D U Grade

D E Docteur

E N Médecine

M Dumont

Président : Monsieur Le Professeur

Aouba Achille

Monsieur Le Professeur Quyntin

Jean-Claude Monsieur Le Dr De Boysson

Hubert Monsieur Le Docteur

Martin-Silva Nicolas Monsieur Le Docteur

Deshayes Samuel

Dr De Boysson

Doyen Professeur

Emmanuel Touzé

Assesseurs Professeur

Paul Milliez

Guy Launoy

Professeur Sonia Dollfus

Evelyne Professeur

Emery

Madame Sarah

Chemtob Professeurs

Des Universités -Praticiens Hospitaliers

M Agostini

M Aide Nicolas

M Allouche

M Alves

Arnaud Chirurgie

M Aouba

M Babin

Emmanuel Oto-Rhino-Laryngologie

M Bénateau

Hervé Chirurgie

M Benoist

Guillaume Gynécologie -Obstétrique

M Berger

Ludovic Chirurgie

M Bergot

Emmanuel Pneumologie

M Bibeau Frédéric

Mme Brazo

Perrine Psychiatrie D'adultes

M Brouard

Jacques Pédiatrie

M Bustany

Pierre Pharmacologie

Mme Chapon

Françoise Histologie

Embryologie Mme

Clin-Godard Bénédicte

M Coquerel

Antoine Pharmacologie

M Dao

Manh Thông

Hépatologie-Gastro-Entérologie M Damaj

Ghandi Laurent

Hématologie M Defer

Gilles Neurologie

M Delamillieure

Pascal Psychiatrie D'adultes

M Denise

Pierre Physiologie

M Derlon

Jean-Michel Éméritat

Mme Dollfus

Sonia Psychiatrie D'adultes

M Dreyfus

Michel Gynécologie -Obstétrique

M Du

Cheyron Damien

Mme Émery

Evelyne Neurochirurgie

M Esmail-Beygui

Cardiologie Farzin

Fauvet Mme

Raffaèle

M Fischer

Marc-Olivier Anesthésiologie

Péri-Opératoire M Gérard

Jean-Louis Anesthésiologie

Péri-Opératoire M Guillois

Bernard Pédiatrie

Mme Guittet-Baud

M Habrand

M Hamon Martial

Cardiologie Mme

Hamon Michèle

M Hanouz

Jean-Luc Anesthésiologie

Péri-Opératoire M Hulet

Ligny Bruno

M Icard Philippe

Lambert Olivier

Bactériologie -Virologie Mme

Joly-Lobbedez Florence

Cancérologie M Joubert

Michael Endocrinologie

Mme Kottler

M Launoy Guy

M Le Hello

Simon Bactériologie-Virologie

Mme Le Mauff

Brigitte Immunologie

Mme Leporrier

Michel Éméritat

M Leroy

François Rééducation

M Lobbedez

Thierry Néphrologie

M Manrique

M Marcélli

Christian Rhumatologie

M Martinaud

Olivier Neurologie

M Maurel

M Milliez

Paul Cardiologie

M Moreau

Sylvain Anatomie

/ Oto-Rhino-Laryngologie

M Moutel Grégoire

M Normand

Hervé Physiologie

M Parienti

M Pelage

Mme Piquet

Marie-Astrid Nutrition

M Quintyn

Jean-Claude Ophtalmologie

M Ravasse

Philippe Chirurgie

M Reznik

Yves Endocrinologie

M Rod

Julien Chirurgie

M Roupie

Eric Médecine D'urgence

Mme Thariat

Juliette Radiothérapie

M Tillou

Xavier Urologie

M Touzé

Emmanuel Neurologie

M Troussard

Xavier Hématologie

Mme Vabret

Astrid Bactériologie -Virologie

M Verdon

Renaud Maladies

Mme Verneuil

Laurence Dermatologie

M Viader

Fausto Neurologie

M Vivien Denis

Professeur Associé

Des Universités

A Temps

Plein M Vabret

François Addictologie

Professeurs Associés

A Mi-Temps M De

La Sayette

Vincent Neurologie

Mme Dompmartin-Blanchère

Anne Dermatologie

Mme Lescure

M Sabatier Rémi

Mme Leleu

Solveig Anglais

Sarah Madame

Chemtob

M Alexandre

Joachim Pharmacologie

Mme Benhaïm

Annie Biologie

M Besnard

Stéphane Physiologie

Mme Bonhomme

Julie Parasitologie

M Bouvier

Nicolas Néphrologie

M Coulbault

M Creveuil

M De Boysson

Mme Debruyne

Danièle Éméritat

Mme Derlon-Borel

Annie Éméritat

Mme Dina

Julia Bactériologie -Virologie

Mme Dupont

Claire Pédiatrie

M Étard

Olivier Physiologie

M Gaberel

Thomas Neurochirurgie

M Gruchy

Nicolas Génétique

M Guénolé

Fabian Pédopsychiatrie

M Hitier

M Isnard

Christophe Bactériologie

Virologie M Legallois

Damien Cardiologie

Mme Lelong-Boulouard Véronique

Nathalie Éméritat

M Lubrano

M Mittre

Hervé Biologie

M Repessé

Yohann Hématologie

