Publications by authors named "Helen J Lachmann"

175 Publications

Change in N-terminal pro-B-type natriuretic peptide at 1 year predicts mortality in wild-type transthyretin amyloid cardiomyopathy.

Heart 2021 May 14. Epub 2021 May 14.

National Amyloidosis Centre, Division of Medicine, University College London, London, UK

Objectives: Wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is a progressive and fatal condition. Although prognosis can be determined at the time of diagnosis according to National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage, the clinical course varies substantially between individuals. There are currently no established measures of rate of disease progression. Through systematic analysis of functional, biochemical and echocardiographic disease-related variables we aimed to identify prognostic markers of disease progression in wtATTR-CM.

Methods: This is a retrospective observational study of 432 patients with wtATTR-CM diagnosed at the UK NAC, none of whom received disease-modifying therapy. The association between mortality from the 12-month timepoint and change from diagnosis to 12 months in a variety of disease-related variables was explored using Cox regression.

Results: Change in N-terminal pro-B-type natriuretic peptide concentration (∆ NT-proBNP) at 12 months from diagnosis was the strongest predictor of ongoing mortality and was independent of both change in other disease-related variables (HR 1.04 per 500 ng/L increase (95% CI 1.01 to 1.07); p=0.003) and a range of known prognostic variables at the time of diagnosis (HR 1.07 per 500 ng/L increase (95% CI 1.02 to 1.13); p=0.007). An increase in NT-proBNP of >500 ng/L, >1000 ng/L and >2000 ng/L during the first year of follow-up occurred in 45%, 35% and 16% of patients, respectively.

Conclusion: Change in NT-proBNP concentration during the first year of follow-up is a powerful independent predictor of mortality in wtATTR-CM.
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http://dx.doi.org/10.1136/heartjnl-2021-319063DOI Listing
May 2021

Cardiac Magnetic Resonance-Derived Extracellular Volume Mapping for the Quantification of Hepatic and Splenic Amyloid.

Circ Cardiovasc Imaging 2021 Apr 20:CIRCIMAGING121012506. Epub 2021 Apr 20.

Division of Medicine, National Amyloidosis Centre, University College London, London, United Kingdom. (L.C., M.B., R.M., S.L., A.M.-N., D.F.H., T.K., R.K.P., Y.R., T.R., O.C.C., J.B., M.S., S.G., T.L., H.L., A.W., S.S., S.M., C.W., D.S.K., J.G., P.N.H., M.F.).

Background: Systemic amyloidosis is characterized by amyloid deposition that can involve virtually any organ. Splenic and hepatic amyloidosis occurs in certain types, in some patients but not others, and may influence prognosis and treatment. SAP (serum amyloid P component) scintigraphy is uniquely able to identify and quantify amyloid in the liver and spleen, thus informing clinical management, but it is only available in 2 centers globally. The aims of this study were to examine the potential for extracellular volume (ECV) mapping performed during routine cardiac magnetic resonance to: (1) detect amyloid in the liver and spleen and (2) estimate amyloid load in these sites using SAP scintigraphy as the reference standard.

Methods: Five hundred thirty-three patients referred to the National Amyloidosis Centre, London, between 2015 and 2017 with suspected systemic amyloidosis who underwent SAP scintigraphy and cardiac magnetic resonance with T1 mapping were studied.

Results: The diagnostic performance of ECV to detect splenic and hepatic amyloidosis was high for both organs (liver: area under the curve, -0.917 [95% CI, 0.880-0.954]; liver ECV cutoff, 0.395; sensitivity, 90.7%; specificity, 77.7%; <0.001; spleen: area under the curve, -0.944 [95% CI, 0.925-0.964]; spleen ECV cutoff, 0.385; sensitivity, 93.6%; specificity, 87.5%; <0.001). There was good correlation between liver and spleen ECV and amyloid load assessed by SAP scintigraphy (r=0.504, <0.001; r=0.693, <0.001, respectively). There was high interobserver agreement for both the liver and spleen (ECV liver intraclass correlation coefficient, 0.991 [95% CI, 0.984-0.995]; <0.001; ECV spleen intraclass correlation coefficient, 0.995 [95% CI, 0.991-0.997]; <0.001) with little bias across a wide range of ECV values.

Conclusions: Our study demonstrates that ECV measurements obtained during routine cardiac magnetic resonance scans in patients with suspected amyloidosis can identify and measure the magnitude of amyloid infiltration in the liver and spleen, providing important clues to amyloid type and offering a noninvasive measure of visceral amyloid burden that can help guide and track treatment.
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http://dx.doi.org/10.1161/CIRCIMAGING.121.012506DOI Listing
April 2021

Autologous stem cell transplantation vs bortezomib based chemotheraphy for the first-line treatment of systemic light chain amyloidosis in the UK.

Eur J Haematol 2021 Apr 27;106(4):537-545. Epub 2021 Jan 27.

National Amyloidosis Centre, University College London, London, UK.

Objectives: The benefit of autologous stem cell transplantation (ASCT) in the treatment of light chain (AL) amyloidosis requires re-evaluation in the modern era. This retrospective case-matched study compares ASCT to bortezomib for the treatment of patients with AL amyloidosis.

Methods: Newly diagnosed patients with AL amyloidosis treated with ASCT or bortezomib between 2001 and 2018 were identified. Patients were excluded if the time from diagnosis to treatment exceeded 12 months. Patients were matched on a 1:1 basis, using a propensity-matched scoring approach.

