Canakinumab reverses overexpression of inflammatory response genes in tumour necrosis factor receptor-associated periodic syndrome.

OBJECTIVE: To explore whether gene expression profiling can identify a molecular mechanism for the clinical benefit of canakinumab treatment in patents with tumour necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS: Blood samples were collected from 20 patients with active TRAPS who received canakinumab 150 mg every 4 weeks for 4 months in an open-label proof-of-concept phase II study, and from 20 aged-matched healthy volunteers. Gene expression levels were evaluated in whole blood samples by microarray analysis for arrays passing quality control checks. RESULTS: Patients with TRAPS exhibited a gene expression signature in blood that differed from that in healthy volunteers. Upon treatment with canakinumab, many genes relevant to disease pathogenesis moved towards levels seen in the healthy volunteers. Canakinumab downregulated the TRAPS-causing gene (TNF super family receptor 1A (TNFRSF1A)), the drug-target gene (interleukin (IL)-1B) and other inflammation-related genes (eg, MAPK14). In addition, several inflammation-related pathways were evident among the differentially expressed genes. Canakinumab treatment reduced neutrophil counts, but the observed expression differences remained after correction for this. CONCLUSIONS: These gene expression data support a model in which canakinumab produces clinical benefit in TRAPS by increasing neutrophil apoptosis and reducing pro-inflammatory signals resulting from the inhibition of IL-1ß. Notably, treatment normalised the overexpression of TNFRSF1A, suggesting that canakinumab has a direct impact on the main pathogenic mechanism in TRAPS. TRIAL REGISTRATION NUMBER: NCT01242813.

Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): an open-label, phase II study.

OBJECTIVE: To evaluate the efficacy of canakinumab, a high-affinity human monoclonal anti-interleukin-1ß antibody, in inducing complete or almost complete responses in patients with active tumour necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS: Twenty patients (aged 7-78 years) with active recurrent or chronic TRAPS were treated with canakinumab 150 mg every 4 weeks for 4 months (2 mg/kg for those ≤40 kg) in this open-label, proof-of-concept, phase II study. Canakinumab was then withdrawn for up to 5 months, with reintroduction on relapse, and 4 weekly administration (subsequently increased to every 8 weeks) for 24 months. The primary efficacy variable was the proportion of patients achieving complete or almost complete response at day 15, defined as clinical remission (Physician's Global Assessment score ≤1) and full or partial serological remission. RESULTS: Nineteen patients (19/20, 95%; 95% CI 75.1% to 99.9%) achieved the primary efficacy variable. Responses to canakinumab occurred rapidly; median time to clinical remission 4 days (95% CI 3 to 8 days). All patients relapsed after canakinumab was withdrawn; median time to relapse 91.5 days (95% CI 65 to 117 days). On reintroduction of canakinumab, clinical and serological responses were similar to those seen during the first phase, and were sustained throughout treatment. Canakinumab was well tolerated and clinical responses were accompanied by rapid and sustained improvement in health-related quality of life. Weight normalised pharmacokinetics of canakinumab, although limited, appeared to be consistent with historical canakinumab data. CONCLUSIONS: Canakinumab induces rapid disease control in patients with active TRAPS, and clinical benefits are sustained during long-term treatment. TRIAL REGISTRATION NUMBER: NCT01242813; Results.

The strategic use of biopsy in the diagnosis of coeliac disease in adults.

BACKGROUND: The paediatric guidelines support the use of the 'No Biopsy Approach' in the diagnosis of coeliac disease (CD). We aimed to determine the correlation between anti tissue transglutaminase (anti-TTG serology) ≥10 times the upper limit of normal (ULN), using the Celikey ® ELiA assay and histological findings. Our secondary aim was to determine the safety of this approach in our centre. METHODS: A retrospective analysis of adult patients referred to a tertiary referral centre with raised anti-TTG titres and/or histological changes of coeliac on D2 biopsies between 2014 - 2019. Excluded patients were those who did not have a biopsy performed, or whose biopsy was unavailable for review, selective IgA deficiency, and gluten elimination prior to biopsy. Biopsies were classified according to Marsh, by two independent pathologists, blinded to the anti-TTG titre. RESULTS: 164 patients had positive anti-TTG serology and duodenal biopsy in our centre prior to starting a gluten free diet (GFD) in the period 2014 - 2019. Of these 164 patients (median age 40yrs, 62% female), 68 (33%) had an anti-TTG titre ≥10 x ULN, 99% of which had a Marsh grading ≥ 3 and 1% had a Marsh of 2 on biopsy. 91% had either a normal index gastroscopy or findings of mild gastritis/oesophagitis. CONCLUSIONS: We found a 98.5% positive predictive value (PPV) of determining CD (i.e., Marsh ≥ 3) in those with an anti-TTG ≥10 x ULN. In those with moderate to high-risk clinical suspicion of CD we propose that duodenal biopsy is unnecessary for diagnosis.

