Secondary Hypogammaglobulinemia Research Articles

Defective kinase activity of IKKα leads to combined immunodeficiency and disruption of immune tolerance in humans.

IKKα is a multifunctional serine/threonine kinase that controls various biological processes, either dependent on or independent of its kinase activity. However, the importance of the kinase function of IKKα in human physiology remains unknown since no biallelic variants disrupting its kinase activity have been reported. In this study, we present a homozygous germline missense variant in the kinase domain of IKKα, which is present in three children from two Turkish families. This variant, referred to as IKKαG167R, is in the activation segment of the kinase domain and affects the conserved (DF/LG) motif responsible for coordinating magnesium atoms for ATP binding. As a result, IKKαG167R abolishes the kinase activity of IKKα, leading to impaired activation of the non-canonical NF-κB pathway. Patients carrying IKKαG167R exhibit a range of immune system abnormalities, including the absence of secondary lymphoid organs, hypogammaglobulinemia and limited diversity of T and B cell receptors with evidence of autoreactivity. Overall, our findings indicate that, unlike a nonsense IKKα variant that results in early embryonic lethality in humans, the deficiency of IKKα's kinase activity is compatible with human life. However, it significantly disrupts the homeostasis of the immune system, underscoring the essential and non-redundant kinase function of IKKα in humans.

Persistently Low IgG2 Levels in a Subset of Patients Following Hematopoietic Cell Transplantation.

Infectious diseases remain a major cause of morbidity and mortality after hematopoietic cell transplantation (HCT). Secondary hypogammaglobulinemia is a risk factor for infectious diseases. Total immunoglobulin G (IgG) levels and the history of infectious diseases are an integral part of determining the indication for immunoglobulin replacement therapy. The clinical significance of IgG2 levels is not well established. Guidelines recommend using pathogen-specific IgG to evaluate patients with potential secondary immunodeficiency. However, it is difficult in practice to perform such testing. IgG2 may correlate well with pathogen-specific IgG but the clinical significance of IgG2 is not well established. To assess the prevalence of low IgG2 levels with normal IgG after HCT, we cross-sectionally measured the levels of several immunoglobulins, including IgG, IgA, IgM, and IgG2, after HCT, and we assessed the correlation between them. Among 121 patients who underwent cross-sectional measurements of IgG, IgA, IgM, and IgG2 levels after HCT, 114 had normal IgG2 levels (normal IgG2 group, ≥ 100mg/dL) and 7 had low IgG2 levels (low IgG2 group, < 100mg/dL). These 7 patients were allogeneic HCT recipients. All 7 patients with low IgG2 had cGVHD and 4/7 patients had normal total IgG levels. IgG2 levels may be low even in patients with normal IgG levels years after allogeneic HCT. Therefore, our study suggests that when patients develop infectious diseases, especially multiple episodes, it is recommended to measure IgG2 levels to exclude the possibility of secondary hypogammaglobulinemia after allogeneic HCT.

Secondary Hypogammaglobulinemia

Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to extrinsic causes, such as a medication or an acquired disease process, resulting in decreased immunoglobulin production or increased immunoglobulin loss. Most published reports of SHG refer to IgG hypogammaglobulinemia and data on isolated IgA or IgM hypogammaglobulinemia is limited. The common causes of SHG include medications, hematological malignancies, and conditions associated with protein loss. Hypogammaglobulinemia can increase the risk of infection, morbidity and mortality, particularly in patients who may already be immunocompromised due to their associated condition or use of immunosuppressive therapies. With growing use of immunosuppressive or immunomodulatory treatments that affect B-cells, it is increasingly important to assess and monitor for SHG. Treatment of the underlying condition or removal of the extrinsic factor often results in resolution of the SHG. A subset of patients presenting with autoimmune or malignant conditions can have a primary immunodeficiency (PID) or primary immune regulatory disorder. It is therefore important to consider both primary and secondary causes when assessing hypogammaglobulinemia. This article will review these common causes and discuss an approach to assessment and management of SHG.

Immunoglobulin Replacement Therapy: Insights into Multiple Myeloma Management.

