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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]

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]

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]

Background Currently, there is no effective treatment for adult-onset immunodeficiency (AOID) syndrome with anti-interferon-gamma autoantibodies (anti-IFN-γ-auto-Abs). This study aimed to investigate the effectiveness of bortezomib (BTZ) for decreasing anti-IFN-γ-auto-Abs. Methods A pre- and post-intervention study was conducted from February 2017 through June 2019 at Siriraj Hospital (Bangkok, Thailand). Five patients were invited to receive once-weekly BTZ (1.3 mg/m2 body surface area) subcutaneously for 8 weeks followed by oral cyclophosphamide (1 mg/kg/d) for 4 months. The primary outcomes were the difference in antibody level at 8 and 48 weeks compared with baseline and the incidence of serious adverse events (AEs). The secondary outcome was the occurrence of opportunistic infections (OIs) during the 72 weeks after starting BTZ. Results The median patient age was 46 years (range, 34–53). All patients had 3–5 OIs prior to enrollment. All patients were receiving antimycobacterial agents for treatment of nontuberculous mycobacterial infection at enrollment. There was no significant difference in the mean optical density of auto-Abs at 8 weeks (3.73 ± 0.72) or 48 weeks (3.74 ± 0.53) compared with baseline (3.84 ± 0.49; P =.336 and P =.555, respectively). However, after serum dilution, the antibody titer nonsignificantly decreased 8–16 weeks after BTZ initiation (P =.345). Ten OIs were observed 24–72 weeks after BTZ initiation. Conclusions Treatment with BTZ followed by cyclophosphamide yielded no significant decrease in antibody titer levels, and 10 OIs were observed during 24–72 weeks of BTZ treatment. No serious AEs were observed. Combining rituximab with BTZ is likely necessary to prevent generation of new autoantibody-producing plasma cells. Clinical Trials Registration. NCT03103555. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma in Western countries. While FL is generally incurable, standard initial therapies are associated with high response rates and durable remissions for most patients. In addition, novel targeted agents and immunotherapies are changing the treatment algorithm for patients with relapsed or refractory disease. This review discusses the initial staging, prognosis, and treatment options for newly diagnosed and relapsed/refractory FL. Initial treatment options for FL include active surveillance, radiotherapy, rituximab monotherapy, and chemoimmunotherapy. Staging with positron emission tomography/ computed tomography and bone marrow biopsy is crucial for identifying early-stage patients. Most patients with FL will receive chemoimmunotherapy as the initial treatment with options including rituximab or obinutuzumab plus cyclophosphamide, vincristine, and prednisone; cyclophosphamide, doxorubicin, vincristine, and prednisone; bendamustine; or lenalidomide. No significant differences in overall survival have been observed in randomized studies comparing these regimens. Maintenance therapy with rituximab or obinutuzumab in responders to initial chemoimmunotherapy improves progression-free survival. For relapsed/refractory FL, treatment options include chemoimmunotherapy, lenalidomide-based regimens, tazemetostat, chimeric antigen receptor (CAR)-T cell therapy (axicabtagene ciloleucel and tisagenlecleucel), and CD3/ CD20 bispecific antibodies (BsAbs). Given the encouraging outcomes obtained with CAR-T cell therapy and BsAbs, multiple trials are testing these highly active agents in earlier lines of therapy and among high-risk patients with early relapse after frontline chemoimmunotherapy. Additional studies and follow-up are needed to understand how these novel agents may further change treatment algorithms for FL. [ABSTRACT FROM AUTHOR]

Simple Summary: In a comprehensive analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and the CLL13 trials, we assessed the impact of first-line treatments with targeted agents (TAs), or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT), on overall survival (OS) compared to age- and sex-matched individuals in the general population. TAs demonstrated a higher 5-year restricted mean survival time (RMST) (58.1 months; 95% CI: 57.4 to 58.8) compared to CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Moreover, the comparison with age- and gender-matched general populations (AGMGP) suggested that TAs may mitigate CLL's impact on OS during the first five years post-treatment initiation. In contrast, CLL patients treated with FCR exhibited sustained OS differences compared to both the Italian and US AGMGP cohorts. These results support TAs as the preferred first-line treatment for younger/fit CLL patients but imply the need for a careful interpretation due to variations in patient selection criteria and clinical profiles across trials. Longer follow-up is essential to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. To assess the impact of first-line treatment with targeted agents (TAs) or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT) on overall survival (OS) compared to age- and sex-matched individuals in the general population, we conducted an aggregated analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and CLL13 trials. The restricted mean survival time (RMST), an alternative measure in outcome analyses capturing OS changes over the entire history of the disease, was used to minimize biases associated with the short follow-up time of trials. Patients treated with TAs demonstrated a higher 5-year RMST (58.1 months; 95% CI: 57.4 to 58.8) compared to those treated with CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Furthermore, the OS comparison of treatment groups with the AGMGP suggests that TAs may mitigate the impact of CLL on OS during the first five years post-treatment initiation. In summary, the 5-year RMST difference was −0.4 months (95% CI: −0.8 to 0.2; p = 0.10) when comparing CLL patients treated with TAs to the Italian age- and gender-matched general population (AGMGP). A similar trend was observed when CLL patients treated with TAs were compared to the US AGMGP (5-year RMST difference, 0.3 months; 95% CI: −0.1 to 0.9; p = 0.12). In contrast, CLL patients treated with FCR exhibited sustained OS differences when compared to both the Italian cohort (5-year RMST difference: −1.6 months; 95% CI: −2.4 to −0.9; p < 0.0001) and the US AGMGP cohort (5-year RMST difference: −0.9 months; 95% CI: −1.7 to −0.2; p = 0.015). Although these results support TAs as the preferred first-line treatment for younger CLL patients, it is crucial to acknowledge that variations in patient selection criteria and clinical profiles across clinical trials necessitate a cautious interpretation of these findings that should be viewed as directional and hypothesis-generating. A longer follow-up is needed to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. [ABSTRACT FROM AUTHOR]