Results: A total of 136 propensity score-matched patients were included (ASCT n = 68, bortezomib n = 68). There was no significant difference in overall survival at two years (P = .908, HR: 0.95, CI: 0.41-2.20). For ASCT vs bortezomib: overall haematological response rate at 6 months was 90.6% vs 92.5%; organ response at 12 months: cardiac (70.0% vs 54%, P > .999), renal (74% vs 24%, P = .463) liver (21% vs 22%, P = .048); median progression-free survival (50 vs 42 months P = .058, HR: 0.61, CI: 0.37-1.02) and time to next treatment (68 vs 45 months, P = .145, HR: 0.61, CI: 0.31-1.19). More patients required treatment in the bortezomib group compared to ASCT group at 24 months (41 vs 23, Chi-squared P = .004) and 48 months (57 vs 41, Chi-squared P = .004).

Conclusions: This small retrospective study suggests that there is no clear survival advantage of ASCT over bortezomib therapy. A prospective randomised controlled trial evaluating ASCT in AL amyloidosis is critically needed.
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http://dx.doi.org/10.1111/ejh.13582DOI Listing
April 2021

Renal transplant outcomes in amyloidosis.

Nephrol Dial Transplant 2021 01;36(2):355-365

National Amyloidosis Centre, University College London, London, UK.

Background: Outcomes after renal transplantation have traditionally been poor in systemic amyloid A (AA) amyloidosis and systemic light chain (AL) amyloidosis, with high mortality and frequent recurrent disease. We sought to compare outcomes with matched transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy (DN), and identify factors predictive of outcomes.

Methods: We performed a retrospective cohort study of 51 systemic AL and 48 systemic AA amyloidosis patients undergoing renal transplantation. Matched groups were generated by propensity score matching. Patient and death-censored allograft survival were compared via Kaplan-Meier survival analyses, and assessment of clinicopathological features predicting outcomes via Cox proportional hazard analyses.

Results: One-, 5- and 10-year death-censored unadjusted graft survival was, respectively, 94, 91 and 78% for AA amyloidosis, and 98, 93 and 93% for AL amyloidosis; median patient survival was 13.1 and 7.9 years, respectively. Patient survival in AL and AA amyloidosis was comparable to DN, but poorer than ADPKD [hazard ratio (HR) = 3.12 and 3.09, respectively; P < 0.001]. Death-censored allograft survival was comparable between all groups. In AL amyloidosis, mortality was predicted by interventricular septum at end diastole (IVSd) thickness >12 mm (HR = 26.58; P = 0.03), while survival was predicted by haematologic response (very good partial or complete response; HR = 0.07; P = 0.018). In AA amyloidosis, recurrent amyloid was associated with elevated serum amyloid A concentration but not with outcomes.

Conclusions: Renal transplantation outcomes for selected patients with AA and AL amyloidosis are comparable to those with DN. In AL amyloidosis, IVSd thickness and achievement of deep haematologic response pre-transplant profoundly impact patient survival.
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http://dx.doi.org/10.1093/ndt/gfaa293DOI Listing
January 2021

Defining colchicine resistance/intolerance in patients with familial Mediterranean fever: a modified-Delphi consensus approach.

Rheumatology (Oxford) 2020 Dec 17. Epub 2020 Dec 17.

Division of Paediatric Rheumatology, Department of Paediatrics and Autoinflammation Reference Center Tuebingen, University Hospital Tuebingen, Tuebingen, Germany.

Objectives: Colchicine is the main treatment for familial Mediterranean fever (FMF). Although a number of individuals with FMF are intolerant/resistant to colchicine, there is no standard definition of colchicine resistance/intolerance. We developed a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF that may serve as a guide for clinicians and health authorities.

Methods: A set of statements was identified using a modified-Delphi consensus-based approach. The process involved development of an initial colchicine resistance/intolerance-related questionnaire derived from a systematic literature review. The questionnaire, which was completed by an international panel of 11 adult and pediatric rheumatologists with expertise in FMF, was analysed anonymously. The results informed draft consensus statements that were discussed by a round-table expert panel, using a nominal group technique to agree on the selection and wording of the final statements.

Results: Consensus among the panel was achieved on 8 core statements defining colchicine resistance/intolerance in patients with FMF. A definition of resistance was agreed upon that included recurrent clinical attacks (average one or more attacks per month over a 3-month period), or persistent laboratory inflammation in between attacks. Other core statements recognize the importance of assessing treatment adherence, and the impact of active disease and intolerance to colchicine on quality of life.

Conclusion: Based on expert opinion, a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF were identified to help guide clinicians and health authorities in the management of patients with FMF.
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http://dx.doi.org/10.1093/rheumatology/keaa863DOI Listing
December 2020

INSAID Variant Classification and Eurofever Criteria Guide Optimal Treatment Strategy in Patients with TRAPS: Data from the Eurofever Registry.

J Allergy Clin Immunol Pract 2021 02 9;9(2):783-791.e4. Epub 2020 Nov 9.

National Amyloidosis Centre, UCL Division of Medicine, Royal Free Campus, University College London, London, United Kingdom. Electronic address:

Background: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNF super family receptor 1A (TNFRSF1A) gene. Data regarding long-term treatment outcomes are lacking.

Objective: To assess correlations of genotype-phenotypes in patients with TRAPS, as defined by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification and Eurofever criteria, with treatment responses.

Methods: Data from 226 patients with variants of the TNFRSF1A gene and enrolled in the Eurofever registry were classified according to the INSAID classification in groups A (pathogenic or likely pathogenic variants), B (variants of uncertain significance or not classified variants), and C (benign or likely benign variants) and screened for Eurofever criteria.

