Publications by authors named "Léa Savey"

31 Publications

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

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

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

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

Tocilizumab in treatment-naïve patients with Takayasu arteritis: TOCITAKA French prospective multicenter open-labeled trial.

Arthritis Res Ther 2020 09 17;22(1):218. Epub 2020 Sep 17.

Sorbonne Universités AP-HP, Hôpital Saint Antoine, service de médecine interne et Inflammation-Immunopathology-Biotherapy Department (DMU 3iD), Faculté de Médecine Sorbonne Université, F-75012, Paris, France.

Objectives: To assess long-term efficacy of tocilizumab in treatment-naive patients with Takayasu arteritis (TAK).

Methods: Prospective open-labeled trial in naïve patients with TAK who received steroids at the dose of 0.7 mg/kg/day and 7 infusions of 8 mg/kg/month of tocilizumab. The primary endpoint was the number of patients who discontinued steroids after 7 infusions of tocilizumab. Secondary endpoints included disease activity and the number of relapses during 18-month follow-up.

Results: Thirteen patients with TAK were included, with a median age of 32 years [19-45] and 12 (92%) females. Six (54%) patients met the primary end-point. A significant decrease of disease activity was observed after 6 months of tocilizumab therapy: decrease of median NIH scale (3 [3, 4] at baseline, versus 1 [0-2] after 6 months; p < 0.001), ITAS-2010 score (5 [2-7] versus 3 [0-8]; p = 0.002), and ITAS-A score (7 [4-10] versus 4 [1-15]; p = 0.0001)]. During the 12-month follow-up after tocilizumab discontinuation, a relapse occurred among 5 patients (45%) out of 11 in which achieved remission after 6 months of tocilizumab.

Conclusion: Tocilizumab seems an effective steroid sparing therapy in TAK, but maintenance therapy is necessary.

Trial Registration: ClinicalTrials.gov NCT02101333 . Registered on 02 April 2014.
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http://dx.doi.org/10.1186/s13075-020-02311-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500024PMC
September 2020

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

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

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

Comments on Tașdemir et al.: A rare cause of AA amyloidosis and end-stage kidney failure.

Pediatr Nephrol 2019 09 27;34(9):1635. Epub 2019 May 27.

Internal Medicine Department, French National Center for Autoinflammatory Diseases and AA Amyloidosis, Tenon Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 4 rue de la Chine, 75970, Paris CEDEX 20, France.

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http://dx.doi.org/10.1007/s00467-019-04278-8DOI Listing
September 2019

Autoinflammatory diseases: State of the art.

Presse Med 2019 Feb 24;48(1 Pt 2):e25-e48. Epub 2019 Jan 24.

AP-HP, hôpital Tenon, Sorbonne université, service de médecine interne, centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), 75020 Paris, France; Assistance publique-Hôpitaux de Paris, hôpital Trousseau, université Pierre-et-Marie-Curie (UPMC)-Paris 6, Inserm UMRS_933, 75012 Paris, France.

Autoinflammatory diseases are characterized by innate immunity abnormalities. In autoinflammatory diseases (AID), inflammatory blood biomarkers are elevated during crisis without infection and usually without autoantibodies. The first 4 described AID were familial Mediterranean fever, cryopyrin-associated periodic fever syndrome (CAPS) or NLRP3-associated autoinflammatory disease (NRLP3-AID), mevalonate kinase deficiency (MKD) and TNFRSF1A-receptor associated periodic fever syndrome (TRAPS). Since their description 20 years ago, and with the progresses of genetic analysis, many new diseases have been discovered; some with recurrent fever, others with predominant cutaneous symptoms or even immune deficiency. After describing the 4 historical recurrent fevers, some polygenic inflammatory diseases will also be shortly described such as Still disease and periodic fever with adenitis, pharyngitis and aphtous (PFAPA) syndrome. To better explore AID, some key anamnesis features are crucial such as the family tree, the age at onset, crisis length and organs involved in the clinical symptoms. An acute phase response is mandatory in crisis.
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http://dx.doi.org/10.1016/j.lpm.2018.12.003DOI Listing
February 2019

Autoinflammatory syndromes.

Presse Med 2019 02 19;48(1 Pt 2):e21-e23. Epub 2019 Jan 19.