Aim: Autoimmune nodopathies have specific clinicopathologic features, antibodies directed against nodal proteins (neurofascin 186) or paranodal proteins (neurofascin 155, contactin 1, contactin‐associated protein 1 (Caspr1)), and usually have a poor response to first‐line therapies for chronic inflammatory demyelinating polyradiculoneuropathy. Anti‐Caspr1 nodopathy treated with autologous hematopoietic stem cell transplantation (AHSCT) has not been previously reported. Methods: We report the first case of an anti‐Caspr1 antibody‐positive nodopathy refractory to high‐intensity immunosuppressive treatment, including rituximab, that responded dramatically to AHSCT. Results: A 53‐year‐old woman presented with a rapidly progressive generalized ataxic, painful motor, and inflammatory neuropathy supported by neurophysiologic and MRI studies. Initial tests for antibodies to nodal/paranodal proteins were negative. She was treated with multiple courses of intravenous immunoglobulin and methylprednisolone, plasma exchange, rituximab, and cyclophosphamide without significant clinical benefit. Repeated testing for antibodies to nodal/paranodal proteins yielded a positive result for anti‐Caspr1/IgG4 isotype antibodies. Given the poor response to multiple high intensity treatments and the relatively young age of the patient, we decided to perform AHSCT at 30 months post‐onset. Immediately after AHSCT, she stopped all immunomodulatory or immunosuppressive therapy. The Overall Neuropathy Limitation Score improved from 8/12 to 4/12 at 6 months post‐AHSCT. At 3 months post‐AHSCT, IgG4 against Caspr1 was negative and no reactivity against paranodes could be detected. Conclusion: We report a particularly severe anti‐Caspr1 antibody autoimmune nodopathy that responded dramatically to AHSCT. Although the rarity of the disease limits the possibility of larger studies, AHSCT may be a valuable therapy in treatment‐refractory cases. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the long-term impact of immunosuppressive therapeutic agents on antibody response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccination in patients with autoimmune rheumatic diseases (AIRD) in order to propose a strategy for annual vaccination. Methods This prospective multicentre cohort study evaluated the humoral response to second and third BNT162b2 and/or mRNA-1273 vaccines in 382 Japanese AIRD patients classified into 12 different medication groups and in 326 healthy controls (HCs). The third vaccination was administered six months after the second vaccination. Antibody titres were measured using the Elecsys Anti-SARS-CoV-2 S assay. Results The seroconversion rate and antibody titres were lower in AIRD patients than in HCs 3–6 weeks after the second vaccination and 3–6 weeks after the third vaccination. Seroconversion rates were <90% after the third vaccination in patients receiving mycophenolate mofetil and rituximab. Antibody levels after the third vaccination were significantly lower in the groups prescribed TNF inhibitor with or without methotrexate, abatacept and rituximab or cyclophosphamide than those of HCs in a multivariate analysis adjusting for age, sex, and glucocorticoid dosage. The third vaccination induced an adequate humoral response in patients treated with sulfasalazine, bucillamine, methotrexate monotherapy, iguratimod, interleukin-6 inhibitors or calcineurin inhibitors including tacrolimus. Conclusions Repeated vaccinations in many immunosuppressed patients produced antibody responses similar to those observed in HCs. In contrast, annual vaccination in patients receiving TNF inhibitors, abatacept, mycophenolate mofetil and rituximab may require caution. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is characterized by deposition of immune complexes leading to thickening of glomerular basement membranes. Over time, the understanding of MN has evolved, with the identification of specific autoantibodies against novel podocyte antigens and the unraveling of intricate pathogenic pathways. Although the anti-CD20 monoclonal antibody rituximab is favored as part of the initial therapy in MN, a subgroup of MN patients may be resistant to rituximab necessitating the use of alternative agents such as cytotoxic therapies. In addition, newer agents such as novel anti-CD20 monoclonal antibodies, therapies targeting the CD38-positive plasma cells and anti-complement therapy are being studied in patients who are resistant to traditional treatment strategies. This manuscript furnishes a review of the novel developments in the pathophysiology of MN including the identification of target antigens and current treatment standards for MN, concentrating on evidenced-based interventions designed to attain remission and to prevent disease progression. [ABSTRACT FROM AUTHOR]

The standard treatment for canine lymphoma is the CHOP chemotherapy regimen. Proteasome inhibitors have been employed with CHOP for the treatment of human haematological malignancies but remain to be fully explored in canine lymphoma. We identified an association between poor response to CHOP chemotherapy and high mRNA expression levels of proteasomal subunits in a cohort of 15 canine lymphoma patients, and sought to determine the effect of proteasome inhibitors on the viability of a canine B‐cell lymphoma cell line (CLBL‐1). The aim of this study was to investigate whether proteasome inhibitors sensitize these cells to the CHOP agents doxorubicin, vincristine and cyclophosphamide (as 4‐hydroxycyclophosphamide/4‐HC). CLBL‐1 cells were sensitive to proteasome inhibition by bortezomib and ixazomib. The IC50 of bortezomib was 15.1 nM and of ixazomib was 59.14 nM. Proteasome inhibitors plus doxorubicin had a synergistic effect on CLBL‐1 viability; proteosome inhibitors plus vincristine showed different effects depending on the combination ratio, and there was an antagonistic effect with 4‐HC. These results may have clinical utility, as proteasome inhibition could potentially be used with a synergizing CHOP compound to improve responsiveness to chemotherapy for canine lymphoma patients. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. The discovery of phospholipase A2 receptor (PLA2R) as a target antigen has led to a paradigm shift in the understanding and management of MN. At present, serum PLA2R antibodies are used for diagnosis, prognostication, and guiding treatment. Now, with the discovery of more than 20 novel target antigens, antigen mapping is almost complete. The clinical association of certain antigens provides clues for clinicians, such as the association of nerve epidermal growth factor-like 1 with malignancies and indigenous medicines. Serum antibodies are detected for most target antigens, except exostosin 1 and 2 and transforming growth factor-beta receptor 3, but their clinical utility is yet to be defined. Genome-wide association studies and studies investigating environmental factors, such as air pollution, shed more light on the underpinnings of MN. The standard therapy of MN diversified from cyclical cyclophosphamide and steroids to include rituximab and calcineurin inhibitors over the past decades. Here, we provide a cutting-edge review of MN, focusing on genetics, immune system and environmental factors, novel target antigens and their clinical characteristics, and currently available and emerging novel therapies in MN. [ABSTRACT FROM AUTHOR]

In the era of target therapy, we face the challenge of the risk of opportunistic infection in patients with B-cell lymphoma who receiving rituximab-based chemotherapy. Opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) and Cytomegalovirus (CMV) pneumonia are life-threatening diseases. However, PJP with CMV coinfection is rare. Here, we report a follicular lymphoma patient who suffered from PJP with CMV coinfection after receiving three cycles of rituximab, cyclophosphamide, vincristine, and prednisone regimen and was successfully rescured after timely identification and treatment. We emphasize that physicians should be alert for the coinfection of PJP and CMV in lymphoma patients receiving rituximab-based chemotherapy and the timely recognition, and treatment that may avoid a deadly outcome. [ABSTRACT FROM AUTHOR]

Les pneumopathies interstitielles diffuses sont fréquentes au cours de la sclérodermie systémique et sont associées à une morbi-mortalité importante. Dans cette revue, nous proposons de synthétiser les principaux facteurs de risque de survenue de l'atteinte interstitielle pulmonaire, ses modes de présentations cliniques, et radiologiques, et ses modalités évolutives, hétérogènes au cours de la sclérodermie. Nous synthétisons les principales données de la littérature concernant les thérapeutiques actuellement proposées, immunosuppressives/immunomodulatrices et anti-fibrosantes. Enfin, les perspectives thérapeutiques pour l'avenir sont présentées. Interstitial lung diseases are common during the course of systemic sclerosis and associated with significant morbidity and mortality. In this review, we propose to synthetize the risk factors for interstitial lung involvement development, its principal clinical and radiological features, and the evolutionary trajectories, which are highly heterogeneous. We synthesize the main data regarding the currently proposed therapies, immunosuppressive/immunomodulatory and anti-fibrotic. Finally, the therapeutic perspectives for the future are presented. [ABSTRACT FROM AUTHOR]

Objective To identify characteristics of granulomatosis with polyangiitis (GPA) associated with induction failure, describe salvage therapies and their efficacy. Methods We conducted a nationwide retrospective case-control study of GPA with induction failure between 2006 and 2021. Each patient with induction failure was randomly paired to three controls matched for age, sex and induction treatment. Results We included 51 patients with GPA and induction failure (29 men and 22 women). At induction therapy, median age was 49 years. Twenty-seven patients received intravenous cyclophosphamide (ivCYC) and 24 rituximab (RTX) as induction therapy. Patients with ivCYC induction failure more frequently had PR3-ANCA (93% vs 70%, P  = 0.02), relapsing disease (41% vs 7%, P  < 0.001) and orbital mass (15% vs 0%, P  < 0.01) compared with controls. Patients with disease progression despite RTX induction therapy more frequently had renal involvement (67% vs 25%, P  = 0.02) with renal failure (serum creatinine >100 µmol/l in 42% vs 8%, P  = 0.02) compared with controls. After salvage therapy, remission was achieved at 6 months in 35 (69%) patients. The most frequent salvage therapy was switching from ivCYC to RTX (or vice versa), showing an efficacy in 21/29 (72%). Remission was achieved in nine (50%) patients with inappropriate response to ivCYC, while in patients with progression after RTX induction, remission was achieved in four (100%) who received ivCYC (with or without immunomodulatory therapy), but only in three (50%) after adding immunomodulatory therapy alone. Conclusion In patients with induction failure, characteristics of GPA, salvage therapies and their efficacy vary according to induction therapy and failure modality. [ABSTRACT FROM AUTHOR]

