Objective To evaluate whether B-cell depletion before enzyme replacement therapy (ERT) initiation can block acid alpha-glucosidase (GAA) antibody responses and improve clinical outcomes. Study design ...Six subjects with Pompe disease (including 4 cross-reacting immunologic material–negative infants) aged 2-8 months received rituximab and sirolimus or mycophenolate before ERT. Four subjects continued to receive sirolimus, rituximab every 12 weeks, and intravenous immunoglobulin monthly for the duration of ERT. Sirolimus trough levels, IgG, CD3, CD4, CD8, CD19, CD20, N-terminal pro-brain natriuretic peptide, creatine kinase, creatine kinase-MB, C-reactive protein, platelets, alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase were measured regularly. Results Immunomodulation achieved B-cell depletion without adverse effects. After 17-36 months of rituximab, sirolimus and ERT, all subjects lacked antibodies against GAA, 4 continued to gain motor milestones, yet 2 progressed to require invasive ventilation. The absence of infusion-associated reactions allowed the use of accelerated infusion rates. Conclusion B-cell depletion and T-cell immunomodulation in infants naïve to ERT was accomplished safely and eliminated immune responses against GAA, thereby optimizing clinical outcome; however, this approach did not necessarily influence sustained independent ventilation. Importantly, study outcomes support the initiation of immunomodulation before starting ERT, because the study regimen allowed for prompt initiation of treatment.
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 1–10 years. 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.
BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical ...hemolytic uremic syndrome-like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODSWe describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.RESULTSGroup 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation.CONCLUSIONSThis study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy.
Juvenile myasthenia gravis is a pediatric autoimmune disorder of the neuromuscular junction associated with substantial morbidity, for which standard therapies are not always efficacious. The ...objective of our study was to assess the tolerability and efficacy of rituximab use in children with refractory juvenile myasthenia gravis.
We conduced a retrospective cohort study at a single tertiary care referral center to evaluate children with juvenile myasthenia gravis who were treated with rituximab. The clinical status of these participants before and after initiation of rituximab therapy was measured, focusing on numbers of hospital admissions, numbers of immunomodulatory or immunosuppressive medications needed, and Myasthenia Gravis Foundation of America severity class.
Five children with juvenile myasthenia gravis were ascertained who received rituximab as part of their regimen, four of whom had elevated acetylcholine receptor antibodies and one of whom had elevated muscle-specific kinase antibodies. After initiation of rituximab therapy, all participants experienced reduced numbers of immunomodulatory medications during the follow-up period (mean 11.6 months). Four of the five subjects experienced fewer juvenile myasthenia gravis-related hospital admissions and reduced (improved) Myasthenia Gravis Foundation of America classes, with no subjects having moderate or severe symptoms following treatment with rituximab. No significant adverse events were recorded for any of the participants.
Rituximab was well-tolerated and efficacious in this juvenile myasthenia gravis cohort. The beneficial effect of rituximab was most pronounced in the one participant with muscle-specific kinase antibodies.
FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency ...(nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.
The aim of this study was to evaluate the clinical validity of early Sjögren's syndrome (SS) autoantibodies (eSjA), which were originally marketed for early diagnosis of SS, for juvenile SS (JSS) in ...a recently identified pediatric cohort.
A total of 105 symptomatic subjects with eSjA results available were evaluated at the Center for Orphaned Autoimmune Disorders at the University of Florida and enrolled for this study. JSS diagnosis was based on the 2016 ACR/EULAR SS criteria. Demographic/clinical/laboratory parameters were compared between JSS (n = 27) and non-JSS (n = 78) for % positivity, sensitivity, and specificity of eSjA (SP1, anti-salivary protein; CA6, anti-carbonic anhydrase VI; PSP, anti-parotid secretory protein) and classic SS-autoantibodies (cSjA; ANA, SSA/SSB, RF, and others) either alone or in combination. Associations between eSjA and diagnostic/glandular parameters were also determined by Fisher's exact test.
