293 Autoimmune autonomic ganglionopathy: the NHNN experience

BackgroundAutoimmune Autonomic Ganglionopathy (AAG) is a rare, immune-mediated condition characterised by subacute pandysautonomia. 50% have auto-antibodies to the ganglionic nicotinic acetylcholine receptor (gAChR), affecting synaptic transmission at autonomic ganglia.MethodsWe describe 13 patients (5 female, median age 47) presenting with widespread autonomic failure, confirmed on cardiovascular, sudomotor and pupillometry testing at the National Hospital for Neurology and Neurosurgery (NHNN), and high gAChR antibody levels (>200 pm) measured by radioimmunoprecipitation assay at Oxford University.ResultsOf the 13 patients, 8 had other autoimmune conditions, 3 had antecedent infection and 3 were paraneoplastic. All had orthostatic hypotension, gastro-intestinal and urinary symptoms, 11 had documented pupillary abnormalities (9 mixed sympathetic and parasympathetic deficits, 2 subclinical sympathetic deficits), 11 had secretomotor dysfunction, 8 had generalised/partial anhidrosis, 8 had sexual dysfunction and 7 had evidence of small fibre dysfunction on neurophysiology.Ten received immunomodulatory treatment; 6 plasma exchange and 4 combination treatment including intravenous immunoglobulin, mycophenolate and rituximab. Earlier treatment was associated with greater clinical response.DiscussionPatients with AAG and high gAChR antibody levels have widespread dysfunction of the autonomic nervous system, which can respond dramatically to immunomodulation. Further research is needed to develop robust clinical biomarkers to guide treatment and monitor response.

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Platelet count recovery and seroreversion in immune HIT despite continuation of heparin: further observations and literature review

Thrombosis and Haemostasis ◽

10.1160/th17-03-0212 ◽

2017 ◽

Vol 117 (10) ◽

pp. 1868-1874 ◽

Cited By ~ 7

Author(s):

Jo-Ann Sheppard ◽

Theodore Warkentin ◽

Andrew Shih

Keyword(s):

Platelet Count ◽

Additional Patient ◽

Heparin Induced Thrombocytopenia ◽

Prophylactic Dose ◽

Heparin Administration ◽

Immune Mediated ◽

Antibody Levels ◽

Count Recovery

SummaryOne of the standard distinctions between type 1 (non-immune) and type 2 (immune-mediated) heparin-induced thrombocytopenia (HIT) is the transience of thrombocytopenia: type 1 HIT is viewed as early-onset and transient thrombocytopenia, with platelet count recovery despite continuing heparin administration. In contrast, type 2 HIT is viewed as later-onset (i. e., 5 days or later) thrombocytopenia in which it is generally believed that platelet count recovery will not occur unless heparin is discontinued. However, older reports of type 2 HIT sometimes did include the unexpected observation that platelet counts could recover despite continued heparin administration, although without information provided regarding changes in HIT antibody levels in association with platelet count recovery. In recent years, some reports of type 2 HIT have confirmed the observation that platelet count recovery can occur despite continuing heparin administration, with serological evidence of waning levels of HIT antibodies (“seroreversion”). We now report two additional patient cases of type 2 HIT with platelet count recovery despite ongoing therapeutic-dose (1 case) or prophylactic-dose (1 case) heparin administration, in which we demonstrate concomitant waning of HIT antibody levels. We further review the literature describing this phenomenon of HIT antibody seroreversion and platelet count recovery despite continuing heparin administration. Our observations add to the concept that HIT represents a remarkably transient immune response, including sometimes even when heparin is continued.