Objective: B‐cell depletion using the anti‐CD20 monoclonal antibody rituximab is a cornerstone in the therapeutic concept of multiple autoimmune diseases. B‐cell depletion is associated with a higher risk for severe infections, and the time span of B‐cell repopulation differs greatly between individuals. Data on factors influencing B‐cell repopulation kinetics are limited. This study aims to identify patient‐specific and therapy‐associated covariates that modulate B‐cell repopulation. Methods: This single‐center retrospective observational study presents data of 839 subjects receiving 2,017 courses of rituximab for autoimmune diseases. Assessed covariates are patient‐specific factors (sex, age, kidney function, and underlying disease) and co‐immunosuppression with common agents (azathioprine, cyclosporine A, cyclophosphamide, hydroxychloroquine, methotrexate, mycophenolate mofetil, tacrolimus, and corticosteroids). The primary end point is the time to B‐cell repopulation (≥5/μl). The secondary end point is the time to B‐cell reconstitution (≥50/μl). Multivariate time‐to‐event analysis and logistic regression models were applied to estimate the influence of covariates. Results: Age over 60 years (hazard ratio [HR] 0.71 for repopulation, P = 0.008), impaired kidney function (HR 0.72, P = 0.001), antineutrophil cytoplasmic antibody‐associated vasculitis (HR 0.61, P < 0.001), solid organ transplantation (HR 0.4, P < 0.001), and co‐immunosuppression with corticosteroids (HR 0.64, P < 0.001) or azathioprine (HR 0.49, P < 0.001) were associated with impaired B‐cell repopulation and reconstitution. Effects of corticosteroids (P = 0.043) and azathioprine (P = 0.025) were dose dependent. Conclusion: Prolonged rituximab dosing intervals may be effective to achieve B‐cell depletion and reduce risk of infection in advanced age or patients with impaired kidney function. Co‐medication with corticosteroids or azathioprine prolongs B‐cell recovery, which may increase therapeutic effects but also the rate of adverse events. [ABSTRACT FROM AUTHOR]

The article focuses on the successful chemotherapy treatment of an elderly patient with double-hit lymphoma, severe renal impairment, and poor performance status. Topics include the challenges of treating double-hit lymphoma, the effectiveness of chemotherapy despite renal dysfunction, and the importance of considering individual patient factors in treatment decisions for elderly patients with malignant lymphoma.

Background. Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE) and often occurs within the first five years after diagnosis. Case report. A 33-year-old woman with SLE (arthritis; cutaneous involvement; Raynaud phenomena, vasculitis, pleural effusion, hematological and immunological abnormalities), under treatment with glucocorticoids and hydroxychloroquine developed focal proliferative LN, which progressed under treatment with belimumab. Consequently, intravenous cyclophosphamide and low-dose rituximab were used to induce LN remission, while maintenance therapy relied on mycophenolate mofetil. Conclusions. The case illustrates an uncommon succession of therapies for SLE and LN, with belimumab preceding cyclophosphamide. The decision to induce remission with cyclophosphamide was based on histological aspects of the renal biopsy. Although current recommendations permit the association of belimumab and cyclophosphamide, there is very little practical experience to support it. [ABSTRACT FROM AUTHOR]

Anaplastic large cell lymphoma (ALCLs) are a group CD30-positive mature T-cell lymphomas, an uncommon subtype of non-Hodgkin lymphomas, characterized by diverse clinical and genetic features. Among the types of ALCL, anaplastic lymphoma kinase (ALK)-negative ALCL, though typically involves the lymph nodes, can infrequently invade other tissues. When soft tissue involvement occurs, it may mimic the clinical presentation of infectious diseases, leading to potential misdiagnosis. Therefore, a histological examination is necessary to differentiate between ALK-negative ALCL and similar phenotypes associated with infectious conditions. This paper reports a case of ALCL, initially misdiagnosed as an infection. [ABSTRACT FROM AUTHOR]

Objective: Treatment regimens combining glucocorticoids with cyclophosphamide or rituximab or both are used to induce remission in ANCA-associated glomerulonephritis (ANCA-GN). There is a paucity of data on the efficacy and safety of these regimens in elderly patients with ANCA-GN. This study aimed to examine outcomes and adverse events in elderly AAV patients with three induction regimens: cyclophosphamide (CYC), cyclophosphamide and rituximab (CYC + RTX), and rituximab (RTX). Methods: This single-center retrospective cohort study included patients 60 years and older diagnosed with ANCA-GN. Baseline characteristics and outcomes across several clinical parameters were recorded and compared for significance using Kruskal–Wallis test, Chi-squared test, Fisher exact test, univariate, and multivariate logistic regression as appropriate. Cox proportional hazard regression model was used for survival analysis. Results: Seventy-five patients were included. The mean (SD) age at diagnosis was 70 (± 6) years. The mean (SD) follow-up duration was 5.17 (± 3.47) years. Remission induction therapy with glucocorticoids plus CYC was used in 25 patients, glucocorticoids plus CYC and RTX in 12 patients, and glucocorticoids plus RTX in 38 patients. RTX-treated patients had a higher baseline estimated glomerular filtration ratio (eGFR) (p = 0.00009). High remission rates were achieved in all groups (100% vs. 100% vs. 94.6% respectively, p = 0.368). The incidence of end-stage renal disease (ESRD) at one year was 8% among all groups (p = 0.999). There was no difference in the number of infections requiring hospitalization (p = 0.822), but a statistical difference in leukopenia was noted (32% vs. 25% vs. 3% respectively, p = 0.005). The use of RTX only was associated with reduced leukopenia (aOR = 0.1, 95% CI = 0.005–0.8) after adjusting for other variables. Conclusions: CYC, CYC + RTX, and RTX are equally effective for remission induction in elderly patients with ANCA-GN. Induction therapy with RTX only was associated with a lower risk of leukopenia compared to CYC-containing regimens. Infections requiring hospitalization were similar among all groups. End-stage kidney disease at one year was comparable among the 3 groups. Key Points • Cyclophosphamide, Rituximab, and Cyclophosphamide+Rituximab are equally effective in remission induction in elderly patients with ANCA glomerulonephritis. • The use of Rituximab only was associated with a lower risk of bone marrow suppression compared to Cyclophosphamide only. • More information is needed on the comparative safety of induction therapy strategies in elderly ANCA glomerulonephritis patients. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to analyze a group of patients with severe and refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) managed with rituximab and to report on treatment outcomes. Patients and methods: A total of 78 patients (41 females, 37 males; mean age: 50.1±13.4 years; range, 18 to 76 years) with AAV on rituximab treatment were included in the single-center, retrospective study conducted between 2009 and 2018. The diagnosis was established based on the 1990 classification criteria of the American College of Rheumatology and the definitions of vasculitis of Chapel Hill Consensus Conference. Laboratory and immunological tests were conducted. Disease activity was determined through the Birmingham Vasculitis Activity Score. Results: Rituximab was preferred over cyclophosphamide in 37 patients and used as a second-line therapy after cyclophosphamide in 41 cases. Rituximab treatment showed favorable outcomes with regard to serum creatinine levels, proteinuria, and hematuria, as well as in cases of isolated lung involvement. Nearly half of patients with pulmonary renal syndrome also improved, with 22.2% achieving remission. ANCAs were positive in 85.9% of patients at the onset of rituximab treatment and became negative in 82% of the positive cases. Adverse events were rare and included infusion reactions (one case of reactivation of a herpes zoster infection and one case of allergic reaction). Conclusion: Rituximab is an efficient and safe therapeutic option in patients with AAV who are difficult to treat, have insufficient response, or have not tolerated other treatments. [ABSTRACT FROM AUTHOR]