Results: In group A (127 of 226 patients, 56%), all fulfilled Eurofever criteria and 20 of 127 patients (16%) developed AA amyloidosis. In group B (78 of 226 patients, 35%), 40 of 78 patients (51%) did not fulfill Eurofever criteria, displaying a lower incidence of abdominal pain (P < .02) and higher efficacy rate of on-demand nonsteroidal anti-inflammatory drugs (P < .02) and colchicine (P < .001). Group C (21 of 226 patients, 9%) presented a milder disease (P < .02) and none fulfilled Eurofever criteria. Anti-IL-1 drugs were the most frequently used in patients fulfilling Eurofever criteria, with the highest efficacy rate (>85% complete response). No patients on anti-IL-1 treatments developed AA amyloidosis, and 7 women with a history of failure to conceive had successful pregnancies.

Conclusion: Anti-IL-1 drugs are the best maintenance treatment in patients with TRAPS. The diagnosis of TRAPS should be considered very carefully in patients of group B not fulfilling Eurofever criteria and group C, and colchicine may be preferable as the first maintenance treatment.
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http://dx.doi.org/10.1016/j.jaip.2020.10.053DOI Listing
February 2021

Cardiovascular disease risk assessment in patients with familial Mediterranean fever related renal amyloidosis.

Sci Rep 2020 10 27;10(1):18374. Epub 2020 Oct 27.

Division of Paediatric Rheumatology, Department of Paediatrics, Schulich School of Medicine & Dentistry, University of Western Ontario, 800 Commissioners Rd E. B1-146, London, ON, N6A 5W9, Canada.

Chronic inflammation and proteinuria is a risk factor for cardiovascular disease (CVD) in patients with chronic kidney diseases and rheumatologic disorders. Our aim was to investigate the CVD events (CVDEs) and survival between the patients with FMF-related AA amyloidosis and glomerulonephropathies (GN) to define possible predictors for CVDEs. A prospective follow-up study with FMF-amyloidosis and glomerulonephropathy (GN) was performed and patients were followed for CVDEs. Flow-mediated dilatation (FMD), FGF-23, serum lipid, hsCRP levels, BMI and HOMA were assessed. A Cox regression analysis was performed to evaluate the risk factors for CVDEs. There were 107 patients in the FMF-amyloidosis group and 126 patients with GN group. Forty-seven CVDEs were observed during the 4.2-years follow up; all 28 patients in the FMF-amyloidosis group and 14/19 patients with GN developed CVDEs before the age of 40 (p = 0.002). CVD mortality was 2.8 times higher (95% CI 1.02-7.76) in patients with FMF-amyloidosis. Across both groups, FMD and FGF23 (p < 0.001) levels were independently associated with the risk of CVDEs. Patients with FMF-amyloidosis are at increased risk of early CVDEs with premature mortality age. FGF 23, FMD and hsCRP can stratify the risk of early CVD in patients with FMF-related AA amyloidosis.
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http://dx.doi.org/10.1038/s41598-020-75433-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591897PMC
October 2020

Somatic Mutations in and Severe Adult-Onset Autoinflammatory Disease.

N Engl J Med 2020 12 27;383(27):2628-2638. Epub 2020 Oct 27.

From the National Human Genome Research Institute (D.B.B., A.K.O., W.P., N.B., D.L.R., D.O.C., K.M., P.H., S.R., L.X., H.O., M.N., A.J., R.S.L., N.D., J.J.C., M.C.V.M., D.N., B.D.S., W.A.G., S.M.B., I.A., D.L.K.), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (M.A.F., K.A.S., S.N., W.L.T., S.G., C.C.-R., W.G., E.R., K.V.W., G.W., S.B., S.D., Z.D., R.A.C., M.J.K., M.G., P.C.G.), the National Institute of Dental and Craniofacial Research (J.C.C., A.J.A., A.W.), the Undiagnosed Diseases Program, Common Fund, Office of the Director (N.B., D.L.R., M.C.V.M., D.N., W.A.G.), the Hematology Branch, National Heart, Lung, and Blood Institute (Z.W., B.P., E.M.G., F.G.-R., L.W.D., C.S.H., N.S.Y.), the National Institute of Allergy and Infectious Diseases (K.S.B.), the Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (C.-C.R.L.), the National Institutes of Health (NIH) Intramural Sequencing Center, National Human Genome Research Institute (J.M.), the Department of Laboratory Medicine (W.W., M.T., A.D.-F., K.R.C.), and the National Eye Institute (M.A.-A.), NIH, Bethesda, and GeneDx, Gaithersburg (K.R.) - both in Maryland; and the National Amyloidosis Centre, Royal Free Hospital London NHS Foundation Trust and University College London, London (D.R., H.J.L.), and the National Institute for Health Research-Leeds Biomedical Research Centre and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds (S.S.) - both in the United Kingdom.

Background: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.

Methods: We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.

Results: We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.

Conclusions: Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
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http://dx.doi.org/10.1056/NEJMoa2026834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847551PMC
December 2020

Disease progression in cardiac transthyretin amyloidosis is indicated by serial calculation of National Amyloidosis Centre transthyretin amyloidosis stage.

ESC Heart Fail 2020 Sep 13. Epub 2020 Sep 13.

National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK.

Aims: Cardiac transthyretin amyloidosis (ATTR-CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow-up and whether it maintains its prognostic value throughout the disease course.

Methods And Results: We performed a retrospective study of 945 patients with wild-type ATTR-CM (wtATTR-CM) or hereditary ATTR-CM associated with the V122I variant (V122I-hATTR-CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease-modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan-Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow-up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR-CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95-2.67; P < 0.001; Stage III vs. II, HRs 1.64-2.25; P < 0.001-0.013]. An increase from NAC ATTR Stage I, which occurred in 21%, 32%, and 44% of evaluable patients at 6, 12, and 24 months of follow-up respectively, was highly predictive of ongoing mortality at each time point (HRs 2.58-3.22; P < 0.001) and in each genotypic subgroup (HRs 1.86-4.38; P < 0.05). Increase in NAC ATTR stage occurred earlier in V122I-hATTR-CM than in wtATTR-CM (43% vs. 27% at 12 months of follow-up; P = 0.003).