Immunoglobulin (Ig) replacement therapy (IgRT) consists of the administration of low-dose human polyclonal Igs for the treatment of primary and secondary hypogammaglobulinemia that are associated with recurrent infections and immune dysfunction. IgRT restores physiological antibody levels and induces an immunomodulatory effect by strengthening immune effector cells, thus reducing infections. Here, we describe the pharmacology of different Ig formulations with a particular focus on their mechanism of action as low-dose IgRT, including the direct anti-microbial effect and the immunomodulatory function. In addition, we describe the use of therapeutic Igs for the management of multiple myeloma (MM), a hematologic malignancy characterized by severe secondary hypogammaglobulinemia associated with poor patient outcome. In MM settings, IgRT prevents life-threatening and recurrent infections showing promising results regarding patient survival and quality of life. Nevertheless, the clinical benefits of IgRT are still controversial. A deeper understanding of the immune-mediated effects of low-dose IgRT will provide the basis for novel combined therapeutic options and personalized therapy in MM and other conditions characterized by hypogammaglobulinemia.

Secondary hypogammaglobulinemia: diagnosis and management of a pediatric condition of clinical importance.

Secondary hypogammaglobulinemia, or low serum immunoglobulins, is associated with a variety of medications or medical conditions and may be symptomatic and lead to increased infectious risk. There is limited data regarding the study of acquired, or secondary, hypogammaglobulinemia (SHG) in pediatrics. The data to date has suffered from methodologic issues including retrospective study design, lack of baseline immunoglobulin measurements, and limited longitudinal follow-up. There is emerging research on the impact of B-cell depleting therapies, specifically rituximab and chimeric antigen T-cells, along with other autoimmune and malignant disease states, in the development of SHG in pediatric patients. This review will also summarize other relevant pediatric conditions related to SHG. The clinical relevance of SHG in pediatrics is increasingly appreciated. Improved understanding of the specific etiologies, risk factors, and natural history of SHG have informed screening and management recommendations.

Impact of Intravenous Immunoglobulin Replacement Therapy on Hypogammaglobulinemia and Infection in Lung Transplant Recipients

Secondary hypogammaglobulinemia (HGG) from immunosuppression therapy in lung transplant recipients has been associated with increased mortality, morbidity and higher risk of infection. Intravenous immunoglobulin (IVIG) for the treatment of HGG post-lung transplant is not well studied with conflicting evidence regarding efficacy. This single-center, retrospective cohort study analyzed adult lung transplant recipients with HGG receiving ≥1 dose of IVIG 0.3-0.5 g/kg. Resolution of HGG (IgG &gt; 600 mg/dL within 30 days of IVIG) was evaluated for optimal dose and duration of IVIG therapy. Incidence of infection, patient survival, rejection, and chronic lung allograft dysfunction-free survival at 1 year were compared between resolved and persistent HGG. Results demonstrated majority of patients 46/58 (79.3%) achieved HGG resolution. Severe HGG (IgG &lt; 400 mg/dL) was significantly associated with persistent HGG (50.5% vs 15.2%, p = 0.02), with comparable cumulative IVIG dose and duration between both groups (p = 0.96 and p = 0.39, respectively). No other variables correlated with HGG resolution. Overall infection rates were similar between groups (69.6% vs 58.3%, p = 0.50), suggesting HGG resolution did not correlate with incidence of infection. Lastly, use of IVIG for the treatment of HGG appears to be safe with minimal incidence of thrombosis found within each group.

Disseminated septic arthritis caused by Ureaplasma urealyticum in an immunocompromised patient with hypogammaglobulinemia after rituximab therapy

Abstract Purpose Ureaplasma urealyticum is a rare pathogen associated with septic arthritis that predominantly affects patients with hypogammaglobulinemia. Bacterial identification of fastidious organisms is challenging because they are undetectable by routine culture testing. To the best of our knowledge, this is the first report of septic arthritis induced by U. urealyticum infection in Japan. Case description We describe the case of a 23-year-old Japanese female with secondary hypogammaglobulinemia (serum immunoglobulin level &lt; 500 mg/dL), identified 8 years after treatment with rituximab. The patient presented with persistent fever and polyarthritis that were unresponsive to ceftriaxone and prednisolone. Contrast-enhanced computed tomography and gallium-67 scintigraphy revealed effusion and inflammation in the left sternoclavicular, hip, wrist, knee, and ankle joints. Although Gram staining and bacterial culture of the drainage fluid from the left hip joint were negative, the condition exhibited characteristics of purulent bacterial infection. The patient underwent empirical treatment with doxycycline, and her symptoms promptly resolved. Subsequent 16S ribosomal RNA (rRNA) gene sequencing of the joint fluid confirmed the presence of U. urealyticum, leading to the diagnosis of septic arthritis. Combination therapy with doxycycline and azithromycin yielded a favorable recovery from the inflammatory status and severe arthritic pain. Conclusion This case highlights U. urealyticum as a potential causative agent of disseminated septic arthritis, particularly in patients with hypogammaglobulinaemia. The 16S rRNA gene analysis proved beneficial for identifying pathogens in culture-negative specimens, such as synovial fluid, in suspected bacterial infections.

