairment, mild hepatic impairment, or other patient and disease characteristics. In the ER analysis, C6 acMMAE AUC was significantly associated with longer progression‐free and event‐free survival (both p = 0.01). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit–risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R‐CHP for six cycles in patients with previously untreated DLBCL. [ABSTRACT FROM AUTHOR]

Interstitial lung disease (ILD) is a common pulmonary complication of rheumatoid arthritis (RA), causing significant morbidity and mortality. Optimal treatment for RA-ILD is not yet well defined. Reliable prognostic indicators are largely byproducts of prior ILD progression, including low or decreasing forced vital capacity and extensive or worsening fibrosis on imaging. In the absence of validated tools to predict treatment response, decisions about whether to initiate or augment treatment are instead based on clinical judgment. In general, treatment should be initiated in patients who are symptomatic, progressing, or at high risk of poor outcomes. Retrospective data suggest that mycophenolate mofetil, azathioprine, and rituximab are likely effective therapies for RA-ILD. Abatacept is also emerging as a potential first-line treatment option for patients with RA-ILD. Further, recent data demonstrate that immunosuppression may be beneficial even in patients with a usual interstitial pneumonia (UIP) pattern on imaging, suggesting that immunosuppression should be considered irrespective of imaging pattern. Recent randomized controlled trials have shown that antifibrotic medications, such as nintedanib and likely pirfenidone, slow forced vital capacity decline in RA-ILD. Consideration can be given to antifibrotic initiation in patients progressing despite immunosuppression, particularly in patients with a UIP pattern. Future research directions include developing tools to predict which patients will remain stable from patients who will progress, discriminating patients who will respond to treatment from nonresponders, and developing algorithms for starting immunosuppression, antifibrotics, or both as first-line therapies. [ABSTRACT FROM AUTHOR]

Background: Despite adverse events associated with the long-term use of immunosuppressants, their long-term discontinuation remains challenging in children with idiopathic nephrotic syndrome. Relapse and resumption of immunosuppressants after discontinuation and associated risk factors were analyzed. Methods: This single-center retrospective cohort study included children with frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS) or steroid-resistant nephrotic syndrome (SRNS) who initiated immunosuppressant treatment between 2010 and 2020. Patients treated with immunosuppressants for less than two years, those with genetic SRNS, and those with continuation of immunosuppressants were excluded. Results: Sixty-eight patients with FRNS/SDNS or SRNS discontinued immunosuppressants. Discontinuation of immunosuppressants was more frequently tried in patients with less relapse on initial immunosuppressants and less rituximab administration. Of 68 patients who discontinued immunosuppressants, 45 (66%) relapsed and 31 (46%) resumed immunosuppressants with a median follow-up of 39.8 months (IQR 24.6–71.2 months) after discontinuation. The relapse-free survival rates were 40.0%, 35.3%, and 35.3% in 1, 2, and 3 years from discontinuation of immunosuppressants, respectively. Relapse on initial immunosuppressants (HR 2.038, 95%CI 1.006–4.128, P = 0.048) and the relapse-free interval before discontinuation of immunosuppressants (HR 0.971, 95%CI 0.944–0.998, P = 0.037) were significant risk factors associated with relapse after the discontinuation of immunosuppressants, adjusting for sex, age at immunosuppressant treatment initiation, SRNS, and rituximab use. Conclusions: Long-term discontinuation of immunosuppressants can be feasible in patients without a relapse on initial immunosuppressants, those with longer relapse-free interval before discontinuation of immunosuppressants, and those without a relapse for one year after discontinuation of immunosuppressants. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Objectives ANCA-associated vasculitis (AAV) is currently categorized under the small vessel vasculitides. There is limited knowledge about large vessel involvement in AAV (L-AAV), mainly described in case reports and small series. L-AAV can involve temporal arteries (TA-AAV), aorta (A-AAV), and periaortic soft tissue (PA-AAV). We sought to characterize the features of patients with L-AAV. Methods Patients older than 18 years at diagnosis of TA-AAV, A-AAV and PA-AAV seen at the Mayo Clinic, Rochester between 1 January 2000 and 31 December 2021 were identified through a proprietary medical text search algorithm. Patients were included if diagnosed with L-AAV, fulfilled 2022 ACR/EULAR classification criteria for GPA, MPA or EGPA, had positive ANCA test results, and had more than one outpatient or inpatient visit. Results The study cohort consists of 36 patients with L-AAV. Of those, 23 had p-ANCA and/or MPO-ANCA, and 13 had c-ANCA and/or PR3-ANCA. Mean (s. d.) age at AAV diagnosis was 63.4 (12.79) years; 20 (56%) were male. Seventeen patients had TA-AAV, 10 had A-AAV and 9 had PA-AAV. Most patients (n  = 25, 69%) were diagnosed with large vessel vasculitis and AAV within a 1-year timespan. Twenty-five (69%) patients had histopathological confirmation of AAV diagnosis in a location other than temporal artery, aorta or periaortic soft tissue. Glucocorticoids (36/36), rituximab (19/36) and methotrexate (18/36) were the most frequent treatments. Conclusion This is the largest single-centre cohort of patients with L-AAV to date. AAV can involve large arteries, albeit infrequent. AAV-targeted therapy should be considered in patients with L-AAV. [ABSTRACT FROM AUTHOR]

Objectives Autologous hematopoietic stem cell transplantation (AHSCT) has been shown to improve long-term survival for early diffuse progressive SSc compared with CYC. CYC, however, does not provide a long-term benefit in SSc. The combination of MMF and rituximab is a potent alternative regimen. We aimed to retrospectively compare the outcomes of SSc patients who underwent AHSCT to patients who met the eligibility criteria for AHSCT but received upfront combination therapy with MMF and rituximab. Methods Repeated assessments of modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), and diffusing capacity (DLCO) values were conducted. Clinical improvement was defined as an mRSS decrease >25% or an FVC increase >10%. Event-free survival (EFS) was defined in the absence of persistent major organ failure or death. Results Twenty-one SSc patients in the combination therapy group were compared with 16 in the AHSCT group. Age, sex and disease duration were similar between the two groups. Clinical improvement at 12 months was seen in 18 (86%) patients in the combination group compared with 13 (81%) in the AHSCT group (P  = 0.7). The hazard ratio for EFS at 24 months favoured the combination group (HR = 0.09, P  = 0.04). During follow-up, both groups exhibited a significant and comparable reduction in mRSS and an increase in FVC values at each time interval up to 24 months. Conclusion MMF and rituximab compared with AHSCT in SSc patients eligible for AHSCT resulted in similar skin and lung clinical improvement with a better safety profile at 24 months. [ABSTRACT FROM AUTHOR]

Objective This study aimed to establish prediction models for respiratory-related mortality in microscopic polyangiitis (MPA) complicated by interstitial lung disease (ILD) using clinical characteristics. Methods We enrolled patients with MPA with ILD between May 2005 and June 2021 in a multicentre cohort of Japanese patients with MPA (REVEAL cohort). We evaluated the demographic, clinical, laboratory, radiological findings, treatments and the presence of honeycombing 1 cm above the diaphragm using chest high-resolution CT (HRCT) on admission. We explored the risk factors predictive of respiratory-related mortality. Results Of 115 patients, 26 cases died of respiratory-related diseases during a median follow-up of 3.8 years. Eighteen patients (69%) died due to respiratory infection, three (12%) had diffuse alveolar haemorrhage, and five (19%) had exacerbation of ILD. In univariate analysis, older age, lower percent forced vital capacity (%FVC), lower percent diffusing capacity of carbon monoxide (%DLCO), and the presence of honeycombing in the right lower lobe were identified as risk factors. Additionally, in multivariate analysis adjusted for age and treatment, %FVC, %DLCO and the presence of honeycombing in the right lower lobe were independently associated with respiratory-related mortality. We created prediction models based on the values of %FVC, %DLCO and presence of honeycombing on chest HRCT (termed "MPF model"). The 5-year respiratory-related death-free rate was significantly different between patients with MPA with ILD stratified by the number of risk factors based on the MPF model. Conclusions Our study indicates that the MPF model may help predict respiratory-related death in patients with MPA with ILD. [ABSTRACT FROM AUTHOR]

