Pericarditis and Autoinflammation: A Clinical and Genetic Analysis of Patients With Idiopathic Recurrent Pericarditis and Monogenic Autoinflammatory Diseases at a National Referral Center.

Background: Idiopathic recurrent pericarditis (IRP) is an orphan disease that carries significant morbidity, partly driven by corticosteroid dependence. Innate immune modulators, colchicine and anti-interleukin-1 agents, pioneered in monogenic autoinflammatory diseases, have demonstrated remarkable efficacy in trials, suggesting that autoinflammation may contribute to IRP. This study characterizes the phenotype of patients with IRP and monogenic autoinflammatory diseases, and establishes whether autoinflammatory disease genes are associated with IRP. Methods and Results: We retrospectively analyzed the medical records of patients with IRP (n=136) and monogenic autoinflammatory diseases (n=1910) attending a national center (London, UK) between 2000 and 2021. We examined 4 genes (MEFV, MVK, NLRP3, TNFRSF1A) by next-generation sequencing in 128 patients with IRP and compared the frequency of rare deleterious variants to controls obtained from the Genome Aggregation Database. In this cohort of patients with IRP, corticosteroid dependence was common (39/136, 28.7%) and was associated with chronic pain (adjusted odds ratio 2.8 [95% CI, 1.3-6.5], P=0.012). IRP frequently manifested with systemic inflammation (raised C-reactive protein [121/136, 89.0%] and extrapericardial effusions [68/136, 50.0%]). Pericarditis was observed in all examined monogenic autoinflammatory diseases (0.4%-3.7% of cases). Rare deleterious MEFV variants were more frequent in IRP than in ancestry-matched controls (allele frequency 9/200 versus 2932/129 200, P=0.040). Conclusions: Pericarditis is a feature of interleukin-1 driven monogenic autoinflammatory diseases and IRP is associated with variants in MEFV, a gene involved in interleukin-1β processing. We also found that corticosteroid dependence in IRP is associated with chronic noninflammatory pain. Together these data implicate autoinflammation in IRP and support reducing reliance on corticosteroids in its management

Amyloidoza pęcherza moczowego — opis przypadku i przegląd piśmiennictwa

Amyloidosis is a heterogeneous group of protein misfolding diseases caused by extracellular deposition of abnormal beta-fibrils resistant to proteolysis. The most common type is light-chain amyloidosis (AL amyloidosis) which can be systemic or localized. Localized amyloidosis mostly affects the respiratory airways, genitourinary tract, gastrointestinal system or skin. We present diagnostic and therapeutic approach in a 25-year-old female patient diagnosed with urinary bladder amyloidosis. The main complaint was macroscopic hematuria occurring periodically for 2 years. Abdominal and pelvic computed tomography revealed single 25-mm-thick soft-tissue lesion of the left bladder wall. Histopathological examination of the lesion biopsied during transurethral resection of bladder tumor showed amyloid deposits with strong positive immunostaining for transthyretin, weaker for light chain (AL) and weak for serum amyloid A (AA). Serum protein electrophoresis and immunofixation did not reveal monoclonal protein. X-rays of flat bones presented without lytic lesions. There were no amyloid deposits both in trephine biopsy and subcutaneous fat biopsy. Primary systemic AL amyloidosis was excluded. According to the results of (99m)Tc-DPD scintigraphy and genetic analysis of transthyretin gene (TTR), the ATTRm amyloidosis was also excluded. Consultative histopathological analysis of the bladder biopsy made in the National Amyloidosis Center in London revealed amyloid deposits stained to lambda light chains, confirming the diagnosis of localized AL lambda bladder amyloidosis. The patient was qualified for surgical treatment. Partial resection of the bladder wall with no need for left ureter transplantation was performed. Primary localized bladder amyloidosis is a very rare entity. In the diagnostic approach the most important is the exclusion of primary systemic amyloidosis due to a completely different treatment method.Amyloidoza to heterogenna grupa chorób wywołanych pozakomórkową depozycją białek o nieprawidłowej strukturze beta-kartki, nieulegających proteolizie. Najczęstszym typem jest amyloidoza łańcuchów lekkich (amyloidoza AL), która może występować w postaci systemowej lub zlokalizowanej — ograniczonej do jednego układu. Amyloidoza zlokalizowana dotyczy głównie dróg oddechowych, układu moczowo-płciowego, przewodu pokarmowego lub skóry. W artykule przedstawiono ścieżkę diagnostyczno-terapeutyczną 25-letniej pacjentki ze zlokalizowaną amyloidozą pęcherza moczowego z wywiadem krwiomoczu pojawiającego się okresowo od 2 lat. W tomografii komputerowej jamy brzusznej i miednicy w ścianie lewobocznej pęcherza moczowego uwidoczniono miękkotkankową zmianę grubości około 25 mm, bez istotnego wzmocnienia pokontrastowego. W badaniu histopatologicznym bioptatu pobranego w czasie przezcewkowej resekcji guza pęcherza moczowego stwierdzono złogi amyloidu, z najsilniejszym odczynem w kierunku transtyretyny, nieco słabszym w kierunku AL i słabym AA. W elektroforezie białek surowicy i immunofiksacji nie ujawniono obecności białka monoklonalnego. Radiogram kości płaskich był pozbawiony zmian litycznych. Złogi amyloidu były nieobecne zarówno w trepanobiopsji, jak i w bioptacie tkanki tłuszczowej. Wykluczono pierwotną układową amyloidozę AL. Na podstawie scyntygrafii serca 99mTc-DPD oraz analizy genetycznej genu transtyretyny (TTR) wykluczono także amyloidozę serca ATTRm. W badaniu konsultacyjnym bioptatu z pęcherza moczowego, wykonanym w National Amyloidosis Centre w Londynie, wykazano obecność amyloidu z łańcuchów lambda, ostatecznie potwierdzając rozpoznanie amyloidozy pęcherza moczowego AL lambda. Pacjentkę zakwalifikowano do leczenia operacyjnego. Ze względu na nasilone objawy ze strony układu moczowego wykonano częściową resekcję ściany pęcherza moczowego metodą klasyczną z zaoszczędzeniem moczowodów. Amyloidoza zlokalizowana pęcherza moczowego jest rzadkością. W postępowaniu diagnostycznym najistotniejsze pozostaje wykluczenie pierwotnej amyloidozy układowej ze względu na całkowicie odmienny sposób leczenia