110 Patient with Trisomy 21 and Congenital Chylothorax with Secondary Hypogammaglobulinemia

110 Patient with Trisomy 21 and Congenital Chylothorax with Secondary Hypogammaglobulinemia

Early Chimeric Antigen Receptor T Cell Expansion Is Associated with Prolonged Progression-Free Survival for Patients with Relapsed/Refractory Multiple Myeloma Treated with Ide-Cel: A Retrospective Monocentric Study

The outcomes of patients with relapsed and refractory multiple myeloma (RRMM) previously treated with the 3 main classes of myeloma therapy-immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies-remain poor. Recently, based on the phase II pivotal KarMMa trial showing prolonged overall survival (OS) and progression-free survival (PFS) in heavily treated patients, idecabtagene vicleucel (ide-cel), a B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy (CAR-T) product, was approved in the United States for the treatment of RRMM. In France, since June 2021, an early access program has authorized the use of ide-cel in the setting of RRMM (defined as progressive myeloma after at least 3 previous regimens, including the 3 main antimyeloma therapies). We report the first French experience through this early access program in a retrospective study of 24 consecutive patients treated with ide-cel at our institution. The patients were evaluated according to International Myeloma Working Group criteria and by positron emission tomography computed tomography (PET-CT) at 1, 3, 6, 9, and 12 months after ide-cel infusion. Most patients had adverse cytogenetic abnormalities, and RRMM with triple-refractory drugs were seen in 79%. Bridging therapy was required for 19 of 24 patients. Before CAR-T cell infusion, lymphodepletion with fludarabine and cyclophosphamide was systematically performed. The median follow-up was 15.2 months. At 3 months after ide-cel infusion, 92% of patients achieved at least a partial response, and 50% achieved a complete response or better (≥CR). At 6 months, 70% of patients had a persistent ≥CR. At 3 and 6 months, bone marrow minimal residual disease (10-6 level) was undetectable in 79% and 75% of patients, respectively. At 6 months, CR as assessed by PET-CT was achieved in 15 of 20 patients (75%). The median PFS was 14.8 months, and median OS was not reached. Notably, an expansion of circulating CAR-T cells to >180/mm3 after infusion was strongly associated with prolonged PFS. Additionally, the level of soluble BCMA measured before infusion was identified as a prognostic factor for PFS, likely correlated to the tumor burden. Grade 1-2 cytokine release syndrome (CRS) occurred in 22 of 24 patients (92%). Only 1 patient (4%) experienced grade ≥3 CRS. The occurrence of neurologic toxicity was infrequent (12.5%) and reversible in all cases. Hematologic toxicity was relatively common, and secondary hypogammaglobulinemia occurred in most patients. Infections (mostly viral) were frequent but most often nonsevere. This study echoes the promising results of the KarMMa trial and identifies possible prognostic indicators in RRMM patients treated with ide-cel, potentially refining treatment strategies and improving outcomes in this challenging context.

Secondary hypogammaglobulinemia in adults—A large retrospective cohort study

Background and objectiveIgG replacement therapy (IgG-RT) has radically changed the clinical evolution of primary immunodeficiencies, yet the information regarding secondary hypogammaglobulinemia (SHG) is insufficient or conflicting. We aim to describe clinical features, evolution and treatment of SHG patients in our center. MethodsDynamic retrospective cohort between January 2001 and July 2021 of adults with gamma globulin fraction <0.6g/dL in a serum protein electrophoresis and a coincident decrease of IgG levels – with a disease-related SHG or treatment that reduces serum immunoglobulins. ResultsWe included 1012 patients with SHG with a median follow-up of 5 years (IQR 2–8). Hematological diseases were identified in 95% of the patients and 61% received drugs related to SHG. Sixty five percent had more than one etiological factor associated with SHG. Infectious diseases were present in 69% of the patients, 48% had respiratory infections and 17% had severe infections. There was statistical association between respiratory and severe infections with multiple myeloma (MM), lymphoma and rituximab. MGUS had less infections and death compared with other etiologies. IgG-RT was indicated in 18.7% of the patients and 4.6% received it for more than 6 months with variable intervals. Among the latter group, there was a significant reduction of all-type infections and respiratory infections with IgG-RT (p<0.001), and it was consistent with similar findings in lymphoma, MM and all IgG levels subgroups. ConclusionSHG was associated with more than one etiological factor and a high frequency of infections. IgG-RT indication was irregular yet still effective. It is relevant to consider IgG levels screening, monitoring and accurate indication of IgG-RT.

