BACKGROUNDAdult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODSWe 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-Cas9edited zebrafish were used as an in vivo model to assess gene function. RESULTSWe identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 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. CONCLUSIONSUsing 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.

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly , in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly , the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally , bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently , this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.

Background: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in older individuals. We sought to characterize the natural history of ATTR-CM and compare outcomes and quality of life among patients with acquired and hereditary forms of the disease. Methods: We studied 711 patients with wild-type ATTR-CM, 205 with hereditary ATTR-CM associated with the V122I variant (V122I-hATTR-CM), and 118 with non-V122I-hATTR-CM at the UK National Amyloidosis Center between 2000 and 2017. Patients underwent prospective protocolized evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test, quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Hospital service usage pre- and postdiagnosis was established using English central health records in a subset of patients. Results: There was substantial diagnostic delay, with patients using hospital services a median (interquartile range) of 17 (9–27) times during the 3 years before diagnosis, by which time quality of life was poor; diagnosis of wild-type ATTR-CM was delayed >4 years after presentation with cardiac symptoms in 42% of cases. Patients with V122I-hATTR-CM were more impaired functionally ( P <0.001) and had worse measures of cardiac disease ( P <0.001) at the time of diagnosis, a greater decline in quality of life, and poorer survival ( P <0.001) in comparison with the other subgroups. Conclusions: ATTR-CM is an inexorably progressive and eventually fatal cardiomyopathy associated with poor quality of life. Diagnosis is often delayed for many years after symptoms develop. Improved awareness and wider use of recently validated diagnostic imaging methods are urgently required for patients to benefit from recent therapeutic developments.

Patient registries are instrumental for clinical research in rare diseases. They help to achieve a sufficient sample size for epidemiological and clinical research and to assess the feasibility of clinical trials. The European Society for Immunodeficiencies (ESID) registry currently comprises information on >25,000 patients with inborn errors of immunity (IEI). The prerequisite of a patient to be included into the ESID registry is an IEI either defined by a defect in a gene included in the disease classification of the international union of immunological societies (IUIS), or verified by applying clinical criteria. Because a relevant number of patients, including those with common variable immunodeficiency (CVID), representing the largest group of patients in the registry, remains without a genetic diagnosis, consensus on classification of these patients is mandatory. Here, we present clinical criteria for a large number of IEI that were designed in expert panels with external review. They were implemented for novel entries and verification of existing datasets from 2014, yielding a substantial refinement. For instance, 8% of adults and 27% of children with CVID (176 out of 1704 patients) were reclassified to 22 different immunodeficiencies, illustrating progress in genetics, but also the previous lack of standardized disease definitions. Importantly, apart from registry purposes, the clinical criteria are also helpful to support treatment decisions in the absence of a genetic diagnosis or in patients with variants of unknown significance.

BackgroundDifferent diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)—familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)—and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.MethodsStep 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients’ diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.ResultsThe panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94–1 and specificity of 0.95–1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98).ConclusionEurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

This article reports the largest series of patients with systemic AL amyloidosis to date treated with first-line bortezomib. With relatively mature follow-up, the data indicate the importance of a stringent dFLC response (difference in involved and uninvolved light chains) as a predictor of prolonged response.

Aims Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. We sought to characterize the structural and functional echocardiographic phenotype across the spectrum of wild-type (wtATTR-CM) and hereditary (hATTR-CM) transthyretin cardiomyopathy and the echocardiographic features predicting prognosis. Methods and results We studied 1240 patients with ATTR-CM who underwent prospective protocolized evaluations comprising full echocardiographic assessment and survival between 2000 and 2019, comprising 766 with wtATTR-CM and 474 with hATTR-CM, of whom 314 had the V122I variant and 127 the T60A variant. At diagnosis, patients with V122I-hATTR-CM had the most severe degree of systolic and diastolic dysfunction across all echocardiographic parameters and patients with T60AhATTR-CM the least; patients with wtATTR-CM had intermediate features. Stroke volume index, right atrial area index, longitudinal strain, and E/e’ were all independently associated with mortality (P &lt; 0.05 for all). Severe aortic stenosis (AS) was also independently associated with prognosis, conferring a significantly shorter survival (median survival 22 vs. 53 months, P = 0.001). Conclusion The three distinct genotypes present with varying degrees of severity. Echocardiography indicates a complex pathophysiology in which both systolic and diastolic function are independently associated with mortality. The presence of severe AS was independently associated with significantly reduced patient survival.

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