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To the Editor,The severe prognosis of Erdheim-Chester disease (ECD) is essentially based on central nervous system involvement and probably on cardiac injuries [1,2]. Recently, treatments blocking ...

Purpose We aimed to describe the initial treatment that was used in a common hospital-based practice in patients with giant-cell arteritis with and without large-vessel involvement at diagnosis as well as the outcomes in both groups. Methods This retrospective multi-center cohort included patients with giant-cell arteritis diagnosed between 2005 and 2015, all of whom had fluorodeoxyglucose (FDG) positron emission tomography combined with computed tomography (FDG-PET/CT) performed at giant-cell arteritis diagnosis and were followed up for ≥12 months. We compared the features, treatment, and outcomes of patients with large-vessel involvement demonstrated on FDG-PET/CT with those of patients with a negative PET/CT. Results Eighty patients (50 women, median age: 71 [53-87] years) were included, 40 of whom had large-vessel involvement demonstrated on FDG-PET/CT and 40 who did not. After a median 56-month follow-up time, 42 (53%) patients had discontinued glucocorticoid (GC) treatment. Patients with and without large-vessel involvement were indistinguishable in the initial median dose of prednisone (0.74 mg/kg vs 0.75 mg/kg, P = .56), overall GC duration ( P = .77), GC discontinuation rate ( P = .65), relapse rate ( P = .50), frequency of GC-dependent disease requiring GC-sparing treatments ( P = .62), and fatality rate ( P = .06). Conclusion In the setting of tertiary hospital recruitment, large-vessel involvement at giant-cell arteritis diagnosis using a PET/CT study had no influence on the choice of initial GC dose and had no impact on outcomes. Prospective studies are required to confirm these findings.

International audience; PURPOSE:The purpose of our study was to assess the concordance of aortic CT angiography (CTA) and FDG-PET/CT in the detection of large-vessel involvement at diagnosis in patients with giant-cell arteritis (GCA).METHODS:We created a multicenter cohort of patients with GCA diagnosed between 2010 and 2015, and who underwent both FDG-PET/CT and aortic CTA before or in the first ten days following treatment introduction. Eight vascular segments were studied on each procedure. We calculated concordance between both imaging techniques in a per-patient and a per-segment analysis, using Cohen's kappa concordance index.RESULTS:We included 28 patients (21/7 women/men, median age 67 [56-82]). Nineteen patients had large-vessel involvement on PET/CT and 18 of these patients also presented positive findings on CTA. In a per-segment analysis, a median of 5 [1-7] and 3 [1-6] vascular territories were involved on positive PET/CT and CTA, respectively (p = 0.03). In qualitative analysis, i.e., positivity of the procedure suggesting a large-vessel involvement, the concordance rate between both procedures was 0.85 [0.64-1]. In quantitative analysis, i.e., per-segment analysis in both procedures, the global concordance rate was 0.64 [0.54-0.75]. Using FDG-PET/CT as a reference, CTA showed excellent sensitivity (95%) and specificity (100%) in a per-patient analysis. In a per-segment analysis, sensitivity and specificity were 61% and 97.9%, respectively.CONCLUSIONS:CTA and FDG-PET/CT were both able to detect large-vessel involvement in GCA with comparable results in a per-patient analysis. However, PET/CT showed higher performance in a per-segment analysis, especially in the detection of inflammation of the aorta's branches.

Objective.Our aim was to describe patients with giant cell arteritis (GCA)–related stroke and to compare them with a control group of GCA patients without stroke.Methods.We created a retrospective multicenter cohort of patients with (1) GCA diagnosed according to the American College of Rheumatology criteria between 1995 and 2015, and (2) stroke occurring at the time of GCA diagnosis or occurring within 4 weeks of starting GCA therapy. The control group consisted of GCA patients without stroke.Results.Forty patients [21 women (53%), median age 78 (60–91) yrs] with GCA-related stroke were included and were compared with 200 control patients. Stroke occurred at GCA diagnosis in 29 patients (73%), whereas it occurred after diagnosis in 11 patients. Vertebrobasilar territory was involved in 29 patients (73%). Seven patients died within a few hours or days following stroke. Compared with the control group, stroke patients had more ophthalmic ischemic symptoms [25 (63%) vs 50 (25%), p < 0.001]. Conversely, they demonstrated lower biological inflammatory variables [C-reactive protein: 61 (28–185) mg/l vs 99 (6–400) mg/l, p = 0.04] and less anemia [22/37 (59%) vs 137/167 (79%), p = 0.03] than patients without stroke. Multivariate logistic regression revealed that the best predictors for the occurrence of stroke were the presence of ophthalmic ischemic symptoms at diagnosis (OR 5, 95% CI 2.14–12.33, p = 0.0002) and the absence of anemia (OR 0.39, 95% CI 0.16–0.99, p = 0.04).Conclusion.Stroke, especially in the vertebrobasilar territory, is more likely to occur in patients with GCA who experience recent ophthalmic ischemic symptoms and who exhibit low inflammatory variables.