Secondary hypogammaglobulinemia in adults—A large retrospective cohort study

Background and objectiveIgG replacement therapy (IgG-RT) has radically changed the clinical evolution of primary immunodeficiencies, yet the information regarding secondary hypogammaglobulinemia (SHG) is insufficient or conflicting. We aim to describe clinical features, evolution and treatment of SHG patients in our center. MethodsDynamic retrospective cohort between January 2001 and July 2021 of adults with gamma globulin fraction <0.6g/dL in a serum protein electrophoresis and a coincident decrease of IgG levels – with a disease-related SHG or treatment that reduces serum immunoglobulins. ResultsWe included 1012 patients with SHG with a median follow-up of 5 years (IQR 2–8). Hematological diseases were identified in 95% of the patients and 61% received drugs related to SHG. Sixty five percent had more than one etiological factor associated with SHG. Infectious diseases were present in 69% of the patients, 48% had respiratory infections and 17% had severe infections. There was statistical association between respiratory and severe infections with multiple myeloma (MM), lymphoma and rituximab. MGUS had less infections and death compared with other etiologies. IgG-RT was indicated in 18.7% of the patients and 4.6% received it for more than 6 months with variable intervals. Among the latter group, there was a significant reduction of all-type infections and respiratory infections with IgG-RT (p<0.001), and it was consistent with similar findings in lymphoma, MM and all IgG levels subgroups. ConclusionSHG was associated with more than one etiological factor and a high frequency of infections. IgG-RT indication was irregular yet still effective. It is relevant to consider IgG levels screening, monitoring and accurate indication of IgG-RT.

Immunoglobulin replacement vs prophylactic antibiotics for hypogammaglobulinemia secondary to hematological malignancy

AbstractImmunoglobulin replacement and prophylactic antibiotics are commonly used to prevent infections in patients with secondary hypogammaglobulinemia due to hematological malignancies but have never been directly compared. In this randomized controlled feasibility trial conducted in 7 hospitals in Australia and New Zealand, we enrolled patients with secondary hypogammaglobulinemia with either a history of recurrent/severe infection or an immunoglobulin G level <4 g/L. Participants were randomized in a 1:2 ratio to immunoglobulin (0.4 g/kg per 4 weeks IV) or daily antibiotics (trimethoprim-sulfamethoxazole 160 mg/800 mg or, if contraindicated, 100 mg doxycycline) for 12 months. Participants allocated to antibiotics were allowed to crossover after grade ≥3 infections. The primary outcome was proportion of patients alive on the assigned treatment 12 months after randomization. Between August 2017 and April 2019, 63 patients were randomized: 42 to antibiotics and 21 to immunoglobulin. Proportion of participants alive on allocated treatment at 12 months was 76% in the immunoglobulin and 71% in the antibiotic arm (Fisher exact test P=.77; odds ratio, 0.78; 95% CI, 0.22-2.52). The lower quartile for time to first major infection (median, not reached) was 11.1 months for the immunoglobulin and 9.7 months for the antibiotic arm (log-rank test, P=.65). Three participants in the immunoglobulin and 2 in the antibiotic arm had grade ≥3 treatment-related adverse events. A similar proportion of participants remained on antibiotic prophylaxis at 12 months to those on immunoglobulin, with similar rates of major infections. Our findings support the feasibility of progressing to a phase 3 trial. Trial registration #ACTRN12616001723471.

