Publications by authors named "Gilles Grateau"

135 Publications

AA amyloidosis complicating monoclonal gammopathies, an unusual feature validating the concept of "monoclonal gammopathy of inflammatory significance"?

Int J Clin Pract 2021 Sep 7:e14817. Epub 2021 Sep 7.

Sorbonne University, AP-HP, Tenon hospital, Department of Internal Medicine, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), GRC -28, Paris, France.

Introduction: AL amyloidosis is caused by the proliferation of an immunoglobulin-secreting B cell clone. AA amyloidosis is a rare complication of chronic inflammation. However, some patients present with diseases combining monoclonal immunoglobulin production and chronic inflammation. The aim of this work was to describe cases of AA amyloidosis associated with monoclonal gammopathies.

Patients And Methods: We reviewed all patients reported in French national amyloid centers presenting with AA amyloidosis and monoclonal gammopathy and performed a literature review. The quality of AA amyloidosis diagnosis and the causal relationship with monoclonal gammopathy were assessed.

Results: In total, 4 patients from our centers and 8 from the literature fulfilled the inclusion criteria. The hematological disorders presenting with monoclonal gammopathy were as follows: Waldenström macroglobulinemia (n=8), Schnitzler syndrome (n=2), multiple myeloma (n=1), and monoclonal gammopathy of undetermined significance (n=1). Treatment strategies varied among the cases, with treatment of the hematological disorder in 4 and anti-inflammatory treatment in 2.

Conclusion: Monoclonal gammopathies might be a rare and poorly known cause of AA amyloidosis. Such monoclonal gammopathies could be named "monoclonal gammopathies of inflammatory significance".
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http://dx.doi.org/10.1111/ijcp.14817DOI Listing
September 2021

AA Amyloidosis in the Course of HIV Infection: A Report of 19 Cases Including 4 New French Cases and a Comprehensive Review of Literature.

Nephron 2021 Jul 15:1-9. Epub 2021 Jul 15.

Department of Internal Medicine, Sorbonne University, AP-HP, Tenon Hospital, Centre De Référence Des Maladies Auto-Inflammatoires Et Des Amyloses D'origine Inflammatoire (CEREMAIA), Paris, France.

Introduction: HIV infection has been recently retained as an unclear cause of AA amyloidosis. Our aim was to investigate cases of AA amyloidosis associated with HIV infection to understand if it could be considered as a cause of AA amyloidosis.

Methods: A comprehensive literature review was conducted as well as retrospective study from French cases collected from our national reference center for AA amyloidosis.

Results: Altogether, 19 patients with AA amyloidosis and HIV infection were found with 68% of men and median age at amyloidosis diagnosis of 38 years (range 28-75 years). Clinical presentation was nephrotic syndrome in 94% (n = 17/18). Among patients with renal involvement and assessable outcome (n = 17), 11 (64.7%) progressed to chronic kidney disease, with 6 (35%) end-stage renal disease. Seventy-five percent of patients had uncontrolled HIV infection and 71.4% CD4 counts <400/mm3 at amyloidosis diagnosis. Repeated or chronic bacterial or fungal infection was found in 47% of cases and a history of parenteral drug use in 55% of patients. Three patients had no classical or at least no suspected AA amyloidosis cause found or reported.

Conclusions: AA Amyloidosis is a rare condition in HIV patients with common renal involvement and significant risk of progression to chronic renal insufficiency. Because of the frequency related to other inflammatory conditions in this population, HIV is probably not an independent risk factor for AA amyloidosis.
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http://dx.doi.org/10.1159/000516982DOI Listing
July 2021

Thyroid disorders in familial Mediterranean fever: think about AA amyloidosis!

Clin Rheumatol 2021 08 6;40(8):3381-3382. Epub 2021 Jul 6.

Department of Internal Medicine, Tenon Hospital, AP-HP, Sorbonne University, 75020, Paris, France.

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http://dx.doi.org/10.1007/s10067-021-05852-yDOI Listing
August 2021

Hemodynamic and biological correlates of glomerular hyperfiltration in sickle cell patients before and under renin-angiotensin system blocker.

Sci Rep 2021 Jun 3;11(1):11682. Epub 2021 Jun 3.

Department of Internal Medicine, Centre de reference de la drepanocytose (AP-HP), Centre Hospitalier Universitaire Tenon, Sorbonne Université, rue de la Chine, 75020, Paris, France.