To explore the optimal treatment for young patients with untreated mantle cell lymphoma (MCL), we compared the efficacy and safety of R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone/rituximab, dexamethasone, cytarabine and cisplatin) and R-BAP (rituximab, bendamustine, cytarabine, and prednisone) plus BTK (Bruton's tyrosine kinase) inhibitors in newly diagnosed patients. Eighty-three young patients (≤ 65 years old) with newly diagnosed MCL admitted to the First Affiliated Hospital of Zhengzhou University from January 1, 2014, to June 1, 2023, using R-CHOP/R-DHAP or R-BAP plus BTK inhibitor were assessed in this study. The median age at presentation was 60 (42–65) years in 83 patients, including 64 males and 19 females; 59 were treated with R-CHOP/R-DHAP regimen chemotherapy, and 24 were treated with R-BAP in combination with the BTK inhibitor regimen. The median follow-up was 17 months (2–86 months) in 83 patients, and the median PFS (progression-free survival) time was not reached. The CRR (complete response rate) of the R-BAP group was higher than that of the R-CHOP/R-DHAP group (87.5% vs. 54.2%, P = 0.005). The ORR (overall response rate) was not significantly different between the two groups (ORR: 91.7% vs. 84.7%, P = 0.497). The PFS (progression-free survival) of the R-BAP group was longer than that of the R-CHOP/R-DHAP group (P = 0.013), whereas OS was not significantly different between the two groups (P = 0.499). The most common adverse effect in both groups was hematotoxicity, with a higher incidence of grade 3–4 lymphopenia and grade 3–4 thrombocytopenia in the R-BAP group than in the R-CHOP/R-DHAP group (P = 0.015 and P = 0.039). Male sex (HR = 4.257, P = 0.013), LDH (lactate dehydrogenase) ≥ 245 U/L (HR = 3.221, P = 0.012), pleomorphic-blastoid (HR = 2.802, P = 0.043) and R-CHOP/R-DHAP regimen (HR = 7.704, P = 0.047) were independent risk factors for PFS. Ki67 ≥ 30% (HR = 8.539, P = 0.005) was an independent risk factor for OS. First-line treatment with R-BAP in combination with BTK inhibitor improved CRR and prolonged PFS in young patients with mantle cell lymphoma and adverse events were tolerable. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinemia (WM) is a chronic B-cell lymphoproliferative disorder characterized by lymphoplasmacytic cell overgrowth in the bone marrow and increased secretion of IgM immunoglobulins into the serum. Patients with WM have a variety of clinical outcomes, including long-term survival but inevitable recurrence. Recent advances in disease knowledge, including molecular and genetic principles with the discovery of MYD88 and CXCR4 mutations, have rapidly increased patient-tolerable treatment options. WM patients may benefit from chemotherapy regimens that include rituximab-based regimens, alkylating drugs, proteasome inhibitors, monoclonal antibodies, and drugs targeting Bruton tyrosine kinase inhibitors. In light of these advancements, patients can now receive treatment customized to their specific clinical characteristics, focusing on enhancing the depth and durability of their response while limiting the adverse effects. Despite the rapidly developing therapeutic armament against WM, a lack of high-quality evidence from extensive phase 3 trials remains a significant challenge in the research. We believe clinical outcomes will keep improving when new medicines are introduced while preserving efficacy and minimizing toxicity. [ABSTRACT FROM AUTHOR]

Objective: Although off‐label use of rituximab is a common alternative to disease‐modifying therapies (DMTs) approved for multiple sclerosis (MS) in several countries, the impact of this on treatment cost‐effectiveness is not well known. Methods: We evaluated the relative cost‐effectiveness of rituximab and MS‐approved DMTs in a register‐based cohort study of Swedish residents with relapsing–remitting MS, aged 18–65 years, starting treatment with rituximab, natalizumab, fingolimod, or dimethyl fumarate between January 2010 and July 2016, and followed through July 2021 (n = 5,924). By linking the population‐based Swedish MS register to several Swedish health care and demographic registers, we estimated health care costs in relation to number of relapses, over 5 years from treatment start. Differences between treatments were estimated in inverse probability of treatment‐weighted regression models, adjusting for a broad range of potential confounders covering demographics, medical history, and MS‐related clinical characteristics. Results: Off‐label rituximab was associated with both lower total health care costs (mean cost savings ranged $35,000–$66,000 vs. each approved DMT), and fewer relapses (mean number of prevented relapses ranged 0.12–0.22), per started therapy over 5 years. Results were robust to variations in discounting and pricing of health care visits, with the main driver of cost‐savings being the price of the index drug itself. Interpretation: The cost‐effectiveness of rituximab dominated the MS‐approved alternatives. Off‐label, low‐dose rituximab should be considered for persons with MS and could reduce barriers to treatment, especially in resource‐limited settings. ANN NEUROL 2024;95:1099–1111 [ABSTRACT FROM AUTHOR]

Specific data regarding outcome of cats with high‐grade and large granular lymphocyte alimentary lymphoma (HGAL and LGL, respectively) treated with multi‐agent chemotherapy are scarce. The aims of this multi‐centric, retrospective study were to describe the outcome of cats with HGAL and LGL treated with COP‐ or CHOP‐based chemotherapy and to identify potential prognostic factors. Cats with a cytological or histological diagnosis of HGAL or LGL lymphoma treated with COP‐ or CHOP‐based protocol as first‐line chemotherapy were included. Data regarding diagnosis, staging, treatment and follow‐up were collected. Fifty‐seven cats treated with CHOP (n = 37) or COP (n = 20) protocols were included. Complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were observed in 20%, 22%, 36% and 22% of cats, respectively, for an overall response rate of 42%. Median progression‐free interval (PFI) was 148 days and overall median survival time (OST) was 131 days. Cats achieving CR, PR or SD showed significantly longer PFI (p <.01) and OST (p <.015) compared with cats with PD. Other positive prognostic factors in multi‐variate analysis were rescue treatment (p <.001) and absence of lymph node involvement (p <.03). Negative prognostic factors were diffuse infiltration of the gastrointestinal tract (p =.035) and infiltration of a non‐haematopoietic organ (p <.01). [ABSTRACT FROM AUTHOR]

Introduction: Over the past few years, anti-CD20 therapies like rituximab, ocrelizumab or ofatumumab have seen an increase in interest in the treatment of neurological autoimmune disorders such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), or resistant forms of generalized myasthenia gravis (MG). They are generally well-tolerated, but recent reports have highlighted severe dental disorders in patients undergoing anti-CD20 therapies. The aim was to describe a series of cases and to compare with the available scientific literature. Methods: We reviewed 6 patient cases with dental disorders during anti-CD20 therapy that were reported to the pharmacovigilance center. A disproportionality analysis was also conducted on Vigibase® for each anti-CD20 and each adverse effect described in the cases. Results: Six cases of dental and gingival conditions in relatively young patients were reported (median age: 40.5 years old [min: 34; max: 79]). Oral conditions were developed in four patients with MS treated with ocrelizumab and in two patients receiving rituximab (one patient with MG and one with NMOSD). The onset of oral conditions ranged from 10 days to 2 years after treatment initiation. Notably, all patients treated with ocrelizumab experienced gingival recession. Various dental pathologies were observed, including tooth loss, dental pain, caries, brittle teeth, dental fractures, dental abscesses, and periodontitis. Analysis of Vigibase® revealed 284 worldwide cases of dental and gingival conditions under ocrelizumab, 386 cases under rituximab, and 80 under ofatumumab. Significant associations were found between these therapies and dental pathologies, particularly tooth abscesses and infections. Conclusion: To our knowledge, this is the first case series reporting dental conditions developed in patients long-term treated with anti-CD20 treatments. This issue, literature data, and Vigilyze® analysis might be considered a safety signal that necessitates being confirmed with more robust data, such as a retrospective study with a control group. Meanwhile, proactive measures are essential like frequent dental checkups and dental hygienic measures to prevent oral health problems associated with anti-CD20 therapies. [ABSTRACT FROM AUTHOR]