Newly identified common variable immunodeficiency in an elderly patient with rheumatoid arthritis

Common variable immunodeficiency is a group of heterogeneous diseases that are primary immunodeficiencies with a predominant lack of antibody synthesis. The most common manifestation is chronic infectious pathology of the respiratory tract, less often of the gastrointestinal tract, as well as septic arthritis. Non-infectious manifestations include autoimmune diseases, non-infectious diarrhea, cancer, benign lymphoid hyperplasia. In one patient, a combination of several syndromes is possible. Unlike most other primary immunodeficiencies that debut in early childhood, this pathology often manifests in the third or fourth decade of life, and sometimes later in apparently healthy people. Although the routine laboratory method for determining the concentration of the main classes of immunoglobulins makes it quite easy to identify patients with common variable immunodeficiency, often the diagnosis is made many years after the onset of the first clinical symptoms, when serious complications have already developed. The disease is characterized by a gradual onset, chronic progressive course and ineffectiveness of standard therapy. The main method of treatment is lifelong replacement therapy with intravenous immunoglobulins. The article considers a clinical case when an elderly patient with seronegative rheumatoid arthritis with a juvenile onset was diagnosed many years later. The results of immunological studies, including immunophenotyping of peripheral blood and bone marrow lymphocytes, are presented. Issues of differential diagnosis with secondary hypogammaglobulinemia and lymphoproliferative diseases are highlighted. It has been stated that until now, doctors of various specialties are not sufficiently familiar with the problem of primary immunodeficiencies, especially when it comes to adults, and non-infectious manifestations dominate in the clinical picture.

Clinical outcomes following cessation of parenteral immunoglobulin therapy following lung transplantation

Broad use of parenteral immunoglobulin (IgG) therapy in lung transplant (LTx) patients occurs without robust clinical evidence or guidelines. Main indications include secondary hypogammaglobulinemia, antibody-mediated rejection (AMR), and treatment or prevention of graft rejection where the use of conventional immunosuppressive therapies is contraindicated. As part of routine auditing of IgG use in our LTx service, we assessed for adverse clinical outcomes related to IgG therapy cessation between November 2017 and February 2022. Of 220 LTx recipients receiving IgG therapy at our center during this period (approximately 20% of our total LTx cohort), 48 patients ceased therapy. No adverse outcomes were experienced in 83.3% patients. About 10.4% recommenced therapy for the same indication within 6months with no longer term sequelae. One AMR patient developed progressive Chronic lung allograft dysfunction and died within 12months, where therapy cessation was patient-initiated and associated with general noncompliance. These data provide reassurance that physician-directed cessation of IgG therapy is safe when based on sound clinical information and part of a robust clinical auditing process.

Thawed plasma (TP) as a substitute for intravenous immune globulin (IVIG) to prevent hypogammaglobulinemia post-therapeutic plasma exchange

Intravenous immune globulin (IVIG) is a common treatment given after plasma exchange procedures to either prevent secondary hypogammaglobulinemia or as an adjunctive treatment for organ transplant rejection. However, side-effects are relatively common with this medication during and after infusion. This case-report describes our alternative to IVIG infusions post-plasma exchange. We hypothesize that in patients unable to tolerate IVIG, using thawed plasma as a replacement fluid provides a suitable increase in the patients post procedure immunoglobulin G (IgG) levels for patients with secondary hypogammaglobulinemia that are unable to tolerate IVIG infusions.

IgG Replacement Therapy Use in Patients with Hypogammaglobulinemia after Lung Transplant

