Persistent Hypogammaglobulinemia Research Articles

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 > 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 < 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.

Flat dose intravenous immunoglobulin (IVIG) for primary infection prophylaxis after CAR-T for B-cell non-Hodgkin lymphoma (B-NHL).

e19004 Background: Prolonged hypogammaglobulinemia is a common side effect of CD19 chimeric antigen receptor (CAR) T-cell therapy for B-NHL. Average infection rates 1 year (yr) post CAR-T are 44-53% (Kampouri, Tran Infect Dis 2023). Prophylactic IVIG is typically dosed by weight; however, optimal dosing strategy remains unknown. We explored the efficacy of reduced flat IVIG dose on infection rates and non-relapse mortality (NRM) post CAR-T. Methods: B-NHL pts who received commercial CD19 CAR-T therapy from Nov 2017 to Mar 2023 at Vanderbilt Medical Center were included. All pts were on trimethoprim-sulfamethoxazole and valacyclovir for prophylaxis. IVIG at a flat dose of 10 grams was given for IgG < 400 mg/dL. Relevant clinical variables were collected from day 30 to 1 yr. Infections were defined as mild (treated outpatient), moderate (required admission), or severe (required intensive care unit) and by CTCAE v5 criteria. Severe neutropenia was defined as ANC<500 and severe lymphopenia was ALC<500. NRM was defined by death without progression or relapse. Estimated cost of therapy was $140/gram of IVIG based on previously published data. Results: A total of 43 pts (35 large cell lymphoma, 7 mantle cell lymphoma, and 1 follicular lymphoma) with median follow up of 445 days (range 134-2141) were included. Axicabtagene ciloleucel was given to 34 pts (79%), tisagenlecleucel to 2 pts (5%), and brexucabtagene autoleucel to 7 pts (16%). Median age was 58 (range 22-81). Median number of pre CAR-T therapies was 3 (range 1-7). There were 52 total infections with median time to first infection of 165 days (range 31-365). Of all infections, 21 (40%) were viral, 29 (56%) bacterial, and 2 (4%) fungal. There were 31 (60%) mild infections, 19 (36%) moderate, and 2 (4%) severe. Multiple G≥3 infections occurred in 14 pts (33%). At first infection, 4 pts (10%) had severeneutropenia and 13 pts (31%) had severelymphopenia. IVIG was given to 27 pts (63%). Median IgG at D30 was 438 mg/dL (range 143–1099) and 414 mg/dL (range 133–842) at D60. Prolonged IgG≤400 at 6 months occurred in 15 pts (35%). Median IVIG cost using flat dosing was $2800 (range $0-12,600) compared to a median cost of $8,075 (range $0-76,642) if weight-based dosing was utilized. NRM was 9% (4 pts). Of those pts, only 1 had a G≥3 infection during the first-year post CAR-T. Conclusions: We demonstrate comparable infection rates 1 yr post CD19 CAR-T and low NRM with the use of 10g flat IVIG dosing for consecutively treated pts. In addition, only 1 of 4 pts with NRM had severe infection within 1 yr. Notably, 35% of pts had persistent hypogammaglobulinemia at 6 mo and use of a flat dosing schedule provided substantial cost reduction. These findings should be validated in a prospective randomized trial.