M Sesboüé

Bruno Physiologie

M Toutirais

Olivier Immunologie

M Veyssiere

Maitres De

Associés Des

Mi-Temps Mme

Abbate-Leray Pascale

M Couette

M Sainmont

Noel Mme

Jaegher De

Sophie

THÈSE POUR L'OBTENTION

A Hubert De Boysson, mon directeur de thèse mais bien plus que cela un ami. Merci pour tout, merci de m'avoir fait découvrir le monde du Horton, de m'avoir toujours soutenu dans ce projet et en plus d'avoir été un chef formidable d'avoir toujours été à mon écoute.

Au Pr Achille AOUBA, merci d'avoir accepté d'être le président de ce jury de thèse, de m'avoir toujours soutenu dans mes projets professionnels et d'avoir été une oreille attentive, c'est un grand honneur pour moi de travailler à tes cotés chaque jour.

A Nicolas MARTIN-SILVA, plus qu'un collègue tu as su me donner l'envie d'être interniste, je suis ravi de pouvoir continuer à travailler à tes cotés dans le futur et de continuer à partager ton goût prononcé pour les (bonnes) blagues.

A Samuel DESHAYES, pour ton soutien et ton amitié au quotidien, un grand merci d'avoir accepté d'être dans mon jury pour ce jour spécial, j'ai hâte de poursuivre l'aventure à tes côtés.

Au Pr Jean-Claude QUYNTIN, c'est un grand honneur pour moi que vous ayez accepté de juger mon travail et d'être parmi les membres du jury.

A mes parents qui m'ont toujours soutenu même avec la distance, si j'en suis là aujourd'hui c'est grâce à vous.

A mon frère Nicolas et ma soeur Néféret pour leur soutien.

A mes grands-parents que je n'ai malheureusement pas le temps de voir aussi souvent que je le voudrais mais qui me font le bonheur d'être présents physiquement ou bien de là-haut.

A Patrice, qui a su me donner goût à d'autre chose que la médecine et notamment aux boissons à base de raisins.

A la famille FOURNAISE, Luc et Elisabeth, Emilien et Elodie ainsi que leurs 3 enfants (dont un m'a rappelé que je ne serais jamais pédiatre) et Camille, qui me font le plaisir d'être présents pour ce jour si particulier.

A mes futurs collègues Jonathan et Gwenola avec qui je vais avoir l'honneur de continuer à travailler.

Aux infirmières de médecine interne et notamment ma seconde maman Isabelle.

Aux « ti' culs », Anne-Charlotte, Marie, Caroline, Annabel, Chloé, Mathieu et Maxime, vous êtes tellement débiles mais je vous aime ! A mes amis caennais, Quitterie, Clément, Amaury, Agnès, William et Cléa.

A mes amis rémois de la faculté de médecine, Lulu, L'Ardennais, Timothésticule, Maguette, Elodie, Nacim, Estelle et Aurélie avec qui le contact reste malgré la distance, merci pour tous les moments passés ensembles, j'aimerais tellement qu'on se voit plus ! A Morgan, les années passent et rien ne change, merci pour ta psychanalyse lors de nos soirées à refaire le monde ! A mes amis du Lycée, en particulier Marion, Manon, Stella, Edouard, Simon et Cyril.

A mes co-internes de DES, Mathieu, Luca, Sophie, Cédric, Martin, Marine, Alex, MC qui sont devenus des amis au fil du temps, merci pour tous ces moments passés ensembles.

A mes collègues pneumologues, Hélène, Laure, Constance, Simon, Robinou, Boris et Lolo, merci pour votre accueil et pour tous ces souvenirs ! A mes co-internes de réanimation médicale, Kevin, Mathieu, Célia, Martin et Roxane merci pour tous les bons moments passés ensembles.

A mes « chefs » rencontrés au fils de mes différents stages qui m'ont tant appris et avec qui j'ai partagé de très bons moments en particulier Antoine, Manuel, Clémence, Jocelyn, Dr Sylvie DARGERE et monsieur le Pr VERDON.

A l'équipe médicale du service de médecine interne de Tenon qui m'ont accueilli pendant 6 mois, tout particulièrement au Dr Sophie GEORGIN-LAVIALLE et au Pr Gilles GRATEAU, un grand merci pour tout.