Introduction: Rapidly increasing costs of medication acquisition can pose a challenge for health-system pharmacy budgets. The impact of dose-rounding in a pediatric oncology population has not previously been well documented and a retrospective review was undertaken to quantify the potential cost benefits. Methods: A retrospective chart review of patients with an oncologic diagnosis was performed for cytotoxic agents, asparaginase products, and biotherapy administered between January 1, 2014, and December 31, 2017. In the analysis, orders that could be rounded down to the nearest vial size by 5 or 10% were included. Medication pricing information was based on wholesale acquisition cost (WAC) and was provided by the Department of Pharmacy. Cost savings per medication were determined by multiplying the WAC of the medication by the number of vials saved. Results: Over a 4-year span, 347 patients were evaluated and 552 out of a possible 3110 orders (17.7%) met criteria for a theoretical cost savings of approximately $1,126,000 (∼$3200 per patient). Rounding down doses by up to 5% resulted in a potential savings of about $529,000. When rounding was extended to 5–10% of the originally ordered dose, an additional $597,000 of approximate cost savings could have been realized. The medications with the largest impact on cost savings were rituximab, pegaspargase, and erwinia asparaginase. Conclusions: For pediatric oncology patients, there exists a unique potential cost savings opportunity if doses are rounded down within 5 or 10% of the originally ordered weight-based or body surface area-calculated dose. [ABSTRACT FROM AUTHOR]

Background: Investigation of infection risk with subcutaneous versus intravenous trastuzumab and rituximab administration in an individual patient data (IPD) and published data meta-analysis of randomised controlled trials (RCTs). Methods: Databases were searched to September 2021. Primary outcomes were serious and high-grade infection. Relative-risk (RR) and 95% confidence intervals (95%CI) were calculated using random-effects models. Results: IPD meta-analysis (6 RCTs, 2971 participants, 2320 infections) demonstrated higher infection incidence with subcutaneous versus intravenous administration, without reaching statistical significance (serious: 12.2% versus 9.3%, RR 1.28, 95%CI 0.93to1.77, P = 0.13; high-grade: 12.2% versus 9.9%, RR 1.32, 95%CI 0.98to1.77, P = 0.07). With exclusion of an outlying study in post-hoc analysis, increased risks were statistically significant (serious: 13.1% versus 8.4%, RR 1.53, 95%CI 1.14to2.06, P = 0.01; high-grade: 13.2% versus 9.3%, RR 1.56, 95%CI 1.16to2.11, P < 0.01). Published data meta-analysis (8 RCTs, 3745 participants, 648 infections) demonstrated higher incidence of serious (HR 1.31, 95%CI 1.02to1.68, P = 0.04) and high-grade (HR 1.52, 95%CI 1.17to1.98, P < 0.01) infection with subcutaneous versus intravenous administration. Conclusions: Results suggest increased infection risk with subcutaneous versus intravenous administration, although IPD findings are sensitive to exclusion of one trial with inconsistent results and identified risk-of-bias. Ongoing trials may confirm findings. Clinical surveillance should be considered when switching to subcutaneous administration. PROSPERO registration CRD42020221866/CRD42020125376. [ABSTRACT FROM AUTHOR]

We present a case of an uncommon presentation of IgG4-related ophthalmic disease (ROD). A 58-year-old female presented with unilateral acute anterior uveitis of the right eye, which progressed to scleritis with the development of an associated orbital mass despite treatment with oral glucocorticoid. Initial histopathology of an orbital biopsy was non-diagnostic and continued progression of the disease lead to complete loss of vision in the right eye. The development of uveitis in the previously unaffected left eye led to the decision for enucleation of the right globe and further orbital biopsy. Histopathology revealed features supporting IgG4-related ophthalmic disease. Oral glucocorticoid therapy failed to induce remission, and rituximab therapy was initiated, leading to a rapid resolution in her symptoms. Other cases with a similar presentation report a poor visual prognosis, highlighting the need for prompt diagnosis and treatment of uveitis associated with signs of orbital or scleral involvement. [ABSTRACT FROM AUTHOR]

Lenalidomide and rituximab (R2) is an effective frontline treatment for patients with indolent B-cell non-Hodgkin lymphoma (iNHL). We investigated the safety and efficacy of addition of the proteasome inhibitor ixazomib to R2 for treatment of iNHL through a phase I/II clinical trial for high-risk patients. Twenty patients were enrolled, 18 were treated. The target dose of ixazomib 4 mg weekly was achieved during dose escalation. The most common treatment-related adverse events (AEs) were low grade gastrointestinal, rash, neuropathy, and myalgia/arthralgia. There were 33% grade 2 and 17% grade 3 infections. With median follow-up of 5.2 years, four patients discontinued treatment due to lymphoma progression. Best overall response rate (ORR) was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. Kaplan-Meier estimates of progression free and overall survival (OS) were 73% and 87% at 36 months, respectively. R2 can safely be combined with ixazomib for treatment-naïve iNHL patients. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Pediatric pemphigus is a rare bullous disease that represents a diagnostic and therapeutic challenge;  evidence on patients' response to various treatments and long‐term surveillance data are lacking. We aimed to investigate pediatric pemphigus patients' characteristics, diagnosis, therapeutics, response, and long‐term follow‐up.This is a retrospective study of all pemphigus patients aged <18 years, diagnosed between 2000 and 2023, from three tertiary medical centers in Israel. The diagnosis was confirmed by positive immunofluorescence.Twelve pediatric pemphigus patients were included (mean age 10.7 ± 4.3 years, male:female ratio 1:1). Mean diagnostic delay was 11.1 ± 12.6 months (range 1.8–36 months). Most patients had pemphigus vulgaris with mucosal involvement (58.3%). First‐line treatment for all patients included systemic corticosteroids (sCS), with a treatment duration (including tapering down) of 28 ± 18.4 months. Hospitalization did not yield better outcomes. Only three patients achieved sustained complete response with sCS treatment (25.0%), and the rest required additional therapeutics, most commonly rituximab. Rituximab showed a good safety profile and therapeutic response. Follow‐up was recorded up to 18.1 years after diagnosis (mean: 5.6 years). Three of five patients with information available more than 5 years after the pemphigus diagnosis still exhibited disease symptoms.Pediatric pemphigus is associated with a significant diagnostic delay. While sCS can induce remission in most patients as a first‐line treatment, long‐term disease control requires additional immunomodulators. Long‐term follow‐up reveals a chronic yet mostly benign disease course in this population and advocates for the use of rituximab in pediatric pemphigus patients. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Conclusion Small series suggest that rituximab could be effective as treatment for autoimmune hepatitis (AIH), although data are scarce. We aimed to evaluate the efficacy and safety of rituximab in different cohorts of patients with AIH.Multicentre retrospective analysis of the 35 patients with AIH and its variant forms treated with rituximab and included in the ColHai registry between 2015 and 2023.Most patients were female (83%), 10 (29%) had cirrhosis and four (11.4%) variant forms of AIH. Indication for rituximab were as follows: 14(40%) refractory AIH, 19(54%) concomitant autoimmune or haematological disorder, 2(6%) intolerance to prior treatments. In three (9%) subjects with a concomitant disorder, rituximab was the first therapy for AIH. Overall, 31 (89%) patients achieved or maintained complete biochemical response (CBR), including the three in first‐line therapy. No difference in CBR was observed according to rituximab indication (refractory AIH 86% vs. concomitant disorders 90%, p = .824) or cirrhosis (80% vs. 92%, p = .319). Rituximab was associated with a significant reduction in corticosteroids (median dose: prior 20 vs. post 5 mg, p < .001) and the discontinuation of ≥1 immunosuppressant in 47% of patients. Flare‐free rate at 1st, 2nd and 3rd year was 86%, 73% and 62% respectively. Flares were not associated with the development of liver failure and were successfully managed with repeated doses of rituximab and/or increased corticosteroids. Three (9%) patients experienced infusion‐related adverse events (1 anaphylaxis and 2 flu‐like symptoms) and five (14%) infections.Rituximab is safe and effective in patients with refractory AIH and those treated due to concomitant autoimmune or haematological disorders. [ABSTRACT FROM AUTHOR]