Introduction Decrire les caracteristiques et le devenir de patients presentant une Arterite a cellules geantes (ACG) avec une manifestation ophtalmologique au diagnostic. Materiels et methodes A partir d’une cohorte monocentrique retrospective de 409 patients consecutifs suivis pour une ACG, les patients ayant presentes une manifestation ophtalmologique au diagnostic ont ete compares a un groupe controle appareille selon l’âge et le sexe sans manifestation ophtalmologique initiale. Chaque symptome ophtalmologique a ete associe a un diagnostic ophtalmologique apres concertation avec un ophtalmologiste. Resultats Parmi les 409 patients, 104 (25 %) ont presente une manifestation ophtalmologique au moment du diagnostic d’ACG. Compares aux 104 temoins, ceux presentant une manifestation ophtalmologique presentaient moins de fievre (p = 0,0006), moins de pseudo-polyarthrite rhizomelique (p = 0,02) et une reaction inflammatoire biologique moins marquee (p = 0,004). Un flou visuel (chez 60 % des patients), une amaurose fugace (chez 18 %), une diplopie (chez 13 %) et une cecite brutale (chez 9 %) etaient les 4 manifestations visuelles decrites au diagnostic. Une neuropathie optique ischemique anterieure aigue (NOIAA) a ete mise en evidence chez 47 (45 %) des patients, suivie de l’occlusion de l’artere centrale de la retine (OACR) chez 15 (15 %). Une recuperation visuelle totale a ete notee chez 62 (60 %) des patients alors que les 42 (40 %) autres patients ont conserve une cecite ou d’importantes sequelles visuelles. Parmi les 47 patients ayant presente une NOIAA, 35 (85 %) patients ont conserve une cecite ou d’importantes sequelles visuelles. Le delai d’initiation de la corticotherapie n’etait pas differents entre les deux groupes (p = 0,06). L’utilisation de boli de methylprednisolone IV etait plus importante chez les patients ayant presente une cecite definitive sequellaire (p = 0,001). Conclusion Les manifestations ophtalmologiques ont ete retrouvees chez ¼ de nos patients presentant une ACG. Dans cette etude, la NOIAA est toujours associee a un pronostic visuel pejoratif sans que l’utilisation d’une corticotherapie a forte dose initiale ne reduise le risque de cecite sequellaire.