A mes co-internes de Tenon, Camille, Victoire, Louise, Tiphaine, Hélène, Rim, Samuel, Martin et Julien, merci d'avoir accueilli un « vieux provincial (et chauve en plus !)» parmi vous, merci pour tous ces souvenirs mémorables ! A très vite peut-être autour d'un verre (juste un petit verre vite fait !), vous me manquerez c'est une certitude.

A Sarah, qui m'a suivi dans cette aventure caennaise et m'a toujours soutenu, quel bonheur d'être à tes côtés chaque jour, je t'aime ma marmotte.

Abréviations :

Intravenous (IV); Giant cell arteritis (GCA); Large vessel vasculitis (LVV); American College of Rheumatology (ACR); Anterior ischemic optic neuropathy (AION); Central retinal artery occlusion (CRAO); Posterior ischemic optic neuropathy (PION); Glucocorticoids (GC); Temporal artery biopsies (TAB); Polymyalgia rheumatica (PMR) Supplemental table 1. Characteristics of the 137 eyes affected by GCA at disease onset and according to their evolution after treatment.

Values are number (%) The more common and faster use of GC as well as higher physician awareness of GCA ischemic complications led to a decrease of definite blindness rates from 70% to less than 10% in some studies [START_REF] Bengtsson | The epidemiology of giant cell arteritis including temporal arteritis and polymyalgia rheumatica. Incidences of different clinical presentations and eye complications[END_REF][START_REF] Vodopivec | Ophthalmic manifestations of giant cell arteritis[END_REF][START_REF] Gonzalez-Gay | Giant cell arteritis i northwestern Spain : a 25-year epidemiologic study[END_REF][START_REF] Gonzalez-Gay | Giant Cell Arteritis: Visual loss is our major concern[END_REF].

Most studies dealing with ophthalmologic involvement in GCA describe selected patients or small series with <100 patients [START_REF] Chen | Evaluating the incidence of arteritic ischemic optic neuropathy and other causes of vision loss from giant cell arteritis[END_REF][START_REF] Hayreh | Ocular manifestations of giant cell arteritis[END_REF][START_REF] Danesh-Meyer | Poor prognosis of visual outcome after visual loss from giant cell arteritis[END_REF][START_REF] Liozon | Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients[END_REF][START_REF] Salvarani | Risk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis[END_REF][START_REF] Cid | Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis[END_REF][START_REF] Singh | Visual manifestations in giant cell arteritis: trend over 5 decades in a population-based cohort[END_REF][START_REF] Gonzalez-Gay | Visual manifestations of giant cell arteritis. Trends and clinical spectrum in 161 patients[END_REF]. Moreover, the link between visual symptoms described by patients and the ophthalmologic diagnosis is poorly studied. In this study, we retrospectively analyzed ophthalmologic involvement in a monocentric cohort of consecutive GCA patients. Each ophthalmologic diagnosis was reassessed by an ophthalmologist. Characteristics and outcomes of patients with ophthalmologic involvement were analyzed and compared with age-and sex-matched controls without such involvement.

We specifically analyzed the outcomes of patients according to the different ophthalmologic diagnoses and the therapeutic regimens they received, especially the impact of intravenous pulses of methylprednisolone.

METHODS

Study design and patients

In this monocentric retrospective study, we included all consecutive patients diagnosed with GCA-related ophthalmologic involvement between 2000 and 2016 in a department of Internal Medicine in a tertiary hospital in Western France. Patients were retrieved in a database of 409 patients diagnosed consecutively with GCA and followed up in our center. This database enrolled patients identified via the centralized hospital diagnostic database via the department of histology where temporal artery biopsies (TAB) were analyzed and via the department of Ophthalmology.

In all patients, the GCA diagnosis was retained based on the presence of at least 3 criteria from the American College of Rheumatology (ACR) [START_REF] Hunder | The American college of rheumatology 1990 criteria for the classification of giant cell arteritis[END_REF] or 2 ACR criteria associated with large-vessel vasculitis (LVV), which was demonstrated by imaging or biopsy-proven giant-cell vasculitis on an extratemporal vascular sample.

Data of the 409 patients are collected in a centralized database that was previously described [START_REF] De Boysson | Giant cell arteritis presenting as isolated inflammatory response and/or fever of unknown origin: a case-control study[END_REF][START_REF] De Boysson | Large-vessel involvement and aortic dilation in giant-cell arteritis. A multicenter study of 549 patients[END_REF][START_REF] Dumont | Factors associated with relapse and dependence to glucocorticoids in giant-cell arteritis[END_REF]. We retrieved all GCA patients with visual symptoms at diagnosis from the cohort and compared them to age-and sex-matched GCA control patients without visual symptoms. We chose to compare patients to matched controls and not to the remaining patients from the cohort in order to avoid an overrepresentation of the control group.