Introduction: Progressive multifocal leukoencephalopathy (PML) is a rare but potentially life-threatening brain infection caused by the John Cunningham virus. PML is a known adverse effect associated with molecular-targeted drugs and immunosuppressive agents. Recent concerns have emerged regarding the link between methotrexate (MTX) and PML. However, limited information exists on the influence of concomitant drug use in rheumatoid arthritis (RA) treatment, where various medications are often used together. Methods: To explore treatment patterns and patient background that affect PML reporting in RA, we analyzed data on RA cases from the Food and Drug Administration Adverse Event Reporting System (FAERS; JAPIC AERS) database between 1997 and 2019. Results and Discussion: Our analysis revealed significantly elevated crude and adjusted reporting odds ratios (aROR) for MTX, rituximab (RIT), azathioprine, and cyclophosphamide. When considering treatment patterns, the concomitant use of MTX and RIT showed a higher aROR than using MTX or RIT alone. Additional TNF-α inhibitors or glucocorticoids did not increase PML reports. Moreover, male sex and older age were associated with increased PML reports. While limitations are inherent in studies using spontaneous reporting data, our exploratory assessment suggests an association between PML and the combination of MTX and RIT and a higher risk in men and older patients. These findings help enhance our understanding of PML risk factors in the context of RA treatment. [ABSTRACT FROM AUTHOR]

Introduction: Progressive multifocal leukoencephalopathy (PML) is a rare but potentially life-threatening brain infection caused by the John Cunningham virus. PML is a known adverse effect associated with molecular-targeted drugs and immunosuppressive agents. Recent concerns have emerged regarding the link between methotrexate (MTX) and PML. However, limited information exists on the influence of concomitant drug use in rheumatoid arthritis (RA) treatment, where various medications are often used together. Methods: To explore treatment patterns and patient background that affect PML reporting in RA, we analyzed data on RA cases from the Food and Drug Administration Adverse Event Reporting System (FAERS; JAPIC AERS) database between 1997 and 2019. Results and Discussion: Our analysis revealed significantly elevated crude and adjusted reporting odds ratios (aROR) for MTX, rituximab (RIT), azathioprine, and cyclophosphamide. When considering treatment patterns, the concomitant use of MTX and RIT showed a higher aROR than using MTX or RIT alone. Additional TNF-a inhibitors or glucocorticoids did not increase PML reports. Moreover, male sex and older age were associated with increased PML reports. While limitations are inherent in studies using spontaneous reporting data, our exploratory assessment suggests an association between PML and the combination of MTX and RIT and a higher risk in men and older patients. These findings help enhance our understanding of PML risk factors in the context of RA treatment. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma, for which cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab(R–CHOP) is one of the standard regimens. Given that R–CHOP is highly emetogenic, chemotherapy-induced nausea and vomiting (CINV) prevention is clinically important. However, there is a paucity of studies focusing on these patients. This study aimed to ascertain the effectiveness of an oral fixed-dose combination of netupitant and palonosetron (NEPA) in preventing CINV in patients with DLBCL undergoing first-line R-CHOP chemotherapy. Seventy patients were enrolled in this single-center prospective non-comparative study conducted between November 2020 and May 2023 in South Korea. NEPA was administered 1 h prior to chemotherapy initiation on day 1. The primary endpoint of the study was the complete response rate (no emesis, and no rescue medication) during the acute, delayed, and overall phases, which were assessed over a period of 120 h post-chemotherapy. The complete response rates for NEPA were 90.0% [95% CI 80.5, 95.9] for the acute phase, 85.7% [95% CI 75.3, 92.9] for the delayed phase, and 84.3% [95% CI 73.6, 91.9] for the overall phase, with no-emesis rates (acute: 97.1% [95% CI 97.1, 99.7], delayed: 95.7% [95% CI 88.0, 99.1], overall: 92.9% [95% CI 84.1, 97.6]). NEPA was well tolerated with no severe treatment-emergent adverse events. NEPA exhibited substantial efficacy in mitigating CINV in DLBCL patients undergoing R–CHOP chemotherapy, demonstrating high CR and no-emesis rates, and favorable safety profiles. [ABSTRACT FROM AUTHOR]

Immunosuppressive treatment in patients with rheumatic diseases can maintain disease remission but also increase risk of infection. Their response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is frequently blunted. In this study we evaluated the effect of immunosuppression exposure on humoral and T cell immune responses to SARS-CoV-2 infection and vaccination in two distinct cohorts of patients; one during acute SARS-CoV-2 infection and 3 months later during convalescence, and another prior to SARS-CoV-2 vaccination, with follow up sampling 6 weeks after vaccination. Results were compared between rituximab-exposed (in previous 6 months), immunosuppression-exposed (in previous 3 months), and non-immunosuppressed groups. The immune cell phenotype was defined by flow cytometry and ELISA. Antigen specific T cell responses were estimated using a whole blood stimulation interferon-γ release assay. A focused post-vaccine assessment of rituximab-treated patients using high dimensional spectral cytometry was conducted. Acute SARS-CoV-2 infection was characterised by T cell lymphopenia, and a reduction in NK cells and naïve CD4 and CD8 cells, without any significant differences between immunosuppressed and non-immunosuppressed patient groups. Conversely, activated CD4 and CD8 cell counts increased in non-immunosuppressed patients with acute SARS-CoV-2 infection but this response was blunted in the presence of immunosuppression. In rituximab-treated patients, antigen-specific T cell responses were preserved in SARS-CoV-2 vaccination, but patients were unable to mount an appropriate humoral response. [ABSTRACT FROM AUTHOR]

Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients. We found that a significantly higher proportion of RRMM patients (86%) exhibited aberrant co-expression of CD28 compared to newly diagnosed MM (NDMM) patients (19%). Furthermore, SAR442257 mediated significantly higher TC activation, resulting in enhanced MM killing compared to bispecific functional knockout controls for all relapse cohorts (Pearson's r = 0.7). Finally, patients refractory to anti-CD38 therapy had higher levels of TGF-β (up to 20-fold) compared to other cohorts. This can limit the activity of SAR442257. Vactoserib, a TGF-β inhibitor, was able to mitigate this effect and restore sensitivity to SAR442257 in these experiments. In conclusion, SAR442257 has high potential for enhancing TC cytotoxicity by co-targeting CD38 and CD28 on MM and CD3/CD28 on T cells. [ABSTRACT FROM AUTHOR]

AbstractWe report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event-free survival (EFS) or overall survival (OS). With a median follow-up of 7.8 years (range: 0.40–18.8), eight patients have experienced disease relapse (5.8%), 4/111 with newly diagnosed HCL (3·6%) and 4/10 with HCLv (40%) (p = 0.002). The 10-year EFS and OS rates were 86.7% and 91.1%, respectively. Grade 3 adverse events were observed in 28 participants (20·1%), mostly due to infections. Treatment of HCL with sequential cladribine followed by rituximab is associated with excellent efficacy and safety results both in the frontline and relapsed settings. [ABSTRACT FROM AUTHOR]

