Recommendations for the management of secondary hypogammaglobulinaemia due to B cell targeted therapies in autoimmune rheumatic diseases

OBJECTIVES: The association of B cell targeted therapies with development of hypogammaglobulinaemia and infection is increasingly recognized. Our aim was to develop consensus recommendations for immunoglobulin replacement therapy for management of hypogammaglobulinaemia following B cell targeted therapies in autoimmune rheumatic diseases. // METHODS: A modified Delphi exercise involved a 17-member Taskforce committee, consisting of immunologists, rheumatologists, nephrologists, haematologists, a gastroenterologist, an immunology specialist nurse and a patient representative. The first round identified the most pertinent topics to address in the recommendations. A search string was agreed upon for the identification of publications in PubMed focusing on these areas, for a systematic literature review. Original data was presented from this review to the Taskforce committee. Recommendations from the British Society for Rheumatology, the UK Department of Health, EULAR, the ACR, and the American Academy of Allergy, Asthma, and Immunology were also reviewed. The evidence was discussed in a face-to-face meeting to formulate recommendation statements. The levels of evidence and statements were graded according to Scottish Intercollegiate Guidelines Network methodology. // RESULTS: Three overarching principles, eight recommendation statements and a research agenda were formulated. The Taskforce committee voted on these statements, achieving 82–100% agreement for each recommendation. The strength of the recommendations was restricted by the low quality of the available evidence, with no randomized controlled trial data. The recommendations cover risk factors, monitoring, referral for hypogammaglobulinaemia; indications, dosage and discontinuation of immunoglobulin replacement therapy. // CONCLUSION: These are the first recommendations specifically formulated for B cell targeted therapies related to hypogammaglobulinaemia in autoimmune rheumatic diseases. The recommendations are to aid health-care professionals with clinical decision making for patients with hypogammaglobulinaemia

Studies on two polyherbal formulations (ZPTO and ZTO) for comparison of their antidyslipidemic, antihypertensive and endothelial modulating activities

Background Cardiovascular disorders (CVDs) are the leading cause of disease burden worldwide. Apart from available synthetic drugs used in CVDs, there are many herbal formulations including POL-10 (containing 10 herbs), which have been shown to be effective in animal studies but POL-10 was found to cause tachycardia in rodents as its side effect. This study was designed to modify the composition of POL-10 for better efficacy and/or safety profile in CVDs. Methods To assess the antidyslipidemic, antihypertensive and endothelial modulatory properties of two herbal formulations, (ZPTO and ZTO) containing Z: Zingiber officinalis, P: Piper nigrum, T: Terminalia belerica and O: Orchis mascula, different animal models including, tyloxapol and high fat diet-induced dyslipidemia and spontaneously hypertensive rats (SHR) were used. Effect on endothelial function was studied using isolated tissue bath set up coupled with PowerLab data acquisition system. The antioxidant activity was carried out using DPPH radical-scavenging assay. Results Based on preliminary screening of the ingredients of POL-10 in tyloxapol-induced hyperlipidemic rats, ZPTO and ZTO containing four active ingredients namely; Z, P, T and O were identified for further studies and comparison. In tyloxapol-induced hyperlipidemic rats, both ZPTO and ZTO caused significant reduction in serum triglyceride (TG) and total cholesterol (TC). In high fat diet-fed rats, ZPTO decreased TC, low-density lipoproteins cholesterol (LDL-C) and atherogenic index (AI). ZTO also showed similar effects to those of ZPTO with additional merits being more effective in reducing AI, body weight and more importantly raising high-density lipoproteins. In SHR, both formulations markedly reduced systolic blood pressure, AI and TG levels, ZTO being more potent in reversing endothelial dysfunction while was devoid of cardiac stimulatory effect. In addition, ZTO also reduced LDL-C and improved glucose levels in SHR. In DPPH radical-scavenging activity test, ZTO was also more potent than ZPTO. Conclusion The modified formulation, ZTO was not only found more effective in correcting cardiovascular abnormalities than ZPTO or POL-10 but also it was free from tachycardiac side-effect, which might be observed because of the presence of Piper nigrum in ZPTO

Tracking Antigen-Specific T-Cells during Clinical Tolerance Induction in Humans

Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3–5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets

Primary antibody deficiency in adults.

Primary antibody deficiency is defined as a reduction or absence of one or more immunoglobulin isotypes or subclasses, when no other contributory disorder is present. Some patients may have normal serum immunoglobulin concentrations but do not respond appropriately to pathogens; such patients also have a primary antibody deficiency. There are three major forms of antibody deficiency: X-linked agammaglobulinaemia (XLA, Bruton's agammaglobulinaemia), common variable immunodeficiency (CVID), which includes IgG subclass and specific antibody deficiencies, and selective IgA deficiency.1 Other antibody deficiency syndromes are rare; in most cases clinical features, diagnosis, and treatment are similar to those of the three major deficiencies. Although all primary immunodeficiencies are rare, IgA deficiency has an estimated frequency of between 1 in 320 and 1 in 800.2 Overall, a prevalence of 11·6 per million of population is reported, of whom 6 per million have XLA, 5 per million have CVID, and the remainder have autosomal recessive antibody deficiencies.3 Swedish data suggest a higher prevalence of 20-40 per million of population.4 Most primary care physicians will never see a patient, and hospital specialists, other than immunologists, will see only 2 or 3 in a lifetime of practice. Consequences of delayed diagnosis are serious: in a study of 32 patients with primary antibody deficiency, more than two-thirds experienced diagnostic delay leading to serious morbidity.5. © 1991

Primary antibody deficiency in adults.