BackgroundSecondary hypogammaglobulinemia (HG) occurs in up to 73% of patients in the first year post-lung transplant (LT). Severe HG (sHG) with immunoglobulin (Ig)G levels <400 mg/dL is associated with increased infections and mortality. Although IgG replacement therapy (IGRT) may mitigate adverse outcomes associated with HG, further investigation is needed to understand the optimal role for IGRT in HG management. MethodsData were reviewed for 191 patients who underwent first LT before 11/30/2021 with HG (at least one IgG < 600 mg/dL) post-transplant. Bacterial and fungal microbiology results (bronchoalveolar lavage, induced sputum culture, bronchial lavage), IGRT prescriptions, and IgG levels were chart-reviewed. Antimicrobial prescriptions were extracted from electronic medical records. Active infection (AI) was defined as prescription of a non-prophylactic antimicrobial; severe AI (SAI) as inpatient or intravenous prescription of a non-prophylactic antimicrobial. Positive microbiology results, AI, and SAI were reported in patient-years for the one year after first IgG < 600 mg/dL in 141 patients who never received IGRT (No-IGRT), and for the time between LT and IGRT initiation (Pre-IGRT) as well as the one year after IGRT initiation (Post-IGRT) in 50 patients who received IGRT. ResultsIGRT was initiated for secondary HG 82% (41/50), donor specific antibodies 12% (6/50), cytomegalovirus 2% (1/50), and both secondary HG and donor specific antibodies 4% (2/50). Thirty-seven patients started intravenous-IGRT (IVIG), of whom 5 switched to subcutaneous-IGRT (SCIG) during the course of treatment. Thirteen started SCIG, of whom 2 switched to IVIG. IVIG was administered for 18 ± 18 (mean ± standard deviation) doses of 41 ± 22 grams/month over 71 ± 74 weeks. SCIG was administered for 74 ± 53 doses of 27 ± 20 grams/month over 86 ± 64 weeks.There were more AI and SAI per patient-year Pre-IGRT (15.8 and 11.7, respectively) than No-IGRT (4.9 and 2.6) and Post-IGRT (8.3 and 5.8). Positive microbiology results per patient-year were 3.8 Pre-IGRT, 3.3 Post-IGRT, and 2.3 No-IGRT. Among 29 patients with sHG, positive microbiology results per patient-year were 4.8 Pre-IGRT, 4.3 Post-IGRT, and 3.1 No-IGRT.Table 1Infectious Agents Detected on Pulmonary MicrobiologyOrganism (n, %)No-IGRT (n = 318)Pre-IGRT (n = 251)Post-IGRT (n = 166)Penicillium spp.52 (16)36 (14)13 (8)Aspergillus spp.59 (18)34 (13)28 (17)Staphylococcus epidermidis8 (3)21 (9)7 (4)Pseudomonas aeruginosa20 (7)17 (7)18 (11)Staphylococcus aureus2 (1)15 (6)12 (7)Enterococcus spp.0 (0)10 (4)3 (2)Mycobacterium spp.7 (2)12 (5)4 (2)Sterile mycelium8 (3)9 (3)3 (2)Stenotrophomonas maltophilia3 (1)9 (3)8 (5)Enterobacter cloacae complex1 (<1)8 (3)3 (2)Escherichia coli4 (1)7 (3)7 (4)Haemophilus parainfluenzae44 (13)4 (2)9 (5)Klebsiella pneumoniae11 (3)2 (1)8 (5)Other99 (31)67 (27)43(26)Legend: The 735 specific microorganisms detected on bronchoalveolar lavage, sputum culture and bronchial lavage are shown. Abbreviation: Species (spp.) ConclusionThese findings suggest that IGRT was utilized for patients who presented with infections in addition to HG, with a possible decrease in antimicrobial use after initiation.

An updated perspective on immunoglobulin replacement in chronic lymphocytic leukaemia in the era of targeted therapies.

Chronic lymphocytic leukaemia (CLL) is a malignancy of clonally expanded antigen-switched, neoplastic, mature B cells. CLL is characterised by a variable degree of immunosuppression and secondary hypogammaglobulinemia. B-cell depleting therapies have historically been deployed with a proportion of patients becoming resistant to multiple lines of treatment with an associated worsening of immunosuppression and heightened infection risk. Advances in molecular diagnostics and the development of new therapies targeting Bruton's tyrosine kinase and B-cell lymphoma-2 have resulted in novel insights into the cellular mechanisms associated with an increased infection risk and T-cell escape from the complex tumour environment found in CLL. Generally, immunoglobulin replacement therapy with polyvalent human immunoglobulin G (IgG) is indicated in patients with recurrent severe bacterial infections and low IgG levels, but there is no consensus on the threshold IgG level for initiation of such therapy. A proportion of CLL patients have residual IgG production, with preserved quality of the immunoglobulin molecules, and therefore a definition of 'IgG quality' may allow for lower dosing or less frequent treatment with immunoglobulin therapy in such patients. Immunoglobulin therapy can restore innate immunity and in conjunction with CLL targeted therapies may allow T-cell antigen priming, restore T-cell function thereby providing an escape from tumour-associated autoimmunity and the development of an immune-mediated anti-tumour effect. This review aims to discuss the mechanisms by which CLL-targeted therapy may exert a synergistic therapeutic effect with immunoglobulin replacement therapy both in terms of reducing tumour bulk and restoration of immune function.

Hypogammaglobulinemia secondary to B-cell depleting therapies in neuroimmunology: Comparing management strategies.