Primary membranous nephropathy (MN) is the most frequent cause of nephrotic syndrome in adults, due to a variety of autoantibodies, most frequently against phospholipase A2 receptor (PLA2R). In severe cases or when spontaneous remission is not achieved, immunosuppression is required. Cyclical therapy, based on glucocorticoids and cyclophosphamide on alternate months for 6 months, has proven effective to induce remission and reduce the risk of end-stage renal disease. Since the early 2000s, rituximab (RTX) has emerged as a key player in the management of MN, showing overall comparable effectiveness and likely better safety compared with the cyclical regimen, despite the lack of adequately powered trials comparing the two approaches head to head. For these reasons, RTX is now considered the agent of choice for most patients with MN. However, there are still uncertainties. Around 20–40% of patients are resistant to RTX, especially in the setting of high anti-PLA2R levels, and this drug remains relatively unexplored in patients with the most severe disease. In these scenarios, although the expanding therapeutic armamentarium is probably going to provide further options, the cyclical regimen still plays a key role as a safety net. The aim of this article is to illustrate the role of cyclical therapy in the RTX era. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is a common cause of nephrotic syndrome (NS) in adults and if untreated can progress to endstage kidney disease. Factors considered to place a patient at high or very high risk for progression include elevated serum creatinine at baseline, declining kidney function, persistent heavy proteinuria (>8 g/24 h), or persistent NS, presence of life-threatening complications related to NS (such as venous thromboembolic events), or very high anti-PLA2R antibody titers (>150 RU/ml). Patients who are at high or very high risk of progression should be treated with immunosuppression therapy to induce remission of proteinuria and to avoid progressive loss of kidney function. Traditional forms of immunosuppression for patients with MN have included the use of cyclic courses of corticosteroids with cyclophosphamide or calcineurin inhibitors. These forms of therapy are associated with significant toxicity, e.g. corticosteroids (infections, diabetes, weight gain), cyclophosphamide (infertility, severe leukopenia, malignancy), and calcineurin inhibitors (hypertension, nephrotoxicity). The introduction of anti-CD20+ B-cell therapies in the late 1990s has changed the landscape. In this article we will argue that anti-CD20+ B therapy should be the treatment of choice for patients at high/very high risk of progression when considering its efficacy and side-effect profile. [ABSTRACT FROM AUTHOR]

Objective: To compare rituximab‐ versus cyclophosphamide‐based remission induction strategies for the long‐term risks of kidney failure and death in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) in a real‐world cohort. Methods: We performed a cohort study using the Mass General Brigham AAV Cohort, which includes proteinase 3–ANCA+ and myeloperoxidase (MPO)‐ANCA+ AAV patients diagnosed from January 1, 2002 to December 31, 2019. We included cases in which the initial remission induction strategy was based either on rituximab or cyclophosphamide. The primary outcome was the composite outcome of kidney failure or death. We used multivariable Cox proportional hazards models and propensity score–matched analyses to assess the association of rituximab‐ versus cyclophosphamide‐based treatment strategies with the composite outcome of kidney failure or death. Results: Of 595 included patients, 352 patients (~60%) received rituximab‐based and 243 patients (~40%) received cyclophosphamide‐based regimens. The mean age was 61 years, 58% of patients were female, 70% of patients were MPO‐ANCA+, and 69% of patients had renal involvement (median estimated glomerular filtration rate 37.3 ml/minute/1.73 m2). There were 133 events at 5 years, and the incidence rates in rituximab‐ and cyclophosphamide‐based regimens were 6.8 and 6.1 per 100 person‐years, respectively. The risk of kidney failure or death was similar in both groups in multivariable‐adjusted analyses (hazard ratio [HR] 1.03 [95% confidence interval (95% CI) 0.55–1.93]) and in propensity score–matched analyses (HR 1.05 [95% CI 0.55–1.99]) at 5 years. Our findings were similar when outcomes were assessed at 1 and 2 years as well as in subgroups stratified according to renal involvement and severity as well as major organ involvement. Conclusion: Rituximab‐ and cyclophosphamide‐based remission induction strategies for AAV are associated with similar risks of kidney failure and death. [ABSTRACT FROM AUTHOR]

Background: Targeting influential factors in resistance to chemotherapy is one way to increase the effectiveness of chemotherapeutics. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway overexpresses in chronic lymphocytic leukemia (CLL) cells and appears to have a significant part in their survival and chemotherapy resistance. Here we produced novel nanoparticles (NPs) specific for CD20-expressing CLL cells with simultaneous anti-Nrf2 and cytotoxic properties. Methods: Chitosan lactate (CL) was used to produce the primary NPs which were then respectively loaded with rituximab (RTX), anti-Nrf2 Small interfering RNA (siRNAs) and Cyclophosphamide (CP) to prepare the final version of the NPs (NP-Nrf2_siRNA-CP). All interventions were done on both peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMNCs). Results: NP-Nrf2_siRNA-CP had satisfying physicochemical properties, showed controlled anti-Nrf2 siRNA/CP release, and were efficiently transfected into CLL primary cells (both PBMCs and BMNCs). NP-Nrf2_siRNA-CP were significantly capable of cell apoptosis induction and proliferation prevention marked by respectively decreased and increased anti-apoptotic and pro-apoptotic factors. Furthermore, use of anti-Nrf2 siRNA was corresponding to elevated sensitivity of CLL cells to CP. Conclusion: Our findings imply that the combination therapy of malignant CLL cells with RTX, CP and anti-Nrf2 siRNA is a novel and efficient therapeutic strategy that was capable of destroying malignant cells. Furthermore, the use of NPs as a multiple drug delivery method showed fulfilling properties; however, the need for further future studies is undeniable. BBVrWc4UysbSA-bTREcqrz Video Abstract [ABSTRACT FROM AUTHOR]

Objectives Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab. Methods This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months. Results The study included 227 patients. IgG levels at 6 months were lower than baseline (P  < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P  = 0.004). Age [β (95% CI): −0.23 (−0.38, −0.08) per 10 years, P  = 0.003], oral glucocorticoid dose at induction [β (95% CI): −0.37 (−0.51, −0.24) per sqrt-transformed mg prednisone, P  < 0.001] and concomitant use of intravenous glucocorticoid pulses [β (95% CI): −0.88 (−1.73, −0.02), P  = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P  = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P  < 0.001]. Conclusions In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses. [ABSTRACT FROM AUTHOR]

Background Focal segmental glomerular sclerosis (FSGS) is a histologic lesion rather than a specific disease entity and represents a cluster of different conditions affecting both children and adults that includes primary, secondary and genetically mediated forms. These forms can be distinguished by electron microscopy and genetic assessment and show different responsiveness to steroids and immunosuppressants. Despite some promising effects of rituximab in nephrotic syndrome in children, the results in adults with FSGS are disappointing. Our group previously explored the effectiveness of rituximab in eight adult patients with unselected forms of FSGS and achieved a consistent reduction in proteinuria in one case. Following this experience, we developed an alternative therapeutic option intended to enhance the potential of rituximab with the support of other synergic drugs. We herein report the results of this therapeutic protocol (six administrations of rituximab plus two of intravenous cyclophosphamide plus glucocorticoids) in seven prospectively enrolled patients with extensive podocyte effacement and recurrent relapses or steroid dependence. Results Patients had a median baseline serum creatinine level of 2.2 mg/dl (range 1–4.7) that decreased to 1.1 mg/dl (range 0.9–2.2) and 1.1 mg/dl (range 0.75–2.21) after 3 and 6 months, respectively, and remained unchanged at 12 months. Three of five patients with renal failure turned to normal function while the other two patients maintained a stable impairment after 18 and 52 months. The median proteinuria decreased from 6.1 g/24 h to 3.5, 3.5 and 1.9 g/24 h at 3, 6 and 12 months, respectively. Specifically, five of seven patients had a partial response at 12 months and became non-nephrotic. One of them had a complete response at 18 months and was still in complete remission at the last follow-up visit at 36 months. Proteinuria persisted unchanged in two of seven patients with a genetic-related disease. No serious late adverse events were observed. Conclusions Our results show that intensive B-cell depletion therapy is able to reverse the nephrotic syndrome of steroid-dependent or frequently relapsing adult patients with putatively idiopathic FSGS (i.e. with extensive podocyte effacement). [ABSTRACT FROM AUTHOR]