AP-HP, hôpital Tenon, Sorbonne université, service de médecine interne, centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), 75020 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.lpm.2018.12.005DOI Listing
February 2019

New data in causes of autoinflammatory diseases.

Joint Bone Spine 2019 Oct 22;86(5):554-561. Epub 2018 Nov 22.

Centre national de référence des maladies auto-inflammatoires et de l'amylose inflammatoire (CEREMAIA), 94270 Le Kremlin-Bicêtre, France; Cellules souches, plasticité cellulaire, médecine régénératrice et immunothérapies, Inserm, Université de Montpellier, 34090 Montpellier, France; Département de génétique médicale, maladies rares et médecine personnalisée, CHU de Montpellier, 34295 Montpellier, France.

The spectrum of factors known to mediate autoinflammation has broadened recently to include not only interleukin-1 (IL-1) and interferon, but also abnormalities that impair NF-κB pathway negative regulation. The NF-κB pathway is activated upon contact of a ligand with tumor necrosis factor receptor 1 (TNFR1) and plays a pivotal role in triggering the inflammatory process by producing major cytokines such as IL-1, IL-6, and TNF. Negative regulation of the NF-κB pathway, which is essential to stop the inflammatory process, depends on the level of ubiquitination of the proteins associated with TNFR1 and of other intermediate compounds. A20 and otulin are proteins that influence the level of ubiquitination, and a deficiency in either can result in NF-κB activation with overproduction of pro-inflammatory cytokines. Similar to Behçet's disease, A20 haploinsufficiency manifests as oral and genital ulcers and, more rarely, as uveitis. However, transmission is dominant, symptom onset occurs at a younger age, and severe gastrointestinal involvement is at the forefront of the clinical picture. Clinical presentations are extremely diverse. Over their lifetime, affected patients simultaneously or sequentially experience autoinflammatory and autoimmune manifestations. Mild immune deficiency predominantly affecting humoral responses is less common. Otulin deficiency results in systemic inflammatory manifestations at a very young age, with panniculitis, lipodystrophy, and inflammatory bowel disease. The main differential diagnosis is proteasome-associated autoinflammatory syndrome. The treatment of A20 haploinsufficiency and otulin deficiency is challenging and remains unstandardized. The symptoms respond to high-dose glucocorticoid therapy. TNF antagonists and IL-1 antagonists have shown some measure of efficacy.
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http://dx.doi.org/10.1016/j.jbspin.2018.11.003DOI Listing
October 2019

Severe infections in sarcoidosis: Incidence, predictors and long-term outcome in a cohort of 585 patients.

Medicine (Baltimore) 2017 Dec;96(49):e8846

Département de Médecine Interne et d'Immunologie Clinique, Hôpital Pitié Salpétrière, Paris, France. Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Université Pierre et Marie Curie, Paris, France. DHU Inflammation, Immunopathology, Biotherapy UPMC, Paris VI Department of Biostatistics and Medical Information (SBIM) Department of Ophtalmology, Université Pierre et Marie Curie Department of Infectious disease, Hôpital Pitié Salpétrière, Paris, France.

Sarcoidosis is associated with cell-mediated immunodeficiency and treatment of symptomatic sarcoidosis usually includes systemic immunosuppressants. Data relative to incidence, prognosis factors, and outcome of infections are scarce.Retrospective cohort study of 585 patients with biopsy proven sarcoidosis in a tertiary referral specialist clinic, with a nested case-control analysis. Twenty nine patients (4.9%) with severe infections were compared to 116 controls subjects with sarcoidosis, matched according to their gender, ethnicity, age at diagnosis, and treatment with corticosteroids.After a median follow-up of 8 years [range; 1-46], 38 severe infections [mycobacterial infections (n = 14), fungal infections (n = 10), bacterial (n = 8), viral (n = 3) and parasitic (n = 1)] were observed in 30 patients. The incidence of severe infections was 0.71% persons-year (CI 95% 0.5-0.98) and 0.43% persons-year (CI 95% 0.27-0.66). Patients with severe infection were more frequently of male gender (60% vs 46%) and were more likely treated by ≥ 3 immunosuppressive agents (OR = 3.8, IC 95% [1.5-9.64], P = .005) and by cyclophosphamide (OR = 5.55, IC 95% [1.9-16.1], P = .002), and with neurological (OR = 3.36 CI 95% [1.37-8.25], P = .008), or cardiac (OR = 2.65 CI 95% [1.09-6.43], P = .031) involvement of the sarcoidosis, compared to the controls. Two patients died within the 6 months following infection, due to progressive multifocal leucoencephalopathy (n = 1), and of peritonitis (n = 1).Severe infections are observed in 5.1% of our patients with sarcoidosis after a median follow-up of 8 years. Risk factors for severe infections included neurological or cardiac involvement of sarcoidosis, the use of immunosuppressive agents and mainly cyclophosphamide.
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http://dx.doi.org/10.1097/MD.0000000000008846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728866PMC
December 2017