Moreover, given that many studies, including ours [START_REF] De Boysson | Giant cell arteritis-related stroke: a retrospective multicenter case-control study[END_REF][START_REF] Gonzalez-Gay | Strokes at time of disease diagnosis in a series of 287 patients with biopsy-proven giant cell arteritis[END_REF], showed an older age of patients with cranial ischemic symptoms, we aimed to limit the influence of age in the comparison of patients.

This study was conducted in compliance with good clinical practices and the Declaration of Helsinki principles. In accordance with French public health law (Art. L 1121-1-1, Art. L 1121-1-2), written consent from the patient is not required for this type of retrospective study. Our local ethics committee confirmed the observational noninterventional retrospective nature of our cohort.

Retrieved data and definitions

For all included patients and controls, we collected demographics, body mass index We defined important visual damage as vision precluding any use of the affected eye in daily activities. We defined visual improvement as sufficient vision improvement allowing the patient to use the affected eye in daily activities (reading, driving,....).

Treatments regimen were collected, especially the GC management, including starting doses, the use of IV pulses before oral route and treatment durations.

We analyzed the rate of relapse defined on the association of 1) a reoccurrence of clinical symptoms attributable to GCA or PMR; 2) an increase of acute phase reactants; 3) a favorable response to an increase or a change of GCA-related treatment(s) and 4) the absence of another cause identified. GC dependence was defined on the presence of > 2 relapses and at least 2 of the following criteria: 1) a daily dose of oral prednisone >20 mg/day (or 0.30 mg/kg) at 6th month; 2) a daily dose of oral prednisone >10 mg/day (or 0.20 mg/kg) at 12th month; 3) a treatment maintained >24 months due to a relapsing disease course.

GC discontinuation rate and the use of immunosuppressants were also noted.

Regarding ophthalmologic outcomes, we analyzed whether treatment improved visual function and whether damage remained at last follow-up. Permanent visual loss corresponded to definite unilateral or bilateral blindness.

Statistical analyses

Categorical variables were expressed as the number (%) and quantitative variables as median (range). Categorical variables were analyzed using the Chi-square or Fisher's exact test, and quantitative variables were analyzed using the Mann-Whitney test.

A logistic regression model was used to assess predictive factors associated with definite blindness. Odds ratios (ORs) and 95% confidence intervals (CI) were computed for each predictor in the univariate analysis and the multivariable model using the backward stepwise approach using variables that reached p<0.1 in univariate analyses.

The statistical analyses were computed using JMP 9.0.1 (SAS Institute Inc., Cary, NC, USA). A p < 0.05 defined statistical significance.

RESULTS

Description of patients with ophthalmologic manifestations and controls

Among the 409 patients from the cohort, 104 (25%) patients presented visual symptoms at GCA diagnosis. Among the patients who presented AION at diagnosis, fluorescein angiography was performed in 23 (50%), which showed a perfusion delay in 15 (65%) of them. Thirteen (28%)

patients with AION presented a bilateral involvement. Both eyes were affected at diagnosis in 9, whereas the 4 others presented the same lesion on the contralateral eye few days later while the treatment was initiated. Among these 4 patients, GC was initiated at a median delay of 3 [START_REF] Bengtsson | The epidemiology of giant cell arteritis including temporal arteritis and polymyalgia rheumatica. Incidences of different clinical presentations and eye complications[END_REF][START_REF] Vodopivec | Ophthalmic manifestations of giant cell arteritis[END_REF][START_REF] Gonzalez-Gay | Giant cell arteritis i northwestern Spain : a 25-year epidemiologic study[END_REF][START_REF] Gonzalez-Gay | Giant Cell Arteritis: Visual loss is our major concern[END_REF][START_REF] Chen | Evaluating the incidence of arteritic ischemic optic neuropathy and other causes of vision loss from giant cell arteritis[END_REF][START_REF] Hayreh | Ocular manifestations of giant cell arteritis[END_REF][START_REF] Danesh-Meyer | Poor prognosis of visual outcome after visual loss from giant cell arteritis[END_REF] days after symptom onset, and 3 received IV pulses of methylprednisolone.

The link between visual symptoms and the ophthalmologic diagnosis is shown in Figure 1.

Outcomes under treatment and differences according to the ophthalmologic diagnosis

In Supplemental Table 1, we separately analyzed the 137 eyes affected by GCA as well as their outcomes with treatment.