Background: M-type phospholipase A2 receptor (PLA2R) is a major auto-antigen of primary membranous nephropathy(PMN). Anti-PLA2R antibody levels are closely associated with disease severity and therapeutic effectiveness. Analysis of PLA2R antigen epitope reactivity may have a greater predictive value for remission compared with total PLA2R-antibody level. This study aims to elucidate the relationship between domain-specific antibody levels and clinical outcomes of PMN. Methods: This retrospective analysis included 87 patients with PLA2R-associated PMN. Among them, 40 and 47 were treated with rituximab (RTX) and cyclophosphamide (CTX) regimen, respectively. The quantitative detection of -immunoglobulin G (IgG)/-IgG4 targeting PLA2R and its epitope levels in the serum of patients with PMN were obtained through time-resolved fluorescence immunoassays and served as biomarkers in evaluating the treatment effectiveness. A predictive PMN remission possibility nomogram was developed using multivariate logistic regression analysis. Discrimination in the prediction model was assessed using the area under the receiver operating characteristic curve (AUC-ROC).Bootstrap ROC was used to evaluate the performance of the prediction model. Results: After a 6-month treatment period, the remission rates of proteinuria, including complete remission and partial remission in the RTX and CTX groups, were 70% and 70.21% (P = 0.983), respectively. However, there was a significant difference in immunological remission in the PLA2R-IgG4 between the RTX and CTX groups (21.43% vs. 61.90%, P = 0.019). Furthermore, we found differences in PLA2R-CysR-IgG4(P = 0.030), PLA2R-CTLD1-IgG4(P = 0.005), PLA2R-CTLD678-IgG4(P = 0.003), and epitope spreading (P = 0.023) between responders and non-responders in the CTX group. Multivariate logistic analysis showed that higher levels of urinary protein (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.26–0.95; P = 0.035) and higher levels of PLA2R-CTLD1-IgG4 (OR, 0.79; 95%CI,0.62–0.99; P = 0.041) were independent risk factors for early remission. A multivariate model for estimating the possibility of early remission in patients with PMN is presented as a nomogram. The AUC-ROC of our model was 0.721 (95%CI, 0.601–0.840), in consistency with the results obtained with internal validation, for which the AUC-ROC was 0.711 (95%CI, 0.587–0.824), thus, demonstrating robustness. Conclusions: Cyclophosphamide can induce immunological remission earlier than rituximab at the span of 6 months. The PLA2R-CTLD1-IgG4 has a better predict value than total PLA2R-IgG for remission of proteinuria at the 6th month. [ABSTRACT FROM AUTHOR]

Tazemetostat, a novel oral selective inhibitor of enhancer of zeste homolog 2 (EZH2), was approved by the Food and Drug Administration (FDA) in 2020 for use in patients with advanced epithelioid sarcoma or relapsed/refractory (R/R) EZH2-mutated follicular lymphoma. These indications were approved by the FDA trough accelerated approval based on objective response rate and duration of response that resulted from phase 2 clinical trials. Tazemetostat competes with S-adenosylmethionine (SAM) cofactor to inhibit EZH2, reducing the levels of trimethylated lysine 27 of histone 3 (H3K27me3), considered as pharmacodynamic marker. Tazemetostat is orally bioavailable, characterized by rapid absorption and dose-proportional exposure, which is not influenced by coadministration with food or gastric acid reducing agents. It highly distributes in tissues, but with limited access to central nervous system. Tazemetostat is metabolized by CYP3A in the liver to 3 major inactive metabolites (M1, M3, and M5), has a short half-life and is mainly excreted in feces. Drug-drug interactions were shown with moderate CYP3A inhibitors as fluconazole, leading the FDA to recommend a 50% dose reduction, while studies investigating coadministration of tazemetostat with strong inhibitors/inducers are ongoing. No dosage modifications are recommended based on renal or hepatic dysfunctions. Overall, tazemetostat is the first-in-class EZH2 inhibitor approved by the FDA for cancer treatment. Current clinical studies are evaluating combination therapies in patients with several malignancies. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy represents the most prevalent cause of glomerulonephritis worldwide and may lead to renal failure in a relevant number of cases in both paediatric and adult subjects. Although their pathogenesis is still largely unclear, evidence of immune abnormalities provides the background for the use of immunosuppressive drugs, such as corticosteroids, calcineurin inhibitors, and antiproliferative and alkylating agents. Unfortunately, these treatments fail to achieve a sustained remission in a significant percentage of affected patients and are burdened by significant toxicities. Recent developments of new biologics, including anti-BAFF/APRIL inhibitors and molecules targeting complement components, offered the opportunity to selectively target immune cell subsets or activation pathways, leading to more effective and safer hypothesis-driven treatments. However, studies testing new biologic agents in IgAN should also consider paediatric populations to address the unique needs of children and close the therapeutic gap between adult and paediatric care. [ABSTRACT FROM AUTHOR]

Intravascular large B-cell lymphoma (IVLBCL) is a rare lymphoma that affects the brain, skin, and bone marrow. We describe the case of a 75-year-old man who was admitted to the hospital after 4 h of stomach aches. A thorough physical examination indicated stomach discomfort and skin discoloration. Laboratory tests revealed thrombocytopenia and elevated lactate dehydrogenase levels. A computed tomography scan of the abdomen revealed that the small intestine wall was thickened, edematous, and necrotic. The necrotic small bowel was surgically removed, revealing many little round, homogenous, and unusual cells in the mesenteric vein. In-situ hybridization revealed that these cells were positive for PAX5, CD20, CD79a, CD10, and BCL2, as well as Epstein-Barr virus-encoded small RNA. After 1 week of hospitalization without treatment, the patient was diagnosed with IVLBCL and died of multiple organ dysfunction syndrome. IVLBCL is a rare illness that affects the small intestine and possibly the gastrointestinal system. It has an insidious start, a fast development, and a dismal prognosis. Knowing its clinicopathologic traits helps in understanding the illness, making an early diagnosis, and preventing rapid worsening. [ABSTRACT FROM AUTHOR]

Introduction: Whole-genome sequencing of diffuse large B-cell lymphoma (DLBCL) has identified recurrent mutations involved in pathogenesis and potentially affecting response to therapy. In this pilot study, a targeted gene panel was created to identify mutations associated with relapse/refractoriness. Material and Methods: A 14-gene targeted panel was designed to sequence thirteen patients who were in remission and 8 cases that had relapsed/refractory to treatment. A paired diagnostic biopsy and a relapse biopsy were sequenced to find genes repeatedly altered in relapse. Results: A total of 751 nonsynonymous and truncating mutations were identified. Truncated mutations in NOTCH1, TNFAIP3, and CD58 were associated with poor treatment outcomes. In cases that did not respond to treatment, a high number of mutations were found in the EZH2 gene, followed by the DNA-binding domain of TP53 and MYD88. Termination mutations in the intracellular domain of NOTCH were found in 75% of non-responsive cases. Co-occurrence of loss of function mutations of TNFAIP3 and missense mutations in MYD88 was associated with a non-responsive cohort. Discussion: The study highlights mutations associated with chemotherapeutic response in DLBCL with implications for initial diagnostic biopsy response prediction. [ABSTRACT FROM AUTHOR]