Simple Summary: The present systematic review and meta-analysis aimed to clarify the role of consolidative RT among patients with advanced-stage DLBCL who achieved complete remission after rituximab-based immunochemotherapy (R-CHOP). Six retrospective studies involving 319 individuals who underwent R-CHOP consolidative RT and 494 individuals who did not undergo consolidative RT were included. Consolidative RT was associated with superior overall survival (HR: 2.01; 95% CI: 1.30–3.12; p = 0.002) and disease-free survival (HR: 2.18; 95% CI: 1.47–3.24; p < 0.0001). These results showed that consolidative RT is superior to no RT in terms of both overall survival and disease-free survival for patients with advanced-stage DLBCL. Further investigation is warranted to determine the optimal radiation fields and the appropriate indications for consolidative RT in patients with advanced-stage DLBCL in the rituximab era. Patients with diffuse large B-cell lymphoma (DLBCL) are treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The role of consolidative radiation therapy (RT) remains unclear among patients with advanced DLBCL who achieved complete remission (CR) after R-CHOP immunochemotherapy. The current systematic review and meta-analysis aimed to clarify the role of consolidative RT among these patients. The MEDLINE, Embase, and Cochrane Library databases were searched for studies comparing RT to no RT following CR after R-CHOP immunochemotherapy in Ann Arbor stage III–IV DLBCL patients. Overall survival (OS) was the primary endpoint, and disease-free survival (DFS) was the secondary endpoint. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the primary and secondary outcomes. Review Manager (version 5.4) was used to analyze the data. Six retrospective studies involving 813 patients who received R-CHOP ± consolidative RT were identified. OS was higher in the consolidative RT group, with an HR of 2.01 and a 95% CI of 1.30 to 3.12 (p = 0.002). DFS was also higher in the RT group, with an HR of 2.18 and a 95% CI of 1.47 to 3.24 (p < 0.0001). The results suggested that consolidative RT improved OS and DFS compared to no RT among advanced-stage DLBCL patients. Further research is needed to determine the optimal radiation fields and the appropriate indications for consolidative RT for advanced-stage DLBCL patients in the rituximab era. [ABSTRACT FROM AUTHOR]

Cutaneous extranodal non-Hodgkin lymphoma is a rare cancer and chemotherapeutic agents like etoposide, vincristine and cyclophosphamide are the drug of choice, which rarely cause hyperpigmentation in skin and nails. However, herein we present a case of hyperpigmentation that was seen in tongue and even in teeth. The hyperpigmentation of the tongue and teeth occurred shortly after the initiation of chemotherapy. Hyperpigmentation was self-limiting and rectified in a week without need of any pharmacological, surgical, or lifestyle interventions. [ABSTRACT FROM AUTHOR]

Objective: Diffuse alveolar haemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). We describe the clinical characteristics, treatment and survival outcomes of SLE patients with DAH in Singapore. Methods: We conducted a retrospective review of the medical records of SLE patients with DAH hospitalised in 3 tertiary hospitals between January 2007 and October 2017. Patient demographics, clinical characteristics, laboratory, radiologic and bronchoscopic findings, as well as the treatments, were compared between survivors and non-survivors. Survival rates were analysed between the various treatment groups. Results: A total of 35 patients with DAH were included in this study. Majority of them were female (71.4%) and of Chinese ethnicity (62.9%). Median age was 40.0 years (IQR: 25–54), with a median disease duration of 8.9 months (IQR: 0.13–102.4). Haemoptysis was the most common clinical presentation, and majority had concomitant cytopaenia and lupus nephritis. All patients received high dose glucocorticoids; 27 (77.1%), 16 (45.7%) and 23 (65.7%) received cyclophosphamide (CYP), rituximab (RTX), and plasmapheresis (PLEX), respectively. Twenty-two patients required mechanical ventilation with a median duration of 12 days. Overall mortality rate was 40%, with a median survival time of 162 days. Twenty-six patients (74.3%) achieved remission, with an overall median time to remission of 12 days (IQR: 6–46) after diagnosis of DAH. Patients on triple therapy (CYP, RTX and PLEX) had a median survival of 162 days as compared to 14 days in patients on PLEX alone (p =.0026). Conclusions: The overall mortality of DAH in SLE patients remained high. There were no significant differences in patient demographics or clinical characteristics between the survivors and non-survivors. However, better survival appears to be associated with treatment with cyclophosphamide. [ABSTRACT FROM AUTHOR]

Drug therapy for patients with systemic lupus erythematosus (SLE) aims to decrease symptom severity. Pharmacologic interventions are divided into four categories: antimalarials, glucocorticoids (GCs), immunosuppressants (ISs), and biological agents. Hydroxychloroquine, the most commonly used antimalarial treatment for this disease, is a mainstay in treating all patients with SLE. The multitude of adverse reactions of GCs has led clinicians to minimize their dosages or discontinue them whenever possible. To speed up the discontinuation or minimization of GCs, ISs are used for their steroid-sparing properties. Furthermore, certain ISs such as cyclophosphamide are recommended as maintenance agents to prevent flares and reduce the reoccurrence and severity of the disease state. Biological agents are recommended when other treatment options have failed due to intolerance or inefficacy. This article presents pharmacologic approaches for managing SLE in patients based on clinical practice guidelines and data from randomized controlled trials. Drug therapy for patients with systemic lupus erythematosus (SLE) aims to decrease symptom severity. Pharmacologic interventions are divided into four categories: antimalarials, glucocorticoids, immunosuppressants, and biological agents. Hydroxychloroquine, an antimalarial, is a mainstay in SLE treatment. Glucocorticoids should be tapered or discontinued whenever possible due to their multitude of adverse reactions. Immunosuppressants are often used for their steroid-sparing properties and as maintenance agents to prevent flares and reduce disease severity. Biological agents may be used for refractory disease. This article presents pharmacologic approaches for managing SLE in patients based on clinical practice guidelines and data from randomized controlled trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-Hodgkin lymphoma (NHL) is one of the most frequent HIV-related neoplasms, and diffuse large B-cell lymphoma (DLBCL) is the most common subtype. In people with HIV (PWH), DLBCL classically presents with aggressive characteristics. As in the general population, HIV-related DLBCL is a heterogeneous disease that includes morphological and molecular subtypes. When combined antiretroviral therapy (cART) became widely available, a strong improvement of the immune function and a better management of infectious complications during lymphoma treatment were observed in PWH with lymphoma. Moreover, the concomitant treatment of cART with chemotherapy was shown to be beneficial. These changes have led to a marked improvement in prognosis for PWH with DLBCL, approaching that of the general population. Despite the widespread use of combined antiretroviral therapy (cART) and the subsequent decrease in AIDS-defining cancers, HIV-related lymphomas remain a leading cause of morbidity and mortality in people with HIV (PWH). Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) subtype in PWH. This lymphoma is a heterogeneous disease including morphological variants and molecular subtypes according to the cell of origin or the mutation profile. In the pre-cART era, treatment with standard-dose chemotherapy induced high rates of toxicity and outcomes were very poor. The introduction of cART and the incorporation of infection prophylaxis allowed the use of conventional intensive chemotherapy regimens used in the general population, such as R-CHOP or R-EPOCH. The use of cART during chemotherapy treatment was initially controversial due to the potential risk of adverse drug–drug interactions. However, the availability of current cART regimens with less potential to cause drug interactions and evidence that cART improves survival rates in NHL strongly support the use of cART in PWH with DLBCL. Consequently, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the optimal treatment of PWH with NHL. [ABSTRACT FROM AUTHOR]

