Rheumatologic diseases in patients with inborn errors of immunity in the USIDNET registry.

There is a gap in clinical knowledge regarding associations between specific inborn errors of immunity (IEIs) and rheumatologic diseases. This study reports the frequency of rheumatologic conditions in a large cohort of patients with IEI using the USIDNET (United States Immunodeficiency Network) registry. We used the USIDNET registry to conduct the analysis. We included all IEI patients within the registry for whom a diagnosed rheumatologic disease was reported. The total number of patients with IEI in our query was 5058. Among those, 278 (5.49%) patients had a diagnosis of rheumatologic disease. This cohort included 172 (61.8%) female and 106 (38.2%) male patients. Rheumatologic complications were highest in the interferonopathies (66.6%), autoimmune lymphoproliferative syndrome (ALPS) (13.7%), and immunoglobulin G subclass deficiency (IgGSD) (11.11%). Additionally, disease patterns were noted to be different in various IEI disease groups. Inflammatory myopathies were the most common rheumatologic condition in patients with X-linked agammaglobulinemia (1.65%), Sjogren's syndrome was the most common rheumatologic disease reported in ALPS patients (6.85%), and systemic lupus erythematosus was the most common rheumatologic disease in patients with chronic mucocutaneous candidiasis (CMC) (7.41%). Rheumatoid arthritis (RA) report rate was highest in patients with IgGSD (3.70%), specific antibody deficiency (SAD) (3.66%), and ALPS (2.74%). This study reports that rheumatologic diseases are frequently observed in patients with IEI. The frequency of different rheumatologic conditions was variable based on the underlying diagnosis. Clinicians caring for patients with IEI should be vigilant to monitor for rheumatologic complications. Key Points • The rates of reported rheumatologic diseases in the USIDNET registry are different in individual IEIs. • Further studies are needed to guide clinicians for detecting rheumatologic conditions earlier in patients with IEI.

Efficacy and safety of a new immunoglobulin G product, Gammaplex(®), in primary immunodeficiency diseases.

This open-label multi-centre study evaluated a new intravenous immunoglobulin, Gammaplex®, in the treatment of 50 patients with primary immunodeficiency and significant hypogammglobulinaemia. Patients treated previously with other intravenous immunoglobulins received Gammaplex® on their same infusion schedule for 1 year; 22 were on a 21-day and 28 on a 28-day regimen (300-800 mg/kg/infusion). There were no serious, acute bacterial infections, whereas six subjects (12·0%) had at least one such infection in the 6 months before enrollment. Forty subjects (80·0%) had at least one non-serious infection; the median number of infective episodes per subject per year was 3·07. Antibiotics were taken by 38 subjects therapeutically and prophylactically by 16 at some time. Fewer than half (46·0%) missed any time off work or school because of infection or other illness. Trough immunoglobulin (Ig)G levels were above 6·00 g/l in all subjects at all assessments after 15 weeks with two exceptions. Overall, 21·2% of infusions were associated with an adverse event up to 72 h after infusion. The frequency of adverse events increased with infusion rate. Headache was the most common product-related adverse event (7·5% of 703 infusions). In conclusion, Gammaplex® is effective in primary immunodeficiency and is well tolerated.

Intravenous immunoglobulin therapy: indications, potential side effects, and treatment guidelines.

Although intravenous immunoglobulin therapy is used mainly as a replacement therapy in humoral immune deficiency disorders and congenital or acquired conditions, the indications for its use have expanded over the last decade to other disease states, such as autoimmune diseases and variable chronic inflammatory syndromes. The ability to administer large achieving rapidly effective serum immunoglobulin G levels under painless conditions are the main advantages of this form of therapy. Intravenous immunoglobulin therapy has a high safety record although side effects range from mild anaphylactoid reactions to potential life-threatening reactions. It is essential to understand the underlying mechanisms of these potential reactions to assure safe administration.

Processing and presentation of cell-associated varicella-zoster virus antigens by human monocytes.