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Patient-led Remote IntraCapillary pharmacoKinetic Sampling (fingerPRICKS) for therapeutic drug monitoring in patients with inflammatory bowel disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab128 ◽

2021 ◽

Author(s):

Desmond Chee ◽

Rachel Nice ◽

Ben Hamilton ◽

Edward Jones ◽

Sarah Hawkins ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Blood Sampling ◽

Therapeutic Drug ◽

Linear Regression Models ◽

Cross Sectional ◽

Immune Mediated ◽

Low Volume ◽

Antibody Levels ◽

At Home

Abstract Background & Aims Because of COVID-19 public health restrictions, telemedicine has replaced conventional outpatient follow up for most patients with chronic immune-mediated inflammatory disorders treated with biologic drugs. Innovative solutions to facilitate remote therapeutic drug monitoring are therefore required. Low-volume intracapillary blood sampling can be undertaken by patients at home and samples returned by post to central laboratories. We sought to report the effect of the COVID-19 pandemic on requests for therapeutic drug monitoring and the equivalence, acceptability and effectiveness of low volume Patient-led Remote IntraCapillary pharmacoKinetic Sampling (fingerPRICKS) compared to conventional venepuncture. Methods We undertook a cross-sectional blood sampling methods comparison study and compared sample types using linear regression models. Drug and antidrug antibody levels were measured using standard ELISAs. Acceptability was assessed using a purpose-designed questionnaire. Results Therapeutic drug monitoring requests for adalimumab (96.5 [70.5 - 106] per week to 52 [33.5 - 57.0], p < 0.001) but not infliximab (184.5 [161.2 - 214.2] to 161 [135 – 197.5], p = 0.34) reduced during the first UK stay-at-home lockdown compared with the preceding six months. Fingerprick sampling was equivalent to conventional venepuncture for adalimumab, infliximab, vedolizumab, and ustekinumab drug, and anti-adalimumab and -infliximab antibody levels. The median (IQR) volume of serum obtained using intracapillary sampling was 195µL (130-210). More than 87% (90/103) patients agreed that intracapillary testing was easy and 69% (71/103) preferred it to conventional venepuncture. In routine care, 75.3% (58/77) patients returned two blood samples within 14 days to permit remote assessment of biologic therapeutic drug monitoring. Conclusions Therapeutic drug monitoring can be undertaken using patient-led remote intracapillary blood sampling and has the potential to be a key adjunct to telemedicine in patients with immune-mediated inflammatory diseases.

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The Intersection of Metformin and Inflammation

AJP Cell Physiology ◽

10.1152/ajpcell.00604.2020 ◽

2021 ◽

Author(s):

Leena P. Bharath ◽

Barbara S. Nikolajczyk

Keyword(s):

Mitochondrial Function ◽

Immune Cells ◽

Immune Cell ◽

Cell Types ◽

Remarkable Effect ◽

Tumor Onset ◽

Age Related ◽

Immune Mediated ◽

Autoimmune Conditions ◽

Near Term

The biguanide metformin is the most commonly used antidiabetic drug. Recent studies show that metformin not only improves chronic inflammation by improving metabolic parameters but also has a direct anti-inflammatory effect. In light of these findings, it is essential to identify the inflammatory pathways targeted by metformin to develop a comprehensive understanding of the mechanisms of action of this drug. Commonly accepted mechanisms of metformin action include AMPK activation and inhibition of mTOR pathways, which are evaluated in multiple diseases. Additionally, metformin's action on mitochondrial function and cellular homeostasis processes such as autophagy, is of particular interest because of the importance of these mechanisms in maintaining cellular health. Both dysregulated mitochondria and failure of the autophagy pathways, the latter of which impair clearance of dysfunctional, damaged, or excess organelles, affect cellular health drastically and can trigger the onset of metabolic and age-related diseases. Immune cells are the fundamental cell types that govern the health of an organism. Thus, dysregulation of autophagy or mitochondrial function in immune cells has a remarkable effect on susceptibility to infections, response to vaccination, tumor onset, and the development of inflammatory and autoimmune conditions. Here we summarize the latest research on metformin's regulation of immune cell mitochondrial function and autophagy as evidence that new clinical trials on metformin with primary outcomes related to the immune system should be considered to treat immune-mediated diseases over the near term.

