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Current Opinion in Pediatrics Apr 2022The aim is to review recent reports on childhood polyarteritis nodosa, including recent reports on treatment and outcome. Recently deficiency of adenosine deaminase-2... (Review)
Review
PURPOSE OF REVIEW
The aim is to review recent reports on childhood polyarteritis nodosa, including recent reports on treatment and outcome. Recently deficiency of adenosine deaminase-2 (ADA2), which may present as a polyarteritis nodosa-mimic, is becoming an important part of our practice. We also aim to highlight differences of childhood polyarteritis nodosa with deficiency of ADA2 as well as adult-onset disease.
RECENT FINDINGS
The few recent childhood series confirm the systemic nature of this vasculitis with predominantly medium-vessel involvement. American College of Rheumatology Vasculitis foundation has suggested recommendations for the management of this vasculitis. Unfortunately, we lack large patient numbers to provide us high evidence for the treatment of these patients. However, for induction mycophenolate mofetil or shorter courses of cyclophosphamide can be considered.Deficiency of ADA2 is now in the differential diagnosis of polyarteritis nodosa patients presenting with a family history and/or stroke with hematological and/or immunological abnormalities.
SUMMARY
We need collaborative work to define management and treatment strategies for childhood polyarteritis nodosa. Distinguishing deficiency of ADA2 is important because the treatment is different.
Topics: Adult; Agammaglobulinemia; Humans; Intercellular Signaling Peptides and Proteins; Polyarteritis Nodosa; Severe Combined Immunodeficiency; Vasculitis
PubMed: 35081554
DOI: 10.1097/MOP.0000000000001106 -
Clinical Reviews in Allergy & Immunology Aug 2022Interruptions or alterations in the B cell development pathway can lead to primary B cell immunodeficiency with resultant absence or diminished immunoglobulin... (Review)
Review
Interruptions or alterations in the B cell development pathway can lead to primary B cell immunodeficiency with resultant absence or diminished immunoglobulin production. While the most common cause of congenital agammaglobulinemia is X-linked agammaglobulinemia (XLA), accounting for approximately 85% of cases, other genetic forms of agammaglobulinemia have been identified. Early recognition and diagnosis of these conditions are pivotal for improved outcomes and prevention of sequelae and complications. The diagnosis of XLA is often delayed, and can be missed if patient has a mild phenotype. The lack of correlation between phenotype and genotype in this condition makes management and predicting outcomes quite difficult. In contrast, while less common, autosomal recessive forms of agammaglobulinemia present at younger ages and with typically more severe clinical features resulting in an earlier diagnosis. Some diagnostic innovations, such as KREC level measurements and serum BCMA measurements, may aid in facilitating an earlier identification of agammaglobulinemia leading to prompt treatment. Earlier diagnosis may improve the overall health of patients with XLA.
Topics: Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Genetic Diseases, X-Linked; Humans; Mutation; Protein-Tyrosine Kinases
PubMed: 34241796
DOI: 10.1007/s12016-021-08870-5 -
Blood Cancer Journal Aug 2023Bispecific antibodies (BsAbs) are emerging as an important novel class of immunotherapeutic agents for the treatment of multiple myeloma (MM), and are set to be more... (Review)
Review
Bispecific antibodies (BsAbs) are emerging as an important novel class of immunotherapeutic agents for the treatment of multiple myeloma (MM), and are set to be more widely used in clinical practice. However, this new class of therapies is associated with a distinct adverse event (AE) profile that includes cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, as well as AEs leading to increased infection risk such as cytopenias and hypogammaglobulinemia, and infections themselves. As preliminary data with this class of agents shows an increased risk of infections as compared with conventional MM treatment regimens, such as immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies (mAbs), guidance on infection monitoring, prophylaxis and treatment is required. This review provides consensus recommendations from a panel of 13 global experts, following a meeting in August 2022. The meeting objective was to review existing literature and identify relevant information on infections with all BsAbs in patients with MM, as well as to discuss clinical experience of experts in managing these infections. The recommendations outlined here can be used to guide management of infection risk factors, such as hypogammaglobulinemia and neutropenia. In addition, they can be used to guide the monitoring, prophylaxis, and treatment of bacterial, viral and fungal infections, including emerging infections of interest, such as coronavirus 2019 (COVID-19), and the use of vaccinations prior to and during BsAb treatment. The recommendations have been graded by the panel based on level of data available. Key recommendations include universal herpes simplex and varicella zoster virus prophylaxis, screening for hepatitis B virus reactivation risk in all patients, monthly intravenous immunoglobulin treatment for immunoparesis and in the absence of life-threatening infectious manifestations, use of colony-stimulating factors in patients with Grade 3 neutropenia, universal pneumocystis jirovecii pneumonia prophylaxis and no routine anti-fungal prophylaxis.