Regarding treatment, patients with visual symptoms received significantly higher doses of GC at initiation (0.87 [0. Once GC started, a total of 4 (4%) previously described patients experienced a new ischemic ophthalmologic event, namely, an AION affecting the second eye; however, 3 of them received IV pulses at 1, 5 and 7 days after symptom onset.

All patients with visual symptoms received acetylsalicylic acid (ASA) at diagnosis (94 patients (90%)); the remaining 10 patients (10%) were already treated with Vitamin-K antagonists or direct oral anticoagulant.

Table 3 presents the factors potentially associated with definite blindness as assessed by a uni-and multivariate model. Ischemic ophthalmologic lesions, i.e., AION or CRAO, were the single factors that were associated with a definite blindness (95% confidence interval, odds ratio: 33.42 [8.99-218.6], p<0.0001).

Description of patients with bilateral ophthalmologic involvement at diagnosis

Among the 33 patients who experienced bilateral ophthalmologic involvement, 13 (39%) presented bilateral AION, 2 (6%) presented AION in one eye and CRAO in second eye, and bilateral cranial nerve palsy was observed in 3 (9%) patients. Thirteen patients (39%) did not have any ophthalmologic diagnosis despite a bilateral examination, and 2 (6%) patients, including one with bilateral diplopia and another with bilateral amaurosis fugax, did not have any ophthalmologic examination.

Among the 33 patients with bilateral involvement, 12 (36%) maintained bilateral blindness, 2 (6%) had a unilateral improvement and 19 (58%) had a total bilateral improvement. The 12 patients with persisting bilateral blindness initially showed AION in 22 eyes and CRAO in 2, and 21 (64%) received methylprednisolone IV pulses. The 2 patients with unilateral improvement initially had AION in both eyes, and they both received IV pulses. Finally, the 19 patients with a total bilateral improvement showed initially a bilateral AION in 1, a bilateral nerve palsy in 3, and no ophthalmologic diagnosis in the other. Eight (42%) of them received IV pulses.

DISCUSSION

Ophthalmologic involvement is frequent in GCA and was observed in one-quarter of all our patients. Despite a prompt diagnosis and initiation of treatment, 40% of our patients with visual symptoms did not recover their vision, and 10% of them remained bilaterally blind. Altogether, the global rate of blindness (affecting one or two eyes) in our cohort is 10%, which is concordant with other studies [START_REF] Cid | Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis[END_REF][START_REF] Singh | Visual manifestations in giant cell arteritis: trend over 5 decades in a population-based cohort[END_REF][START_REF] Yates | The association of vascular risk factors with visual loss in giant cell arteritis[END_REF]. A new ischemic event (AION in all cases) occurred in 5% of patients with visual symptoms despite the initiation of treatment, including methylprednisolone pulses in four of them.

Our study provided a relevant analysis of the GCA-related ophthalmologic involvement and focused on the link between the visual signs described by the patient and the ophthalmologic diagnosis.

AION was the ophthalmologic diagnosis the more frequently observed in half of our patients with visual symptoms and in three-quarters of patients who were admitted with persistent visual impairment (visual loss or blurred vision), which is concordant with other studies [5-7, 11, 12, 20]. Indeed, Gonzalez-Gay et al. [START_REF] Gonzalez-Gay | Visual manifestations of giant cell arteritis. Trends and clinical spectrum in 161 patients[END_REF], observed AION in 22 patients out of 24 with visual loss; Liozon et al. [START_REF] Liozon | Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients[END_REF], in 20 out of 23; and Chen et al. [START_REF] Chen | Evaluating the incidence of arteritic ischemic optic neuropathy and other causes of vision loss from giant cell arteritis[END_REF] in 85% of patients with permanent visual loss.

Patients with visual symptoms showed some particular characteristics at diagnosis compared with controls, namely, less PMR, less fever and lower acute phase reactants.

These results are in accordance with other studies [START_REF] Chen | Evaluating the incidence of arteritic ischemic optic neuropathy and other causes of vision loss from giant cell arteritis[END_REF][START_REF] Salvarani | Risk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis[END_REF][START_REF] Cid | Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis[END_REF][START_REF] Gonzalez-Gay | Visual manifestations of giant cell arteritis. Trends and clinical spectrum in 161 patients[END_REF].

As observed in another study [START_REF] Gonzalez-Gay | Biopsy-negative giant cell arteritis: clinical spectrum and predictive factors for positive temporal artery biopsy[END_REF], we also found more biopsy-proven GCA in patients with visual symptoms.