Large-vessel vasculitis in human immunodeficiency virus-infected patients.

J Vasc Surg 2018 05 11;67(5):1501-1511. Epub 2017 Dec 11.

Department of Internal Medicine and Clinical Immunology, Centre de référence des maladies autoimmunes et systémiques rares, Sorbonne University, UPMC Paris VI, AP-HP, Hôpital Pitié-Salpétrière, Paris, France; DHU I2B, Inflammation, Immunopathologie, Biothérapie, Sorbonne University, UPMC Paris VI, AP-HP, Hôpital Pitié-Salpétrière, Paris, France. Electronic address:

Objective: The objective of this study was to describe large-vessel vasculitis (LVV) in patients with human immunodeficiency virus (HIV) infection. It is a retrospective single-center study conducted between 2000 and 2015 through a university hospital of 11 HIV-infected patients with LVV.

Methods: The characteristics and outcome of 11 HIV-infected patients with LVV (7 patients fulfilled international criteria for Takayasu arteritis, 5 patients had histologic findings of vasculitis, and 5 patients had imaging features of aortitis) were analyzed and compared with those of 82 patients with LVV but without HIV infection.

Results: Concerning the HIV-infected patients with LVV (n = 11), the mean age was 40 years (range, 36-56 years), and 55% of patients were female. At diagnosis of LLV, the mean initial CD4 cell count was 455 cells/mm (range, 166-837 cells/mm), and the median HIV viral load was 9241 copies. Vascular lesions were located in the aorta (n = 7), in supra-aortic trunks (n = 7), and in digestive arteries (n = 3). Inflammatory aorta infiltrates showed a strong expression of interferon-γ and interleukin 6. In HIV-negative LVV patients (n = 82), the median age was 42 years, and 88% of the patients were women. Thirty patients had an inflammatory syndrome. Seventy patients had been treated with glucocorticosteroids and 57 with immunosuppressive treatments. Compared with their negative counterparts, HIV-positive patients with LVV were more frequently male (P = .014), had more vascular complications (ie, Ishikawa score; P = .017), and had more frequent revascularization (P = .047). After a mean follow-up of 96 months, four relapses of vasculitis were reported, and one patient died. Regardless of the HIV virologic response, antiretroviral therapy improved LVV in only one case.

Conclusions: LVV in HIV-infected patients is a rare and severe entity.
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http://dx.doi.org/10.1016/j.jvs.2017.08.099DOI Listing
May 2018

Diversification of human plasmacytoid predendritic cells in response to a single stimulus.

Nat Immunol 2018 Jan 4;19(1):63-75. Epub 2017 Dec 4.

Institut Curie, Centre de Recherche, PSL Research University, Paris, France.

Innate immune cells adjust to microbial and inflammatory stimuli through a process termed environmental plasticity, which links a given individual stimulus to a unique activated state. Here, we report that activation of human plasmacytoid predendritic cells (pDCs) with a single microbial or cytokine stimulus triggers cell diversification into three stable subpopulations (P1-P3). P1-pDCs (PD-L1CD80) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1CD80) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1CD80) displayed both innate and adaptive functions. Each subpopulation expressed a specific coding- and long-noncoding-RNA signature and was stable after secondary stimulation. P1-pDCs were detected in samples from patients with lupus or psoriasis. pDC diversification was independent of cell divisions or preexisting heterogeneity within steady-state pDCs but was controlled by a TNF autocrine and/or paracrine communication loop. Our findings reveal a novel mechanism for diversity and division of labor in innate immune cells.
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http://dx.doi.org/10.1038/s41590-017-0012-zDOI Listing
January 2018

Catastrophic antiphospholipid syndrome (CAPS)-induced ischemic pancreatic ducts injury mimicking intraductal papillary mucinous neoplasm (IPMN).