Glomerular hyperfiltration alone or associated with albuminuria is a well-known feature of sickle cell associated nephropathy. Though, glomerular hyperfiltration is currently considered to be related to a high renal plasma flow and chronic hemolysis, cardiac output influence on measured glomerular filtration rate (mGFR) have not been investigated so far. Thirty seven homozygous sickle cell patients (SCA) from the RAND study investigated before and under angiotensin converting enzyme inhibitor (ACEI) were included. Both mGFR and cardiac index (CI) were high (> 110 ml/min/1.73 m and > 3.5 l/m in 81% and 97% of cases) with low systemic vascular resistance (SVR) (< 700 dynes/s/cm) in 38% of cases. mGFR association with CI and SVR were significant at baseline (respectively ρ: 0.44, p = 0.008 and ρ: - 0.37, p = 0.02) and under ACEI (p = 0.007 and 0.01 respectively), in accordance with previous data showing that hyperfiltration was linked to an increased glomerular perfusion and a glomerulomegaly rather than increased capillary hydrostatic pressure. Of notice, after adjustment on CI, mGFR remained associated with reticulocyte count and albuminuria under ACEI (p = 0.006 and 0.02 respectively). Our results suggest that hyperfiltration is tightly linked to an increased cardiac output which may account for an increased renal blood flow. Chronic hemolysis could be a relevant factor accounting for hyperfiltration potentially acting on glomerular enlargement which appears as a key factor. Our data suggest that cardiac output assessment is a relevant tool in the routine management and monitoring of SCA nephropathy.
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http://dx.doi.org/10.1038/s41598-021-91161-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175337PMC
June 2021

Amyloid Goiter in Familial Mediterranean Fever: Description of 42 Cases from a French Cohort and from Literature Review.

J Clin Med 2021 May 5;10(9). Epub 2021 May 5.

Internal Medicine Department and National Reference Center for Autoinflammatory Diseases and Inflammatory Amyloidosis (CEREMAIA), APHP, Tenon Hospital, Sorbonne University, 4 rue de la Chine, 75020 Paris, France.

Our aim was to describe the main features of amyloid goiter in adults with amyloidosis secondary to familial Mediterranean fever. Therefore, we analyzed cases from a French cohort of familial Mediterranean fever patients with amyloidosis and from literature review. Forty-two cases were identified: 9 from the French cohort and 33 from literature review. Ninety percent of patients were on hemodialysis for renal amyloidosis before the development of goiter. The goiter grew up rapidly in 88% of cases; 75.6% of patients were euthyroid, 58% displayed dyspnea, and 44.8% dysphagia. Various features were seen on ultrasound, from diffuse to multinodular goiter. When it was performed, fine-needle aspiration biopsy almost always revealed amyloidosis. Thirty-one patients underwent thyroidectomy: to manage compressive symptoms (72%) or rule out malignancy (27%). Histology showed mature adipose tissue in 64% of cases and lymphocytic infiltration in 21.4%. In conclusion, amyloid goiter in familial Mediterranean fever preferentially occurs in patients with end stage renal failure. Fine-needle aspiration biopsy seems to be a sensitive exam for diagnosis, but thyroidectomy remains sometimes necessary to rule out malignancy or release compressive symptoms.
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http://dx.doi.org/10.3390/jcm10091983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125620PMC
May 2021

[Familial Mediterranean fever in 2020].

Nephrol Ther 2021 Apr;17S:S119-S125

Service de médecine interne, hôpital Tenon, AP-HP, 4, rue de la Chine, 75020 Paris, France; Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (Cerémaia), 4, rue de la Chine, 75020 Paris, France; Sorbonne université, 4, rue de la Chine, 75020 Paris, France.

Familial Mediterranean fever is the most frequent autoinflammatory disease with autosomal recessive transmission. Most patients carry mutations in the MEFV gene encoding the protein marenostrin/pyrin. It is characterised by short ant recurrent attacks of fever and serositis with abdominal or thoracic pain, usually lasting less than 3 days, raised inflammatory biologic markers in an individual of Mediterranean origin. Colchicine has been shown to be effective in prevention of inflammatory attacks and development of amyloidosis which is responsible of nephrotic syndrome and chronic renal failure. Better knowledge in pathogenic mechanisms permitted identification of interleukin-1 beta (Il-1 β) as the main cytokine target. Anti-IL-1 therapy must be considered as a second line treatment in case of persistent inflammation or colchicine intolerance.
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http://dx.doi.org/10.1016/j.nephro.2020.02.013DOI Listing
April 2021

Tumor necrosis factor receptor-1 assciated periodic syndrome (TRAPS) related AA amyloidosis: a national case series and systematic review.

Rheumatology (Oxford) 2021 Mar 14. Epub 2021 Mar 14.

Sorbonne University, GRC GRAASU, Department of Internal Medicine, APHP, Tenon Hospital, Paris, France.

Objectives: Tumor necrosis factor (TNF) receptor-1 associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder associated with mutations in the TNF receptor super family 1A (TNFRSF1A) gene. AA amyloidosis (AA) is the most severe complication of TRAPS. To study the occurrence and prognosis of AA in TRAPS, we conducted a retrospective study of all French cases and a systematic literature review.

Methods: This case series includes TRAPS patients followed by our center from 2000 to 2020 presenting with histologically confirmed AA. We conducted a systematic literature review on the PubMed and Embase databases for articles published up February 2021 following the PRISMA guidelines and using the keywords: amyloidoisis, amyloid, TNF receptor-associated periodic syndrome, TNF Receptor-associated Periodic Syndrome, Tumor necrosis factor receptor-associated periodic syndrome, TRAPS, TNFRSF1A, Familial Hibernian fever and Hibernian Familial Fever.