Atherosclerosis remains the main differential diagnosis in a patient with an ischemic ophthalmologic complication, especially in CRAO. The study of Yates et al. [START_REF] Yates | The association of vascular risk factors with visual loss in giant cell arteritis[END_REF] showed that in the setting of GCA, a history of cerebrovascular accident and peripheral vascular disease was associated with blindness at 6 months, suggesting the possible participation of atherosclerosis in the occurrence of the ophthalmologic event. The possible link between atherosclerosis and ocular manifestations was also suggested in another GCA populationbased study showing that permanent visual loss and arterial hypertension were predictive factors of stroke [START_REF] Gonzalez-Gay | Strokes at time of disease diagnosis in a series of 287 patients with biopsy-proven giant cell arteritis[END_REF]. In contrast, we did not observe cardiovascular risk factors or previous cardiovascular diseases as risk factors for visual involvement in GCA. However, we observed that patients who progressed to blindness were older than those with an improvement of vision, suggesting a possible impact of atherosclerosis, which is probably more frequent in older patients. Moreover, in this study, we did not analyze the impact of cardiovascular treatments, such as statins, but all patients in this cohort had a concomitant prescription of aspirin or anticoagulant treatment.

A study from Lopez-Diaz et al suggested an association between a high ESR level at diagnosis and the risk of developing visual ischemic manifestations and permanent visual loss [START_REF] Lopez-Diaz | The erythrocyte sedimentation rate is associated with the development of visual complications in biopsy-proven giant cell arteritis[END_REF]. We did not observe higher acute phase reactant levels at diagnosis in our patients who stayed visually impaired, but other studies are required to more extensively analyze the link between systemic inflammation and ischemic events.

To date, the best management of GCA-related ophthalmologic involvement remains the prompt prescription of high GC doses, and the first-line use of IV pulses is often in accordance with different guidelines, such as the French or British recommendations [START_REF] Bienvenu | Management of giant cell arteritis: recommendations of the French study group for large vessel vasculitis (GEFA)[END_REF][START_REF] Dasgupta | BSR and BHPR guidelines for the management of giant cell arteritis[END_REF]. However, our results and other studies did not indicate a better effect of IV pulses compared with oral administration in preventing further visual loss [START_REF] Hayreh | Visual improvement with corticosteroid therapy in giant cell arteritis. Report of a large study and review of literature[END_REF][START_REF] Hayreh | Visual deterioration in giant cell arteritis patients while on high doses of corticosteroid therapy[END_REF]. In addition, patients with AION particularly experienced poor outcomes without visual improvement, although they more likely received IV pulses. In this setting, the use of GC is probably insufficient to stop or reverse the ischemic process. Further studies with the adjunction of other drugs, especially tocilizumab, are expected with the hope to improve the visual prognosis in patients with AION. Altogether, our results did not suggest a good improvement of vision under GC in patients with initial ischemic ophthalmologic involvement, i.e., AION or CRAO. Furthermore, despite treatment initiation, 4 (4%) patients presented a new ischemic ophthalmologic event affecting the second eye. However, in these 4 patients, one did not receive IV pulses, and two others had a delay of initiation of GC treatment at five and seven days, separately. In the literature, 1 to 4% of patients experience a new ischemic event despite GC therapy, which is concordant with our results [START_REF] Liozon | Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients[END_REF][START_REF] Hayreh | Visual deterioration in giant cell arteritis patients while on high doses of corticosteroid therapy[END_REF].

Some studies showed that the presence of transient cranial manifestations before treatment initiation was associated with the development of ischemic complications and permanent visual loss [START_REF] Hayreh | Ocular manifestations of giant cell arteritis[END_REF][START_REF] Liozon | Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients[END_REF][START_REF] Cid | Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis[END_REF]. In our study, 44% of patients with visual loss at diagnosis presented a transient visual symptom before treatment initiation, which is concordant with the literature where 32 to 58% of patients experienced previous transient visual symptoms [START_REF] Hayreh | Ocular manifestations of giant cell arteritis[END_REF][START_REF] Liozon | Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients[END_REF][START_REF] Cid | Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis[END_REF].