Semin Arthritis Rheum 2018 02 10;47(4):565-568. Epub 2017 Jul 10.

Université Paris-Descartes, Paris, France; AP-HP, Hôpital Cochin, Centre de référence des maladies auto-immunes et systémiques rares, Service de Médecine Interne, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; INSERM U 1153, Center for Epidemiology and Statistics, Sorbonne Paris Cité (CRESS) Paris, France. Electronic address:

Objectives: Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening disease characterized by multiple small-vessel occlusions of rapid onset. Ischemic pancreatic duct lesions secondary to CAPS have never been reported.

Methods: We describe 4 patients who presented lesions suspected to be intraductal papillary mucinous neoplasm (IPMN) of the pancreas following a CAPS.

Results: All patients had a history of CAPS months or years before the IPMN diagnosis. They had abdominal pain or abnormal liver test results and had undergone radiography. In a 36-year-old man, endoscopic ultrasonography and magnetic resonance cholangiopancreatography demonstrated parietal thickening, stenoses and dilatations of the main pancreatic duct, which suggested IPMN. A pancreatic resection was performed because of presumed risk of malignancy. Histology revealed pancreatitis and thrombosis of small pancreatic vessels but no IPMN. The 3 other cases had lesions consistent with IPMN disclosed on MRI. From the first case experience, regular radiography surveillance was decided for the 3 other patients. After more than 4 years of follow-up, lesions remained unchanged.

Conclusion: Physicians must be aware that these lesions may be encountered in CAPS and may closely mimic IPMN, with subsequent risk of performing unnecessary pancreatectomy.
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http://dx.doi.org/10.1016/j.semarthrit.2017.07.001DOI Listing
February 2018

Sarcoidosis with Takayasu arteritis: a model of overlapping granulomatosis. A report of seven cases and literature review.

Int J Rheum Dis 2018 Mar 8;21(3):740-745. Epub 2017 Aug 8.

Department of Internal Medicine and Clinical Immunology, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France.

Objective: To describe the features of exceptional coexisting Takayasu arteritis (TA) and sarcoidosis, two conditions of unknown cause associated with a common immunologic pattern.

Methods: We report seven cases of concomitant sarcoidosis-Takayasu or Takayasu-like vasculitis, observed in two referral centers between 1995 and 2015.

Results: All patients were female. The mean age at sarcoidosis diagnosis and TA diagnosis was 36 and 37 years, respectively. Sarcoidosis occurred in 86% of cases before or together with TA. Sarcoidosis always had a classic expression except for one renal localization. Sarcoidosis was not severe and mostly non-treated (86%). In all cases of TA, supra-aortic arteries were involved; in only two TA cases a more diffuse inflammatory arterial involvement was noted. In one case, Takayasu arteritis occurred despite immunosuppressive therapy given for sarcoidosis. All patients received for TA a treatment with corticosteroids associated with methotrexate (four cases), infliximab (one case) or tocilizumab (one case). After a mean follow-up of 89 months, TA always improved and no death was observed.

Conclusions: TA stands as pathology associated with sarcoidosis. TA occurred in three cases among 50. When sarcoidosis preceded TA, a recovery of sarcoidosis was achieved mostly without treatment. TA is a prognostic and therapeutic factor. Immunosuppressive treatment, including steroids, led to a good prognosis for TA as well as for sarcoidosis.
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http://dx.doi.org/10.1111/1756-185X.13137DOI Listing
March 2018

De Novo Human Herpesvirus 8 Tumors Induced by Rituximab in Autoimmune or Inflammatory Systemic Diseases.

Arthritis Rheumatol 2017 11 12;69(11):2241-2246. Epub 2017 Oct 12.

Sorbonne University, UPMC University of Paris 6, Unité fonctionnelle de Dermatologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, INSERM, UMR-S 959, and Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie, Paris, France.

Objective: Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is involved in KS and other tumors, including multicentric Castleman's disease and primary effusion lymphoma. Rituximab (RTX) is currently used for the treatment of several autoimmune or inflammatory diseases and humoral organ transplant rejection. De novo HHV-8 tumors induced by RTX used for these indications have not been reported previously. This study was undertaken to evaluate de novo HHV-8 tumors induced by RTX.