Results: A total of 41 TRAPS with AA were studied: 3 new patients and 38 cases from the literature. AA diagnosis preceded that of TRAPS in 96% of cases, and 17/36 (47%) required renal replacement therapy. Death occurred in 5/36 (14%) with a median follow-up of 23 months. Effect of biologics on AA were available for 21 regimens in 19 patients: 10 improved renal function, 7 stabilized and 4 worsened. Four patients (36% of transplanted patients) relapse AA on kidney graft (only one under etanercept).

Conclusion: TRAPS is revealed by AA in most cases. Therefore, clinical features of TRAPS should be screened for in AA patients. IL-1 antagonist can help to normalize inflammation and to preserve renal function.
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http://dx.doi.org/10.1093/rheumatology/keab252DOI Listing
March 2021

Association between familial Mediterranean fever and multiple sclerosis: A case series from the JIR cohort and systematic literature review.

Mult Scler Relat Disord 2021 May 10;50:102834. Epub 2021 Feb 10.

Sorbonne University; Internal Medicine Department; AP-HP; Hôpital Tenon; Paris; France; Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses Inflammatoire (CEREMAIA)-JIR Cohort; France. Electronic address:

Introduction: Familial Mediterranean fever (FMF) is the most frequent monogenic autoinflammatory disorder; and leads to the uncontrolled production of interleukin (IL)-1β. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system; and its development seems to be partly correlated with IL-1β levels. It is hypothesized that FMF could be associated with MS. We aim to describe the features of patients displaying both diseases and to investigate the MEFV mutation rate in MS patients.

Methods: Patients with definite MS were retrieved from the cohort of FMF patients in the Reference Center for Rare Auto-inflammatory Diseases and Amyloidosis (CEREMAIA). We also performed a systematic literature review of articles from PubMed that were published from 1990 to 2020.

Results: Twenty-four patients were included in the case series: five patients (1.3%) from our cohort of 364 and 19 patients from the literature. The sex ratio was 2:1. The mean age at diagnosis of FMF was 19 years old; and that for MS was 29 years old. Seven studies investigating the MEFV mutation rate in MS patients were included. Three studies found a higher mutation rate in MS patients than in the control group.

Conclusion: FMF and MS features were comparable to those of patients with unrelated diseases; and MEFV mutation carriage was not positively correlated with MS. However; MS prevalence in FMF patients was higher than was expected in a healthy population. To a lesser extent; FMF prevalence in MS patients was higher than expected in a healthy population and the difference might not be significant. These data suggest that FMF could be associated with MS; and further studies are needed to investigate a potential causal association.
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http://dx.doi.org/10.1016/j.msard.2021.102834DOI Listing
May 2021

"Helicobacter pylori in familial mediterranean fever: A series of 120 patients from literature and from france".

Helicobacter 2021 Apr 15;26(2):e12789. Epub 2021 Feb 15.

Department of Internal Medicine, AP-HP, Tenon Hospital, Sorbonne University, Paris, France.

Introduction: Familial Mediterranean Fever (FMF), the most common monogenic auto-inflammatory disease, is characterized by recurrent febrile abdominal pain. Helicobacter pylori infection (HPI), one of the most frequent infections worldwide, can mimic an FMF attack.

Objectives: Identify FMF patients with HPI in a cohort of French FMF patients and the literature and identify features allowing to distinguish HPI from an FMF attack.

Methods: A retrospective study of all HPI cases was performed on the cohort of FMF patients fulfilling the Livneh criteria from the French Reference Center for rare Auto-Inflammatory Diseases and Amyloidosis (CEREMAIA). A systematic literature review of HPI in FMF patients was conducted according to the PRISMA guidelines.

Results: Eight French patients developed HPI, whose symptoms of epigastralgia, diarrhea, anorexia/weight loss, and nausea/vomiting differed from their typical abdominal FMF attacks. A total of 112 FMF patients with HPI have been described in the literature, including 61 adults. Diagnosis of HPI was made by gastroscopy (n = 43), labelled urea test (n = 55) or IgG serology by ELISA (n = 12). When performed, C-reactive protein was always elevated. Ten cases of interaction between colchicine and antibiotic therapy for HPI (clarithromycin (n = 9) and azithromycin (n = 1)) were reported.

Conclusion: We described a total of 120 patients with typical FMF and HPI. When FMF patients develop atypical abdominal symptoms, upper gastrointestinal endoscopy with biopsies is essential to eliminate underlying HPI. Untreated HPI can lead to misdiagnosis of colchicine resistance with inappropriate prescription of an interleukin-1 inhibitor at a non-negligible cost.
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http://dx.doi.org/10.1111/hel.12789DOI Listing
April 2021

Long-Term Follow-Up and Optimization of Interleukin-1 Inhibitors in the Management of Monogenic Autoinflammatory Diseases: Real-Life Data from the JIR Cohort.

Front Pharmacol 2020 11;11:568865. Epub 2021 Jan 11.

Department of Internal Medicine, National Reference Center for Auto-Inflammatory Diseases and Amyloidosis, CEREMAIA, Tenon Hospital, AP-HP, Sorbonne University, Paris, France.