Background: Lupus nephritis (LN) is a frequent manifestation of childhood-onset systemic lupus erythematosus (cSLE) with a potential risk for kidney failure and poor outcomes. This study aimed to evaluate stages III, IV, and V of chronic kidney disease (CKD) and investigate risk factors for CKD in cSLE patients. Methods: We performed a nationwide observational cohort study in 27 pediatric rheumatology centers, including medical charts of 1528 cSLE patients. Data were collected at cSLE diagnosis, during follow-up, and at last visit or death, between September 2016 and May 2019. Results: Of 1077 patients with LN, 59 (5.4%) presented with CKD, 36/59 (61%) needed dialysis, and 7/59 (11.8%) were submitted for kidney transplantation. After Bonferroni's correction for multiple comparisons (p < 0.0013), determinants associated with CKD were higher age at last visit, urinary biomarker abnormalities, neuropsychiatric involvement, higher scores of disease activity at last visit and damage index, and more frequent use of methylprednisolone, cyclosporine, cyclophosphamide, and rituximab. In the regression model analysis, arterial hypertension (HR = 15.42, 95% CI = 6.12–38.83, p ≤ 0.001) and biopsy-proven proliferative nephritis (HR = 2.83, 95%CI = 1.70–4.72, p ≤ 0.001) increased the risk of CKD, while children using antimalarials had 71.0% lower CKD risk ((1.00–0.29) × 100%) than children not using them. The Kaplan–Meier comparison showed lower survival in cSLE patients with biopsy-proven proliferative nephritis (p = 0.02) and CKD (p ≤ 0.001). Conclusions: A small number of patients manifested CKD; however, frequencies of dialysis and kidney transplantation were relevant. This study reveals that patients with cSLE with hypertension, proliferative nephritis, and absence of use of antimalarials exhibited higher hazard rates of progression to CKD. [ABSTRACT FROM AUTHOR]

Simple Summary: The standard treatment of patients affected by diffuse large B-cell lymphomas (DLBCLs) is represented by a chemoimmunotherapeutic regimen (R-CHOP) that is successful in about 60% of patients. Currently, we cannot know in advance if their disease will respond to R-CHOP. This study aimed at identifying predictive genetic biomarkers for R-CHOP response through the analysis of a very high number of host genetic polymorphisms. Of the 216 enrolled chemonaïve patients candidate to R-CHOP, 185 were eligible. Highly statistically significant associations were found between progression-free survival and six polymorphisms (i.e., rs116665727, rs1607795, rs75614943, rs77241831, rs117500207, rs78466241), and between the overall survival (OS) and five polymorphisms (i.e., rs74832512, rs117500207, rs35789195, rs11721010, rs12356569). Overall, wild-type patients (i.e., without these polymorphisms) showed prolonged survival compared with polymorphic patients. In the future, these polymorphisms, alone or in combination, after a proper validation in a further number of patients, could contribute to improving the prediction of R-CHOP response. R-CHOP standard chemotherapy is successful in about 60% of diffuse large B-cell lymphoma (DLBCL) patients. Unresponsive patients have a poor prognosis, and predictive biomarkers of response to R-CHOP are lacking. We conducted the first prospective GWAS study aimed at exploring constitutional biomarkers predictive of R-CHOP efficacy and toxicity. Overall, 216 any-stage chemonaïve DLBCL patients candidate to R-CHOP were enrolled. The median age of the 185 eligible patients was 59.2 years, 49.7% were women and 45.4% were stage I–II patients. According to the Revised International Prognostic Index (R-IPI), 14.1%, 56.8% and 29.2% were in the very good, good and poor prognosis groups, respectively. Of the patients, 85.9% produced a complete response. Highly significant associations (i.e., p < 5 × 10−8) were found between progression-free survival (PFS) and six SNPs (i.e., rs116665727, rs1607795, rs75614943, rs77241831, rs117500207, rs78466241). Additionally, five SNPs (i.e., rs74832512, rs117500207, rs35789195, rs11721010, rs12356569) were highly associated with overall survival (OS). Wild-type patients showed a prolonged PFS or OS compared with patients carrying deleterious alleles (p < 0.001). No association with the adequate significant threshold was observed between SNPs and the objective response or toxicity. In the future, these SNPs, alone or in combination, after a proper validation in an independent cohort, could contribute to improving the prediction of R-CHOP response. [ABSTRACT FROM AUTHOR]

The article discusses review of three trials describing the use of combination therapy with rituximab (RTX) and belimumab in lupus nephritis (LN) and non-renal lupus. Topics covered include the differences in the design of the trials, the characteristics of their study population, and the endpoints and outcomes of the three trials.

OBJECTIVES: To explore symptom clusters (SCs) in lymphoma survivors before, during, and after chemotherapy. SAMPLE & SETTING: 61 lymphoma survivors from a medical center in central Taiwan were enrolled in the study. METHODS & VARIABLES: A prospective observational study design was adopted. The MD Anderson Symptom Inventory was used to measure symptoms. The 13 symptoms assessed by the MD Anderson Symptom Inventory were evaluated after diagnosis and before chemotherapy (T1), after the fourth cycle of chemotherapy (T2), and after completion of chemotherapy (T3). Data were analyzed using mean, frequency, and latent profile analysis. RESULTS: Three SCs were identified at T1, four at T2, and three at T3. Fatigue was the predominant symptom in each SC for the participants over time. Fatigue, disturbed sleep, and numbness constituted an SC at T2 and T3. An SC consisting of multiple psychological symptoms was found only at T1. IMPLICATIONS FOR NURSING: This study describes methods for grouping SCs. An SC of fatigue, disturbed sleep, and numbness was identified at T2 and T3. By familiarizing themselves with this SC, clinicians can be attentive to patients’ concurrent symptoms and implement early prevention measures and timely symptom management. [ABSTRACT FROM AUTHOR]

When first introduced, rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, brought about an alternative therapeutic paradigm for primary membranous nephropathy (PMN). Rituximab was shown to be effective and safe in PMN patients with kidney dysfunction, with. patients receiving second-line rituximab therapy achieving remission as effectively as those patients who had not previously received immunotherapy. No safety issues were reported. The B cell-driven protocol seems to be as efficient as the 375 mg/m2 × 4 regimen or 1 g × 2 regimen in achieving B cell depletion and remission, but patients with high M-type phospholipase A2 receptor (PLA2R) antibody levels may benefit from a higher dose of rituximab. While rituximab added another therapeutic option to the treatment regimen, it does have limitations as 20 to 40% of patients do not respond. Not all patients respond to RTX therapy for lymphoproliferative disorders either, therefore further novel anti-CD20 monoclonal antibodies have been developed and these may provide alternative therapeutic options for PMN. Ofatumumab, a fully human monoclonal antibody, specifically recognizes an epitope encompassing both the small and large extracellular loops of the CD20 molecule, resulting in increased complement-dependent cytotoxic activity. Ocrelizumab binds an alternative but overlapping epitope region to rituximab and displays enhanced antibody-dependent cellular cytotoxic (ADCC) activities. Obinutuzumab is designed to have a modified elbow-hinge amino acid sequence, leading to increased direct cell death induction and ADCC activities. In PMN clinical studies, ocrelizumab and obinutuzumab showed promising results, while ofatumumab displayed mixed results. However, there is a lack of randomized controlled trials with large samples, especially direct head-to-head comparisons. Alternative molecular mechanisms have been suggested in this context to explore novel therapeutic strategies. B cell activator-targeted, plasma cell-targeted and complement-directed treatments may lead to novel therapy paradigms for PMN. Exploratory strategies for the use of drugs with different mechanisms, such as a combination of rituximab and cyclophosphamide and a steroid, a combination of rituximab and a calcineurin inhibitor, may provide more rapid and efficient remission, but the combination of standard immunosuppression with rituximab could increase infection risk. [ABSTRACT FROM AUTHOR]