Methods: In this retrospective study, we investigated the clinical, virologic, and pathologic features of 5 HIV-negative male patients with HHV-8 tumors induced by RTX therapy.

Results: Patients were all immunocompromised by previous treatments, which consisted of steroids and/or immunosuppressive agents, and received RTX for insufficient response, disease progression, or transplant rejection. They developed HHV-8 tumors a median of 4 months after beginning treatment with RTX (range 3-13 months). Four patients had at least 1 risk factor for HHV-8, including a high Fitzpatrick skin phototype (of >3) (n = 3) and homosexuality (n = 1). Four patients developed KS (all 4 had skin lesions and 2 had visceral involvement), and 1 patient developed a solid primary effusion lymphoma. RTX was discontinued in all patients, and immunosuppressants were reduced when feasible. After a median follow-up of 20 months, 2 patients died. Remission of KS was complete in 1 patient and partial in 1 patient, and 1 patient had progression.

Conclusion: Our findings indicate that patients who have a high skin phototype and are at risk of HHV-8 should be carefully screened for HHV-8 before RTX therapy. The safety of RTX, especially in nonlymphomatous disorders, should be carefully evaluated in patients at risk of HHV-8 tumors.
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http://dx.doi.org/10.1002/art.40217DOI Listing
November 2017

Systemic vasculitis associated with vemurafenib treatment: Case report and literature review.

Medicine (Baltimore) 2016 Nov;95(46):e4988

APHP, Service de Médecine Interne et Immunologie clinique, Groupe Hospitalier Pitié-Salpêtrière DHU Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie APHP, Service de Dermatologie, Groupe Hospitalier Pitié-Salpêtrière APHP, Service de Néphrologie et Dialyse, Hôpital Tenon APHP, Service d'Anatomopathologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

Rationale: Vemurafenib, an inhibitor of mutated B-rapidly accelerated fibrosarcoma, is frequently used in the treatment of melanoma and Erdheim-Chester disease (ECD) patients. Inflammatory adverse effects have been increasingly reported after vemurafenib treatment.

Patient Concerns And Diagnose: We report 6 cases of vemurafenib-associated vasculitis, of whom a personal case of a 75-year-old man with history of ECD who developed purpura and rapidly progressive pauci-immune glomerulonephritis during treatment with vemurafenib.

Intervention: In the 5 others cases from the literature, all patients presented skin vasculitis, and with joint involvement in 60% of them. Vemurafenib treatment was stopped (n = 3), continued at reduced doses (n = 1), or continued at the same dose (n = 2).

Outcomes: Three patients (50%) received corticosteroids combined with cyclophosphamide (n = 1), and all achieved remission of vasculitis. One patient experienced vasculitis relapse after vemurafenib therapy was restarted.

Lessons: Systemic vasculitis is a rare vemurafenib-associated adverse event that may be life-threatening.
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http://dx.doi.org/10.1097/MD.0000000000004988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120889PMC
November 2016

Extrahepatic manifestations of chronic hepatitis C virus infection.

Ther Adv Infect Dis 2016 Feb;3(1):3-14

Sorbonne Universités, UPMC Univ Paris 06, and Inflammation Immunopathology Biotherapy Department (DHU i2B), Paris, France.

During hepatitis C virus (HCV) chronic infection, extrahepatic manifestations are frequent and polymorphous. This article reports on a large cohort of patients with HCV-related autoimmune or lymphoproliferative disorders, from mixed cryoglobulinemia vasculitis to frank lymphomas. The relationship between HCV infection and such immune-related diseases has been formally demonstrated by epidemiological, clinical, immunological and pathological data, and results of therapeutic trials. More recently, other nonliver-related HCV disorders have been reported, including cardiovascular (i.e. stroke, ischemic heart disease), renal, metabolic and central nervous system diseases. For these manifestations, most evidence comes from large epidemiological studies; there is a need for mechanistic studies and therapeutic trials for confirmation. Beyond the risk of developing liver complications, that is, cirrhosis and liver cancer, patients with HCV infection have an increased risk of morbidity and mortality related to nonliver diseases. HCV chronic infection should be analyzed as a systemic disease in which extrahepatic consequences increase the weight of its pathological burden. The need for effective viral eradication measures is underlined.
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http://dx.doi.org/10.1177/2049936115585942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735500PMC
February 2016

Cryoglobulinemia Vasculitis.