The major role of interleukin (IL)-1 in the pathogenesis of hereditary recurrent fever syndromes favored the employment of targeted therapies modulating IL-1 signaling. However the best use of IL1 inhibitors in terms of dosage is difficult to define at present. In order to better understand the use of IL1 inhibitors in a real-life setting, our study assessed the dosage regimens of French patients with one of the four main hereditary recurrent fever syndromes (Familial Mediterranean Fever (FMF), TNF receptor associated periodic syndrome (TRAPS), cryopyrin associated periodic fever (CAPS) and mevalonate kinase deficiency). The patients were retrieved retrospectively from the JIR cohort, an international platform gathering data of patients with pediatric inflammatory diseases. Forty five patients of the JIR cohort with a hereditary recurrent fever syndrome had received at least once an IL1 inhibitor (anakinra or canakinumab). Of these, 43% received a lower dosage than the one suggested in the product recommendations, regardless of the type of the IL1 inhibitor. Especially patients with FMF and TRAPS seemed to need lower treatment regimens; in our cohort none of the FMF or TRAPS patients received an intensified dose of IL-inhibitor. On-demand treatment with a short half-life IL-1 inhibitor has also been used successfully for some patients with one of these two conditions The standard dose was given to 42% of the patients; whereas an intensified dose of IL-1 inhibitors was given to 15% of the patients (44% of CAPS patients and 17% of mevalonate kinase deficiency patients). In our cohort each individual patient's need for treatment seemed highly variable, ranging from on demand treatment regimens to intensified dosage maintenance therapies depending on the activity and the severity of the underlying disease. IL-1 inhibitors are a good treatment option for patients with a hereditary recurrent fever syndrome, but the individual need of the dosage of IL-1 inhibitors to control the disease effectively seems highly variable. Severity, activity but also the type of the underlying disease, belong to the parameters underpinning the treat-to-target strategy implemented in an everyday life practice.
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http://dx.doi.org/10.3389/fphar.2020.568865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832034PMC
January 2021

Infections and AA amyloidosis: An overview.

Int J Clin Pract 2021 Jun 20;75(6):e13966. Epub 2021 Jan 20.

Sorbonne Université, Service de médecine interne, GRC-28 (GRAASU), Centre national de référence des maladies autoinflammatoires et des amyloses inflammatoires (CEREMAIA), hôpital Tenon, AP-HP, Paris, France.

Background: Amyloidoses are a heterogeneous group of systemic diseases characterised by extracellular accumulation of insoluble amyloid fibrils derived from unfolded proteins. Inflammatory (AA) amyloidosis can complicate various inflammatory disorders that are associated with a sustained acute phase response and serum amyloid A (SAA) protein overproduction. Chronic infections were the first recognised cause of amyloidoses. However, with the better management of underlying diseases, the frequency of AA amyloidosis is decreasing.

Purpose: The aim of this overview was to discuss the several infections associated with AA amyloidosis and the relative frequency of infections as aetiological factors.

Methods: A search of the literature was performed using the PubMed database using the MeSH terms "Amyloidosis" and "Infections," from inception to December 31st, 2019. Articles written in other languages than English or French were excluded.

Results: The frequency of AA amyloidosis secondary to infections decreased from more than 50% to less than 20% after the 2000s, with a parallel increase in the frequency of AA amyloidosis secondary to inflammatory diseases and to an unknown cause.

Conclusion: Whereas new antibiotics have been developed and sanitary conditions are better, infections still represent 5%-30% of the causes of AA amyloidosis, including in developed countries. These data argue for better screening of chronic infections to prevent AA amyloidosis and the development of new strategies to manage recurrent infections.
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http://dx.doi.org/10.1111/ijcp.13966DOI Listing
June 2021

Could we measure hair colchicine to assess colchicine observance in familial Mediterranean fever?

Rheumatology (Oxford) 2021 03;60(3):1563-1564

Paris Saclay University, Pharmacology and Toxicology Laboratory, Inserm U-1173, Raymond Poincaré hospital, AP-HP, Garches, France.

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http://dx.doi.org/10.1093/rheumatology/keaa811DOI Listing
March 2021

Attacks of TNF-receptor associated periodic syndrome are associated with higher inflammatory markers than familial Mediterranean fever.

Clin Exp Rheumatol 2020 Sep-Oct;38 Suppl 127(5):131. Epub 2020 Dec 10.

Service de Médecine Interne, Hôpital Tenon, Université Pierre et Marie Curie, Assistance Publique-Hôpitaux de Paris, France.

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February 2021

Prescription of interleukin-1 inhibitors in a French adult cohort of familial Mediterranean fever.

Eur J Intern Med 2021 02 19;84:109-111. Epub 2020 Nov 19.

Sorbonne Université, Service de médecine interne, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France; French Reference Center for rare Auto-Inflammatory Diseases and Amyloidosis (CEREMAIA).. Electronic address:

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http://dx.doi.org/10.1016/j.ejim.2020.11.001DOI Listing
February 2021

COVID-19 Presenting With Confusion: An Unusual but Suggestive Electroencephalography Pattern of Encephalitis.