Topics: Humans; Multiple Myeloma; Antibodies, Bispecific; Consensus; Agammaglobulinemia; COVID-19; Neutropenia
PubMed: 37528088
DOI: 10.1038/s41408-023-00879-7 -
International Journal of Experimental... Aug 2023Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence. Their heterogeneity, diversity, and nature pose daunting... (Review)
Review
Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence. Their heterogeneity, diversity, and nature pose daunting clinical challenges for both management and treatment. In this review, we discuss recent advances in clinical applications of gene therapy for rare diseases, focusing on a variety of viral and non-viral strategies. The use of adeno-associated virus (AAV) vectors is discussed in the context of Luxturna, licenced for the treatment of RPE65 deficiency in the retinal epithelium. Imlygic, a herpes virus vector licenced for the treatment of refractory metastatic melanoma, will be an example of oncolytic vectors developed against rare cancers. Yescarta and Kymriah will showcase the use of retrovirus and lentivirus vectors in the autologous ex vivo production of chimeric antigen receptor T cells (CAR-T), licenced for the treatment of refractory leukaemias and lymphomas. Similar retroviral and lentiviral technology can be applied to autologous haematopoietic stem cells, exemplified by Strimvelis and Zynteglo, licenced treatments for adenosine deaminase-severe combined immunodeficiency (ADA-SCID) and β-thalassaemia respectively. Antisense oligonucleotide technologies will be highlighted through Onpattro and Tegsedi, RNA interference drugs licenced for familial transthyretin (TTR) amyloidosis, and Spinraza, a splice-switching treatment for spinal muscular atrophy (SMA). An initial comparison of the effectiveness of AAV and oligonucleotide therapies in SMA is possible with Zolgensma, an AAV serotype 9 vector, and Spinraza. Through these examples of marketed gene therapies and gene cell therapies, we will discuss the expanding applications of such novel technologies to previously intractable rare diseases.
Topics: Humans; Rare Diseases; Severe Combined Immunodeficiency; Genetic Therapy; Agammaglobulinemia
PubMed: 37177842
DOI: 10.1111/iep.12478 -
Annals of Allergy, Asthma & Immunology... Jun 2023Rituximab is a chimeric anti-CD20 monoclonal antibody that targets CD20-expressing B lymphocytes, has a well-defined efficacy and safety profile, and is broadly used to... (Review)
Review
Rituximab is a chimeric anti-CD20 monoclonal antibody that targets CD20-expressing B lymphocytes, has a well-defined efficacy and safety profile, and is broadly used to treat a wide array of diseases. In this review, we cover the mechanism of action of rituximab and focus on hypogammaglobulinemia and late-onset neutropenia-2 immune effects secondary to rituximab-and subsequent infection. We review risk factors and highlight key considerations for immunologic monitoring and clinical management of rituximab-induced secondary immune deficiencies. In patients treated with rituximab, monitoring for hypogammaglobulinemia and infections may help to identify the subset of patients at high risk for developing poor B cell reconstitution, subsequent infections, and adverse complications. These patients may benefit from early interventions such as vaccination, antibacterial prophylaxis, and immunoglobulin replacement therapy. Systematic evaluation of immunoglobulin levels and peripheral B cell counts by flow cytometry, both at baseline and periodically after therapy, is recommended for monitoring. In addition, in those patients with prolonged hypogammaglobulinemia and increased infections after rituximab use, immunologic evaluation for inborn errors of immunity may be warranted to further risk stratification, increase monitoring, and assist in therapeutic decision-making. As the immunologic effects of rituximab are further elucidated, personalized approaches to minimize the risk of adverse reactions while maximizing benefit will allow for improved care of patients with decreased morbidity and mortality.
Topics: Humans; Rituximab; Agammaglobulinemia; Antineoplastic Agents; Antibodies, Monoclonal; Neutropenia
PubMed: 36706910
DOI: 10.1016/j.anai.2023.01.018 -
The Journal of Allergy and Clinical... May 2022Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody...
Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.
Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the hypogammaglobulinemia is secondary or primary is important because this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (eg, discontinuation of an offending drug) or treatment of the underlying condition (eg, management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin replacement therapy. This report serves to summarize the existing literature regarding immunosuppressive medications and populations (autoimmune, neurologic, hematologic/oncologic, pulmonary, posttransplant, protein-losing) associated with SHG and highlights key areas for future investigation.
Topics: Agammaglobulinemia; Common Variable Immunodeficiency; Humans; Iatrogenic Disease; Immunity; Immunoglobulins; Immunologic Deficiency Syndromes
PubMed: 35176351
DOI: 10.1016/j.jaci.2022.01.025 -
Clinical Journal of the American... Apr 2023Rituximab is an established therapy in children with idiopathic nephrotic syndrome to sustain short- to medium-term disease remission and avoid steroid toxicities.... (Review)
Review
Rituximab is an established therapy in children with idiopathic nephrotic syndrome to sustain short- to medium-term disease remission and avoid steroid toxicities. Recent trials focus on its use as a first-line agent among those with milder disease severity. Rituximab is used in multidrug refractory nephrotic syndrome and post-transplant disease recurrence, although the evidence is much less substantial. Available data suggest that the treatment response to rituximab depends on various patient factors, dosing regimen, and the concomitant use of maintenance immunosuppression. After repeated treatments, patients are found to have an improving response overall with a longer relapse-free period. The drug effect, however, is not permanent, and 80% of patients eventually relapse and many will require an additional course of rituximab. This underpins the importance of understanding the long-term safety profile on repeated treatments. Although rituximab appears to be generally safe, there are concerns about long-term hypogammaglobulinemia, especially in young children. Reliable immunophenotyping and biomarkers are yet to be discovered to predict treatment success, risk of both rare and severe side effects, e.g. , persistent hypogammaglobulinemia, and guiding of redosing strategy. In this review, we highlight recent advances in the use of rituximab for childhood nephrotic syndrome and how the therapeutic landscape is evolving.