Am J Med 2015 Sep 30;128(9):950-5. Epub 2015 Mar 30.

Sorbonne Universités, University Pierre and Marie Curie (UPMC), UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France; Institute National de la Santé et de la Recherche Medicalé (INSERM), UMR_S 959, Paris, France; Centre National de la Recherche Scientifique (CNRS), FRE3632, Paris, France; Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

Cryoglobulinemic vasculitis (CryoVas) is a small-vessel vasculitis involving mainly the skin, the joints, the peripheral nervous system, and the kidneys. Type I CryoVas is single monoclonal immunoglobulins related to an underlying B-cell lymphoproliferative disorder. Type II and III cryoglobulins, often referred to as mixed cryoglobulinemia, consist of polyclonal immunoglobulin (Ig)G with or without monoclonal IgM with rheumatoid factor activity. Hepatitis C virus (HCV) infection represents the main cause of mixed CryoVas. The 10-year survival rates are 63%, 65%, and 87% in HCV-positive mixed CryoVas, HCV-negative mixed CryoVas, and type I CryoVas patients, respectively. In HCV-positive patients, baseline poor prognostic factors include the presence of severe liver fibrosis, and central nervous system, kidney, and heart involvement. Treatment with antivirals is associated with a good prognosis, whereas use of immunosuppressants (including corticosteroids) is associated with a poor outcome. In HCV-negative patients, pulmonary and gastrointestinal involvement, renal insufficiency, and age > 65 years are independently associated with death. Increased risk of lymphoma also should be underlined. Treatment of type I CryoVas is that of the hemopathy; specific treatment also includes plasma exchange, corticosteroids, rituximab, and ilomedine. In HCV-CryoVas with mild-to-moderate disease, an optimal antiviral treatment should be given. For HCV-CryoVas with severe vasculitis (ie, worsening of renal function, mononeuritis multiplex, extensive skin disease, intestinal ischemia…) control of disease with rituximab, with or without plasmapheresis, is required before initiation of antiviral therapy. Other immunosuppressants should be given only in case of refractory forms of CryoVas, frequently associated with underlying B-cell lymphoma.
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http://dx.doi.org/10.1016/j.amjmed.2015.02.017DOI Listing
September 2015

Ethnicity and association with disease manifestations and mortality in Behçet's disease.

Orphanet J Rare Dis 2014 Mar 27;9:42. Epub 2014 Mar 27.

Department of Internal medicine and Clinical Immunology, Centre de référence des maladies autoimmunes et systémiques rares, AP-HP, Hôpital Pitié-Salpétrière, Paris, France.

Background: Behçet's disease (BD) significantly increases morbidity and mortality. BD mainly affects young adults with a peculiar geographical distribution. It has been suggested that BD varies in its phenotypic expression in different ethnic groups.

Methods: We investigated potential ethnicity-related differences relative to phenotype and prognosis of BD patients in a French multiethnic country. We included 769 consecutive patients fulfilling the international criteria of classification for BD, in the 3 largest ethnic groups of our cohort [European (n = 369), North African (n = 350) and sub Saharan African (n = 50)]. Factors that affect prognosis were assessed by multivariate analysis.

Results: 535 (69.6%) patients were male and the median (IQR) age at diagnosis was of 30.9 (24.9-37.2) years. Sub Saharan African BD patients had a higher frequency of CNS involvement (48% vs 32.3% vs 29.5%, p = 0 .035), a higher rate of death (12% vs 6% vs 3.5%, p = 0.029) and a lower frequency of HLA B51 allele (29.4% vs 49.2% vs 55.8%, p = 0.009) compared to those from North Africa and Europe, respectively. Multivariate analysis showed that male gender (HR: 5.01, CI: 1.51-16.65), cardiovascular involvement (HR: 2.24, CI: 1.15-4.36), and sub Saharan African origin (HR 2.62 (0.98-6.97) were independently associated with mortality. The 15-year mortality rate was of 19%, 9% and 6% in sub Saharan African, North African and European BD patients, respectively (p = 0.015).

Conclusion: We reported ethnicity-related differences with respect to phenotype of BD. Sub Saharan Africans patients exhibited a worse prognosis.
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http://dx.doi.org/10.1186/1750-1172-9-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986678PMC
March 2014
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