J Clin Neurophysiol 2021 May;38(3):e11-e13

Hôpital Tenon, Assistance Publique Hôpitaux de Paris (APHP), Paris, France.

Summary: A 78-year-old man was admitted for acute confusion. At initial investigation physical examination, blood and cerebrospinal fluid tests were unremarkable and EEG showed synchronous bifrontal periodic discharges, an evocative pattern of encephalitis. Coronavirus disease 2019 was diagnosed later after fever onset. Isolated mild confusion may thus be an initial clinical picture of Coronavirus disease 2019 infection.
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http://dx.doi.org/10.1097/WNP.0000000000000795DOI Listing
May 2021

Clinical course of COVID-19 in a cohort of 342 familial Mediterranean fever patients with a long-term treatment by colchicine in a French endemic area.

Ann Rheum Dis 2020 Nov 2. Epub 2020 Nov 2.

Sorbonne Université, AP-HP, DMU3ID, Tenon hospital, Internal medicine department, national reference center of autoinflammatory diseases and inflammatory amyloidosis (CEREMAIA), Paris, France

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http://dx.doi.org/10.1136/annrheumdis-2020-218707DOI Listing
November 2020

Fast diagnostic test for familial Mediterranean fever based on a kinase inhibitor.

Ann Rheum Dis 2021 01 9;80(1):128-132. Epub 2020 Oct 9.

Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard-Lyon 1, CNRS, Ecole Normale Supérieure de Lyon, Lyon, France

Background And Objective: Familial Mediterranean fever (FMF) is the most frequent hereditary autoinflammatory disease. Its diagnosis relies on a set of clinical criteria and a genetic confirmation on identification of biallelic pathogenic variants. encodes pyrin, an inflammasome sensor. Using a kinase inhibitor, UCN-01, we recently identified that dephosphorylation of FMF-associated pyrin mutants leads to inflammasome activation. The aim of this study was to assess whether quantifying UCN-01-mediated inflammasome activation could discriminate FMF patients from healthy donors (HD) and from patients with other inflammatory disorders (OID).

Methods: Real-time pyroptosis and IL-1β secretion were monitored in response to UCN-01 in monocytes from FMF patients (n=67), HD (n=71) and OID patients (n=40). Sensitivity and specificity of the resulting diagnostic tests were determined by receiver operating characteristic curve analyses.

Results: Inflammasome monitoring in response to UCN-01 discriminates FMF patients from other individuals. Pyroptosis assessment leads to a fast FMF diagnosis while combining pyroptosis and IL-1β dosage renders UCN-01-based assays highly sensitive and specific. UCN-01-triggered monocytes responses were influenced by gene dosage and mutations in a similar way as clinical phenotypes are.

Conclusions: UCN-01-based inflammasome assays could be used to rapidly diagnose FMF, with high sensitivity and specificity.
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http://dx.doi.org/10.1136/annrheumdis-2020-218366DOI Listing
January 2021

AA Amyloidosis Secondary to Primary Immune Deficiency: About 40 Cases Including 2 New French Cases and a Systematic Literature Review.

J Allergy Clin Immunol Pract 2021 02 30;9(2):745-752.e1. Epub 2020 Sep 30.

Sorbonne Université, AP-HP, Hôpital Tenon, Service de médecine interne, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), GRC-28 (Groupe de recherche clinique amylose AA Sorbonne univeristé), Paris, France. Electronic address:

Background: Primary immune deficiencies (PIDs) are a heterogeneous group of disorders resulting from defects in immune system. They lead to increased susceptibility to infections and immune dysregulation. The resulting chronic inflammation can induce long-term complications, including AA amyloidosis (AAA).

Objectives: To present the French cases of PID-related AAA and perform a systematic literature review to determine its main features and predisposing factors.

Methods: A systematic literature review was performed by searching MEDLINE up until 2019. New French cases were identified with the help of the Reference Center for Auto-Inflammatory Diseases and AA Amyloidosis and the Reference Center for Hereditary Immune Deficiencies.

Results: Forty patients were identified including 2 new French cases. PIDs were varied: immunoglobulin deficits (n = 30), chronic granulomatous disease (n = 3), hyper-IgM syndrome (n = 3), hereditary complete C4 deficiency (n = 1), leucocyte adhesion deficiency type 1 (n = 1), hyper-IgE syndrome (n = 1), and Chediak-Higashi syndrome (n = 1). The mean age at PID diagnosis was 22.2 ± 16.02 years. Renal involvement was the most common manifestation of AAA (80%). Infections were extremely heterogeneous; bacterial infection with pulmonary involvement was the most frequent. Bronchiectasis was particularly common (52.5%). The delay between the first symptoms of PID and AAA diagnosis was 16.18 ± 7 years. Thirteen concomitant diagnoses were made. Twenty patients died during follow-up.

Conclusion: AAA is a rare life-threatening complication of PID, especially in cases of long diagnostic and therapeutic delays. Bronchiectasis should be considered as a warning sign of chronic inflammation and increased risk of AAA.
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http://dx.doi.org/10.1016/j.jaip.2020.09.023DOI Listing
February 2021

Cause of death and risk factors for mortality in AA amyloidosis: A French retrospective study.

