Single-cycle rituximab-induced immunologic changes in children: Enhanced in neuroimmunologic disease?

OBJECTIVE: To investigate the immunologic impact of a single cycle of rituximab (RTX) in children and adolescents with immune-mediated disorders, we evaluated B cells and immunoglobulin levels of 20 patients with neuroimmunologic, nephrologic, dermatologic, and rheumatologic disorders treated under recommended guidelines. METHODS: Retrospective study of immunologic changes in children (aged ≤18 years) diagnosed with immune-mediated disorders in which RTX was prescribed between June 2014 and February 2019. Patients were excluded if they had prior diagnosis of malignant disease or primary immunodeficiency. Patients were clinically and immunologically followed up every 3 months. Only patients having received a single cycle of RTX and with a follow-up greater than 12 months were included in the analysis of persistent dysgammaglobulinemia. RESULTS: Twenty children were included. Median age at RTX treatment was 12.8 years (interquartile range [IQR] 6.6-15.5 years). Median follow-up was 12.6 months (IQR 10.2-24 months). Of the 14 patients eligible for persistent dysgammaglobulinemia analysis (3 had received RTX retreatment, 2 had <12 months post-RTX follow-up, and in 1 data for this time point was missing), 2/14 (14%) remained with complete B-cell depletion, and 5/14 (36%) had dysgammaglobulinemia. Patients with dysgammaglobulinemia were younger (7.8 vs 15.6 years, p = 0.072), had more underlying neuroimmunologic diseases (5/5 vs 0/9, p < 0.001), and had received more frequently concentrated doses of RTX (3/5 vs 1/9, p = 0.05) than patients without dysgammaglobulinemia. Kinetics of immunoglobulins in the 20 patients revealed a decrease as early as 3 months after RTX in patients with neuroimmunologic disorders. CONCLUSION: In our cohort, single-cycle RTX-induced dysgammaglobulinemia was enhanced in patients with neuroimmunologic diseases. Further studies are needed to confirm this observation.

Tolerability and safety of long-term rituximab treatment in systemic inflammatory and autoimmune diseases.

Rituximab, an anti-CD20 monoclonal antibody causing selective B-cell depletion, is used for various systemic inflammatory and autoimmune diseases (SIADs). Long-term safety data on rituximab are limited. The objectives of this study were to evaluate the long-term safety and tolerability of rituximab treatment for SIADs. A retrospective, single-center observational study including all patients ≥ 16 years treated with rituximab for SIADs was performed. The electronic medical records were reviewed, and data concerning indication and duration of rituximab treatment, prior and concurrent immunosuppressive therapy, and adverse events such as infections requiring hospitalization, dysgammaglobulinemia and end organ damage, were collected. A total of 70 patients were included, with a median treatment duration of 54 months, ranging 30-138 months. The most common indications for rituximab treatment were granulomatosis with polyangiitis (22.9%), primary Sjögren's syndrome (20.0%) and systemic lupus erythematosus (14.3%). Infections and persistent dysgammaglobulinemia were the most common adverse events, occurring in 34.3% and 25.7%, respectively. A total of 64 infections were observed in 24 (34.3%) patients, including 1 case of fatal infection. Seventeen patients performed B-cell quantitation during the first 2 years following discontinuation, of which only four (19.0%) demonstrated B-cell reconstitution. End organ damage occurred in two patients, presenting as pyoderma gangrenosum and interstitial pneumonitis. No opportunistic infections were observed. Three patients died during the observational period, of which one was due to lethal infection. This study presents observational data with long treatment duration. It demonstrates that long-term rituximab treatment is relatively well tolerated, and that no cumulative side effects were observed.

Rituximab salvage therapy in adults with immune thrombocytopenia: retrospective study on efficacy and safety profiles.

Splenectomy remains the preferred treatment for chronic immune thrombocytopenia (ITP) after corticosteroid failure, despite the risks of despite surgical complications and infection. The aim of this study was to assess the efficacy of and tolerance to rituximab through a retrospective analysis of 35 refractory/relapsing ITP patients treated from 2004 to 2013. The median age of subjects was 46 years (14-80). Rituximab was given at a weekly dose of 375 mg/m(2) for 4 weeks. Median time from diagnosis to first infusion was 17 months (1-362) and follow-up was 47 months (2-133). The overall response rates at 1 and 2 years after the first infusion were 47 and 38 %, with complete response rates of 24 and 25 %, respectively. Median duration of response was 38 months (1-123), with 37 % of patients maintaining a durable response (>1 year). Twenty-nine percent of patients had undergone splenectomy. A durable response after rituximab was more frequently observed in patients undergoing second-line therapy than those in third or later (83 versus 35 %, P = 0.01). Forty-four percent of patients experienced mild hypogammaglobulinaemia after rituximab, and no clinical infection occurred. To conclude, rituximab should be considered as an alternative treatment to splenectomy. Its efficacy and safety profile should lead us to choose this medical option therapy before surgery for ITP patients.

Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes.

BACKGROUND: Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature. METHODS: We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out. RESULTS: We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia. CONCLUSION: With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.

Effects of sulfasalazine treatment on serum immunoglobulin levels in children with juvenile chronic arthritis.

This article describes the effects of sulfasalazine (SSZ) treatment on serum immunoglobulin (Ig) levels in 6 children with oligoarticular- or polyarticular onset juvenile chronic arthritis (JCA). None of the children who developed dysimmunoglobulinemia during treatment showed clinical symptoms of this adverse event, in particular none developed severe infections. All patients regained normal immunoglobulin levels after discontinuing SSZ treatment. One patient with a partial IgA deficiency at the start of SSZ treatment showed a slow increase in the IgA level during treatment. During follow-up (4-6 years), one patient spontaneously developed a dysimmunoglobulinemia and one patient developed diabetes mellitus. Based on these case reports and review of the literature we advocate monitoring of serum immunoglobulin levels while on SSZ treatment.

IgG subclass imbalance in children with acute lymphoblastic leukemia receiving maintenance chemotherapy.

Serum levels of IgG subclasses were measured in 18 children with acute lymphoblastic leukemia (ALL) receiving maintenance chemotherapy and in 36 age-matched controls in order to attempt to analyse the effects of chemotherapy. The IgG subclasses were measured by enzyme linked immunosorbent assay. Serum IgG1, IgG2 and IgG4 levels in the patients were significantly (p less than 0.01, p less than 0.005, p less than 0.005) lower than in the controls, but serum IgG3 levels in patients were as high as in controls. Suppression on IgG2 and IgG4 were more profound than IgG1. In six children, the levels of the IgG subclasses were measured at diagnosis, during maintenance chemotherapy and one year after cessation of chemotherapy. The levels of the four IgG subclasses at diagnosis and after cessation of chemotherapy were as high as those in control children except for the IgG4 levels in the post-chemotherapy group. IgG2 and IgG4 may be more susceptible to suppression by chemotherapy than IgG1 and IgG3 may not be suppressed by chemotherapy.

Immunodeficiencies associated with sulphasalazine therapy in inflammatory arthritis.

Abnormalities in serum immunoglobulin levels (Igs) are documented in a series of 350 patients with rheumatoid arthritis (RA) and other inflammatory joint diseases treated with sulphasalazine (SASP) for up to 10 years. Low Ig levels occurred in just over 10% of patients after therapy. Three per cent developed selective IgA deficiency between 8 and 20 weeks after starting SASP. Low IgG levels occurred in 2% at 4-52 weeks and low IgM levels in 5% after 3-7 months. One per cent developed panhypogammaglobulinaemia (hypo gamma) 3-7 months after commencing therapy. Most immunodeficiencies were not accompanied by other toxic reactions and SASP was continued in all but one patient with a rash and thrombocytopenia. A good clinical response was observed in most patients particularly those with selective IgA deficiency and hypo gamma. Two patients with hypo gamma developed chest infections which responded to antibiotics. A low level of individual Igs is not usually an indication to stop SASP unless accompanied by other reactions. Panhypo gamma is potentially serious and should be monitored carefully and replacement therapy should be considered in these patients if infections occur.

[Synergistic effect of organic solvents and tobacco smoke on the indicators of humoral immunity in humans]. / Sinergicheskoe vliianie organicheskikh rastvoritelei i tabachnogo dyma po pokazateliam gumoral'nogo immuniteta cheloveka.

Medical examinations were performed among 49 non-smokers, 47 workers who had been smoking for more than 10 years, 19 non-smokers exposed to organic solvents and 41 smoking persons occupationally exposed to organic solvents. Both cigarette smoking and the action of organic solvents. decreased the levels of IgA, AgG, IgM and that of lysozyme. In persons exposed to the actions of both cigarette smoking and benzol and its homologues, more significant decreases of IgA, AgG, IgM and lysozyme concentrations were revealed as compared to those affected by one of the factors. The same concerned the IgD level. The contributors proposed that cigarette smoking should be taken into account when evaluating the immunotoxic properties of industrial factors.