To determine whether viral antigens associated with infected cells were processed for presentation to T cells, we cultured human blood mononuclear cells (MNC) from varicella-zoster virus (VZV) immune donors with VZV-infected fibroblasts of known HLA type which had been fixed in 0.05% glutaraldehyde. After 7-8 days of culture thymidine uptake by T4+ cells exceeded that of T8+ cells. Stimulated cells were depleted of adherent cells and restimulated with VZV-infected fibroblasts from donors matched or unmatched with the responder for HLA type in the presence or absence of fresh adherent cells. Proliferation of the VZV-specific blasts required the presence of adherent cells matched with the responder lymphocytes for HLA-DR; conversely, the VZV specific response was not restricted by the MHC of the fibroblasts used in the restimulation assay. Preincubation of the adherent cells with chloroquine inhibited the proliferative response in a dose-dependent manner. These results suggest that VZV antigens on infected cells may be processed by monocytes for presentation to T cells.

A standard method of intermittent inhaled therapy via a jet nebulizer.

Current methods of inhaled therapy using gas-propelled nebulizers lack standardization. The frequent use of nebulized therapy in a continuous flow may be the major reason for the inconsistency of the actual fraction of nebulized drug delivered to the patient. In an effort to achieve consistency in the amount of drug delivered to the patient, we evaluated an intermittent system of nebulized therapy, using a fingertip controlled nebulizer, in 18 adolescent asthmatics. This mode of delivery was found to be highly efficient, providing a nebulized fraction of more than 70% of the initial volumes used (0.75 to 2.6 mL). Initial volumes of 0.9 mL and above were equally efficacious, indicating no further benefit of using higher volumes. Nebulized fractions were found to be highly consistent from one patient to another (+/- 1 SD of 14.1%). We conclude that control of the actual dose delivered to the patient can be best achieved through an intermittent mode of delivery.

Excessive accumulation of mucus in children with asthma: a potential role for erythromycin? A case discussion.

A case of severe, life-threatening, reactive airway disease with excessive accumulation of mucus was treated with erythromycin. A sudden remarkable improvement in mobilization of mucus was observed after erythromycin treatment. With the addition of aerosol steroids and cromolyn, the incidence of acute respiratory distress diminished considerably. This occurred after ineffective trials of nebulized beta-adrenergic agents, atropine, cromolyn, aerosol beclomethasone, N-acetylcysteine, and high-dose daily prednisone.

Genetic control of HLA-linked immune responsiveness to (H,G)-A-L.

Fifty-three donors belonging to seven families were tested for their immune response potential to (H,G)-A-L. Most of these donors had been previously tested for their ability to respond to (T,G)-A-L and were all HLA typed as well. The heredity of the ability to respond to (H,G)-A-L by the production of an antigen-specific helper T cell factor is compatible with an autosomal dominant trait linked to HLA. The genotype of an HLA-A/B recombinant individual suggested that a gene controlling the immune response to (H,G)-A-L is linked to HLA-A. Lod scores also suggested a linkage between immune response potential to (H,G)-A-L and HLA-A. The different patterns of responses to (T,G)-A-L and (H,G)-A-L observed in many individuals are compatible with the notion that separate loci are governing the immune responses to the two synthetic polypeptides.

HLA-linked immune responsiveness to (T,G)-A-L: a family study.

The heredity of the immune response potential to the synthetic polypeptide poly(LTyr,LGlu)-poly(DLAla)-poly(LLys) [(T,G)-A-L] and its possible linkage to the major histocompatibility complex of man were studied in 24 families. Peripheral blood lymphocytes (PBL) obtained from 174 donors belonging to 24 unrelated families were educated to (T,G)-A-L on autologous antigen-pulsed adherent cells. The supernatants obtained from these activated PBL were tested for their antigen-specific helper activity in an in vitro antibody production system. All donors were typed for their HLA haplotypes. The results obtained indicated that the ability to respond to (T,G)-A-L by production of an antigen-specific T cell helper factor is inherited as an autosomal dominant trait linked to the responder HLA haplotype.

Phenotyping of proliferating cells in cultures of human lymphocytes.

Lymphocytes stimulated with mitogens, alloantigens or soluble antigens were pulsed with tritiated thymidine to label proliferating cells. Aliquots of the cells were labeled with OKT 4 or OKT 8 mouse monoclonal antibodies and then incubated in microtiter wells coated with goat anti-mouse immunoglobulin G (IgG). Unattached cells were flushed out of the wells: individual wells were then separated for counting in scintillation fluid in a B counter. This method permits simple characterization of the relative T cell subset proliferative responses and is clinically applicable.