Eur J Intern Med 2020 12 14;82:130-132. Epub 2020 Aug 14.

Sorbonne University, AP-HP, Tenon hospital, Department of Internal Medicine, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), Paris GRC -28, France; Inserm UMRS_933, et laboratoire de génétique, Trousseau hospital, AP-HP, Faculté de médecine - Sorbonne University, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejim.2020.08.012DOI Listing
December 2020

β-Glucan-induced reprogramming of human macrophages inhibits NLRP3 inflammasome activation in cryopyrinopathies.

J Clin Invest 2020 09;130(9):4561-4573

Immunology of Fungal Infections, Department of Mycology, Institut Pasteur, Paris, France.

Exposure of mononuclear phagocytes to β-glucan, a naturally occurring polysaccharide, contributes to the induction of innate immune memory, which is associated with long-term epigenetic, metabolic, and functional reprogramming. Although previous studies have shown that innate immune memory induced by β-glucan confers protection against secondary infections, its impact on autoinflammatory diseases, associated with inflammasome activation and IL-1β secretion, remains poorly understood. In particular, whether β-glucan-induced long-term reprogramming affects inflammasome activation in human macrophages in the context of these diseases has not been explored. We found that NLRP3 inflammasome-mediated caspase-1 activation and subsequent IL-1β production were reduced in β-glucan-reprogrammed macrophages. β-Glucan acted upstream of the NLRP3 inflammasome by preventing potassium (K+) efflux, mitochondrial ROS (mtROS) generation, and, ultimately, apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and speck formation. Importantly, β-glucan-induced memory in macrophages resulted in a remarkable attenuation of IL-1β secretion and caspase-1 activation in patients with an NLRP3-associated autoinflammatory disease, cryopyrin-associated periodic syndromes (CAPS). Our findings demonstrate that β-glucan-induced innate immune memory represses IL-1β-mediated inflammation and support its potential clinical use in NLRP3-driven diseases.
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http://dx.doi.org/10.1172/JCI134778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456248PMC
September 2020

Systemic autoinflammatory diseases: Clinical state of the art.

Best Pract Res Clin Rheumatol 2020 08 13;34(4):101529. Epub 2020 Jun 13.

Service de pédiatrie générale, CH de Versailles, 177 rue de Versailles, 78150, Le Chesnay Cedex, France; Centre de référence des maladies auto-inflammatoires et des amyloses inflammatoire (CEREMAIA), France. Electronic address:

Systemic autoinflammatory diseases (SAIDs) are defined as disorders of innate immunity. They were initially defined in opposition to autoimmune diseases due to the lack of involvement of the adaptive immune system and circulating autoantibodies. The four historical monogenic diseases are familial Mediterranean fever (associated with MEFV mutations), cryopyrinopathies (NLRP3 mutations), tumor necrosis factor receptor-associated periodic syndrome (TNFRSF1A mutations), and mevalonate kinase deficiency (MVK mutations). In the last 10 years, more than 50 new monogenic SAIDs have been discovered thanks to advances in genetics. Diagnosis is largely based on personal and family history and detailed analysis of signs and symptoms associated with febrile attacks, in the setting of elevated inflammatory markers. Increasingly efficient techniques of genetic analysis can contribute to refining the diagnosis. This review is a guide for the clinician in suspecting and establishing a diagnosis of SAID.
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http://dx.doi.org/10.1016/j.berh.2020.101529DOI Listing
August 2020

AA amyloidosis associated with Fabry disease.

Int J Clin Pract 2020 Oct 27;74(10):e13577. Epub 2020 Aug 27.

Service de médecine interne, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), AP-HP, Hôpital Tenon, Sorbonne Université, Paris, France.

Background: Fabry disease (FD) is the second most common lysosomal storage disorder, carrying a large morbidity and mortality. It has been recently reported that lysosomal storage disorders could cause inflammation and, subsequently, AA amyloidosis (AAA). Our aim was to describe AAA cases occurring in the course of FD.

Patients And Methods: We described two patients displaying both AAA and FD and an additional case from the literature.

Results: Three female patients originating from Europe (n = 2) and Algeria (n = 1) harboured heterozygous GLA mutations. The median age at AAA diagnosis was 61 years old. The diagnosis of Fabry was made before the diagnosis of AAA (n = 1) or concomitantly (n = 2). At AAA diagnosis, two patients displayed a nephrotic syndrome; all had inflammation.

Conclusion: Fabry disease can be associated with AAA, suggesting that an inflammatory component could exist in this genetic disease.
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http://dx.doi.org/10.1111/ijcp.13577DOI Listing
October 2020

AA amyloidosis revealing mevalonate kinase deficiency: A report of 20 cases including two new French cases and a comprehensive review of literature.

Semin Arthritis Rheum 2020 12 19;50(6):1370-1373. Epub 2020 Mar 19.