Altogether, these results support maximal and early identification of GCA-related ophthalmic involvement to start GC therapy as early as possible. Hocevar et al. [START_REF] Hocevar | Do early diagnosis and glucocorticoid treatment decrease the risk of permanent visual loss and early relapses in giant cell arteritis: a prospective longitudinal study[END_REF] showed that permanent visual loss was more common in late-diagnosed GCA. Laskou et al. [START_REF] Laskou | A probability score to aid the diagnosis of suspected giant cell arteritis[END_REF] developed a probability score to aid the diagnosis of GCA for generalist physicians to start GC therapy promptly. The need of an early GCA diagnosis led to the development of fast track strategies [START_REF] Diamantopoulos | The fast-track ultrasound clinic for early diagnosis of giant cell arteritis significantly reduces permanent visual impairment: towards a more effective strategy to improve clinical outcome in giant cell arteritis?[END_REF][START_REF] Patil | Fast track pathway reduces sight loss in giant cell arteritis: results of a longitudinal observational cohort study[END_REF]. Diamantopolous et al. [START_REF] Diamantopoulos | The fast-track ultrasound clinic for early diagnosis of giant cell arteritis significantly reduces permanent visual impairment: towards a more effective strategy to improve clinical outcome in giant cell arteritis?[END_REF] showed an 88% lower risk of permanent visual loss in GCA patients examined through a fast-track ultrasound clinic compared with a control group conventionally assessed; only one patient in the fast-track strategy experienced a permanent visual loss versus 6 patients in the conventional group. In another study from Patil et al. [START_REF] Patil | Fast track pathway reduces sight loss in giant cell arteritis: results of a longitudinal observational cohort study[END_REF] a reduction of irreversible visual loss from 37% to 9% was observed with a fast track pathway. Some limitations should be discussed in this study. First, the retrospective design limits the completeness of data retrieval. Furthermore, 7% of our patients did not have an ophthalmologic exam at diagnosis and were treated immediately with GC.

Second, initial clinical visual symptoms described by patients and visual outcomes were subjective, based on patients' appreciations. The absence of visual acuity or visual field testing at diagnosis and during follow-up is an important limitation, mainly due to the retrospective design and because many of our patients are addressed and followed-up by non-hospital ophthalmologists. However, this also reflects real-life practices in a French GCA referral department of internal medicine. Visual acuity testing information is mainly used by ophthalmologists and is not used to guide the diagnosis and therapeutic strategy. Given the absence of consensual recommendations regarding GC tapering and the use of IV pulses, differences regarding GC management exist within the cohort. Indeed, the initial treatment was at the discretion of each physician in charge of the patient.

CONCLUSION

In conclusion, GCA-related ophthalmologic involvement affected one-quarter of patients in this monocentric cohort of consecutive patients, and 10% did not recover their vision. These data confirm and encourage the need to develop fast-track strategies to prevent these ophthalmologic complications that are often irreversible. AOIN remained the most frequent ophthalmologic diagnosis with the poorer outcomes despite GC IV pulses.

Further prospective studies are therefore required to improve specific outcomes in such patients, and new therapeutic strategies using available biotherapies, such as tocilizumab, are awaited.

RESUME DE LA THESE EN ANGLAIS :

Purpose: To describe the characteristics and outcome of patients with giant-cell arteritis (GCA)related ophthalmologic involvement at diagnosis. Methods: In a retrospective single-center cohort of 409 consecutive patients with GCA, we retrieved 104 patients with visual symptoms at GCA diagnosis and we compared them to 104 age-and sexmatched controls without ophthalmologic involvement. Each visual symptom was associated to an ophthalmologic diagnosis that was centrally re-assessed by an ophthalmologist. Results: Compared to controls, patients with visual symptoms showed less fever (p=0.0006), less polymyalgia rheumatica (p=0.02) and lower acute phase reactants (p=0.004). Blurred vision (in 60% of patients), amaurosis fugax (in 18%), diplopia (in 13%) and permanent visual loss (in 9%) were the four visual symptoms described by patients before GCA diagnosis. Anterior ischemic optic neuropathy (AION) was found in 47 (45 %) patients, followed by central retinal artery occlusion (CRAO) in 15 (15%). Two patients had both involvements. The delay of glucocorticoids initiation was not different between patients with and without visual symptoms (p=0.06). Among the 60 patients with initial AION and/or CRAO, 39 (65%) kept definite blindness or important visual damage, although 45 (75%) had received intravenous (IV) pulses of methylprednisolone. A new ischemic event (AION in all cases) occurred in 4% of patients with visual symptoms despite the initiation of treatment. Conclusion: Ophthalmologic involvement was observed in one-quarter of our GCA patients. AION is still associated with the worst visual prognosis, and IV methylprednisolone pulses did not reduce the risk of blindness in our study.

KEY WORDS : giant-cell arteritis; ophthalmologic involvement; visual loss; glucocorticoids; methylprednisolone pulses.

Figure 1 .