Crusted scabies in acquired selective IgA deficiency.

Crusted scabies, an unusual clinical variant of human scabies mite infestation, is usually reported in cases of gross debility, mental deficiency, or immunosuppression. We report here the occurrence of crusted scabies in a 40-year-old man with acquired selective IgA deficiency suspected to be caused by long-term medication with phenytoin for epilepsy.

[Immunological effects of captopril and ramipril in patients with hypertension]. / Immunologicheskii éffekt kaptoprila i ramiprila u bol'nykh gipertonicheskoi bolezn'iu.

Fifteen patients with essential hypertension underwent treatment with captopril (7 patients) and ramipril (8 patients). The drugs belong to angiotensin-converting enzyme (ACE) inhibitors. Pretreatment immunological examination and that after a 10-15-week course of the above therapy involved measurements of IgG, IgA, IgE and beta 2-microglobulin. The analysis of the trend in the immunological indices demonstrated that captopril, distinct from ramipril by the presence of a sulfhydryl group, caused a decrease in immunological parameters suggesting a potential role of culfhydryl groups in mediating ACE inhibitor action on the immune system. The immunological properties of captopril may appear useful in various systemic diseases.

Serum IgA deficiency induced by prolonged phenytoin treatment.

In a longitudinal study we have evaluated several immunological parameters in thirty three epileptic children and adolescents 4 to 14 years old treated with phenytoin, and matched normal controls. The patients had significantly lower levels than normal controls of IgA (153 +/- 89 vs 236 +/- 128 mg/dL p less than 0.001) and IgM (155 +/- 58 vs 217 +/- 105 mg/dL p less than 0.01). The decrease in serum IgA levels correlated with the length of treatment (r = 0.44, p less than 0.03). Eight of the patients had IgA deficiency. In 7 of these children, T lymphocytes subpopulations were determined. The results did not differ significantly from the matched controls.

[Synergistic effect of organic solvents and tobacco smoke on serum immunoglobulin levels in humans]. / Synergistyczny wplyw rozpuszczalników organicznych i dymu tytoniowego na poziom immunoglobulin surowicy krwi u czlowieka.

The IgG, IgA, IgM, IgD and IgE levels in the blood serum was determined using the radial immunodiffusion method--the Tri-Partigen and the Partigen plated produced by Behringin 49 male non-smokers, 47 subjects who had been smoking for more than 10 years, 19 non-smokers occupationally exposed to organic solvents and 41 smokers exposed to the above-mentioned chemical compounds. It was found that both tobacco smoke and organic solvents, when acting separately, diminish the IgA and IgG level in the serum. Additionally, in the smokers the lowering of the IgM level occurred. In smokers occupationally exposed to benzene and its homologues the decrease in the IgA, IgG and IgM level in the serum was more significant than in those exposed to either tobacco smoke or organic solvents. The authors emphasize the role of smoking in the evaluation of the immunotoxic effect of various factors of industrial origin.

[Immunoelectrophorogram and serum levels of immunoglobulins G, A and M in automobile tire factory workers]. / Immunoelektroforogram oraz stezenia immunoglobulin G, A i M w surowicy krwi pracowników zakladow opon samochodowych.

Electrophoresis and immunoelectrophoresis of serum proteins and concentrations of IgG, IgA and IgM in serum were estimated in 87 rubber tire workers producing rubber mixtures (44 males) and tubes (25 males and 18 females). The total serum protein concentration, as compared with controls, was not changed, however the percentage of gamma globulins was elevated and that of albumins and alpha and beta globulins reduced. The immunoelectrophoretic distribution frequently showed a rise of acute phase proteins and immunoglobulins, most frequently those of IgG and IgA. Quantitative determinations showed a significant rise of serum IgG and IgA and in workers employed at the production of rubber mixtures also a fall of IgM concentrations, as compared to control groups.

Transient phenytoin induced IgA deficiency and permanent IgE increase.

This is a report of a 9-year-old epileptic boy, who was studied over a period of 7 years. The seizures started when he was 2 months old. He was treated with phenytoin from the age of 2 years and 7 months. Serum and salivary IgA were absent with high IgE serum total. The routine immunologic studies were normal. The IgA was normalized after phenytoin withdrawal, but IgE determination increased progressively without any atopic symptoms. The T4 (helper)/T8 (suppressor) ratio decreased (1.0 and 1.2) on two different days, although above the normal limit. The phenytoin only modified the IgA levels. These data suggest that a primary immunoregulatory abnormality may be present in drug induced IgA deficiency.