Focal Segmental Glomerulosclerosis Complicating Therapy With Inotersen, an Antisense Oligonucleotide Inhibitor: A Case Report

Inotersen is an antisense oligonucleotide inhibitor licensed for the treatment of polyneuropathy complicating hereditary transthyretin amyloidosis (ATTRv). Nephrotoxicity has been reported with inotersen, including progression to end stage renal disease. We describe the first reported case of inotersen-associated nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS) and review the literature concerning inotersen-induced nephrotoxicity. We report a woman in her early 30s with ATTRv associated with the (p.V50M) transthyretin (TTR) variant, who presented with nephrotic syndrome 7 months after commencement of inotersen. Renal histology demonstrated focal segmental glomerulosclerosis and scanty glomerular amyloid deposition. Discontinuation of inotersen alone resulted in complete clinical and biochemical resolution of nephrotic syndrome. Inotersen is associated with significant nephrotoxicity. In the phase III NEURO-TTR clinical trial, 3% of patients in the treatment arm developed a crescentic glomerulonephritis. All affected patients carried the (p.V50M) TTR variant which is known to be associated with renal amyloid deposition. This case adds to spectrum of renal disease associated with inotersen and indicates that discontinuation of the drug alone may result in resolution of renal complications without additional immunosuppression. Monitoring of renal function is essential in patients with ATTRv receiving inotersen, particularly if there is evidence of existing renal amyloid

The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre

INTRODUCTION: Hereditary apolipoprotein A-I (AApoAI) amyloidosis is a rare heterogeneous disease with variable age of onset and organ involvement. There are few series detailing the natural history and outcomes of solid organ transplantation across a range of causative APOA1 gene mutations. METHODS: We identified all patients with AApoAI amyloidosis who presented to the National Amyloidosis Centre (NAC) between 1986 and 2019. RESULTS: In total, 57 patients with 14 different APOA1 mutations were identified including 18 patients who underwent renal transplantation (5 combined liver-kidney (LKT) and 2 combined heart-kidney (HKT) transplants). Median age of presentation was 43 years and median time from presentation to referral was 3 (0-31 years). Involvement of the kidneys, liver and heart by amyloid was detected in 81%, 67% and 28% of patients, respectively. Renal amyloidosis was universal in association with the most commonly identified variant (Gly26Arg, n = 28). Across all variants, patients with renal amyloidosis had a median creatinine of 159 µmol/L and median urinary protein of 0.3 g/24 h at the time of diagnosis of AApoAI amyloidosis and median time from diagnosis to end-stage renal disease was 15.0 (95% CI: 10.0-20.0) years. Post-renal transplantation, median allograft survival was 22.0 (13.0-31.0) years. There was one early death following transplantation (infection-related at 2 months post-renal transplant) and no episodes of early rejection leading to graft failure. Liver transplantation led to regression of amyloid in all four cases in whom serial 123I-SAP scintigraphy was performed. CONCLUSIONS: AApoAI amyloidosis is a slowly progressive disease that is challenging to diagnose. The outcomes of transplantation are encouraging and graft survival is excellent