Introduction L’angioscanner aortique et la tomographie par emission de positons (TEP) ont tous deux demontre leur bonne sensibilite dans la detection des atteintes des gros vaisseaux lies a l’arterite a cellules geantes (ACG). L’objectif de notre etude est d’evaluer la concordance des deux examens dans la detection de ces atteintes au diagnostic. Patients et methodes A partir d’une cohorte multicentrique de patients atteints d’ACG diagnostiques entre 2010 et 2015, et suivis dans 3 services de medecine interne, nous avons selectionne les patients qui ont beneficie d’un angioscanner aortique et d’une TEP avant ou dans les 10 premiers jours suivant l’introduction de la corticotherapie. Huit territoires vasculaires etaient analyses sur les deux examens. La concordance entre les deux techniques d’imagerie etait calculee par patients et par territoires vasculaires en utilisant l’indicex de concordance kappa de Cohen. Resultats Nous avons inclus 28 patients (21/7 femmes/hommes, âge median : 67 [56–82] ans). Dix-neuf patients avaient une atteinte des gros vaisseaux a la TEP et 18 d’entre eux avaient egalement une telle atteinte sur l’angioscanner aortique. L’analyse par territoires vasculaires montrait une mediane de 5 (1–7) et 3 (1–6) segments vasculaires atteints sur les TEP et angioscanners positifs, respectivement ( p = 0,03). L’analyse qualitative, c’est a dire positivite de l’imagerie suggerant une atteinte des gros vaisseaux, montrait que le taux de concordance entre les deux examens etait de 0,85 (0,64–1). L’analyse quantitative, c’est-a-dire, une analyse par territoires vasculaires sur les deux examens, montrait un taux de concordance de 0,64 (0,54–0,75). En utilisant la TEP comme examen de reference, l’angioscanner aortique montrait une excellente sensibilite (95 %) et specificite (100 %) dans une analyse par patients. Dans une analyse par territoires vasculaires, la sensibilite et specificite de l’angioscanner etaient respectivement de 61 % et 98 %. L’angioscanner perdait en sensibilite par rapport a la TEP sur la detection de l’inflammation des branches aortiques. Conclusion L’angioscanner aortique et la TEP peuvent tous deux detecter l’atteinte des gros vaisseaux avec des resultats comparables dans une analyse par patients. En revanche, la TEP montrait des performances plus importantes dans une analyse par territoires vasculaires, principalement dans la detection de l’inflammation des branches aortiques.

A few reports suggest combination of ANCA-associated vasculitis (AAV) and neutrophilic dermatoses (ND). We aimed to describe the main characteristics of patients presenting with both AAV and ND in a French cohort and through a systematic literature review, and to discuss the possible common pathogenic process involved. We conducted a retrospective study of patients with both conditions. Patients were selected via the French Internal Medicine Society (SNFMI) and the French Vasculitis Study Group (FVSG). A literature review focusing on a combination of both conditions, concentrated only on publications with well-established diagnoses and individual detailed data. Seventeen patients diagnosed with AAV and ND were identified in this cohort. Twelve patients had granulomatosis with polyangiitis (GPA), 4 had microscopic polyangiitis (MPA) and one had eosinophilic GPA (EGPA). Eight patients, all with GPA, displayed pyoderma gangrenosum (PG). Sweet's syndrome was observed in 6 patients (4 with MPA, one with GPA and one with EGPA) and erythema elevatum diutinum in the other three (2 with GPA and 1 with MPA). The literature review identified 33 additional patients with both conditions, including 26 with GPA. Altogether, of the 50 patients (17 from our study and 33 from the literature review), 33 (66%) patients presented with PG associated with GPA in 29 cases (89%). Corticosteroids were the first-line treatment in conjunction with an immunosuppressive agent in most cases. Outcomes were good and a total of 15 patients experienced a relapse. Patients who relapsed were more likely to have ear, nose and throat manifestation than patients who did not [12/15 (80%) relapsing patients vs. 15/35 (43%) non-relapsing patients; p = 0.03)]. In our stud, the most frequent association concerned GPA and PG. ND should be considered and specifically researched within the spectrum of cutaneous manifestations observed in AAV.

Introduction To identify characteristics and factors associated with relapse and glucocorticoid (GC) dependence in a large cohort of consecutive patients with giant-cell arteritis (GCA). Patients and methods We retrospectively analyzed 326 consecutive patients with GCA diagnosed between 2000 and 2016 and followed them for at least 12 months. Factors associated with relapse were identified in a Cox proportional hazards model. Factors associated with GC dependence were identified in a multivariate logistic regression analysis. Results The 326 patients (73% women; median age at diagnosis: 74 [48–92] years) were followed up for 62 [12–262] months. During follow-up, 171 (52%) patients relapsed, including 113 (35%) who developed a GC dependence. Relapsing patients more frequently showed a past history of stroke (P = 0.01) and large-vessel involvement (LVI) on imaging (P = 0.01) than patients without relapse. Therapeutic strategy did not differ among relapsing and non-relapsing patients. GC-dependent patients were younger (P = 0.0001) and more frequently showed a past history of stroke (P = 0.004) and LVI on imaging (P = 0.005) than patients without GC-dependent disease. In multivariate analyses, LVI was an independent predictive factor of relapse [hazards ratio (HR): 1.49 (95% IC: 1.002–2.12), P = 0.04] and GC dependence [odds ratio (OR): 2.19 (95% IC: 1.19–4.05), P = 0.01]. Conversely, stroke was a protective factor against relapse [HR: 0.21 (95% CI: 0.03–0.68), P = 0.005] and GC dependence disease [OR: 0.10 (95% CI: 0.001–0.31), P = 0.0005]. Conclusion LVI was an independent predictive factor of relapse and GC dependence. Conversely, a previous stroke was protective against both unfavorable treatment outcomes. Further prospective studies are needed to confirm these findings and determine if patients with LVI require a different treatment.