Equine common variable immunodeficiency: Lessons from 100 clinical cases

SummaryThe clinical manifestation of recurrent fevers and infections alerts the clinician to the possibility of an underlying immunodeficiency. Common variable immunodeficiency (CVID) in the horse is a rare late‐onset, nonfamilial immunological disorder of B cell depletion and/or dysfunction with resultant inadequate antibody production. The most common clinical presentations in horses with CVID are recurrent upper and/or lower respiratory infections, meningitis and/or ataxia, cholangiohepatitis, infectious colitis, infectious dermatitis and severe gastrointestinal parasitism. Immune‐mediated and lymphoproliferative conditions are additional clinical features. The diagnosis of CVID in horses is based on a persistent hypogammaglobulinaemia primarily caused by a serum IgG concentration below 10.00 g/L in at least two different measurements, often accompanied by a serum IgM concentration below 0.50 g/L. Most horses with CVID show a persistent peripheral blood B cell distribution below 6% of total circulating lymphocytes, indicating severe B cell paucity or depletion, but the B cell distribution can be within the normal reference interval. Post‐mortem findings add diagnostic information about the distribution of B and T cells in lymphoid tissues. Clinical management of horses with immunodeficiency is intense and expensive, and these factors weigh on the difficult decision of elective euthanasia. To date, no genetic mutation has been identified in horse patients with CVID, and the large number of breeds of single‐affected individuals in a same herd or immediate lineage from various parts of the United States and the world do not point at an obvious inheritable mechanism of disease or environmental risk factors. This article describes the clinical and immunological findings in 100 equine cases, and comparisons with the disease in human patients.

Persistent Hypogammaglobulinemia after Receiving Rituximab Post-HSCT Is Not Caused by an Intrinsic B Cell Defect.

In the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or autoimmune phenomena such as autoimmune hemolytic anemia (AIHA). Persistent hypogammaglobulinemia and immunoglobulin substitution dependence has been observed in several patients after RTX treatment despite the normalization of total B cell numbers. We aimed to study whether this is a B cell intrinsic phenomenon. We analyzed four patients with different primary diseases who were treated with myeloablative conditioning and matched unrelated donor HSCT who developed persistent hypogammaglobulinemia after receiving RTX treatment. They all received RTX early after HSCT to treat EBV infection or AIHA post-HSCT. All patients showed normalized total B cell numbers but absent to very low IgG positive memory B cells, and three lacked IgA positive memory B cells. All of the patients had full donor chimerism, and none had encountered graft-versus-host disease. Sorted peripheral blood naïve B cells from these patients, when stimulated with CD40L, IL21, IL10 and anti-IgM, demonstrated intact B cell differentiation including the formation of class-switched memory B cells and IgA and IgG production. Peripheral blood T cell numbers including CD4 follicular T-helper (Tfh) cells were all within the normal reference range. In conclusion, in these four HSCT patients, the persistent hypogammaglobulinemia observed after RTX cannot be attributed to an acquired intrinsic B cell problem nor to a reduction in Tfh cell numbers.

Patterns of CMV infection after letermovir withdrawal in recipients of posttransplant cyclophosphamide–based transplant

AbstractReactivation of latent cytomegalovirus (CMV) is increased in recipients of allogeneic hematopoietic cell transplantation (allo-HCT) with seropositive CMV using posttransplant cyclophosphamide (PT-Cy)–based graft-versus-host disease (GVHD) prophylaxis. Letermovir, a novel DNA terminase complex inhibitor, reduces the incidence of clinically significant CMV infection (csCMVi) in this population; however, parameters that predict csCMVi after letermovir withdrawal are not well described. Here, we examined clinical and immunological parameters in 294 recipients of PT-Cy–based allo-HCT, including 157 patients with CMV, of whom 80 completed letermovir prophylaxis without csCMVi and subsequently stopped letermovir. In this population, the median duration of letermovir exposure was 203 days (interquartile range [IQR], 160-250 days). After letermovir withdrawal, the 90-day cumulative incidence of csCMVi was 23.0% (95% confidence interval, 14.3-32.8). There were no episodes of CMV end-organ disease. Hypogammaglobulinemia before letermovir discontinuation was predictive of csCMVi (hazard ratio, 0.33; 95% confidence interval, 0.12-0.93; P = .03), whereas T-cell and B-cell reconstitution before letermovir withdrawal were not predictive of csCMVi. Higher numbers of natural killer cells were found before letermovir withdrawal in patients who experienced csCMVi (median, 202 vs 160; P = .03). In recipients with seropositive CMV, CD3+CD4–CD8+ T-cell reconstitution was faster in patients with CMV regardless of letermovir exposure. Taken together, these data suggest that csCMVi after letermovir withdrawal was frequent in patients treated with PT-Cy, despite prolonged exposure. Strategies to boost CMV-specific adaptive immunity in patients with persistent hypogammaglobulinemia is a logical pathway to reduce csCMVi after letermovir withdrawal.