Prevalence, Characteristics and Outcomes of Older Patients with Hereditary versus Wild-Type Transthyretin Amyloid Cardiomyopathy

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is often assumed to be associated with wild-type TTR genotype (ATTRwt) in elderly patients (aged >70), some of whom are not offered genetic testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of TTR variants among elderly patients diagnosed with ATTR-CM. METHODS: Data from consecutive patients over 70 years of age diagnosed with ATTR-CM at the UK National Amyloidosis Centre between January 2010 and August 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all-cause mortality. RESULTS: The study population consisted of 2029 patients with ATTR-CM (median age 79 years at diagnosis, 13.2% females, 80.4% Caucasian). Variant ATTR-CM (ATTRv-CM) was diagnosed in 20.7% (n=421) of the study population of whom 329 (76.3%) carried V122I, 49 (11.4%) T60A, 18 (4.2%) V30M and 35 (8.1%) other pathogenic TTR variants. During a median (range) follow up of 29 (12-48) months, ATTRv-CM was associated with increased all-cause mortality compared to ATTRwt-CM, with the poorest survival observed in V122I-associated ATTRv-CM (p<0.001). Univariable and multivariable logistic regression analyses in those with ATTR-CM showed younger age at diagnosis (odds ratio [OR] 0.85 per year, p<0.001), female sex (OR 2.73, p<0.001), Afro-Caribbean ethnicity (OR 65.5, p<0.001), atrial fibrillation (OR 0.65, p=0.015), ischemic heart disease (OR 0.54, p=0.007), peripheral polyneuropathy (OR 5.70, p<0.001) and orthostatic hypotension (OR 6.29, p<0.001) to be independently associated with ATTRv-CM. CONCLUSION: Up to 20.7% of elderly patients with ATTR-CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR-CM regardless of age. This article is protected by copyright. All rights reserved

Sex differences among patients with transthyretin amyloid cardiomyopathy – from diagnosis to prognosis

Aims: transthyretin amyloid cardiomyopathy (ATTR-CM) is predominantly diagnosed in men. The few available studies suggest affected women have a more favourable cardiac phenotype. We aimed to characterize sex differences among consecutive patients with non-hereditary and two prevalent forms of hereditary (h)ATTR-CM diagnosed over a 20-year period. Methods and results: analysis of deep phenotyping at presentation, changes on serial echocardiography and overall prognosis were evaluated. In total, 1732 consecutive patients were studied, comprising: 1095 with wild-type (wt)ATTR-CM; 206 with T60A-hATTR-CM; and 431 with V122I-hATTR-CM. Female prevalence was greater in T60A-hATTR-CM (29.6%) and V122I-hATTR-CM (27.8%) compared to wtATTR-CM (6%). At presentation, females were 3.3 years older than males (wtATTR-CM: 81.9 vs. 77.8 years; T60A-hATTR-CM: 68.7 vs. 65.1 years; V122I-hATTR-CM: 77.1 vs. 74.9 years). Body size significantly influenced measures of disease severity; when indexed, overall structural and functional phenotype was similar between sexes, the few significant differences suggested a mildly worse phenotype in females. No significant differences were observed in both disease progression on serial echocardiography and mortality across the overall population (p = 0.459) and when divided by genotype (wtATTR-CM: p = 0.730; T60A-hATTR-CM: p = 0.161; V122I-hATTR-CM: p = 0.056). Conclusion: this study of a well-characterized large cohort of ATTR-CM patients did not demonstrate overall differences between sexes in either clinical phenotype, when indexed, or with respect to disease progression and prognosis. Non-indexed wall thickness measurements may have contributed to both under-representation and delays in diagnosis for affected females and highlights the potential role of utilizing indexed echocardiographic parameters for a more accurate assessment of patients at diagnosis and for disease prognostication

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

Abstract 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