COVID-19 in adults: test menu for hospital blood science laboratories.

INTRODUCTION: Coronavirus disease 2019 (COVID-19), is a respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Clinical Blood Sciences Laboratory (CBSL) plays a key role in supporting the monitoring and management of patients with COVID-19 disease. OBJECTIVE: To provide a comprehensive CBSL testing protocol to support the medical management of SARS-CoV-2 infection. METHODS: Description of the biochemical, haematological and immunological tests that have a role in the assessment and monitoring of patients with COVID-19 infection. RESULTS: We provide a test menu for clinical laboratories to ensure the effective monitoring, management and prognostication of COVID-19 patients in hospital. CONCLUSION: Given the rapidity with which patients with COVID-19 disease can deteriorate, we recommend regular testing with vigilance paid to the rate and trajectory of change in each of these parameters.

Clinical presentation of cashew nut allergy in a paediatric cohort attending an allergy clinic in the West of Ireland.

BACKGROUND: Cashew nut (CN) allergy appears to be increasing. Reactions are variable and may include anaphylaxis. AIM: To describe the clinical features of CN allergy in a group of children attending an allergy clinic with suspected peanut allergy and confirmed sensitisation to CN. METHODS: Patients were identified retrospectively by reviewing the Immunology Database at University Hospital Galway over a 5-year period, Oct. 2010 to Sept. 2015. Patients confirmed sensitised to CN (specific IgE > 0.35 kUa/L, ImmunoCAP Assay) were selected and contacted. RESULTS: Over the 5-year period, 115 children were identified; 102/115 were individually contacted. Of the 102 children, 55 had a history of prior CN exposure with confirmed clinical reaction, 43 had no prior CN exposure, and 4 were sensitised and tolerating CN. For those with clinical CN allergy (N = 55), 30 (55%) were male and median age of onset was 2 years (lower quartile 1.5, upper quartile 4.8). Severity of reaction was graded as mild for 13 children, moderate in 13 additional children, and severe in 29 children. Median CN serum IgE level was 3.2 kUa/L (range 0.36 to > 100) in the clinical reaction group, 2.91 kUa/L (range 0.36 to > 100) in the sensitised group, and 3.4 kUa/L (range 0.94 to 5.21) in those tolerating CN. IgE values were not significantly different between those with mild, moderate, or severe reaction to CN (p = 0.346). CONCLUSION: Children are ingesting CN at a young age with more than half of allergic reactions reportedly severe in nature. The specific CN IgE value was not helpful in predicting severity of reactions.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) or familial Hibernian fever: presentation in a four-day-old infant.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is one of a number of well described hereditary periodic febrile syndromes. We report a case in an infant, with a strong family history of this disorder, who presented on day-of-life 4 with high fever, irritability, diarrhea, lethargy, and raised acute phase reactants. An extensive work-up, including a full sepsis evaluation, proved negative. Symptoms resolved spontaneously. Representation with similar symptoms at 7 months of age prompted successful diagnosis after full evaluation. Subsequent genetic mutation analysis has proven positive for the T50M mutation in exon 2 of the TNFRSF1A gene. To our knowledge, this is the youngest reported age of presentation of this rare autoinflammatory disorder which should be considered even at such a young age.

Investigating Idiopathic Inflammatory Myopathy; Initial Cross Speciality Experience with Use of the Extended Myositis Antibody Panel.

The discovery of unique autoantibodies has informed and altered our approach to the diagnosis and management of the inflammatory myopathies. This study reports the initial clinical experience of use of the Extended Myositis Antibody (EMA) panel in the largest university teaching hospital in Ireland. We conducted a retrospective review of all patients who had serum samples tested for myositis specific antibodies and myositis associated antibodies from April 2014 to March 2015. A positive EMA panel was of significant clinical utility in facilitating decisions on appropriate investigations, and need for onward referral to other physicians. Furthermore, this paper highlights the diversity of possible presentations of idiopathic inflammatory myopathy with subsequent need for multi-speciality involvement, and serves to heighten awareness among clinicians of the diagnostic use of extended myositis antibody testing in these cases.

Effect of anti-CD20 (rituximab) on resistant thrombocytopenia in autoimmune lymphoproliferative syndrome.

Fas (CD95) plays an important role in apoptosis. Patients with defects in Fas have an autoimmune lymphoproliferative syndrome (ALPS) characterized by lymphadenopathy, autoimmune cytopenias and an increased incidence of lymphomas. There are approximately 70 known cases described worldwide. The autoimmune cytopenias are difficult to treat in this group. We describe a patient with a defect in the death domain of the FAS molecule who had autoimmune thrombocytopenia resistant to conventional therapy but which responded to a combination of rituximab and vincristine.