Objectives. In Erdheim-Chester disease (ECD), the empirical single dose (SD, 100 mg/day) anakinra sometimes induces only partial responses. Since SD is usually well tolerated, doubling the dose might improve response while maintaining an acceptable safety profile. Methods. A retrospective analysis was performed of outcomes under double-dose (DD) of anakinra in 4 ECD patients who did not exhibit a complete response (CR) under SD treatment. Bone, retroperitoneal, neurologic/orbital, peritoneal, pericardial, right atrium, and pleural involvements were recorded. CR, partial response (PR), stable disease, progressive disease (PD) and tolerance of DD were assessed. Results. SD treatment was a second or third line treatment in three patients after interferon-therapy failure. Two patients, including one with a BRAF mutation, achieved a CR and one patient with a NRAS mutation achieved a PR with DD treatment. The fourth patient, wild-type for both genes, did not respond to a first DD treatment, but then achieved CR under SD associated with a reduced dose of vemurafenib (960 mg/d). Bone and retroperitoneal lesions partially improved on imaging with SD in all patients, but were further improved under DD with two patients achieving CR. With SD treatment, two patients with right atrial masses showed sustained CR. Under DD treatment, two patients with massive serositis refractory to SD, showed PR. Conclusion. DD improved the response to anakinra and lead to two CRs and a PR in three out of four ECD patients, with minor and comparable side-effects to those of SD, while failures were essentially related to massive serositis.

Introduction L’arterite a cellules geantes (ACG) est communement evoquee dans le bilan diagnostic de fievre, d’alteration de l’etat general (AEG) et/ou de syndrome inflammatoire biologique isoles et prolonges (fever of unknown origin chez les anglo-saxons). Les donnees disponibles sur ces formes reposent sur la description de cas singuliers ou de petites series. L’objectif de ce travail est, au sein d’une large cohorte bicentrique, de decrire les caracteristiques cliniques, paracliniques, therapeutiques et evolutives de ces patients avec une forme systemique d’ACG ne s’exprimant que par une AEG, une fievre et/ou un syndrome inflammatoire biologique. Patients et methodes Il s’agit d’une etude retrospective, menee dans deux CHU (Limoges et Caen), disposant d’une cohorte de 920 patients diagnostiques avec une ACG selon les criteres de l’ACR. Pour la presente etude, nous avons selectionne les patients disposant d’une histologie positive, avec dans le groupe cible ceux n’ayant au diagnostic ni manifestations crâniennes (dont ophtalmologiques), ni manifestations vasculaires peripheriques, ni pseudopolyarthrite rhizomelique. Le groupe comparatif etait constitue de tous les autres patients qui disposaient de signes typiques de la maladie. Resultats Parmi les 627 patients avec un diagnostic d’ACG porte sur une biopsie, 57 (9 %) patients (39 [68 %] femmes, âge median 75 [48–92]) avaient une forme systemique isolee de la maladie. Le delai diagnostic etait de 75 (6–1825) jours, contre 45 (1–580) jours pour le groupe comparatif ( p = 0,001). Une imagerie de l’aorte etait realisee au diagnostic chez 36 (63 %) patients avec une forme systemique et montrait une atteinte des gros vaisseaux chez 21 (37 %) d’entre eux. Comparativement aux patients avec une presentation typique de la maladie, outre un delai diagnostic plus long, les patients avec une forme systemique avaient au diagnostic significativement plus de signes generaux (79 % dans les formes systemiques contre 64 % dans le groupe controle, p = 0,03), des CRP plus elevees (120 [18–382] mg/L versus 80 [2–535] mg/L, p = 0,02), un taux d’hemoglobine plus bas (10,6 [7,1–15,4] g/dL versus 11,6 [6,9–16,1] g/dL, p = 0,0001) et plus d’atteintes iconographiques des gros vaisseaux (37 % versus 20 %, p = 0,003). En revanche, la gestion de la corticotherapie (doses initiales, a m3, m6 et m12, ainsi que les delais d’arret), le recours aux traitements d’epargne cortisonique, le taux de rechute et de deces n’etaient pas differents. Conclusion Notre large etude montre que les formes systemiques representent pres de 10 % des patients avec ACG certaine. Cette forme de la maladie ne semble pas etre associee avec un pronostic different des formes typiques, meme si elle est souvent plus inflammatoire et plus souvent associee a une atteinte des gros vaisseaux. Son pronostic vasculaire tardif doit neanmoins etre precise.