Anti-CD20 agents are commonly used in MS, NMOSD, and MOGAD. Few studies have compared strategies to address hypogammaglobulinemia. To compare strategies to manage secondary hypogammaglobulinemia in neuroimmunology patients, including reducing anti-CD20 dose and dosing frequency, IVIG/SCIG, anti-CD20 cessation, and DMT switches. All MS, NMOSD, and MOGAD patients at our institution with hypogammaglobulinemia on anti-CD20 agents from 2001 to 2022 were analyzed. The median change in IgG, infection frequency, and infection severity before and after the treatment was calculated. In total, 257 patients were screened, and 30 had a treatment for hypogammaglobulinemia. IVIG/SCIG yielded the largest increase in IgG per year (674.0 mg/dL), followed by B-cell therapy cessation (34.7 mg/dL), and DMT switch (5.9 mg/dL). Dose reduction had the largest decrease in yearly infection frequency (2.7 fewer infections), followed by IVIG/SCIG (2.5 fewer), DMT switch (2 fewer), and reduced dosing frequency (0.5 fewer). Infection grade decreased by 1.9 for reduced dosing frequency (less severe infections), by 1.3 for IVIG/SCIG, and by 0.6 for DMT switch. This data suggests that IVIG/SCIG may yield the greatest recovery in IgG while also reducing infection frequency and severity. Stopping anti-CD20 therapy and/or switching DMTs also increase IgG and may lower infection risk.

Bortezomib is efficacious in the treatment of severe childhood-onset neuropsychiatric systemic lupus erythematosus with psychosis: a case series and mini-review of B-cell immunomodulation in antibody-mediated diseases.

Childhood-onset neuropsychiatric systemic lupus erythematosus (cNPSLE) with psychosis is a challenging manifestation of SLE. Pathogenic long-lived plasma cells (LLPCs) are not specifically targeted by standard immunosuppression and their persistence contributes to chronic autoimmunity. Bortezomib is approved for the treatment of multiple myeloma and has shown benefits in a variety of other antibody-mediated diseases. Bortezomib may be efficacious for severe or treatment-refractory cNPSLE through eradication of LLPCs, decreasing autoantibody production. We describe the first pediatric case series of five patients with unrelenting cNPSLE with psychosis who were treated safely and effectively with bortezomib between 2011 and 2017. Most patients had persistent cNPSLE with psychosis despite aggressive immunosuppression with methylprednisolone, cyclophosphamide, rituximab, and usually plasmapheresis. All patients demonstrated rapid clinical improvement in their psychotic manifestations with the ability to quickly taper immunosuppression after the introduction of bortezomib. No patient had a recurrence of overt psychosis during a follow-up period of 1-10years. Secondary hypogammaglobulinemia developed in all five patients and required immunoglobulin replacement. No other severe side effects or adverse events were observed. Bortezomib-mediated LLPC depletion is a promising therapy for severe recalcitrant cNPSLE with psychosis when used as adjunctive therapy to conventional immunosuppression, B-cell, and antibody-depleting therapies. After initiation of bortezomib, patients had rapid, demonstrable improvement in psychosis as well as reduction in glucocorticoids and antipsychotics. Further investigation is needed to determine the therapeutic role of bortezomib in severe cNPSLE and cSLE. We present a mini-review of the rationale for bortezomib use and novel B-cell immunomodulation in rheumatic disease.

Les déficits immunitaires communs variables : définition, physiopathologie et diagnostic biologique

AbstractCommon variable immunodeficiency (CVID) is a primary immunodeficiency characterized by a defect in the production of immunoglobulins, it is the most frequent of the primary immunodeficiencies. It mainly affects humoral immunity and results, among other biological signs, in severe hypogammaglobulinemia with a decrease in IgG associated with a decrease in IgA and more rarely IgM. Clinical manifestations are recurrent respiratory and digestive infections, frequently associated with autoimmune diseases and lymphoproliferative syndromes. In most cases, this hypogammaglobulinemia is linked to a decrease in switched memory B lymphocytes, and abnormalities of other element in the immune response (T lymphocytes, cytokines, dendritic cells, etc.). Genetic abnormalities affecting genes coding for many proteins involved in the immune response are described in about 35 % of patients. The diagnosis is a diagnosis of exclusion, by ruling out all other causes of secondary hypogammaglobulinemia. The treatment is injection of polyvalent immunoglobulins, and prophylactic treatment such as antibiotics and vaccinations.