Objectives Cardiac magnetic resonance imaging (CMRI) is increasingly used to evaluate cardiac involvement in SSc. We assessed changes, including inflammatory and/or fibrotic myocardial lesions detected by CMRI, following therapeutic interventions for SSc-associated symptomatic myocarditis. Methods In this retrospective study, myocarditis was diagnosed by CMRI (2018 revised Lake Louise criteria) in 14 diffuse and 4 limited SSc patients [16/18 women, age 56 years (s. d. 11), disease duration 8 years (s. d. 11), 17/18 with lung involvement] with cardiac symptoms and abnormal findings on echocardiography (4/18) and/or in 24-hour Holter monitoring (12/14). CMRI was repeated after 8 months (s. d. 3) following administration of cyclophosphamide (n  = 11, combined with corticosteroids in 3 and rituximab in 1), mycophenolate (n  = 1), tocilizumab (n  = 1), methotrexate/corticosteroids (n  = 2), corticosteroids (n  = 1) or autologous stem cell transplantation (n  = 2). Results Functional cardiac improvement was evident by increases in left [by 5.8% (s. d. 7.8), P  = 0.006] and right ventricular ejection fraction [by 4.5% (s. d. 11.4), P  = 0.085] in the second CMRI compared with the first. Notably, late gadolinium enhancement, currently considered to denote replacement fibrosis, decreased by 3.1% (s. d. 3.8; P  = 0.003), resolving in six patients. Markers of myocardial oedema, namely T2 ratio and T2 mapping, decreased by 0.27 (s. d. 0.40; P  = 0.013) and 6.0 (s. d. 7; P  = 0.025), respectively. Conversely, both T1 mapping, considered to reflect acute oedema and diffuse fibrosis, and extracellular volume fraction, reflecting diffuse fibrosis, remained unchanged. Conclusions CMRI may distinguish between reversible inflammatory/fibrotic and irreversible fibrotic lesions in SSc patients with active myocarditis, confirming the unique nature of primary cardiac involvement in SSc. Whether, and how, CMRI should be used to monitor treatment effects in SSc-associated myocarditis warrants further study. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the comparative efficacy of triple combination therapies of cyclophosphamide/dexamethasone containing either bortezomib or rituximab in treatment-naïve patients diagnosed with lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia, LPL/WM). Methods: Symptomatic, untreated patients with LPL/WM diagnosed in the First Affiliated Hospital of Soochow University were enrolled in this study and divided into two groups (BCD and RCD). Group BCD consisted of 16 patients administered bortezomib/cyclophosphamide/dexamethasone, while group RCD (15 patients) received rituximab/cyclophosphamide/dexamethasone. The efficacy of the two therapies and the Kaplan-Meier survival curve of the groups were evaluated. Results: With regard to overall response rate (ORR) and minimal response rate (MRR), there was no statistically significant difference between the 2 groups (100 vs 86.6 %, p = 0.226, and 81.25 vs 60.0 %, p = 0.252, respectively). The median time to minimal response (MR) in the BCD group was 1.3 months, which was shorter compared with that of RCD group (3.5 months, p = 0.026). Treatment-related toxicities (grade>2) were leukopenia, neutropenia, hypohepatia and pneumonia. With a median study follow-up of 27 months, disease in 18 patients (8 vs 10) progressed while 4 patients died (all in RCD group). The estimated median progression free survival (PFS) was 43 and 35 months in groups BCD and RCD, respectively, but the overall survival (OS) rate in 25 months significantly differed between the 2 groups (100 % vs 66.1 %，p = 0.033). Conclusion: The two regimens are active, produced responses and are safe as primary therapies for patients with LPL/WM. However, the response median time was much shorter in group BCD patients, and thus might have better survival benefits. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we assessed changes in bone mineral density at disease onset and at the end of therapy in follicular lymphoma patients treated with R-CHOP and R-Bendamustine regimens. Another aim was to assess whether low bone mineral density at the onset of the disease is an unfavorable prognostic index. We also evaluated changes in other radiomic parameters, such as the musculoskeletal index, visceral adipose tissue, and subcutaneous adipose tissue in patients treated with R-Bendamustine and R-CHOP, with the latter containing high doses of steroids, which we know are associated with negative bone balance, a loss of muscle mass, and metabolic and cardiovascular issues. This is particularly relevant in elderly patients, in whom these changes could have an important impact on outcomes and the quality of life. As R-CHOP and R-Bendamustine are two effective treatment regimens in follicular lymphoma, this study, together with other clinical-laboratory parameters, could help in the choice of therapy. In patients with follicular lymphoma (FL), therapeutic advances have led to improved survival, and within this framework, it is important to identify treatment strategies offering a better quality of life. Using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT), in patients treated with R-CHOP-like or R-Bendamustine regimens, we assessed changes in the bone mineral density (BMD), musculoskeletal index (SMI), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) at disease onset and at the end of therapy. We evaluated whether the high-steroid regimen could lead to more significant radiological changes than those induced by the steroid-free regimen and whether a low BMD at disease onset is an unfavorable prognostic index. Seventy-nine patients between 60 and 80 years old with a new diagnosis of FL were included in the study. Evaluation of Delta values (pre- and post-therapy mean values) in the two immunochemotherapy regimens showed differences in radiomic parameters within the two patient cohorts. The R-CHOP-like regimen was associated with a significant reduction in BMD, an increase in SAT and VAT, and a reduction in skeletal muscle density (SMD) and SMI. Moreover, patients with high FLIPI showed a BMD below the cut-off value. This study represents the first study demonstrating a prognostic correlation between FLIPI and low BMD. [ABSTRACT FROM AUTHOR]

Objectives To assess the feasibility of reduced cyclophosphamide dosing in the setting of mobilization chemotherapy prior to high dose chemotherapy and autologous stem cell transplantation in patients with SSc. The primary end point was the occurrence of 'poor mobilization' when using different cyclophosphamide dosing. The second end point was to analyse potential risk factors for difficult stem cell mobilization in this cohort of patients with SSc. Methods This single-centre study retrospectively reviewed 32 patients with SSc who underwent autologous stem cell transplantation. We analysed the occurrence of 'poor mobilization' (defined as CD34+ progenitor cell count <2 × 106/kg body weight, the use of increasing G-CSF dose, the use of plerixafor, or leukapheresis on >2 consecutive days) in different cyclophosphamide mobilization regimens: We herein compared low dose (2 × 1–1.5 g/m2) cyclophosphamide vs high dose (2 × 2 g/m2) for mobilization. Results Higher dosing of cyclophosphamide seems not to be beneficial regarding stem cell collection as there was no significant difference in stem cell yield between high dose and reduced dose cyclophosphamide (6.2 vs 5.2 × 106/kg bodyweight after CD34+ enrichment). Furthermore, higher doses of cyclophosphamide might be associated with more side effects; this difference was, however, not statistically significant. Lower bodyweight and BMI (P  < 0.001) as well as rituximab pre-therapy (P  < 0.05) and cardiac involvement (P  < 0.01) might negatively impact stem cell collection independently from the chosen regimen. Conclusion Our data demonstrate that a reduced cyclophosphamide mobilization regimen seems to be feasible. Risk factors for poor mobilization might be low bodyweight, prior rituximab therapy and cardiac involvement. [ABSTRACT FROM AUTHOR]

Objective: In chronic lymphocytic leukemia, growing evidence has accumulated about long‐term outcomes of first‐line treatments. Our objective was to perform indirect comparisons across first‐line treatments. Methods: We applied the Shiny method, an artificial intelligence technique that analyses Kaplan–Meier curves and reconstructs patient‐level data. Reconstructed patient data were then evaluated through standard survival statistics and indirect head‐to‐head comparisons. The endpoint was progression‐free survival (PFS). Results: Seven first‐line treatments were studied (1983 patients). Three treatments based on either ibrutinib or venetoclax (i.e., ibrutinib monotherapy, ibrutinib+ rituximab/obinutuzumab, and venetoclax+obinutuzumab) showed a very similar survival pattern. The PFS for these three treatments was significantly better than that of the remaining four treatments (fludarabine+cyclophosphamide+rituximab, chlorambucil+obinutuzumab, bendamustine+rituximab, and chlorambucil monotherapy). Regarding chlorambucil+ obinutuzumab, a significant between‐trial variability was found. Conclusions: Long‐term results are particularly favorable to ibrutinib (alone or in combination) and discourage further use of chlorambucil. As in other studies based on the Shiny method, the multi‐treatment Kaplan–Meier graph summarized the available evidence in comparative terms. The evidence generated this way contributes to define the place in therapy of individual agents. [ABSTRACT FROM AUTHOR]