International audience; BACKGROUND:Primary immunodeficiencies (PIDs) are inherited diseases associated with a considerable increase in susceptibility to infections. It is known that PIDs can also predispose to cancer and immune diseases, including allergy, autoimmunity, and inflammation.OBJECTIVE:We aimed at determining the incidence of autoimmunity and inflammation in patients with PIDs.METHODS:We have retrospectively screened 2183 consecutive cases of PID in the Centre de Référence Déficits Immunitaires Héréditaires registry (CEREDIH; the French national PID registry) for the occurrence of autoimmunity and inflammation.RESULTS:One or more autoimmune and inflammatory complications were noted in 26.2% of patients, with a risk of onset throughout the patient's lifetime. The risk of autoimmune cytopenia was at least 120 times higher than in the general population, the risk of inflammatory bowel disease in children was 80 times higher, and the risk of other autoimmune manifestations was approximately 10 times higher. Remarkably, all types of PIDs were associated with a risk of autoimmune and inflammatory complications, although the greatest risk was associated with T-cell PIDs and common variable immunodeficiency. The occurrence of autoimmune disease is a negative prognostic factor for survival.CONCLUSIONS:Our results provide the basis for a detailed prospective evaluation of autoimmunity and inflammation in the context of PIDs, with a view to accurately assessing these risks and describing the possible effect of medical intervention.

Intravenous immunoglobulin (IVIG) represents a therapeutic alternative in antineutrophil cytoplasmic antibody-associated vasculitides (AAV), but its efficacy has been evaluated in only 2 small prospective trials. The aim of this study was to evaluate the efficacy and safety of IVIG in patients with AAV.We conducted a nationwide retrospective study of patients who received IVIG as immunomodulatory therapy for AAV.A total of 92 patients (mean age 51 years) presenting with either granulomatosis with polyangiitis (Wegener's) (68%), eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (22%), or microscopic polyangiitis (10%) received at least 1 course of IVIG. Antineutrophil cytoplasmic antibodies were present in 72% during the flare that required IVIG, as determined by immunofluorescence assay. IVIG was initiated because of relapsing disease in 83% of cases. IVIG was given for a median of 6 months (range 1-156 months) and in combination with corticosteroids in 21% of the patients or with other immunosuppressive agents in 77%. Efficacy of IVIG was assessed in the entire population and in a subset of 34 patients with unmodified background therapy. Remission rates at 6 months were 56% in the entire population and 58% in the unmodified background therapy group. Refractory disease and treatment failure at 6 months were observed in 7% and 18% in the whole population and 3% and 21% in the unmodified background therapy group, respectively. Adverse events (AEs) occurred in 33%, including serious AEs in 12% and AEs leading to discontinuation of IVIG in 7%.This large study shows the clinical benefit of IVIG as adjunctive therapy, with an acceptable tolerance profile, and thus supports its use in AAV patients with refractory or relapsing disease.