Rituximab therapy for childhood onset idiopathic nephrotic syndrome: experience of a Portuguese tertiary center.

Rituximab (RTX) is a therapeutic option in pediatric difficult-to-treat idiopathic nephrotic syndrome (NS). We aimed to assess the efficacy and safety of RTX use in these patients. A retrospective study of all patients with idiopathic NS treated with RTX was conducted in a pediatric nephrology division of a tertiary hospital. Demographic, anthropometric, clinical and analytical data were collected prior to treatment and at 6, 12, and 24 months. Sixteen patients were included (11 males), with a median (25th-75th percentile, P25-P75) age at diagnosis of 2 (2.0-2.8) years. Fifteen were steroid-sensitive and 1 was steroid-resistant and sensitive to cyclosporine. The median age at administration of RTX was 10 (6.3-14.0) years. Throughout a median follow-up time of 2.5 (1.0-3.0) years, 6 (37.5%) patients achieved partial remission and 7 (43.8%) had no relapses and were not taking any immunosuppressants at the 24-month follow-up visit. Regarding complications, 1 patient presented persistent hypogammaglobulinemia. Compared with the 12-month period before RTX, there was a decrease in the median number of relapses at 6 and 12 months [3 (3.0-4.0) vs 0 (0-0.8) and 0.50 (0-1.0), respectively; p = 0.001] and in the daily steroids dose (mg/kg/day) at 6, 12, and 24 months [0.29 (0.15-0.67)vs [0.10 (0.07-0.13); p = 0.001], [0.12 (0.05-0.22); p = 0.005] and [0.07(0.04-0.18); p = 0.021]], respectively. There was also a reduction in the median BMI z score at 24 months [2.11 (0.45-3.70) vs. 2.93 (2.01-3.98); p = 0.049]. Our results confirm the efficacy and safety of RTX use in pediatric idiopathic NS and highlight its' potential cardiometabolic benefits.

Predictive factors of long-term disease remission after rituximab administration in patients with childhood-onset complicated steroid-dependent nephrotic syndrome: a single-center retrospective study.

Despite the fact that rituximab (RTX)-associated adverse events may be relatively frequent in younger patients, recent studies have reported RTX as a suitable first-line steroid-sparing agent for maintaining remission in children with steroid-dependent nephrotic syndrome (SDNS). However, the impact of age at RTX initiation on the long-term outcome remains unknown in this cohort. We retrospectively reviewed the clinical course of 61 patients with complicated SDNS who received a single dose of RTX (375mg/m2) followed by maintenance immunosuppressive agents (IS) from January 2008 to March 2021. In patients who achieved > 12months of prednisolone-free remission, IS tapering within 6months was tried to achieve. The primary endpoint was the probability of achieving long-term treatment-free remission at the last follow-up. After RTX initiation, 52 patients (85.2%) relapsed after a median of 665days, and 44 patients (72.1%) received additional RTX doses (total, 226 infusions). At the last follow-up (median observation period, 8.3years; median age, 18.3years), 16 patients (26.2%) achieved long-term remission. Multivariate analysis showed that older age at RTX initiation was the independent predictive factor for achieving long-term remission (odds ratio, 1.25; p < 0.05). The proportion of those who achieved long-term remission was significantly higher in patients aged ≥ 13.5years than in those aged < 13.5years at RTX initiation (52.6 vs 14.3%, p < 0.05). Persistent severe hypogammaglobulinemia did not develop in older children (≥ 13.5years) at RTX initiation. For older children with complicated SDNS, RTX appeared to be a suitable disease-modifying therapy without persistent adverse events.