Conclusions: National Amyloidosis Centre ATTR stage predicts ongoing survival throughout the disease natural history in ATTR-CM, and an increase from NAC ATTR Stage I at diagnosis to a higher NAC ATTR stage predicts mortality throughout follow-up. Serial calculation of NAC ATTR stage suggests a more aggressive phenotype in V122I-hATTR-CM than in wtATTR-CM.
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http://dx.doi.org/10.1002/ehf2.12989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755026PMC
September 2020

Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

Turk J Med Sci 2020 11 3;50(SI-2):1591-1610. Epub 2020 Nov 3.

National Amyloidosis Centre, Royal Free London NHS Foundation Trust and University College London, London, UK

Familial Mediterranean fever (FMF) (OMIM #249100) is the most common hereditary autoinflammatory disease in the world. FMF is caused by gain of function mutations of MEFV gene which encodes an immune regulatory protein, pyrin. Over the last few years, we have witnessed several new developments in the pathogenesis, genetic testing, diagnosis, comorbidities, disease related damage and treatment approaches to FMF. Elucidation of some of the pathogenic mechanisms has led to the discovery of pathways involved in inflammatory, metabolic, cardiovascular and degenerative diseases. The use of next generation sequencing in FMF has revealed many new gene variants whose clinical significance may be clarified by developing functional assays and biomarkers. Clinically, although FMF is considered an episodic disease characterized by brief attacks, recent systematic studies have defined several associated chronic inflammatory conditions. Colchicine is the mainstay of FMF treatment, and interleukin (IL)-1 antagonists are the treatment of choice in refractory or intolerant cases. Experience of IL-1 antagonists, anakinra and canakinumab, is now available in thousands of colchicine resistant or intolerant FMF patients. In this contemporary review, we surveyed current FMF knowledge in the light of these recent advances.
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http://dx.doi.org/10.3906/sag-2008-11DOI Listing
November 2020

Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate.

Nat Commun 2020 07 8;11(1):3412. Epub 2020 Jul 8.

Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, King's College London, London, SE1 1UL, UK.

Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.
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http://dx.doi.org/10.1038/s41467-020-17179-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343868PMC
July 2020

The value of screening biopsies in light-chain (AL) and transthyretin (ATTR) amyloidosis.

Eur J Haematol 2020 Sep 23;105(3):352-356. Epub 2020 Jun 23.

National Amyloidosis Centre, Centre for Amyloidosis & Acute Phase Proteins, Division of Medicine, University College London, London, UK.

Introduction: Systemic amyloidosis is a histological diagnosis, often achieved via critical organ biopsy. Screening biopsies represent a low-risk approach to diagnosis.

Objectives And Methods: All patients with systemic AL and ATTR amyloidosis who underwent abdominal fat aspiration (AFA) and either a bone marrow (BM) or gastrointestinal (GI) biopsy at the UK National Amyloidosis Centre (2006-2019) were identified. We sought to determine diagnostic sensitivity in relation to whole body amyloid burden, amyloid type and organ involvement.

Results: Diagnostic sensitivity established in 471 patients with AL (n = 321) and ATTR (n = 150) amyloidosis, respectively, was 73.2% and 27.3% for AFA (P< .001), 59.7% and 42.2% for BM (P< .001), and 74.6% and 44.6% for GI biopsy (P< .001). ATTR amyloid deposits were detected in 35.4% BMs and 33.3% of GI biopsies when AFA did not demonstrate amyloid. In AL amyloidosis, sensitivity of combined AFA and BM biopsy in AL amyloidosis was 82.9%. There was a strong association between whole body amyloid burden and sensitivity of each screening biopsy method. The diagnostic sensitivity of screening biopsies ranged from 80.0% to 90.5% for patients with a large amyloid load on I-SAP scintigraphy in comparison with 53.9%-79.0% in those with no visceral amyloid visible on imaging.

Conclusion: Performing both AFA and BM biopsy should be considered in suspected AL amyloidosis to substantially reduce the clinical risk associated with critical organ biopsy. The sensitivity of screening biopsies in ATTR amyloidosis is poor.
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http://dx.doi.org/10.1111/ejh.13458DOI Listing
September 2020

Rapid response to single agent daratumumab is associated with improved progression-free survival in relapsed/refractory AL amyloidosis.

Amyloid 2020 Sep 15;27(3):200-205. Epub 2020 May 15.

National Amyloidosis Centre, University College London, London, UK.

Daratumumab is a monoclonal antibody, which targets CD38; an antigen expressed on malignant plasma cells in AL amyloidosis thus providing a rationale for its use. Patients treated with daratumumab monotherapy (2016-2019) for relapsed/refractory systemic AL amyloidosis were identified from the database at the UK National Amyloidosis Centre. Of 50 evaluable patients, haematological responses at 3 months were: CR - 19 (38%), VGPR - 14 (28%), PR - 9 (18%) and no response - 8 (16%). Median time to response was 1 (1-6) month. Of assessable patients, cardiac, renal and hepatic responses were seen in 43.8%, 25.0% and 0% of patients whilst progression occurred in 25.0%, 12.5% and 37.5% respectively. Patients achieving a CR had longer median OS (not reached vs. 22.7 months [95% CI 17.0-28.4 months]) ( = .036). Furthermore, patients achieving a rapid response (at 1 month) had a longer median PFS (not reached vs. 9 months [95% CI 5.8-12.2 months]) ( = .013). Daratumumab monotherapy is effective in multiply-relapsed systemic AL amyloidosis and should be considered, if available, in patients who have not received prior daratumumab therapy. Responses are achieved rapidly and overall response rate was 84%. CR predicts overall survival whilst speed of response is predictive of a longer PFS.
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http://dx.doi.org/10.1080/13506129.2020.1765768DOI Listing
September 2020

Two types of systemic amyloidosis in a single patient.