Objectives APS-associated heart valve disease (HVD) is well described. Nonetheless, limited data exist on clinical parameters associated with the course of primary APS (pAPS) patients with HVD. The goal of this study was to assess clinical features and related outcomes in patients with APS-associated HVD. Methods In this multicentre retrospective study, we identified 33 pAPS patients with HVD (pAPS-HVD group) and compared their clinical course with 128 pAPS patients with normal heart valves on echocardiography (pAPS-control group). Results pAPS-HVD patients had more cerebrovascular events (56.3% vs 25%, P  = 0.005) and livedo reticularis (24.2% vs 7.8%, P  = 0.013) than pAPS-controls. Furthermore, catastrophic-APS (CAPS) (12.1% vs 2.4%, P  = 0.034), recurrent thrombosis (33.3% vs 4.7%, P  < 0.001) and need for advanced therapy (i.e. IVIG, plasmapheresis or rituximab) were more frequent in pAPS-HVD patients. Anti-β2-glycoprotein 1 IgG (84.8% vs 63.2%, P  = 0.034), anti-cardiolipin IgG (90.9% vs 64.8%, P  = 0.005) and triple positive aPL (75.8% vs 56.5%, P  = 0.047) were commoner in pAPS-HVD patients vs pAPS-controls. Ten of the 33 patients with pAPS-HVD underwent valve surgery, which was associated with male gender, smoking, arterial limb ischaemia and livedo reticularis. Conclusion pAPS-HVD patients had a more severe APS clinical course including CAPS and thrombotic events as well as a specific serology, namely IgG isotype aPL antibodies and triple positivity. Our data suggest that pAPS-HVD represents a high-risk subgroup of APS patients. [ABSTRACT FROM AUTHOR]

Objectives Rituximab (RTX) is a safe and effective treatment for RA. However, there are some concerns about infection risk and preliminary data suggest dose and time dependency. This study aims to determine the infection incidence in a large real-life population of RA patients using RTX, with special focus on (ultra-)low dosing and time since last infusion. Methods RA patients treated with 1000, 500 or 200 mg RTX per cycle between 2012 and 2021 at the Sint Maartenskliniek were included in a retrospective cohort study. Patient-, disease-, treatment- and infection characteristics were retrieved from electronic health records. Infection incidence rates, dose and time relations with RTX infusion were analysed using mixed-effects Poisson regression. Results Among 490 patients, we identified 819 infections in 1254 patient years. Most infections were mild and respiratory tract infections were most common. Infection incidence rates were 41, 54 and 71 per 100 patient years for doses of 200, 500 and 1000 mg. Incidence rate ratio (IRR) was significantly lower for 200 mg compared with 1000 mg (adjusted IRR 0.35, 95% CI 0.17, 0.72, P  = 0.004). In patients receiving 1000 or 500 mg RTX, infections seemed to occur more frequently within the first two months after infusion compared with later on in the treatment cycle, suggesting an association with peak concentration. Conclusion Ultra-low dosing (200 mg) of RTX is associated with a lower risk of infections in RA. Future interventions focusing on ultra-low dosing and slow release of RTX (e.g. by subcutaneous administration) may lower infection risk. [ABSTRACT FROM AUTHOR]

Vasculitic neuropathy has a broad range of etiologies, and roughly comprises nonsystemic vasculitic neuropathy and neuropathies accompanied by antineutrophil cytoplasmic antibody‐associated vasculitis (AAV). Recent morphological analyses of sural nerve specimens from patients with vasculitic neuropathy showed some distinct pathogeneses within vasculitic neuropathy. Several randomized, controlled studies and updated practice guidelines cover immunotherapies for AAV, whereas there is a paucity of evidence for vasculitic neuropathy, including neuropathies associated with AAV. Corticosteroids have been the mainstay of immunotherapy for vasculitic neuropathy, and cyclophosphamide is indispensable for refractory cases. Recent AAV guidelines are shifting their recommendations toward minimizing the harm caused by corticosteroids and cyclophosphamide with a reduced‐dose corticosteroid regimen and the recent advent of various optional drugs, especially molecular‐targeted agents. Clinicians expect the efficacy of reduced‐dose corticosteroid regimens and molecular‐targeted agents in treating vasculitic neuropathy to be verified, and clarification of the mechanism of vasculitic neuropathy might lead to the development of the best treatment based on the background pathogenesis of individual cases. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus-related post-transplantation lymphoproliferative disorder (EBV-PTLD) is a serious complication following hematopoietic stem cell transplantation (HSCT). A pre-emptive strategy using rituximab, which aims to manage patients early at the time of EBV reactivation to avoid PTLD, has been recommended by the most recent ECIL-6 guidelines in 2016. However, there is still a great heterogeneity of viral-load monitoring protocols, targeted patient populations, and pre-emptive treatment characteristics between centers, making precise EBV monitoring recommendations difficult. We conducted a literature review from the most recent publications between 1 January 2015 and 1 August 2023, to summarize the emerging data on EBV-PTLD prevention strategies in HSCT recipients, including the EBV-DNA threshold and use of rituximab. We also present the results of a survey of current practices carried out in 12 of the main HSCT centers across Canada. We confirm that pre-emptive rituximab remains an efficient strategy for EBV-PTLD prevention. However, there is an urgent need to perform prospective, randomized, multicentric trials with larger numbers of patients reflecting current practices to determine the best clinical conduct with regards to rituximab dosing, timing of treatment, and criteria to initiate treatments. Longer follow-ups will also be necessary to assess patients' long-term outcomes. [ABSTRACT FROM AUTHOR]

Introduction: The transplantation of highly sensitized patients remains a major obstacle. Immunized patients wait longer for a transplant if not prioritized, and if transplanted, their transplant outcome is worse. Case Presentation: We report a successful AB0- and HLA-incompatible living donor kidney transplantation in a 35-year-old female patient with systemic lupus erythematosus (SLE) and antiphospholipid syndrome. The patient had a positive T- and B-cell complement-dependent cytotoxicity (CDC) crossmatch and previous graft loss due to renal vein thrombosis. We treated the patient with intravenous immunoglobulins, rituximab, horse anti-thymocyte globulin, daratumumab, and imlifidase, besides standard immunosuppression. All IgG antibodies were sensitive to imlifidase treatment. Besides donor-specific HLA antibodies, anti-dsDNA antibodies and antiphospholipid antibodies were cleaved. The patient initially had delayed graft function. Two kidney biopsies (day 7 and day 14) revealed acute tubular necrosis without signs of HLA antibody-mediated rejection. On posttransplant day 30, hemodialysis was stopped, and creatinine levels declined over the next weeks to a baseline creatinine of about 1.7 mg/dL after 12 months. Conclusion: In this case, a novel multimodal treatment strategy including daratumumab and imlifidase enabled successful kidney transplantation for a highly immunized patient with antiphospholipid antibodies. [ABSTRACT FROM AUTHOR]

Non-Hodgkin lymphoma (NHL) is among the five most common pediatric cancer diagnoses in children and adolescents and consists of a heterogeneous group of lymphoid tissue malignancies –with B-cell-derived NHL accounting for nearly 80% of cases. Novel and high-throughput diagnostic tools have significantly increased our understanding of B-NHL biology and molecular pathogenesis, leading to new NHL classifications and treatment options. This retrospective cohort study investigated 17 cases of both mature B-cell NHL (Burkitt lymphoma or BL; Diffuse large B-cell lymphoma or DLBCL; Primary mediastinal large B-cell lymphoma or PMBCL; Follicular lymphoma or FL) and immature B-cell progenitor NHL (B-lymphoblastic lymphoma or BLL) that were treated in a tertiary Pediatric Hematology-Oncology Department during the last 20 years. Modern NHL protocols for children, adolescents, and young adults, along with the addition of rituximab, are safe and efficient (100% overall survival; one relapse). Elevated ESR was more prevalent than elevated LDH. Analyses have focused on immune reconstitution (grade ≥3 infections, lymphocyte and immunoglobulin levels recovery) and body-mass-index changes post-treatment, late effects (in 53% of patients), and the presence of histology markers BCL2, BCL6, CD30, cMYC, and Ki-67%. One patient was diagnosed with a second malignant neoplasm (papillary thyroid cancer). [ABSTRACT FROM AUTHOR]