Rituximab-associated hypogammaglobulinemia in children with idiopathic nephrotic syndrome: results of an ESPN survey

BackgroundThere is paucity of information on rituximab-associated hypogammaglobulinemia (HGG) and its potential infectious consequences in children treated for idiopathic nephrotic syndrome (INS).MethodsA survey was distributed by the European Society Pediatric Nephrology to its members. It addressed the screening and management practices of pediatric nephrology units for recognizing and treating RTX-associated HGG and its morbidity and mortality. Eighty-four centers which had treated an overall 1328 INS children with RTX responded.ResultsThe majority of centers administered several courses of RTX and continued concomitant immunosuppressive therapy. Sixty-five percent of centers routinely screened children for HGG prior to RTX infusion, 59% during, and 52% following RTX treatment. Forty-seven percent had observed HGG prior to RTX administration, 61% during and 47% >9 months following treatment in 121, 210, and 128 subjects respectively. Thirty-three severe infections were reported among the cohort of 1328 RTX-treated subjects, of whom 3 children died. HGG had been recognized in 30/33 (80%) of them.ConclusionsHGG in steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS) children is probably multifactorial and can be observed prior to RTX administration in children with SDNS/FRNS. Persistent HGG lasting >9 months from RTX infusion is not uncommon and may increase the risk of severe infections in this cohort. We advocate for the obligatory screening for HGG in children with SDNS/FRNS prior to, during, and following RTX treatment. Further research is necessary to identify risk factors for developing both HGG and severe infections before recommendations are made for its optimal management.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Hypogammaglobulinemia in Children After Hematopoietic Stem Cell Transplantation and Rituximab Treatment: Relevance of B Cell Subsets.

Rituximab (RTX) is widely employed to treat Epstein-Barr virus reactivation in children undergoing Hematopoietic Cell Transplantation (HCT). The resulting loss of B cells may cause persistent hypogammaglobulinemia. This retrospective cross-sectional study aims to identify flow cytometry biomarkers associated with persistent hypogammaglobulinemia in patients receiving RTX after HCT. We analyzed 5 patients (cases group) requiring immunoglobulin substitution due to low level of IgG (IgG <5g/L) detected after RTX treatment and 5 patients (controls group) not requiring long-term immunoglobulin (Ig) substitution. We investigated the B cell reconstitution, and in patients group we observed a significantly lower count in B total, IgD+CD27+ marginal B cells and IgD-CD27+ switched-memory B cells, after a median of 5 years from HCT, compared with the control group. Despite the importance limits of our study and the heterogeneity of our data (age of included patients, time of evaluation, interval between RTX dose and assessment) we conclude that RTX given early after HCT might cause a deranged B cell maturation, contributing to the delation in B cell recovery following HCT, and switched memory and marginal zone B cell counts could be a promising biomarker to identify patients requiring long-term Ig substitution.

X-LINKED INHIBITOR OF APOPTOSIS DEFICIENCY IN A PATIENT WITH ADULT-ONSET RECURRENT FEBRILE ILLNESSES

<h3>Introduction</h3> X-linked inhibitor of apoptosis (XIAP) deficiency is a primary immunodeficiency caused by a mutation in the gene XIAP. It is commonly associated with hemophagocytic lymphohistiocytosis (HLH), recurrent splenomegaly, and inflammatory bowel disease (IBD), as well as hypogammaglobulinemia. We report a case of an adult with late diagnosis of XIAP deficiency in the setting of recurrent febrile illnesses. <h3>Case Description</h3> An 18-year-old Caucasian male presented with fever and generalized lymphadenopathy without other localizing symptoms, which was attributed to cytomegalovirus infection. He recovered without specific treatment, but throughout adulthood he had recurrent infections including pneumonia, appendicitis, cholecystitis, epididymitis, sinusitis, and aseptic meningitis. These infections were often associated with high fever, transaminase elevation, and inflammatory marker elevation. At age 41 he demonstrated persistent hypogammaglobulinemia (IgG 610-635, reference range 767-1590 mg/dl; IgM 28-33, reference range 37-286 mg/dl), elevated antinuclear antibodies, and poor Pneumovax response (adequate response to serotypes 9V, 2, 6B). He denied family history of similar issues. Common variable immunodeficiency (CVID) was considered, but subsequent genetic testing showed a pathologic variant in XIAP gene (c.712C>T/p.Arg238*), leading to a diagnosis of XIAP deficiency. The patient was started on IVIG and Anakinra with good response to treatment. <h3>Discussion</h3> This case highlights the importance of considering genetic testing even in adults with delayed onset of symptoms. The clinical phenotype and presentation of XIAP deficiency is variable and can often mimic more common diseases such as CVID. Even in patients without a history of IBD or HLH, genetic testing to detect XIAP deficiency should still be considered given its variable presentation.