Internal medicine department, Tenon hospital, Assistance Publique - Hôpitaux de Paris, Sorbonne University, 4 rue de la Chine, 75020 Paris, France. Electronic address:

Introduction: Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease that can lead to an inflammatory A amyloidosis (AA).

Methods: To study the occurrence of AA in MKD patients we performed a systemic review of the literature and described two novel patients.

Results: Amyloidosis occurred in 20 MKD patients, renal impairment being always the revealing symptom of AA. Although an accurate prevalence estimation is not possible since exact MKD prevalence is unknown, AA seems rare in MKD (about 6% if we estimate MKD prevalence at 300 patients worldwide). MVK gene study, available in 18 out of the 20 patients, confirmed two pathogenic mutations in all tested individuals. The most frequent genotype was V377I/I268T (n = 9/18). Retrospective search of clinical signs of MKD established, in all patients carrying MVK pathogenic mutations, a disease onset within the first four years of life. Nephrotic syndrome (n = 15), end-stage renal failure (n = 5) or both (n = 8) pointed out kidney amyloidosis. The youngest patient with renal amyloidosis was a European four-year-old girl previously misdiagnosed with PFAPA syndrome. Five patients died of AA amyloidosis despite the use of a biotherapy for two of them; kidney transplant was performed in nine individuals. Colchicine was not effective in any patient. Anti-interleukin-1 anakinra (n = 8), anti TNF etanercept (n = 7) and anti-interleukin 6 tocilizumab (n = 5) treatments were partially effective.

Conclusion: Inflammatory A amyloidosis, a rare complication of MKD, can cause death or necessitate kidney transplantation. Early diagnosis and cytokine blocking biotherapy using anti-IL1, anti-TNF or anti-IL6 agents are required to prevent terminal renal failure.
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http://dx.doi.org/10.1016/j.semarthrit.2020.03.005DOI Listing
December 2020

Response to Letter to the Editor.

Innate Immun 2020 04;26(3):232-233

Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), Assistance Publique - Hôpitaux de Paris, Hôpital Tenon, France.

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http://dx.doi.org/10.1177/1753425920908681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144028PMC
April 2020

Prognostic Value of Hyponatremia During Acute Painful Episodes in Sickle Cell Disease.

Am J Med 2020 09 19;133(9):e465-e482. Epub 2020 Mar 19.

Department of Internal Medicine, Sickle Cell Disease Reference Center, Tenon Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Groupe de Recherche Clinique Drépanocytose Recherche à Paris Sorbonne Université, Sorbonne University, Paris, France. Electronic address:

Background: Low plasma sodium concentration has been recognized as a prognostic factor in several disorders but never evaluated in sickle cell disease. The present study evaluates its value at admission to predict a complication in adult patients with sickle cell disease hospitalized for an initially uncomplicated acute painful episode.

Methods: The primary outcome of this retrospective study, performed between 2010 and 2015 in a French referral center for sickle cell disease, was a composite criterion including acute chest syndrome, intensive care unit transfer, red blood cell transfusion or inpatient death. Analyses were adjusted for age, sex, hemoglobin genotype and concentration, lactate dehydrogenase (LDH) concentration, and white blood cell count.

Results: We included 1218 stays (406 patients). No inpatient death occurred during the study period. Hyponatremia (plasma sodium ≤135 mmol/L) at admission in the center was associated with the primary outcome (adjusted odds ratio [OR] 1.95, 95% confidence interval [CI] 1.3-2.91, P = 0.001), with acute chest syndrome (OR 1.95 [95% CI 1.2-3.17, P = 0.008]), and red blood cell transfusion (OR 2.71 [95% CI 1.58-4.65, P <0.001]) but not significantly with intensive care unit transfer (OR 1.83 [95% CI 0.94-3.79, P = 0.074]). Adjusted mean length of stay was longer by 1.1 days (95% CI 0.5-1.6, P <0.001) in patients with hyponatremia at admission.

Conclusions: Hyponatremia at admission in the medical department for an acute painful episode is a strong and independent prognostic factor of unfavorable outcome and, notably, acute chest syndrome. It could help targeting patients who may benefit from closer monitoring.
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http://dx.doi.org/10.1016/j.amjmed.2020.02.017DOI Listing
September 2020

Non-amyloid liver involvement in familial Mediterranean fever: A systematic literature review.

Liver Int 2020 06 15;40(6):1269-1277. Epub 2020 Apr 15.

Service de médecine interne, Hôpital Tenon, APHP, Université Sorbonne, Paris, France.

Introduction: Familial Mediterranean fever (FMF), the most frequent autoinflammatory disease, is caused by mutations in the MEFV gene. It is characterized by recurrent febrile attacks of polyserositis. Liver abnormalities may develop during its course, but they remain poorly defined.

Objective: To describe liver involvement in FMF patients.

Methods: A systematic search was conducted through PubMed/Medline and Embase from 1946 to January 2020. All articles describing children and adults with FMF and liver involvement were included. Patients with amyloidosis were excluded. The selected full-text articles were independently reviewed by three investigators.