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Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation

Hematology ◽

10.1182/asheducation-2009.1.225 ◽

2009 ◽

Vol 2009 (1) ◽

pp. 225-232 ◽

Cited By ~ 14

Author(s):

Thomas L. Ortel

Keyword(s):

Platelet Count ◽

Heparin Therapy ◽

Severe Thrombocytopenia ◽

Drug Induced ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Immune Mediated ◽

Number Of Patients ◽

Increased Risk ◽

Antibody Levels

Abstract Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of ~50 to 60 × 109 platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). The timing of the thrombocytopenia in relation to the initiation of heparin therapy is critically important, with the platelet count beginning to drop within 5 to 10 days of starting heparin. A more rapid drop in the platelet count can occur in patients who have been recently exposed to heparin (within the preceding 3 months), due to preformed anti-heparin/PF4 antibodies. A delayed form of HIT has also been described that develops within days or weeks after the heparin has been discontinued. In contrast to other drug-induced thrombocytopenias, HIT is characterized by an increased risk for thromboembolic complications, primarily venous thromboembolism. Heparin and all heparin-containing products should be discontinued and an alternative, non-heparin anticoagulant initiated. Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.

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Significance of Crescentic Glomeruli in Acute Kidney Injury with Rheumatoid Arthritis

Case Reports in Nephrology and Dialysis ◽

10.1159/000500105 ◽

2019 ◽

Vol 9 (1) ◽

pp. 42-48

Author(s):

Ali Ayaash ◽

Dipesh Maan ◽

Anastasios Kapetanos ◽

Mark Bunker ◽

Mary Chester Wasko ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Acute Kidney Injury ◽

Kidney Injury ◽

Renal Outcome ◽

Primary Role ◽

Tubular Necrosis ◽

Immune Mediated ◽

Autoimmune Conditions ◽

Spontaneous Improvement

Crescentic glomerulonephritis (GN) without immune reactants or deposits (referred to as pauci-immune) is typically characterized by the presence of anti-neutrophilic cytoplasmic antibodies (ANCA). While ANCA-negative patients might be expected to have a more benign course, they often have poor renal outcomes, especially without treatment with steroids and immune-modulating therapy. Pauci-immune crescentic GN can also co-exist with other autoimmune conditions, including rheumatoid arthritis (RA). Here, we describe an ANCA-negative patient with RA who developed dialysis-requiring acute kidney injury (AKI) with findings consistent with focal pauci-immune crescentic GN (i.e., no IgG or immune complex on kidney biopsy). Coexistent conditions included Klebsiella sepsis attributed to pneumonia, rhabdomyolysis, leukocytoclastic immune-mediated skin vasculitis, and positive ANA. He had spontaneous improvement in renal function without immunosuppressive therapy. This crescentic GN was not associated with poor renal outcome as AKI resolved with supportive care and treatment of his infection. The AKI was likely multifactorial with co-existing acute tubular necrosis in the setting of Kebsiella sepsis and rhabdomyolysis, and the crescentic GN was felt more likely to be related to the infection rather than having a primary role. This case highlights the importance of viewing crescentic GN in the context of the clinical picture, as it may not always lead to the need of aggressive immune suppression and is not a universally poor prognostic kidney finding. However, these cases do warrant close follow-up as our patient had recurrent RA disease manifestations over the next 2 years that eventually led to his death from severe pulmonary hypertension.

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Ganglionic Acetylcholine Receptor Antibodies and Autonomic Dysfunction in Autoimmune Rheumatic Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21041332 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1332 ◽

Cited By ~ 2

Author(s):

Michie Imamura ◽

Akihiro Mukaino ◽

Koutaro Takamatsu ◽

Hiroto Tsuboi ◽

Osamu Higuchi ◽

...