Secondary rituximab-associated versus primary immunodeficiencies: The enigmatic border.

Rituximab (RTX), a chimeric monoclonal antibody targeting CD20-positive cells, is a valuable treatment option for malignant and benign immune-related disorders. The rationale of targeting the CD20 antigen relies on depletion of both healthy and autoreactive/malignant CD20-espressing cells, but normal B-cell reconstitution is expected within months after treatment. Nevertheless, a number of recent studies have documented prolonged B-cell deficiency associated with new-onset hypogammaglobulinemia in patients receiving RTX. Awareness of post-RTX hypogammaglobulinemia has become wider among clinicians, with a growing number of reports about the increased incidence, especially in children. Although these patients were previously regarded as affected by secondary/iatrogenic immunodeficiency, atypical clinical and immunological manifestations (e.g., severe or opportunistic infections; prolonged B-cell aplasia) raise concerns of delayed manifestations of genetic immunological disorders that have been unveiled by B-cell perturbation. As more patients with undiagnosed primary immune deficiency receiving RTX have been identified, it remains the challenge in discerning those that might display a higher risk of persistent RTX-associated hypogammaglobulinemia and need a tailored immunology follow-up. In this review, we summarize the principal evidence regarding post-RTX hypogammaglobulinemia and provide a guideline for identifying patients at higher risk of RTX-associated hypogammaglobulinemia that could harbor an inborn error of immunity.

Chronic hypogammaglobulinemia after allogeneic stem cell transplantation and their treatment with subcutaneous immunoglobulin in pediatric patients

IntroductionHypogammaglobulinemia in the first months after allogeneic hematopoietic stem cell transplantation (HSCT) is common in paediatric patients. During this phase, replacement therapy with human immunoglobulin must be administered parenterally to prevent infections. In some cases, this hypogammaglobulinemia persists over time, which forces further treatment when the patient is usually no longer a carrier of a central line, making them ideal candidates for subcutaneous replacement therapy. There is little published literature describing the use of this method in paediatric patients undergoing HSCT, widely described in replacement treatment in children with primary immunodeficiencies with very good results. Patients and methodsAn observational, descriptive, longitudinal and retrospective study is carried out. During the years 2008–2019, we evaluated all paediatric patients undergoing HSCT in our center with persistent chronic hypogammaglobulinemia (for over a year). The treatment phase with intravenous immunoglobulin (Privigen®) and the first four years of treatment with subcutaneous immunoglobulin (Hizentra®) are evaluated using a questionnaire. ResultsDuring the years 2008–2019, 175 patients underwent HSCT, 143 (82%) of whom exceeded three months after transplantation. Three (2%) of them had persistent hypogammaglobulinemia. All three share factors described in the literature involved in immune reconstitution. After analysing the questionnaire, it is observed that switching from intravenous to subcutaneous gammaglobulin has involved a great improvement in their quality of life. ConclusionsThe origin of chronic hypogammaglobulinemia in our patients shows different factors and cannot be attributed to a single cause. Due to the limited number of patients no conclusions can be drawn at the population level. We have been able to observe that replacement treatment with Hizentra 20% has been as effective as the intravenous administration without evidence of an increase in bacterial infections. Furthermore, it has also led to an improvement in quality of life and increased comfort, as the patients themselves have stated.