Amyloid 2020 Dec 6;27(4):275-276. Epub 2020 May 6.

National Amyloidosis Centre, University College London Medical School, Royal Free Hospital Campus, London, United Kingdom.

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http://dx.doi.org/10.1080/13506129.2020.1760238DOI Listing
December 2020

Epidemiologic and Survival Trends in Amyloidosis, 1987-2019.

N Engl J Med 2020 04;382(16):1567-1568

National Amyloidosis Centre, London, United Kingdom

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http://dx.doi.org/10.1056/NEJMc1917321DOI Listing
April 2020

ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era.

Clin Chem 2020 04;66(4):525-536

Department of Medical Genetics, Rare Diseases and Personalized Medicine, Reference Center CEREMAIA, CHU Montpellier, University of Montpellier, Montpellier, France.

Background: Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential.

Methods: The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting.

Results: In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease.

Conclusions: These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.
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http://dx.doi.org/10.1093/clinchem/hvaa024DOI Listing
April 2020

A randomised placebo controlled trial of anakinra for treating pustular psoriasis: statistical analysis plan for stage two of the APRICOT trial.

Trials 2020 Feb 10;21(1):158. Epub 2020 Feb 10.

Imperial Clinical Trials Unit, Imperial College London, W12 7RH, London, UK.

Background: Current treatment options for Palmoplantar Pustulosis (PPP), a debilitating chronic skin disease which affects the hands and feet, are limited. The Anakinra for Pustular psoriasis: Response in a Controlled Trial (APRICOT) aims to determine the efficacy of anakinra in the treatment of PPP. This article describes the statistical analysis plan for the final analysis of this two-staged trial, which was determined prior to unblinding and database lock. This is an update to the published protocol and stage one analysis plan.

Methods: APRICOT is a randomised, double-blind, placebo-controlled trial of anakinra versus placebo, with two stages and an adaptive element. Stage one compared treatment arms to ensure proof-of-concept and determined the primary outcome for stage two of the trial. The primary outcome was selected to be the change in Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. Secondary outcomes include other investigator-assessed efficacy measures of disease severity, participant-reported measures of efficacy and safety measures. This manuscript describes in detail the outcomes, sample size, general analysis principles, the pre-specified statistical analysis plan for each of the outcomes, the handling of missing outcome data and the planned sensitivity and supplementary analyses for the second stage of the APRICOT trial.

Discussion: This statistical analysis plan was developed in compliance with international trial guidelines and is published to increase transparency of the trial analysis. The results of the trial analysis will indicate whether anakinra has a role in the treatment of PPP.

Trial Registration: ISCRTN, ISCRTN13127147. Registered on 1 August 2016. EudraCT Number 2015-003600-23. Registered on 1 April 2016.
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http://dx.doi.org/10.1186/s13063-020-4103-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011285PMC
February 2020

Amyloidosis Diagnosed in Solid Organ Transplant Recipients.

Transplantation 2020 02;104(2):415-420

Centre for Amyloidosis & Acute Phase Proteins, Division of Medicine (Royal Free Campus), London, UK.

Background: Development of amyloidosis post solid-organ transplantation has not been reported, although plasma cell neoplasms are a rare form of posttransplant lymphoproliferative disorder, which could be complicated by light chain amyloidosis (AL) amyloidosis.

Methods: We searched our database of 5112 patients seen between 1994 and 2018 with a diagnosis of amyloidosis post solid-organ transplant. Patients were excluded if the amyloid diagnosis preceded the transplant date. The indication and type of organ transplant were recorded in addition to the amyloidosis type, organs involved, treatment given, and survival.

Results: Thirty patients were identified. The median age at diagnosis with amyloidosis was 52 years (range 33-77). The median time from transplantation to diagnosis was 10.5 years (0.58-36). The grafts were kidney (N = 25, 83.3%), liver (N = 2, 6.7%), heart (N = 2, 6.7%), and combined heart, lung, and kidney (N = 1, 3.3%). The type of amyloidosis was systemic AL (N = 14, 47%), serum amyloid A amyloidosis (AA) (N = 11, 37%), localized AL (N = 3, 10%), wild-type transthyretin amyloidosis (ATTR) (N = 1, 3.3%), and amyloid of uncertain type (N = 1, 3.3%). Renal graft dysfunction was seen in 11 of 25 (44%) cases. Median graft survival was 185 months (96-269), and median survival from diagnosis with amyloidosis was 45 months (2-89); median survival by amyloidosis type was localized AL: 64 months (20-67), systemic AL: 23.5 months (0-95), ATTR amyloidosis: 17 months, and AA, 15 months (0-77).

Conclusions: This series is the first description of amyloidosis post solid-organ transplant; 30 cases among 5112 amyloid patients >24 years suggests that amyloidosis may occur post solid-organ transplantation with an overall poor survival.
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http://dx.doi.org/10.1097/TP.0000000000002813DOI Listing
February 2020

Use of ixazomib, lenalidomide and dexamethasone in patients with relapsed amyloid light-chain amyloidosis.

Br J Haematol 2020 05 26;189(4):643-649. Epub 2020 Jan 26.

National Amyloidosis Centre, University College London (Royal Free Campus), London, UK.