Compared to non-JSS, JSS patients exhibited sicca symptoms demonstrating reduced unstimulated salivary flow rate (USFR) and abnormal glandular features revealed by salivary gland ultrasound (SGUS). Among cSjA, ANA demonstrated the highest sensitivity of 69.2%, while SSA, SSB, and RF showed around 95% specificities for JSS diagnosis. The % positive-SSA was notably higher in JSS than non-JSS (56% vs. 5%). Of eSjA, anti-CA6 IgG was the most prevalent without differentiating JSS (37%) from non-JSS (32%). Sensitivity and specificity of eSjA were 55.6 and 26.9%, respectively. Autoantibodies with potentially applicable specificity/sensitivity for JSS were seen only in cSjA without a single eSjA included. There were no associations detected between eSjA and focus score (FS), USFR, SSA, SGUS, and parotitis/glandular swelling analyzed in the entire cohort, JSS, and non-JSS. However, a negative association between anti-PSP and parotitis/glandular swelling was found in a small group of positive-SSA (n = 19, p = 0.02) whereas no such association was found between anti-PSP-positive compared to anti-PSP-negative. JSS and non-JSS groups differed in FS, USFR, and EULAR SS Patient Reported Index Dryness/Mean in CA6/PSP/ANA, SP1, and SSA-positive groups, respectively. Additionally, a higher FS was found in RF-positive than RF-negative individuals.
eSjA underperformed cSjS in differentiating JSS from non-JSS. The discovery of clinical impact of eSjA on early diagnosis of JSS necessitates a longitudinal study.
Gene replacement therapy is a rational therapeutic strategy and clinical intervention for neurodegenerative disorders like Canavan disease, a leukodystrophy caused by biallelic mutations in the ...aspartoacylase (ASPA) gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for Canavan disease. Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid. The patient served as his own control, and change from baseline was assessed by clinical pathology tests, vector genomes in the blood, antibodies against ASPA and AAV capsids, levels of cerebrospinal fluid (CSF) N-acetylaspartate (NAA), brain water content and morphology, clinical status, and motor function tests. Two years post treatment, the patient’s white matter myelination had increased, motor function was improved, and he remained free of typical severe epilepsy. NAA level was reduced at 3 months and remained stable up to 4 years post treatment. Immunomodulation prior to AAV exposure enables repeat dosing and has prevented an anti-transgene immune response. Dual-route administration of gene therapy may improve treatment outcomes.
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Byrne and colleagues demonstrated that simultaneous intravenous and intracerebroventricular administration of rAAV9-CB6-AspA in a single patient with Canavan disease is a safe approach to improve the patient’s white matter myelination and overall motor function. Prophylactic immunomodulation and the dual route of administration might have improved the outcome.
Objective
To characterize the early disease course in childhood‐onset antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and the 12‐month outcomes in children with AAV.
Methods
...Eligible subjects were children entered into the Pediatric Vasculitis Initiative study who were diagnosed before their eighteenth birthday as having granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg‐Strauss), or ANCA‐positive pauci‐immune glomerulonephritis. The primary outcome measure was achievement of disease remission (Pediatric Vasculitis Activity Score PVAS of 0) at 12 months with a corticosteroid dosage of <0.2 mg/kg/day. Secondary outcome measures included the rates of inactive disease (PVAS of 0, with any corticosteroid dosage) and rates of improvement at postinduction (4–6 months after diagnosis) and at 12 months, presence of damage at 12 months (measured by a modified Pediatric Vasculitis Damage Index PVDI; score 0 = no damage, score 1 = one damage item present), and relapse rates at 12 months.
Results
In total, 105 children with AAV were included in the study. The median age at diagnosis was 13.8 years (interquartile range 10.9–15.8 years). Among the study cohort, 42% of patients achieved remission at 12 months, 49% had inactive disease at postinduction (4–6 months), and 61% had inactive disease at 12 months. The majority of patients improved, even if they did not achieve inactive disease. An improvement in the PVAS score of at least 50% from time of diagnosis to postinduction was seen in 92% of patients. Minor relapses occurred in 12 (24%) of 51 patients after inactive disease had been achieved postinduction. The median PVDI damage score at 12 months was 1 (range 0–6), and 63% of patients had ≥1 PVDI damage item scored as present at 12 months.
Conclusion
This is the largest study to date to assess disease outcomes in pediatric AAV. Although the study showed that a significant proportion of patients did not achieve remission, the majority of patients responded to treatment. Unfortunately, more than one‐half of this patient cohort experienced damage to various organ systems early in their disease course.
Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and ...recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in
IKK-gamma (
NEMO) have been shown to cause familial incontinentia pigmenti (IP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. IKK-gamma is required for the activation of the transcription factor known as “nuclear factor kappa B” and plays an important role in T and B cell function. We hypothesize that “milder” mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor–like signaling pathway, with the IKK signalsome complex playing a significant role.