Hipogammaglobulinemia crónica postrasplante de precursores hematopoyéticos y su tratamiento con gammaglobulina subcutánea en pacientes pediátricos

IntroductionHypogammaglobulinemia in the first months after allogeneic hematopoietic stem cell transplantation (HSCT) is common in pediatric patients. During this phase, replacement therapy with human immunoglobulin must be administered parenterally to prevent infections. In some cases, this hypogammaglobulinemia persists over time, which forces further treatment when the patient is usually no longer a carrier of a central line, making them ideal candidates for subcutaneous replacement therapy.There is little published literature describing the use of this method in pediatric patients undergoing HSCT, widely described in replacement treatment in children with primary immunodeficiencies with very good results. Patients and methodsAn observational, descriptive, longitudinal and retrospective study is carried out. During the years 2008–2019, we evaluated all pediatric patients undergoing HSCT in our center with persistent chronic hypogammaglobulinemia (for over a year). The treatment phase with intravenous immunoglobulin (Privigen®) and the first four years of treatment with subcutaneous immunoglobulin (Hizentra®) are evaluated using a questionnaire. ResultsDuring the years 2008-2019, 175 patients underwent HSCT, 143 (82%) of whom exceeded three months after transplantation. 3 (2%) of them had persistent hypogammaglobulinemia. All three share factors described in the literature involved in immune reconstitution. After analyzing the questionnaire, it is observed that switching from intravenous to subcutaneous gammaglobulin has involved a great improvement in their quality of life. ConclusionsThe origin of chronic hypogammaglobulinemia in our patients shows different factors and cannot be attributed to a single cause. Due to the limited number of patients no conclusions can be drawn at the population level. We have been able to observe that replacement treatment with Hizentra® 20% has been as effective as the intravenous administration without evidence of an increase in bacterial infections. Furthermore, it has also led to an improvement in quality of life and increased comfort, as the patients themselves have stated.

Hypogammaglobulinemia Following Anti-CD20 Therapy: Retrospective Analysis of Patient Risk Factors

Rituximab, an anti-CD20 biologic depletes peripheral B-cells, preventing production of antibodies. Some patients subsequently develop persistent hypogammaglobulinemia resulting in serious infections requiring the use of prophylactic antibiotics or immune globulin supplementation. We suspect this patient subset may have unmasked primary immunodeficiencies presenting after rituximab exposure. In our retrospective review, we characterized risk factors used to identify patients at risk of rituximab induced immunodeficiency who may benefit from monitoring surrounding rituximab therapy.

Serum IgG and lymphocyte counts are useful for the early detection of infection in patients receiving bendamustine-rituximab therapy.

Bendamustine-rituximab (BR) therapy has been established as a highly effective regimen for indolent non-Hodgkin lymphoma (NHL). However, patients who receive BR therapy exhibit persistent hypogammaglobulinemia and lymphopenia, resulting in an increased incidence of infections. As a sustained immunosuppressive state is a risk factor for infections, early predictive biomarkers for infections related to BR therapy need to be identified. We retrospectively analyzed 61 patients with indolent NHL who were followed up for 2 years after the end of BR therapy. Progression-free survival was significantly influenced by the incidence of infections. Patients with infections related to BR therapy exhibited persistent hypogammaglobulinemia and lymphopenia. In addition, we determined the cutoff values of serum IgG values and lymphocyte counts for infections using receiver operating characteristic curve analysis. Minimum serum IgG and lymphocyte counts at the first BR treatment cycle were significantly associated with the incidence of infections during and after BR treatment. Furthermore, the development of skin reactions during BR therapy was significantly associated with the incidence of infections after BR therapy. Our study suggested that these values and symptom are predictive biomarkers for infections related to BR therapy. Based on these findings, better management of indolent NHL patients will be possible.

M180 PERSISTENT HYPOGAMMAGLOBULINEMIA IN A PEDIATRIC PATIENT FOLLOWING RITUXIMAB TREATMENT FOR AUTOIMMUNE ENCEPHALITIS

Rituximab, a chimeric anti-CD20 monoclonal antibody that depletes pre-plasma B-cells, is used for the treatment of autoimmune disease. While proven effective in disease management, anti-CD20 therapies are also associated with prolonged (>6-9 months) hypogammaglobulinemia and subsequent infectious risk. We describe an adolescent patient with autoimmune encephalitis who experienced prolonged B-cell depletion and persistent hypogammaglobulinemia following Ritixumab, with eventual B-cell recovery but persistent hypogammaglobulinemia and absence of isotype-switched memory B cells(CD19+CD27+IGD-IgM-).