Topics: Child; Humans; Child, Preschool; Rituximab; Nephrotic Syndrome; Agammaglobulinemia; Glucocorticoids; Treatment Outcome
PubMed: 36456193
DOI: 10.2215/CJN.08570722 -
Expert Review of Hematology Apr 2022The unprecedented success of chimeric antigen receptor (CAR)-T-cell therapy in the management of B-cell malignancies comes with a price of specific side effects. Healthy... (Review)
Review
INTRODUCTION
The unprecedented success of chimeric antigen receptor (CAR)-T-cell therapy in the management of B-cell malignancies comes with a price of specific side effects. Healthy B-cell depletion is an anticipated 'on-target' 'off-tumor' side effect and can contribute to severe and prolonged hypogammaglobulinemia. Evidence-based guidelines for the use of immunoglobulin replacement therapy (IGRT) for infection prevention are lacking in this population.
AREAS COVERED
This article reviews the mechanisms and epidemiology of hypogammaglobulinemia and antibody deficiency, association with infections, and strategies to address these issues in CD19- and BCMA-CAR-T-cell recipients.
EXPERT OPINION
CD19 and BCMA CAR-T-cell therapy result in unique immune deficits due to depletion of specific B-lineage cells and may require different infection prevention strategies. Hypogammaglobulinemia before and after CAR-T-cell therapy is frequent, but data on the efficacy and cost-effectiveness of IGRT are lacking. Monthly IGRT should be prioritized for patients with severe or recurrent bacterial infections. IGRT may be more broadly necessary to prevent infections in BCMA-CAR-T-cell recipients and children with severe hypogammaglobulinemia irrespective of infection history. Vaccinations are indicated to augment humoral immunity and can be immunogenic despite cytopenias; re-vaccination(s) may be required. Controlled trials are needed to better understand the role of IGRT and vaccines in this population.
Topics: Agammaglobulinemia; B-Cell Maturation Antigen; Cell- and Tissue-Based Therapy; Child; Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Chimeric Antigen
PubMed: 35385358
DOI: 10.1080/17474086.2022.2063833 -
The Journal of Allergy and Clinical... Feb 2022Chimeric antigen receptor (CAR) T-cell therapy is a dynamic therapy of engineered T cells targeting neoplastic cells, which offers impressive long-term remissions for... (Review)
Review
Chimeric antigen receptor (CAR) T-cell therapy is a dynamic therapy of engineered T cells targeting neoplastic cells, which offers impressive long-term remissions for aggressive relapsed/refractory hematologic malignancies. However, side effects including severe infections can be life-threatening. Multiple factors, including cytokine release syndrome, B-cell aplasia, and hypogammaglobulinemia, contribute to infection risk. B-cell aplasia is an expected on-target, off-tumor effect of CD19-targeted CAR T cells and leads to hypogammaglobulinemia. We review hypogammaglobulinemia observed in the 5 currently Food and Drug Administration-approved CAR T-cell therapies and other CAR T-cell products evaluated in clinical trials, and discuss hypogammaglobulinemia onset, duration, and immune recovery. We review associations between hypogammaglobulinemia and infections, with a discussion informed by other known B-cell-depleting contexts. Differences in hypogammaglobulinemia between children and adults are identified. We integrate management strategies for evaluation and immunoglobulin replacement from clinical studies, expert recommendations, and organizational guidelines. Notably, our review also highlights newer CAR T-cell products targeting different B-cell antigens, including B-cell maturation antigen, signaling lymphocytic activation molecule, and κ light chains. Finally, we identify key areas for future study to mitigate and treat hypogammaglobulinemia resulting from this transformative therapy.
Topics: Agammaglobulinemia; Cell- and Tissue-Based Therapy; Humans; Immunotherapy, Adoptive; Neoplasm Recurrence, Local; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 34757064
DOI: 10.1016/j.jaip.2021.10.037 -
The New England Journal of Medicine May 2021Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency.
BACKGROUND
Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency.
METHODS
We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human . Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up.
RESULTS
Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade.
CONCLUSIONS
Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.).
Topics: Adenosine Deaminase; Adolescent; Agammaglobulinemia; Child; Child, Preschool; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lentivirus; Lymphocyte Count; Progression-Free Survival; Prospective Studies; Severe Combined Immunodeficiency; Transplantation, Autologous
PubMed: 33974366
DOI: 10.1056/NEJMoa2027675