With improving outcomes in amyloid light-chain (AL) amyloidosis, there is a need to study novel agents in this setting. We report outcomes of 40 patients with relapsed AL amyloidosis treated with ixazomib + lenalidomide + dexamethasone (IRd). Haematological responses were assessed on an intention-to-treat basis at three months: complete response (CR) - 8 (20·5%), very good partial response (VGPR) - 8 (20·5%), partial response (PR) - 7 (17·9%) and no response (NR) - 16 (41·0%). One patient had missing data. Six patients subsequently improved response. Best responses were: CR - 10 (25·6%), VGPR - 8 (20·5%), PR - 7 (17·9%), NR - 14 (35·9%). Cardiac and renal organ responses occurred in 5·6% and 13·3% respectively. Median progession-free survival (PFS) was 17·0 months (95% CI 7·3-20·7 months), improving to 28·8 months (95% CI 20·6-37·0 months) in those achieving CR/VGPR. Median overall survival was 29·1 months (95% CI 24-33 months). Serious adverse events were seen in 14 (35·0%) patients inclusive of 15 admissions due to: infection (6/15, 40·0%), fluid overload (5/15, 33·3%), cardiac arrhythmia (2/15, 13·3%), renal dysfunction (1/15, 6·6%) and anaemia (1/15, 6·6%). In summary, IRd is an oral treatment option with a manageable toxicity profile leading to deep responses in 47% of patients with relapsed AL amyloidosis.
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http://dx.doi.org/10.1111/bjh.16401DOI Listing
May 2020

A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib.

Blood 2019 12;134(25):2271-2280

National Amyloidosis Centre, University College London, Royal Free Campus, London, United Kingdom.

Bortezomib is a standard therapy in light-chain amyloidosis (AL), but little is known about response duration. A difference in involved amyloidogenic and uninvolved serum-free light chains (dFLC) < 10 mg/L (low dFLC response) predicts survival in AL patients with low presenting dFLC (20-50 mg/L). We report outcomes in the largest AL cohort treated with upfront bortezomib and explore the impact of posttreatment dFLC < 10 mg/L ("stringent dFLC response"). A total of 915 newly diagnosed AL patients treated with bortezomib and assessed at our center were included. Hematologic responses, 6-month dFLC, organ responses, overall survival (OS), and time-to-next-treatment (TNT) (excluded patients who died without starting second-line treatment) were evaluated. Overall response rate (intent-to-treat) was 65%, with 49% complete response (CR)/very good partial response/low dFLC response and with a stringent dFLC response, dFLC 10-40 mg/L, and dFLC > 40 mg/L was 30%, 22%, and 48%, respectively. Median OS was 72 months. A total of 289 patients died without progressing to second-line treatment. Median TNT was not reached, and 55% had not progressed to further treatment at 7 years. Patients with stringent dFLC responses had significantly better OS and TNT than did those with lesser responses. A total of 72% of CR patients did not progress to further treatment at 3 years compared with 84% with stringent dFLC responses. Cardiac responses were better in those with stringent dFLC responses (61%) compared with lesser responses (45%; P = .005). Upfront bortezomib confers durable hematologic responses. A stringent dFLC response predicts prolonged TNT and impressive organ responses.
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http://dx.doi.org/10.1182/blood.2019000834DOI Listing
December 2019

IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis.

J Invest Dermatol 2020 04 17;140(4):816-826.e3. Epub 2019 Sep 17.

Department of Medical and Molecular Genetics, School of Basic & Medical Biosciences, King's College London, London, United Kingdom. Electronic address:

Psoriasis is an immune-mediated skin disorder associated with severe systemic comorbidities. Whereas IL-36 is a key disease driver, the pathogenic role of this cytokine has mainly been investigated in skin. Thus, its effects on systemic immunity and extracutaneous disease manifestations remain poorly understood. To address this issue, we investigated the consequences of excessive IL-36 activity in circulating immune cells. We initially focused our attention on generalized pustular psoriasis (GPP), a clinical variant associated with pervasive upregulation of IL-36 signaling. By undertaking blood and neutrophil RNA sequencing, we demonstrated that affected individuals display a prominent IFN-I signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 deregulation and IFN-I over-expression in patients with severe psoriasis vulgaris (PV). We also found that the activation of IFN-I genes was associated with extracutaneous morbidity, in both GPP and PV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates toll-like receptor (TLR)-9 activation and IFN-α production. This effect was mediated by the upregulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/ IFN-I axis contributing to extracutaneous inflammation in psoriasis.
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http://dx.doi.org/10.1016/j.jid.2019.08.444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097848PMC
April 2020

A 24-year experience of autologous stem cell transplantation for light chain amyloidosis patients in the United Kingdom.

Br J Haematol 2019 12 13;187(5):642-652. Epub 2019 Aug 13.

National Amyloidosis Centre, University College London, London, UK.

Autologous stem cell transplantation (ASCT) is considered to be the best method to achieve deep haematological/organ responses and improve survival in selected patients with AL amyloidosis. This field has been led by US centres and is less utilised in Europe. The introduction of effective chemotherapy agents for AL prompted us to re-evaluate UK outcomes of ASCT in affected patients. A total of 264 AL amyloidosis patients treated with an ASCT between 1994 and 2018 were identified. Patient baseline characteristics, transplant-related mortality (TRM) and overall survival (OS) were analysed. The median OS post-ASCT was 87 months [95% confidence interval (CI): 77-106 months]. The median time from ASCT to next treatment was 48 months (95% CI: 29-55 months). A haematological response was achieved in 94·8% of patients and was a strong predictor of time to next treatment [P < 0·0001, hazard ratio (HR) = 1·75, 95% CI = 1·35-2·28] and OS (P = 0·007, HR = 1·91, 95% CI = 1·19-3·07). Organ response was: cardiac (n = 28, 60·9%), renal (n = 101, 76%) and liver (n = 7, 13·5%). Overall TRM was 8·7%, with a significant reduction over time (1994-2000: 18·8%; 2001-2006: 13·6%; 2007-2012: 6·2%; 2013-2018: 1·1%). In conclusion, ASCT is significantly safer and remains a highly effective treatment with excellent long-term survival; it should be more widely considered as a treatment option for systemic AL amyloidosis.
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http://dx.doi.org/10.1111/bjh.16143DOI Listing
December 2019

Cardiac biomarkers are prognostic in systemic light chain amyloidosis with no cardiac involvement by standard criteria.