Multisystem Autoimmune Inflammatory Disease, Including Colitis, Due to Inborn Error of Immunity

Our understanding of inflammatory bowel disease is changing as we identify genetic variants associated with immune dysregulation. Inflammatory bowel disease undetermined, even when diagnosed in older children and adolescents, in the setting of multiple inflammatory and infectious diseases should raise the suspicion of complex immune dysregulation with a monogenic basis. We report a case of inflammatory bowel disease undetermined triggered by exposure to a nonsteroidal antiinflammatory drug in a 16-year-old girl with a background history of juvenile idiopathic arthritis, cytopenias, recurrent respiratory tract and middle ear infections, and esophageal candidiasis. Immunologic assessment included measurement of immunoglobulin levels, lymphocyte immunophenotyping, B-cell functional tests, and whole-exome sequencing. Laboratory investigation revealed defects of humoral immunity, including mild persistent hypogammaglobulinemia affecting all 3 isotypes and absent isohemagglutinins. Whole exome sequencing revealed a heterozygous TNFRSF13B (Tumor Necrosis Factor Receptor Superfamily Member 13B, or Transmembrane Activator and Calcium-modulating cyclophilin ligand Interactor, TACI) gene variant, which is associated with common variable immunodeficiency and the development of autoimmune diseases. In conclusion, a clinical history of recurrent infections, atypical histologic features of inflammatory bowel disease, additional autoimmune manifestations, and an inadequate response to conventional therapy should prompt the physician to refer to an immunologist with the query of inborn error of immunity. We report how extensive immune evaluation and genetic diagnosis can individualize care and facilitate a multidisciplinary team approach.

Incidence and risk factors of rituximab-associated hypogammaglobulinemia in patients with complicated nephrotic syndrome.

Hypogammaglobulinemia is a major adverse event after rituximab treatment; however, the precise incidence and risk factors are unclear in complicated steroid-dependent or frequently relapsing nephrotic syndrome (SDNS/FRNS) patients. This was a single-center, retrospective, observational study. Patients who received a single dose of rituximab for complicated SDNS or FRNS between February 2007 and May 2019 were enrolled. Serum IgG levels were plotted, and their trends were evaluated after rituximab treatment. The incidence of transient and persistent hypogammaglobulinemia was examined, and risk factors were calculated by multivariate analysis using logistic regression. We enrolled 103 patients who received 238 single doses of rituximab. Hypogammaglobulinemia was observed in 58.4% of the patients at least once after a single dose of rituximab treatment and 22.3% developed persistent hypogammaglobulinemia. Serum IgG levels gradually increased during B-cell depletion, and patients with low serum IgG levels at rituximab treatment had persistent hypogammaglobulinemia. Repeated courses of rituximab treatment increased the incidence of hypogammaglobulinemia. A past history of steroid-resistant nephrotic syndrome (SRNS) (odds ratio [OR] = 10.02; 95% confidence interval [CI] = 2.65-37.81; P < 0.001) and low serum IgG levels at rituximab treatment (OR = 7.63; 95% CI = 2.10-27.71; P = 0.002) was significantly associated with hypogammaglobulinemia in multivariate analysis. Hypogammaglobulinemia is a frequent adverse event after rituximab treatment, although IgG levels slightly increase during B-cell depletion. Low serum IgG levels at rituximab treatment and a past history of SRNS are significant risk factors for the development of hypogammaglobulinemia after rituximab treatment.