Keyword(s):

Autonomic Dysfunction ◽

Rheumatic Diseases ◽

Lupus Erythematosus ◽

Acetylcholine Receptors ◽

Case Reports ◽

Pathophysiological Mechanism ◽

Autoimmune Rheumatic Diseases ◽

Immune Mediated ◽

Autonomic Disturbance ◽

Antibody Levels

Autonomic neuropathy has been reported in autoimmune rheumatic diseases (ARD) including Sjögren’s syndrome, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. However, the pathophysiological mechanism underlying autonomic dysfunction remains unknown to researchers. On the other hand, autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder, which causes dysautonomia that is mediated by autoantibodies against ganglionic acetylcholine receptors (gAChRs). The purpose of this review was to describe the characteristics of autonomic disturbance through previous case reports and the functional tests used in these studies and address the importance of anti-gAChR antibodies. We have established luciferase immunoprecipitation systems to detect antibodies against gAChR in the past and determined the prevalence of gAChR antibodies in various autoimmune diseases including AAG and rheumatic diseases. Autonomic dysfunction, which affects lower parasympathetic and higher sympathetic activity, is usually observed in ARD. The anti-gAChR antibodies may play a crucial role in autonomic dysfunction observed in ARD. Further studies are necessary to determine whether anti-gAChR antibody levels are correlated with the severity of autonomic dysfunction in ARD.

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Autoimmune Comorbid Conditions in Multiple Sclerosis

US Neurology ◽

10.17925/usn.2011.07.02.132 ◽

2011 ◽

Vol 07 (02) ◽

pp. 132 ◽

Cited By ~ 11

Author(s):

Regina Berkovich ◽

Dawood Subhani ◽

Lawrence Steinman ◽

◽

...

Keyword(s):

Multiple Sclerosis ◽

Autoimmune Disease ◽

Autoimmune Diseases ◽

Genetic Susceptibility ◽

Interferon Beta ◽

Comorbid Conditions ◽

Factors Influencing ◽

Immune Mediated ◽

Autoimmune Conditions ◽

Autoimmune Comorbidity

Autoimmune comorbidities occur frequently in multiple sclerosis (MS). They may arise as a consequence of a genetic susceptibility to autoimmunity. Certain pathological mechanisms are common to several autoimmune conditions. In the presence of comorbid autoimmune conditions, certain MS therapeutics may be preferable to others. Autoimmune comorbidity associated with MS could be a factor in predicting response to specific MS therapeutics. Treatment with interferon beta has been reported to precipitate immune-mediated abnormalities or to exacerbate existing autoimmune diseases. In comparison, there are fewer reported cases of treatment-associated comorbidities linked with autoimmune disease in patients taking glatiramer acetate. Knowledge of the factors influencing autoimmune comorbidities may provide insights into the complex pathogenesis of MS and help inform treatment choices.

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A Case Report of Congenital Fiber Type Disproportion with an Increased Level of Anti-ACh Receptor Antibodies

Case Reports in Pediatrics ◽

10.1155/2013/607678 ◽

2013 ◽

Vol 2013 ◽

pp. 1-3

Author(s):

Shigemi Kimura ◽

Shiro Ozasa ◽

Keiko Nomura ◽

Hirofumi Kosuge ◽

Kowasi Yoshioka

Keyword(s):

Fiber Type ◽

Achr Antibody ◽

Immune Mediated ◽

Long Time ◽

Muscle Hypotonia ◽

Antibody Levels ◽

The Relationship ◽

Receptor Antibodies

Congenital fiber type disproportion (CFTD) is a form of congenital myopathy, which is defined by type 1 myofibers that are 12% smaller than type 2 myofibers, as well as a general predominance of type 1 myofibers. Conversely, myasthenia gravis (MG) is an acquired immune-mediated disease, in which the acetylcholine receptor (AChR) of the neuromuscular junction is blocked by antibodies. Thus, the anti-AChR antibody is nearly specific to MG. Herein, we report on a case of CFTD with increased anti-AChR antibody levels. A 23-month-old boy exhibited muscle hypotonia and weakness. Although he could walk by himself, he easily fell down and could not control his head for a long time. His blood test was positive for the anti-AChR antibody, while a muscle biopsy revealed characteristics of CFTD. We could not explain the relationship between MG and CFTD. However, we considered different diagnoses aside from MG, even when the patient’s blood is positive for the anti-AChR antibody.