Introduction Le myelome multiple est frequemment responsable d’une atteinte renale, dont le mecanisme peut etre divers. Parmi ceux-ci, la glomerulonephrite a depots isoles de C3 (GP-C3) est secondaire a une dysregulation de la voie alterne du complement (AP). Cette dysregulation peut etre liee a un auto-anticorps anti-facteur H (FH), une activite cofacteur du facteur I et est un inhibiteur competitif pour la liaison du C3b avec le facteur B. Observation Une patiente de 68 ans etait hospitalisee pour un acrosyndrome vasculaire douloureux. Ses antecedents comprenaient un diabete de type II, une hypertension arterielle et une dyslipidemie. Depuis 8 mois, elle avait une anemie normocytaire aregenerative et une deterioration progressive de sa fonction renale (creatininemie passant de 113 a 247 μmol/L et hemoglobinemie de 9,2 a 7,6 g/dL). L’examen etait sans particularite, en dehors de l’acrosyndrome. L’electrophorese des proteines plasmatiques, confirmee par l’immunofixation, revelait une immunoglobuline monoclonale G kappa (IgG κ) a 10,4 g/L. Le myelogramme confirmait le diagnostic de myelome a caryotype normal, avec 15 % de cellules plasmocytaires dystrophiques. Il n’existait pas d’hypercalcemie ni de lesions osteolytiques. La proteinurie etait non selective a 2 g/jour, avec des traces d’IgG κ. La biopsie renale etait en faveur d’une GP-C3. Les taux de C3, C4, CH50, facteurs H et I, CD46 etaient normaux, mais il existait une augmentation des taux du facteur Bb et du C5b-9 soluble. Il n’etait pas retrouve de C3nef et le Western Blot du CHFR1 etait normal. Des auto-anticorps anti-FH etaient mis en evidence (950 UA/mL, N Discussion L’originalite de ce cas est liee a l’association d’une GP-C3 avec des ischemies digitales sans stigmate de microangiopathie thrombotique, liee a des auto-anticorps anti-FH. La chimiotherapie du myelome n’a pas permis d’ameliorer les differentes atteintes malgre une reponse hematologique, alors que le blocage de l’AP a permis une amelioration rapide des lesions ischemiques et renales. Le FH a un effet inhibiteur sur l’activation du facteur XII, comparable a celui de β2-GP1. Des anticorps anti-FH ont ainsi ete detectes dans le syndrome des antiphospholipides. Le FH possede aussi une activite reductase du facteur von Willebrand sur les multimeres de haut poids moleculaire. Ces multimeres pourraient favoriser des thromboses microvasculaires. L’eculizumab a ete utilise avec succes dans les GP-C3, particulierement en cas de progression rapide avec des depots glomerulaires importants de C5b-9, ainsi que dans des cas de gangrenes ischemiques distales associees a des auto-anticorps anti-FH, mais uniquement au cours de SHU atypiques. Conclusion Une dysregulation de l’AP peut etre suspectee en cas d’angiopathie distale sans etiologie retrouvee, particulierement en cas d’association avec une gammapathie monoclonale. Dans ce cas, l’eculizumab, en association avec le traitement etiologique de la dyscrasie plasmocytaire, peut trouver sa place pour controler de facon plus rapide les manifestations thrombotiques et renales liees aux anticorps anti-FH.

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Erdheim–Chester disease (ECD) pathophysiology remains largely unknown. Its treatment is not codified and usually disappointing. Interferon (IFN)-α therapy lacks efficacy for some life-threatening manifestations and has a poor tolerance profile. Because interleukin (IL)-1Ra synthesis is naturally induced after stimulation by IFN-α, we hypothesized that recombinant IL-1Ra (anakinra) might have some efficacy in ECD. We treated 2 patients who had poor tolerance or contraindication to IFN-α with anakinra as a rescue therapy and measured their serum C-reactive protein, IL-1β, IL-6, and monocytic membranous IL-1α (mIL-1α) levels before, under, and after therapy. Another untreated ECD patient and 5 healthy subjects were enrolled as controls. After treatment, fever and bone pains rapidly disappeared in both patients, as well as eyelid involvement in one patient. In addition, retroperitoneal fibrosis completely or partially regressed, and C-reactive protein, IL-6, and mIL-1α levels decreased to within the normal and control range. Beside injection-site reactions, no adverse event was reported. Therefore, our results support a central role of the IL-1 network, which seemed to be overstimulated in ECD. Its specific blockade using anakinra thereby opens new pathophysiology and therapeutic perspectives in ECD.