Long-term persistent mixed chimerism in a patient with Wiskott–Aldrich syndrome after allogeneic hematopoietic stem cell transplantation

The article describes a clinical case of a patient with Wiskott–Aldrich syndrome, in whom long- term persistence of mixed chimerism was determined after hematopoietic stem cell transplantation (HSCT) from a haploidentical donor. Based on the analysis of the patient's clinical picture after HSCT, it was shown that the presence of&gt; 50% of donor cells in the myeloid lineage is necessary for the correction of thrombocytopenia. In addition, the presence of mixed chimerism in B-lymphocytes possibly contributed to the development of autoimmune complications in the patient, as well as to the persistent hypogammaglobulinemia, despite the restoration of the normal numbers of lymphocytes in all main sub-populations. The role of mixed chimerism in the pathogenesis of immune post-transplant complications requires study in large groups of patients with primary immunodeficiencies. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.

Rituximab for rheumatic diseases in children: Results of a retrospective study of the safety of therapy

Objective: to analyze the safety of rituximab (RTM) in children with various rheumatic diseases.Materials and methods. The retrospective study included 81 pediatric patients with a confirmed diagnosis of rheumatic disease. Data on the safety of RTM were analyzed for all patients who received at least one infusion of the drug. All patients underwent a standard clinical, laboratory and instrumental examination in accordance with the verified diagnosis before the appointment of RTM therapy. The dose of RTM for administration was calculated based on 375 mg/m 2 of body surface area, the drug was administered once a week for 1 to 4 consecutive weeks, depending on the number of CD19 lymphocytes determined after the infusion, and the tolerability of therapy.Results. Among the patients included in the study, 38 (46.9%) were with systemic lupus erythematosus (SLE), 16 (19.75%) – with juvenile idiopathic arthritis (JIA), polyarticular variant (14 (87,5%) of them – RF-positive), 9 (11,1%) – with juvenile idiopathic arthritis with systemic onset (sJIA), 6 (7.4%) – with systemic sclerosus (SSc), 5 (6.2%) – with primary Sjogren’s syndrome, 2 (2.5%) – with juvenile dermatomyositis, 4 (4.9%) – with mixed connective tissue disease, and 1 – with livedoid vasculopathy. 53 (65.4%) patients underwent more than one course of RTM therapy, with a maximum of 10 courses. The total number of infusions was 198. The median time between each course was 182 [156–315] days. RTM was effective in 67 (95%) patients, ineffective in 2 (2.5%) patients with sJIA, 2 (2.5%) patients with SLE and macrophage activation syndrome (MAS).Adverse reactions (AE) of mild to moderate severity were reported in 23 (28.4%) patients, including upper respiratory tract infections – in 7 (8.6%), urinary tract infections – in 2 (2.5%), mild infusion reactions that did not require discontinuation of therapy – in 2 (2.5%), clinically insignificant neutropenia (I–II degree) – in 4 (4.9%), a decrease in IgG levels – in 14 (17.5%) patients (median – 5.5 [4.0; 6.9] g/l). Two patients with sJIA had persistent hypogammaglobulinemia for 3 and 5 years after the last RTM infusion, respectively. The incidence of infections in patients with low IgG levels was 35.7%, and no cases were registered in patients with neutropenia. Serious AE was reported in 16 (19.7%) patients: sepsis – in 4 (4.9%), pneumonia – in 3 (3.7%), herpes zoster – in 1 (1.2%), serious infusion reactions – in 2 (2.5%), serious postinfusion reactions within 3–10 days – in 4 (4.9%) (in 3 patients (3.7%) – MAS, in 1 (1.2%) – hemorrhagic vasculitis); death was registered in 2 cases of SLE and MAS (therapy of RTM was inefficient). In general, various AE were reported in 55.6% of patients with sJIA, 52.6% of patients with SLE, 50% of patients with SSc and juvenile dermatomyositis, and 80% of patients with primary Sjogren’s syndrome. Discontinuation of therapy due to serious AE was observed in 15 (18.5%) patients.Conclusion. Our study demonstrated that RTM therapy is highly effective with an acceptable safety profile in children with rheumatic diseases. The safety data obtained indicate the need for careful monitoring of therapy, primarily taking into account the risk of infection, despite the fact that in this study the frequency of infectious complications was not high. A decrease in IgG level was observed in a small proportion of patients and did not correlate with the incidence of infections.