To streamline drug development, the United States Food and Drug Administration (FDA) can consider the extrapolation of adult efficacy data to children when the disease and drug effects are sufficiently similar. This study explored whether the relationship between drug exposure and response for selected drugs in systemic lupus erythematosus (SLE) was sufficiently similar to support a consideration of the extrapolation of adult efficacy data to children of ≥5 years of age. An exposure–response analysis of drugs used to treat SLE was conducted using published exposure versus response and efficacy versus time data. Statistical analyses included noncompartmental analysis of a drug's area under the effect curve and direct Imax pharmacodynamic (PD) modeling. Six drugs were included: azathioprine, belimumab, cyclophosphamide, hydroxychloroquine, mycophenolate/mycophenolic acid, and rituximab. For belimumab, the net change in responders at week 52 (the primary end point) was nearly identical between 1 adult trial and the pediatric trial. For mycophenolate, PD modeling suggested no significant differences in exposure and SLE disease activity between adults and children. For azathioprine, cyclophosphamide, hydroxychloroquine, and rituximab the data were not sufficient to quantitatively characterize the exposure–response relationship, but the clinical or pharmacologic response between children and adults was similar overall. Adult SLE data should be leveraged to guide pediatric drug development programs and identify areas with residual uncertainty regarding the effectiveness or safety of a drug in children. The degree to which efficacy extrapolation can reduce clinical trial requirements in pediatric SLE should be individualized for each new drug product, depending in part on the mechanism of action of the drug and the similarity of disease manifestations in children and adults. [ABSTRACT FROM AUTHOR]

The objective of the study is to report the outcomes of COVID-19 in ANCA-associated vasculitis (AAV) patients. This was a registry-based observational study conducted at a tertiary care center in north India. AAV patients with at least one follow-up visit between March 2020 and September 2021 were included. Demographic features, clinical manifestations, disease activity, and treatment details of underlying AAV were noted in all patients. Details of COVID-19 infection including severity, treatment, and outcomes were noted. Predictors of COVID-19 severity were determined using univariate analysis. A total of 33 (18.3%) out of 180 AAV patients contracted COVID-19 infection. Moderate COVID-19 infection was seen in 33.3% and severe or critical infection was seen in 36.3% of patients. Seventeen patients (51.5%) required supplemental oxygen therapy. Nine patients had active disease at the time of COVID-19 infection and three of them died due to COVID-19 infection. The risk of COVID-19 infection and its severity did not differ between patients receiving different immunosuppressants including rituximab induction. Hypothyroidism (p = 0.046) and ocular (p = 0.038) involvement due to AAV predicted the development of moderate to severe/critical COVID-19. Three (9.1%) patients died from COVID-19 and the rate of AAV flare after COVID-19 was similar to that in non-COVID-19 patients (15.3/100 person-year vs. 15.6/100 person-year, p = 0.95). Majority of the patients with AAV had moderate to severe or critical COVID-19 infection. The rate of death due to COVID-19 in AAV is higher than in general population. Use of standard remission induction regimens did not lead to increased risk of COVID-19 infection in our AAV cohort. [ABSTRACT FROM AUTHOR]

Anti‐Neutrophil Cytoplasmic Antibody associated Vasculitides (AAV) comprise a rare group of disorders in which respiratory tract involvement is variable and often severe. The rarity and heterogeneity of AAV makes this a challenging condition to diagnose and manage. In this single‐centre case series of 44 patients with AAV‐associated respiratory disease, we provide an overview of disease manifestations, management aspects and treatment outcomes. Data from this case series highlight the real‐world diagnostic and therapeutic challenges of the AAV respiratory disease spectrum; including uncertainties in the management of fibrosing interstitial lung disease, tracheobronchial stenosis and diffuse alveolar haemorrhage. [ABSTRACT FROM AUTHOR]

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic autoimmune disorder classified under anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, predominantly affecting small- to medium-sized vessels, characterized by asthma, eosinophilia, and necrotizing granulomatous inflammation. Most patients with EGPA experience peripheral neuropathy, whereas intracerebral hemorrhage is rare as EGPA-related presentation in central nervous system involvement, causing severe morbidity and mortality. Here, we present a 45-year-old man with refractory EGPA who developed intracerebral hemorrhage as the first manifestation, followed by cardiac involvement. This patient with a history of bronchial asthma developed a right putaminal hemorrhage caused by EGPA. Although intravenous cyclophosphamide (IVCY) and mepolizumab (MPZ) induced remission, relapse was frequently observed. Subsequently, he developed cardiomyopathy despite administration of rituximab (RTX) substituted from IVCY and MPZ. Combined immunosuppressive therapy, including IVCY, MPZ, and RTX was required to inhibit vascular inflammation, leading to sustained remission. We review previously published literature while focusing on the clinical features of patients with intracerebral hemorrhage caused by EGPA and describe clinical characteristics for detecting EGPA in patients with intracerebral hemorrhage, emphasizing rapid evaluation and recognition of EGPA and adequate intervention in the early vasculitic phase of this disease. We also refer to the immunological aspects of this case. It is important to consider "multi-targeted therapy" through interleukin-5 suppression and B cell depletion in the management of refractory EGPA. [ABSTRACT FROM AUTHOR]

Primary angiitis of central nervous system (PACNS) is a rare idiopathic disorder affecting blood vessels of brain, spinal cord, and meninges, consequently leading to infarct and less frequently hemorrhage. CNS vasculitis can also occur as part of systemic vasculitis or secondary to autoimmune diseases or infections. The clinical manifestations of PACNS are non specific and no single laboratory investigation or neuroimaging finding can reliably diagnose this condition. Histopathological evidence of transmural inflammation of blood vessels of CNS is the gold standard, but is generally pursued subsequent to conventional angiogram (CA) because of its invasive nature. The differentials of PACNS are exhaustive and include systemic vasculitis, secondary vasculitis, non inflammatory intracranial vasculopathies, demyelination, and neoplasm. These alternative conditions can often be distinguished by history, examination, immunological testing, cerebrospinal fluid analysis, and neuroimaging. CA can detect vasculitic changes in the large to medium cerebral arteries but the specificity is low. Recent advancements in vessel wall imaging techniques have further enabled the distinction of various intracranial vasculopathies from CNS vasculitis. The disease has considerable morbidity and fatality unless timely treatment with immunosuppressive agents is initiated. Induction therapy with glucocorticoids and cyclophosphamide followed by azathioprine, mycophenolate mofetil, or methotrexate as maintenance therapy is the cornerstone of management. Biological agents such as rituximab and anti tumour necrosis factor alpha inhibitors (infliximab and etanercept) may be used in refractory cases. This review discusses the approach to the diagnosis, determinants of outcome, and management. [ABSTRACT FROM AUTHOR]

The authors comment on a study published within the issue which examined the role of B cells in the pathogenesis of systemic sclerosis (SSc). Topics covered include study findings supporting the notion that restoring B cell homeostasis in scleroderma with specific intervention could promote disease control, the clinical benefits of rituximab (RTX) identified by the study, and the clinical implications of study findings.

The article describes the case of a 21-year-old woman with flaring of malar rash and rash on the anterior chest wall after discontinuation of her drugs due to an inter-current infection. Topics discussed include findings on blood tests, a diagnosis of severe cutaneous and neuropsychiatric flare of systematic lupus erythematosus (SLE), and resolution of her skin lesions with appropriate therapy.