Aim: Rituximab (RTX) is a genetically engineered chimeric monoclonal antibody which binds directly to CD20 antigen and mediates inhibition of B cell development. Although RTX has been widely used in paediatric nephrology, there is no routine protocol for its use. In this study, paediatric nephrologists in Türkiye were asked to fill out a questionnaire to understand their practice in using RTX. This study aimed to determine common practices and clarify the uncertainties regarding the use of RTX in paediatric nephrology. Methods: This was a nationwide, multicenter, retrospective cohort study based on data evaluating the use of RTX in paediatric nephrology practice. An online questionnaire was sent to all paediatric nephrology centers in Türkiye. The questionnaire forms included information about how many patients in total applied RTX treatment, for which indications they use RTX, and whether they made any preparations before using RTX. Results: According to this survey on RTX use in Türkiye, paediatric nephrologists use it most commonly in SSNS and followed by SRNS, ABMR, SLE and AAV, respectively. Dosing was highly standard but there is significant heterogeneity in pre‐exposure tests and patient monitoring in the clinical practice of RTX. Also, the rate of encountering RTX‐related allergic and infectious side effects at least once during the professional experience of our physicians can be quite high. Conclusion: There is an increasing need for the preparation of a guideline on the indications for RTX use for each diagnosis, posology, and the practices to be performed before and after infusion. [ABSTRACT FROM AUTHOR]

Background: This study aims to establish and validate a predictive nomogram for the short‐term clinical outcomes of myasthenia gravis (MG) patients treated with low‐dose rituximab. Methods: We retrospectively reviewed 108 patients who received rituximab of 600 mg every 6 months in Huashan Hospital and Tangdu Hospital. Of them, 76 patients from Huashan Hospital were included in the derivation cohort to develop the predictive nomogram, which was externally validated using 32 patients from Tangdu Hospital. The clinical response is defined as a ≥ 3 points decrease in QMG score within 6 months. Both clinical and genetic characteristics were included to screen predictors via multivariate logistic regression. Discrimination and calibration were measured by the area under the receiver operating characteristic curve (AUC‐ROC) and Hosmer–Lemeshow test, respectively. Results: Disease duration (OR = 0.987, p = 0.032), positive anti‐muscle‐specific tyrosine kinase antibodies (OR = 19.8, p = 0.007), and genotypes in FCGR2A rs1801274 (AG: OR = 0.131, p = 0.024;GG:OR = 0.037, p = 0.010) were independently associated with clinical response of post‐rituximab patients. The nomogram identified MG patients with clinical response with an AUC‐ROC (95% CI) of 0.875 (0.798–0.952) in the derivation cohort and 0.741(0.501–0.982) in the validation cohort. Hosmer–Lemeshow test showed a good calibration (derivation: Chi‐square = 3.181, p = 0.923; validation: Chi‐square = 8.098, p = 0.424). Conclusions: The nomogram achieved an optimal prediction of short‐term outcomes in patients treated with low‐dose rituximab. [ABSTRACT FROM AUTHOR]

Background and purpose: Rituximab (RTX) is frequently used off‐label in multiple sclerosis. However, studies on the risk–benefit profile of RTX in pediatric‐onset multiple sclerosis are scarce. Methods: In this multicenter retrospective cohort study, patients with pediatric‐onset multiple sclerosis from Sweden, Austria and Germany, who received RTX treatment were identified by chart review. Annualized relapse rates, Expanded Disability Status Scale scores and magnetic resonance imaging parameters (new T2 lesions and contrast‐enhancing lesions) were assessed before and during RTX treatment. The proportion of patients who remained free from clinical and disease activity (NEDA‐3) during RTX treatment was calculated. Side effects such as infusion‐related reactions, infections and laboratory abnormalities were assessed. Results: Sixty‐one patients received RTX during a median (interquartile range) follow‐up period of 20.9 (35.6) months. The annualized relapse rate decreased from 0.6 (95% confidence interval [CI] 0.38–0.92) to 0.03 (95% CI 0.02–0.14). The annual rate of new T2 lesions decreased from 1.25 (95% CI 0.70–2.48) to 0.08 (95% CI 0.03–0.25) and annual rates of new contrast‐enhancing lesions decreased from 0.86 (95% CI 0.30–3.96) to 0. Overall, 70% of patients displayed no evidence of disease activity (NEDA‐3). Adverse events were observed in 67% of patients. Six patients discontinued treatment due to ongoing disease activity or adverse events. Conclusion: Our study provides class IV evidence that RTX reduces clinical and radiological activity in pediatric‐onset multiple sclerosis. [ABSTRACT FROM AUTHOR]

Summary: Vaccinations are fundamental tools in preventing infectious diseases, especially in immunocompromised patients like those affected by non‐Hodgkin lymphomas (NHLs). The COVID‐19 pandemic made clinicians increasingly aware of the importance of vaccinations in preventing potential life‐threatening SARS‐CoV‐2‐related complications in NHL patients. However, several studies have confirmed a significant reduction in vaccine‐induced immune responses after anti‐CD20 monoclonal antibody treatment, thus underscoring the need for refined immunization strategies in NHL patients. In this review, we summarize the existing data about COVID‐19 and other vaccine's efficacy in patients with NHL and propose multidisciplinary team‐based recommendations for the management of vaccines in this specific group of patients. [ABSTRACT FROM AUTHOR]

Purpose: To report the uveitic manifestations of patients with systemic lupus erythematosus (SLE). Methods: This was a retrospective analysis of all SLE cases with ocular manifestations seen by a single ophthalmologist between 2015 and December 2021. Results: In total, seven patients with a median age of 40 (range 18-50) years were included in the study. Female (85.7%) predominance was noted. Ocular findings were bilateral in 71% (five patients) of cases. Majority (10 eyes, 83%) of the patients had retinal vasculitis as the common finding. Antinuclear antibodies were positive in all the patients. The vision improved in two (16.6%) eyes, was stable in eight (66%) eyes, and worsened in one (8%) eye. All the patients were treated with oral steroids along with immunosuppressive agents. Conclusion: Though SLE is rare cause of uveitis, it can be associated with significant ocular morbidity. Hence, early diagnosis and treatment can salvage vision in many cases. [ABSTRACT FROM AUTHOR]

Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against Factor VIII, with a high mortality risk. Treatments aim to control bleeding and eradicate antibodies by immunosuppression. International recommendations rely on registers and international expert panels. CREHA, an open-label randomized trial, compared the efficacy and safety of cyclophosphamide and rituximab in association with steroids in patients with newly diagnosed AHA. Participants were treated with 1 mg/kg prednisone daily and randomly assigned to receive either 1.5–2 mg/kg/day cyclophosphamide orally for 6 weeks, or 375 mg/m2 rituximab once weekly for 4 weeks. The primary endpoint was complete remission over 18 months. Secondary endpoints included time to achieve complete remission, relapse occurrence, mortality, infections and bleeding, and severe adverse events. Recruitment was interrupted because of new treatment recommendations after 108 patients included (58 cyclophosphamide, 50 rituximab). After 18 months, 39 cyclophosphamide patients (67.2 %) and 31 rituximab patients (62.0 %) were in complete remission (OR 1.26; 95 % CI, 0.57 to 2.78). In the poor prognosis group (FVIII < 1 IU/dL, inhibitor titer > 20 BU mL−1), significantly more remissions were observed with cyclophosphamide (22 patients, 78.6 %) than with rituximab (12 patients, 48.0 %; p = 0.02). Relapse rates, deaths, severe infections, and bleeding were similar in the 2 groups. In patients with severe infection, cumulative doses of steroids were significantly higher than in patients without infection (p = 0.03). Cyclophosphamide and rituximab showed similar efficacy and safety. As first line, cyclophosphamide seems preferable, especially in poor prognosis patients, as administered orally and less expensive. French Ministry of Health. ClinicalTrials.gov number: NCT01808911. • Cyclophosphamide and rituximab have similar efficacy and safety in AHA. • Cyclophosphamide seems preferable in patients with low FVIII and high inhibitor titer. • If immunosuppressant is added to steroids, cyclophosphamide should be preferred. • It is crucial to reduce total steroid intake in AHA as much as possible. • Cumulative dose and duration of steroid are correlated with the risk of serious sepsis. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This report highlights the risk of latent tuberculosis (TB) reactivation after treatment with Polatuzumab Vedotin (PV), Rituximab, and Bendamustine (PBR protocol) despite appropriate chemoprophylaxis. A 48‐year‐old male with refractory Burkitt's lymphoma (BKL) was treated with PBR protocol. At baseline, the patient had a negative QuantiFERON test result, which turned out to be positive prior to starting PBR. He received chemoprophylaxis for 9 months and was compliant with treatment. One year later, he was admitted with COVID‐19 pneumonia and was treated according to the protocol. His symptoms persisted for 1 month. Investigations yielded disseminated TB‐infiltrated bone marrow and pleura. Downstream B‐cell and T‐cell depletion secondary to CD20 and CD79b antagonism may potentially explain the increased risk of TB reactivation associated with the combination of PV and rituximab. Further research is necessary to monitor the risk of TB reactivation among patients receiving a combination of PV and rituximab, especially in endemic areas with high prevalence and incidence of TB. [ABSTRACT FROM AUTHOR]