Haematologica 2020 05 8;105(5):1405-1413. Epub 2019 Aug 8.

National Amyloidosis Centre, University College London, London, UK.

Patients with systemic immunoglobulin light chain amyloidosis (AL) with no evidence of cardiac involvement by consensus criteria have excellent survival, but 20% will die within 5 years of diagnosis and prognostic factors remain poorly characterised. We report the outcomes of 378 prospectively followed Mayo stage I patients (N-terminal pro b-type natriuretic peptide <332 ng/L, high sensitivity cardiac troponin <55 ng/L). The median presenting N-terminal pro b-type natriuretic peptide was 161 ng/L, high sensitivity cardiac troponin 10 ng/L, creatinine 76 μmol/L and mean left ventricular septal wall thickness, 10 mm. Median follow up was 42 (1-117 months), with 71 deaths; median overall survival was not reached (78% survival at 5 years). Although no patients had cardiac involvement by echocardiogram, a proportion (n=25/90, 28%) had cardiac involvement by cardiac magnetic resonance imaging. Age, autonomic nervous system involvement, N-terminal pro b-type natriuretic peptide >152 ng/L, high sensitivity cardiac troponin >10 ng/L and cardiac involvement by magnetic resonance imaging were predictive for survival; on multivariate analysis only N-terminal pro b-type natriuretic peptide >152 ng/L (<0.008, hazard ratio [HR] 3.180, confidence interval [CI]: 1.349-7.495) and cardiac involvement on magnetic resonance imaging (=0.026, HR=5.360, CI: 1.219-23.574) were prognostic. At 5 years, 70% of patients with N-terminal pro b-type natriuretic peptide >152 ng/L were alive. In conclusion, N-terminal pro b-type natriuretic peptide is prognostic for survival in patients with no cardiac involvement by consensus criteria and cardiac involvement is detected by magnetic resonance imaging in such cases. This suggests that N-terminal pro b-type natriuretic peptide thresholds for cardiac involvement in AL may need to be redefined.
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http://dx.doi.org/10.3324/haematol.2019.217695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193493PMC
May 2020

Carfilzomib is an effective upfront treatment in AL amyloidosis patients with peripheral and autonomic neuropathy.

Br J Haematol 2019 12 6;187(5):638-641. Epub 2019 Aug 6.

National Amyloidosis Centre, University College London (Royal Free Campus), London, UK.

Bortezomib is standard treatment in AL amyloidosis (AL), but is contraindicated in patients with significant neuropathy. Carfilzomib, a second-generation proteosomal inhibitor, results in a lower incidence of neuropathy than bortezomib, but data in AL is scant. We report a cohort of five AL patients treated with upfront carfilzomib. All had cardiac, peripheral and autonomic neuropathy at presentation. All achieved at least a very good partial haematological response. There was no worsening in cardiac function, peripheral or autonomic neuropathy. Carfilzomib is an effective upfront treatment option in AL patients with peripheral and/or autonomic neuropathy (without severe cardiac or renal involvement).
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http://dx.doi.org/10.1111/bjh.16122DOI Listing
December 2019

British kindred with dominant FMF associated with high incidence of AA amyloidosis caused by novel MEFV variant, and a review of the literature.

Rheumatology (Oxford) 2020 03;59(3):554-558

National Amyloidosis Centre, University College London, UK.

Objectives: Hereditary systemic autoinflammatory diseases are rare genetic disorders, which if untreated, can be complicated by AA amyloidosis leading to renal failure and premature death. Our objective was to find a genetic cause in a British family with a dominantly inherited autoinflammatory disease complicated by AA amyloidosis.

Methods: The index patient and his sister underwent comprehensive clinical and laboratory assessment including the next-generation sequencing panel targeting autoinflammatory genes. Subsequently, other relatives underwent clinical evaluation and genetic testing. Screening of the SAA1 gene was performed in all symptomatic cases.

Results: The index case and his sister presented with proteinuria due to AA amyloidosis. They have been suffering from episodes of fever accompanied by severe abdominal and chest pain, arthritis and erythema since childhood. Their father died aged 52 years from complications following a cadaveric renal transplantation. The post-mortem examination demonstrated AA amyloidosis. The index case's grandmother, two paternal cousins and two of their children described similar symptoms. All symptomatic individuals had excellent responses to colchicine. Next-generation sequencing analysis identified a single MEFV p.P373L variant in the index case, his sister and subsequently, in symptomatic family members. Sequencing of the SAA1 gene revealed all cases were heterozygous for the SAA1.1 allele.

Conclusion: Typically FMF is an autosomal recessive disorder; nonetheless rare cases of dominantly inherited disease have previously been described. Here we report a novel MEFV variant p.P373L, causing dominant FMF complicated by AA amyloidosis in four generations of a British family.
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http://dx.doi.org/10.1093/rheumatology/kez334DOI Listing
March 2020

Retrospective case series describing the efficacy, safety and cost-effectiveness of a vial-sharing programme for canakinumab treatment for paediatric patients with cryopyrin-associated periodic syndrome.