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The Role of Sex Hormones in Multiple Sclerosis

European Neurology ◽

10.1159/000494262 ◽

2018 ◽

Vol 80 (1-2) ◽

pp. 93-99 ◽

Cited By ~ 8

Author(s):

Mirla Avila ◽

Arpana Bansal ◽

John Culberson ◽

Alan N. Peiris

Keyword(s):

Multiple Sclerosis ◽

Sex Hormones ◽

Treatment Strategies ◽

Female Gender ◽

Current Treatment ◽

Sex Hormone ◽

Immune Mediated ◽

Autoimmune Conditions ◽

The Central Nervous System

Multiple sclerosis (MS) is a chronic inflammatory demyelination disorder with an immune-mediated pathophysiology that affects the central nervous system (CNS). Like other autoimmune conditions, it has a predilection for female gender. This suggests a gender bias and a possible hormonal association. Inflammation and demyelination are hallmarks of MS. Oligodendrocytes are the myelinating cells of the CNS and these continue to be generated by oligodendrocyte precursor cells (OPCs). The process of remyelination represents a major form of plasticity in the developing adult CNS. Remyelination does occur in MS, but the process is largely inadequate and/or incomplete. Current treatment strategies primarily focus on reducing inflammation or immunosuppression, but there is a need for more extensive research on re-myelination as a possible mechanism of treatment. Previous studies have shown that pregnancy leads to an increase in OPC proliferation, oligodendrocyte generation and the number of myelinated axons in the maternal CNS. Studies have also suggested that this remyelination is possibly mediated by estriol. Sex hormones in particular have been shown to have an immuno-protective effect in TH1-driven autoimmunity diseases. The aim of our article is to review the available research on sex hormone-specific immune modulatory effects, assess its remyelination potential in MS, and suggest a future path for more extensive research on sex hormone as a target for therapeutics in MS.

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Relationships between immune indicators of parasitic gastroenteritis, nematode burdens and faecal dry matter in sheep

Animal Production Science ◽

10.1071/an09144 ◽

2010 ◽

Vol 50 (3) ◽

pp. 219 ◽

Cited By ~ 12

Author(s):

A. R. Williams ◽

D. G. Palmer ◽

I. H. Williams ◽

P. E. Vercoe ◽

D. L. Emery ◽

...

Keyword(s):

Light Chain ◽

Dry Matter ◽

Serum Antibody ◽

Enzyme Linked Immunosorbent Assay ◽

Interleukin 5 ◽

Teladorsagia Circumcincta ◽

Immune Mediated ◽

Before And After ◽

Parasitic Gastroenteritis ◽

Antibody Levels

Immune-mediated scouring in sheep is a mucosal hypersensitivity response caused by ingesting infective parasite larvae. In this experiment we tested the hypothesis that levels of parasite-specific antibodies and also interleukin-5 (IL-5) would be negatively correlated with worm numbers, but also faecal dry matter (FDM), in parasite-resistant Merino sheep. Forty Merino rams were challenged with Trichostrongylus colubriformis and Teladorsagia circumcincta larvae every day for 6 weeks, after which they were euthanised and total worm burdens determined. Faecal samples were taken for measurement of worm egg counts and FDM. Serum was collected from the rams before and after the larval challenge commenced, and levels of ovine immunoglobulin light chain, IgG, IgM, IgA and IgE specific for T. colubriformis and T. circumcincta as well as IL-5 were determined by sandwich enzyme-linked immunosorbent assay. IL-5 and all serum antibodies apart from T. colubriformis-specific light chain were significantly increased by the larval challenge. However, none of the antibodies, or IL-5, was correlated with FDM. Negative correlations were observed between the number of adult T. circumcincta and antibody levels; however, there was little relationship between antibodies and numbers of T. colubriformis. It was concluded that serum antibody levels are a poor indicator of the susceptibility of sheep to immune-mediated scouring. Because of these results, sheep breeders should continue to select for low worm egg count and focus on phenotypic indicators of scouring, such as dags, as a means to reduce diarrhoea.

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