• Exercise increases the frequency of NK-cells and CLL cells in the blood of patients with treatment-naïve CLL. • Exercise improves the efficacy of rituximab against autologous CLL cells in treatment-naïve CLL ex vivo. • Exercise increases the frequency of CLL cells in blood with a phenotype indicating recent egress from lymphoid tissue. Chronic lymphocytic leukaemia (CLL) is characterised by the clonal proliferation and accumulation of mature B-cells and is often treated with rituximab, an anti-CD20 monoclonal antibody immunotherapy. Rituximab often fails to induce stringent disease eradication, due in part to failure of antibody-dependent cellular cytotoxicity (ADCC) which relies on natural killer (NK)-cells binding to rituximab-bound CD20 on B-cells. CLL cells are diffusely spread across lymphoid and other bodily tissues, and ADCC resistance in survival niches may be due to several factors including low NK-cell frequency and a suppressive stromal environment that promotes CLL cell survival. It is well established that exercise bouts induce a transient relocation of NK-cells and B-cells into peripheral blood, which could be harnessed to enhance the efficacy of rituximab in CLL by relocating both target and effector cells together with rituximab in blood. In this pilot study, n = 20 patients with treatment-naïve CLL completed a bout of cycling 15 % above anaerobic threshold for ∼ 30-minutes, with blood samples collected pre-, immediately post-, and 1-hour post-exercise. Flow cytometry revealed that exercise evoked a 254 % increase in effector (CD3−CD56+CD16+) NK-cells in blood, and a 67 % increase in CD5+CD19+CD20+ CLL cells in blood (all p < 0.005). NK-cells were isolated from blood samples pre-, and immediately post-exercise and incubated with primary isolated CLL cells with or without the presence of rituximab to determine specific lysis using a calcein-release assay. Rituximab-mediated cell lysis increased by 129 % following exercise (p < 0.001). Direct NK-cell lysis of CLL cells – independent of rituximab – was unchanged following exercise (p = 0.25). We conclude that exercise improved the efficacy of rituximab-mediated ADCC against autologous CLL cells ex vivo and propose that exercise should be explored as a means of enhancing clinical responses in patients receiving anti-CD20 immunotherapy. [ABSTRACT FROM AUTHOR]

• The desensitization protocol (IVIG + rituximab) allows highly immunized patients to undergo organ transplantation. • In short-term analysis, no acute rejection was observed and graft function was satisfactory. • Desensitization was associated with an increased risk of infection, especially fungal pneumonia. The increasing number of highly immunized patients waiting for kidney transplantation is a significant problem in Europe as the proportion of such patients has doubled in the last decade. Transplantation in this group is enabled by desensitization methods, i.e., intravenous pharmacotherapy with human immunoglobulin (IVIG), anti-CD20 monoclonal antibody (rituximab), and plasma exchange. The objective was to evaluate the efficacy and safety of this protocol. The inclusion criteria: presence of established anti-HLA antibodies with complement-binding capacity, i.e., anti-HLAC1q+ (>MFI 15,000 for the most common antigens), no renal transplantation within 1 year after activation on the waiting list. Thirteen patients were selected for the procedure. IVIG was administered twice (2 g/kg-maximum 140 g/dose). Between IVIG doses, patients received rituximab (375 mg/m2). Anti-HLA was tested after 1 and 2 months after completion of the procedure. All patients have completed the protocol. No significant changes after desensitization in the amount/profile of alloantibodies were observed. However, with negative vCM for HLA-A/B/DR (no DSA against the reported donor) and negative CM-CDC, according to the allocation system, patients were given priority on the recipient list. Seven out of 13 patients received a transplant within 12 months after treatment (mean 11.5 weeks). Renal graft function was good (mean creatinine level after 1 month: 1.5 mg/dL). No incidents of acute rejection were reported. The most common complications were infections (especially pneumonia). The desensitization protocol (IVIG + rituximab) allows highly immunized patients to undergo organ transplantation. In short-term analysis, no acute rejection was observed, graft function was satisfactory. Desensitization was associated with an increased risk of infection. [ABSTRACT FROM AUTHOR]

Statin-induced immune-mediated necrotizing myopathy (IMNM) is a rare systemic neuromuscular condition. We present a case of a patient with a severe phenotype of the disease that was found to have an increase in anti-HMGCR and anti-ACHR antibodies. A potential association between these antibodies have not been previously described. A 67-year-old male with hyperlipidemia, who was recently initiated on atorvastatin therapy, presented to the ED with progressive muscle weakness. Within a few days of admission, the patient developed complete flaccid paralysis and respiratory distress requiring intubation. The patient's CK was elevated to 24,000 and there was an increase of anti-HMGCR and anti-ACHR antibodies. Impressions from MRI and thigh biopsy solidified a diagnosis of statin-induced IMNM. The patient was treated with methylprednisolone, IVIG, and rituximab, which provided resolution of symptoms. [ABSTRACT FROM AUTHOR]

Background: Treatment with anti‐CD20 antibodies (rituximab) is used in both adults and children to treat various autoimmune and oncological diseases. Rituximab depletes B CD20+ cells and, thereby, antibody response to vaccines. This study aimed to examine the antibody response to mRNA‐based COVID‐19 vaccines in children aged 5–18 years undergoing rituximab treatment compared to healthy matched children. Methods: Between 31 January and 18 July 2022, we conducted a prospective observational study at the Geneva University Hospitals, enrolling children aged 5–18 years under rituximab treatment who had received two mRNA‐based SARS‐CoV‐2 vaccine doses. Controls were healthy volunteers with no significant medical conditions. Exclusion criteria included a recent SARS‐CoV‐2 infection. Blood samples were collected at day 60 (±30) and day 270 (±90) after the second vaccination. Results: The rituximab‐treated group exhibited significantly lower levels of antibodies specific to the anti‐receptor binding domain (RBD) of the SARS‐CoV‐2 spike (S) protein than healthy controls at 60 (±30) days after the second vaccine dose (geometric mean concentration: 868.3 IU/mL in patients and 11,393 IU/mL in controls; p =.008). However, patients with a rituximab‐to‐vaccine interval shorter than 6 months and with evidence of a past infection (based on positive anti‐N antibody levels) had a high level of anti‐RBD antibodies. Conclusion: A past infection with SARS‐CoV‐2 may induce anti‐RBD‐specific memory B cells that can be re‐activated by SARS‐CoV‐2 vaccination, even after rituximab‐induced B‐cell depletion. This suggests that it is possible to vaccinate earlier than 6 months after rituximab to develop a good antibody response, especially in the case of past SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]