Pediatr Rheumatol Online J 2019 Jul 8;17(1):36. Epub 2019 Jul 8.

Infection Inflammation and Rheumatology Section, University College London Institute of Child Health, 30 Guilford St, London, WC1N1EH, UK.

Background: Cryopyrin-associated periodic syndrome (CAPS) is a rare autoinflammatory disease, caused by gain of function mutation in NLRP3 resulting in excess production of interleukin-1 (IL-1). Canakinumab is a human monoclonal antibody against Interleukin-1 beta (IL-1β), licensed for the treatment of CAPS. The objective of the study was to describe the feasibility and cost-effectiveness of a canakinumab vial-sharing programme for paediatric patients with CAPS.

Method: Retrospective case series and clinical service description of a national specially commissioned CAPS clinic at Great Ormond Street Hospital (GOSH). Effectiveness was assessed using a CAPS disease activity score (DAS) and serum amyloid A protein (SAA). Adverse events were collected to determine safety. The number of canakinumab vials saved was considered when investigating the cost-effectiveness of vial-sharing.

Results: Nineteen/20 (95%) of our paediatric patients achieved minimally active clinical disease activity with canakinumab monotherapy; and 75% achieved both minimally active clinical disease and serological remission using a pre-specified definition based on the CAPS DAS and SAA level. Canakinumab was well tolerated, with only one child developing an infection requiring hospitalisation during the study. Canakinumab vial sharing resulted in 117 vials of canakinumab saved over a 24-month period, equating to a direct drug-related cost saving of £1,385,821, and a conservative estimated 5-year cost-saving of £3,464,552.50.

Conclusion: We provide further evidence for the effectiveness and safety of canakinumab in children with CAPS, and highlight the cost-effectiveness of a vial-sharing programme for this high cost medicine. We suggest that this could have important implications for the delivery of other high cost medicines used in paediatric practice.
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http://dx.doi.org/10.1186/s12969-019-0335-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615159PMC
July 2019

Exploratory Study of MYD88 L265P, Rare NLRP3 Variants, and Clonal Hematopoiesis Prevalence in Patients With Schnitzler Syndrome.

Arthritis Rheumatol 2019 12 14;71(12):2121-2125. Epub 2019 Oct 14.

NIHR, Leeds, UK.

Objective: To assess the prevalence of the MYD88 L265P mutation and variants within NLRP3 and evaluate the status of oligoclonal hematopoiesis in 30 patients with Schnitzler syndrome (SchS).

Methods: Thirty patients with SchS were recruited from 3 clinical centers. Six patients with known acquired cryopyrin-associated periodic syndromes (aCAPS) were included as controls. Allele-specific oligonucleotide-polymerase chain reaction was used for the detection of the MYD88 L265P variant, next-generation sequencing was applied to analyze NLRP3 and 28 genes associated with myelodysplastic syndrome, and gene scanning was performed for the detection of X chromosome inactivation.

Results: Activating NLRP3 mutations were not present in 11 SchS patients who had not been sequenced for this gene previously. The MYD88 L265P variant was present in 9 of 30 SchS patients, and somatic mutations associated with clonal hematopoiesis were identified in 1 of 30 patients with SchS and 1 of 6 patients with aCAPS. Evidence of nonrandom X chromosome inactivation was detected in 1 female patient with SchS and 1 female patient with aCAPS.

Conclusion: A shared molecular mechanism accounting for the pathogenesis of inflammation in SchS remains elusive. Clonal hematopoiesis is not associated with other somatic mutations found in individuals with SchS or aCAPS.
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http://dx.doi.org/10.1002/art.41030DOI Listing
December 2019

Noncontrast Magnetic Resonance for the Diagnosis of Cardiac Amyloidosis.

JACC Cardiovasc Imaging 2020 01 12;13(1 Pt 1):69-80. Epub 2019 Jun 12.

National Amyloidosis Centre, University College London, Royal Free Campus, London, United Kingdom. Electronic address:

Objectives: This study aimed to assess the diagnostic use of native T1 to detect cardiac amyloidosis (CA) in a large prospective cohort of patients referred for suspected systemic amyloidosis.

Background: CA is a progressive and fatal underdiagnosed cause of heart failure. Cardiovascular magnetic resonance (CMR) has emerged as an extremely useful test for the non-invasive diagnosis of CA, but administration of contrast is still required to make a diagnosis.

Methods: In this study, 868 patients with suspected CA referred between 2015 and 2017 underwent CMR with late gadolinium enhancement (LGE), T1 mapping, and an array of clinical investigations.

Results: The final diagnosis was cardiac light-chain (AL) amyloidosis in 222, cardiac transthyretin (ATTR) amyloidosis in 214, and no cardiac involvement in 427 cases. T1 was significantly elevated in both types of CA and this was associated with high diagnostic accuracy in the overall population (area under the curve, 0.93). A native T1 <1,036 ms was associated with 98% negative predictive value for CA whereas a native T1 >1,164 ms was associated with 98% positive predictive value for CA. We propose the use of these cut-offs to exclude or confirm CA and to restrict the administration of contrast only to patients with intermediate probability (native T1 between 1,036 and 1,164 ms), 58% of patients in this population.

Conclusions: Native myocardial T1 enables diagnosis of CA to be made without need for gadolinium contrast in a large proportion of patients with suspected systemic amyloidosis. We propose a diagnostic algorithm for non-contrast CMR applicable to patients with suspected amyloidosis.
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http://dx.doi.org/10.1016/j.jcmg.2019.03.026DOI Listing
January 2020