Primary antibody deficiency is defined as a reduction or absence of one or more immunoglobulin isotypes or subclasses, when no other contributory disorder is present. Some patients may have normal serum immunoglobulin concentrations but do not respond appropriately to pathogens; such patients also have a primary antibody deficiency. There are three major forms of antibody deficiency: X-linked agammaglobulinaemia (XLA, Bruton's agammaglobulinaemia), common variable immunodeficiency (CVID), which includes IgG subclass and specific antibody deficiencies, and selective IgA deficiency.1 Other antibody deficiency syndromes are rare; in most cases clinical features, diagnosis, and treatment are similar to those of the three major deficiencies. Although all primary immunodeficiencies are rare, IgA deficiency has an estimated frequency of between 1 in 320 and 1 in 800.2 Overall, a prevalence of 11·6 per million of population is reported, of whom 6 per million have XLA, 5 per million have CVID, and the remainder have autosomal recessive antibody deficiencies.3 Swedish data suggest a higher prevalence of 20-40 per million of population.4 Most primary care physicians will never see a patient, and hospital specialists, other than immunologists, will see only 2 or 3 in a lifetime of practice. Consequences of delayed diagnosis are serious: in a study of 32 patients with primary antibody deficiency, more than two-thirds experienced diagnostic delay leading to serious morbidity.5. © 1991

Does a gating policy for ANCA overlook patients with ANCA associated vasculitis? An audit of 263 patients.

BACKGROUND: Antineutrophil cytoplasm antibodies (ANCA) are used as diagnostic markers for small-vessel vasculitis of the Wegener Granulomatosis-microscopic polyangiitis (WG-MPA) spectrum, but if testing is applied indiscriminately, its value is diminished. The authors measured the effect of a targeted ANCA testing policy introduced in our institution in an attempt to improve the diagnostic value of testing in patients with suspected vasculitis. METHODS: The authors measured the rate of ANCA requests at a single regional centre in the year prior to and following the introduction of clinical guidelines to ensure appropriate test usage. The authors also audited clinical outcomes in patients in whom ANCA testing was declined. RESULT: Following implementation of the antineutrophil cytoplasm antibodies (ANCA) gating policy, the number of monthly ANCA tests carried out fell from 287+/-30 to 143+/-18 (p<0.0001) and was associated with an increased rate of positivity, from 18.5% (95% CI 17.0 to 20.1%) to 30.3% (27.5 to 33.1%; p<0.0001). The authors undertook a careful review of the case records from 263 patients in whom testing was declined according to the gating policy over an 8-month period. After 6 months' follow-up, no diagnoses of small-vessel vasculitis of the WG-MPA spectrum were reached. CONCLUSIONS: The rational use of ANCA testing to aid in the diagnosis of vasculitis should include a clinical gating policy to improve diagnostic performance. Adherence to a gating policy for ANCA testing coupled with close liaison between clinician and laboratory does not result in either a missed or delayed diagnosis of small-vessel vasculitis belonging to the WG-MPA spectrum

Vitamin E deficiency induced neurological disease in common variable immunodeficiency: two cases and a review of the literature of vitamin E deficiency.

Vitamin E deficiency causes a neurological disorder characterised by sensory loss, ataxia and retinitis pigmentosa due to free radical mediated neuronal damage. Symptomatic vitamin E deficiency has been reported in genetic defects of the vitamin E transport protein and in malabsorption complicating cholestasis, abetalipoproteinaemia, celiac disease, cystic fibrosis and small bowel resection. There are no reports to date of vitamin E deficiency in patients with primary immunodeficiencies. We describe two CVID patients with the associated enteropathy who developed neurological disease because of vitamin E deficiency, suggesting a possible predisposition to developing this complication. We recommend that all CVID patients with evidence of an enteropathy be screened for vitamin E deficiency, as early detection and consequent treatment may prevent, halt or reverse the neurological sequelae

Intravenous immunoglobulin-induced haemolysis: a case report and review of the literature.

OBJECTIVES: To review the incidence and clinical features of intravenous immunoglobulin (IVIg)-induced haemolysis. BACKGROUND: Haemolysis can be a severe complication of IVIg administration. It is due to the passive transfer of blood group antibodies and may result in significant anaemia and renal failure. METHODS: We report a case of severe IVIg-induced haemolysis; review the data reported to vigilance groups (The Medicines and Healthcare Products Regulatory Agency, European Union Drug Regulatory Authorities, Food and Drug Administration and the Canada Vigilance Centre) between January 1998 and May 2012; and systematically review IVIg-induced haemolysis case reports (between January 1948 and January 2013). RESULTS: Nine hundred-twenty five cases of IVIg-induced haemolysis were identified from a review of cases reported to vigilance groups; 62 case reports were included in the systematic review. The majority of these were due to administration of doses of at least 2 g kg(-1) of IVIg (97%). IVIg-induced haemolysis was reported most commonly for patients with blood group A (65%) or AB (26%). One case report noted that in two patients with IVIg-induced haemolysis both received IVIg from the same batch. CONCLUSION: We make the following recommendations for the management of suspected cases of IVIg-induced haemolysis: Stop IVIg infusion and perform tests for haemolysis. Check titres of anti-blood group antibodies in IVIg. Provide supportive management for patient with fluid and/or red blood cell transfusions if necessary. Consider quarantine of the IVIg batch if found to be high titre for anti-A/B. Report reaction to regulatory/vigilance body