Results: Forty-three articles were identified, of which 20 articles with a total of 99 patients were included: 74 adults, 23 children and two patients of unknown age. Ten patients had cryptogenic cirrhosis, 48 had nonalcoholic fatty liver disease (NAFLD), four had Budd-Chiari syndrome (BCS), 12 had isolated hyperbilirubinaemia and 25 had elevated liver enzymes.

Conclusion: Despite a low prevalence of metabolic risk factors, FMF may be associated with NAFLD and cryptogenic cirrhosis as a consequence of chronic or recurrent inflammation. FMF patients should be regularly screened for liver injury. The latter may be prevented and treated by daily colchicine intake. The evidence was insufficient to establish an association with BCS, hyperbilirubinaemia or autoimmune hepatitis.
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http://dx.doi.org/10.1111/liv.14445DOI Listing
June 2020

Do we need the PFAPA syndrome in adults with non-monogenic periodic fevers?

Ann Rheum Dis 2019 Dec 31. Epub 2019 Dec 31.

Service de médecine interne, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.

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http://dx.doi.org/10.1136/annrheumdis-2019-216827DOI Listing
December 2019

NLRP3-associated autoinflammatory diseases: Phenotypic and molecular characteristics of germline versus somatic mutations.

J Allergy Clin Immunol 2020 04 6;145(4):1254-1261. Epub 2019 Dec 6.

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), "Childhood genetic disorders", Paris, France; Département de Génétique Médicale, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address:

Background: NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) include conditions of various severities, due to germline or somatic mosaic NLRP3 mutations.

Objective: To identify mosaic- versus germline-specific NLRP3 mutations' characteristics, we reinterpreted all the mutations reported in NLRP3-AIDs and performed an in-depth study of 3 novel patients.

Methods: The pathogenicity of all reported mosaic/germline mutations was reassessed according to international recommendations and their location on the NLRP3 3-dimensional structure. Deep-targeted sequencing and NLRP3-inflammasome-activation assays were used to identify the disease-causing mutation in 3 patients.

Results: We identified, in 3 patients, mosaic mutations affecting the same NLRP3 amino acid (Glu569). This residue belongs to 1 of the 2 mosaic mutational hot spots that face each other in the core of the NLRP3 ATPase domain. The review of the 90 NLRP3 mutations identified in 277 patients revealed that those hot spots account for 68.5% of patients (37 of 54) with mosaic mutations. Glu569 is affected in 22% of the patients (12 of 54) with mosaic mutations and in 0.4% of patients (1 of 223) with germline mutations. Only 8 of 90 mutations were found in mosaic and germinal states. All of the germline mutations were associated with a severe phenotype. These data suggest that mutations found only in mosaic state could be incompatible with life if present in germinal state. None of the 5 most frequent germline mutations was identified in mosaic state. Mutations found only in germinal state could, therefore, be asymptomatic in mosaic state.

Conclusions: The phenotypic spectrum of NLRP3-AIDs appears to be related to the germinal/mosaic status and localization of the underlying mutations.
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http://dx.doi.org/10.1016/j.jaci.2019.11.035DOI Listing
April 2020

The NLRP3 p.A441V Mutation in -AID Pathogenesis: Functional Consequences, Phenotype-Genotype Correlations and Evidence for a Recurrent Mutational Event.

ACR Open Rheumatol 2019 Jun 6;1(4):267-276. Epub 2019 Jun 6.

Sorbonne Université INSERM, Hôpital Trousseau Paris France.

Objective: To determine the molecular and cellular bases of autoinflammatory syndromes in a multigenerational French family with Muckle-Wells syndrome and in a patient originating from Portugal with familial cold autoinflammatory syndrome.

Methods: Sequencing of exon 3 was performed in all accessible patients. Microsatellite and whole-genome single nucleotide polymorphism genotyping was used i) to test the intrafamilial segregation of the identified variant and ii) to look for a founder effect. Functional analyses included the study of i) apoptosis-associated speck-like protein containing a CARD (ASC) speck formation in HEK293T cells (stably expressing ASC-green fluorescent protein and pro-caspase 1-FLAG) transiently expressing the wild-type or mutated NLRP3 protein, ii) levels of IL-1β secreted from transfected THP-1 cells, and iii) inflammasome-related gene expression and cytokine secretion from monocytes isolated from patients in crisis (probands from the two families), related patients out of crisis, and from controls.

Results: The same heterozygous mutation (c.1322C>T, p.A441V) located in the NACHT domain, segregating with the disease within the first family, was identified in the two families. This mutation was found to be associated with different core haplotypes. NLRP3-A441V led to increased ASC speck formation and high levels of secreted IL-1β. Monocyte inflammasome-related gene expression and cytokine secretion, which were within the normal range in patients out of crisis, were found to be differentially regulated between the two probands, correlating with their phenotypic status.

Conclusion: These molecular and cellular findings, which indicate a recurrent mutational event, clearly demonstrate the pathogenicity of the p.A441V missense mutation in -associated autoinflammatory disease and point to the interest of studying patients' primary cells to assess disease activity.
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http://dx.doi.org/10.1002/acr2.1039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857991PMC
June 2019
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