 1 Figure 1. The link between visual symptoms, ophthalmologic diagnosis and visual outcomes in 104 patients with GCA-related ophthalmologic involvement

2 2. 2 3 2. 3 5 3. 1 5 3. 2 3 . 3 9 4

 22335152339 Retrieved data and definitions ……………………………………………………...Statistical analyses …………………………………………………………………..5 3. Results ………………………………………………………………………………………...Description of patients with ophthalmologic manifestations and controls ……..Outcomes under treatment and differences according to the ophthalmologic diagnosis ………………………………………………………………………………7 Description of patients with bilateral ophthalmologic involvement at diagnosis..arteritis (GCA) is the most frequent form of vasculitis in patients over 50 years old. Involvement of cranial vessels, especially from the internal carotid, exposes patients to ischemic complications, such as visual impairment or stroke. Ophthalmologic manifestations include different symptoms from transient visual loss or blurred vision to definite blindness, affecting one or two eyes. Typically, visual symptoms are linked to the inflammatory involvement of the ophthalmologic arteries and their branches, especially the posterior ciliary arteries and the central retinal artery, leading to acute anterior ischemic optic neuropathy (AION) or central retinal artery occlusion (CRAO), respectively. More rarely, visual impairment is linked to III or VI nerves' palsy or posterior ischemic optic neuropathy (PION). As soon as a GCA diagnosis is presumed in a patient with visual symptoms, glucocorticoids (GC) have to be started often with intravenous pulses of methylprednisolone with the aim to improve visual function and avoid involvement of the contralateral eye and the occurrence of a new ischemic event.

(

  BMI), cardiovascular risk factors (tobacco use, diabetes mellitus, dyslipidemia, hypertension, previous coronary disease or stroke), laboratory tests (including erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), hemoglobin and platelet levels), TAB status, the results of another vascular sample when available, and the results of imaging searching for an LVV in patients who performed the procedure. Many patients undergo large-vessel imaging in our center as a systematic research of LVV regardless of whether they complained of large-vessel symptoms. Cranial manifestations included headaches, temporal artery pulse absence, jaw claudication, scalp tenderness and visual symptoms. Extracranial symptoms include polymyalgia rheumatica (PMR) and peripheral vascular signs (pulseless limb, peripheral vascular bruits). Each ophthalmologic medical file was reanalyzed by an ophthalmologist (AL), especially fundus photography and fluorescein angiography when available. We distinguished four different visual clinical symptoms described by patients before GCA diagnosis: visual loss (i.e., total absence of visual perception, or difficulties counting fingers or distinguishing hand motion or light perception at the first examination, or also defined by a visual acuity <1/20 if this data was available), amaurosis fugax (defined as transient visual loss lasting <1 hour), diplopia and blurred vision (defined as reduced vision that did not satisfy the definition of visual loss).Ophthalmologic diagnoses reassessed by our ophthalmologist included AION when fundus photography showed an optic disc edema (unilateral or bilateral) +/-with peri-papillary splinter hemorrhage and CRAO when fundus photography showed the occlusion of the central retinal artery +/-with a "cherry red spot" in the macula or with an ischemic retinal whitening. PION was retrospectively diagnosed based on the presence of persistent visual impairment and a fundus showing an optic atrophy at distance while the first fundus was initially normal. Cranial nerve palsy was diagnosed upon clinical examination. When performed, we recorded the results of the fluorescein angiography. A delay of perfusion or a hypoperfusion of the choroid retina on angiography were suggestive of choroidal ischemia and especially an AION when other cranial GCA-related signs existed or when acute phase reactants were increased. AION and CRAO corresponded to ophthalmologic ischemic involvements.

Table 1 . Characteristics of GCA patients with ophthalmologic involvement and of GCA age-and sex-matched controls.

 1

		Patients with	Controls without
		ophthalmologic	ophthalmologic	p
		involvement	involvement
		(n=104)	(n=104)
	Cardiovascular risk factors
	Tobacco use	27 (26)	19 (18)	0.18
	Hypertension	56 (54)	69 (66)	0.07
	Dyslipidemia	34 (33)	41 (39)	0.31
	Diabetes mellitus	17 (16)	12 (12)	0.32
	History of coronary disease	13 (13)	14 (14)	0.83
	History of strokes	8 (8)	11 (11)	0.47
	Clinical manifestations
	Body Mass Index	25.1 [16.2-34.2]	24 [16-36.8]	0.10
	Fever	11 (11)	31 (30)	0.0006
	Cranial manifestations	104 (100)	90 (87)	0.0001
	Headaches	72 (69)	84 (81)	0.054
	Scalp tenderness	38 (37)	41 (39)	0.67
	Temporal artery abnormalities	26 (25)	25 (24)	0.94
	Jaw claudication	45 (43)	37 (36)	0.26
	Polymyalgia rheumatica	41 (39)	58 (56)	0.02
	Positive Histology	79 (76)	59 (57)	0.003
	Large vessel vasculitis on	8/55 (15)	15/65 (23)	0.24
	imaging at GCA diagnosis
	Laboratory Tests
	ESR, mm	63 [16-130]	67 [7-141]	0.25
	CRP, mg/L	54 [3-535]	103 [3-421]	0.004
	Hemoglobin, g/dL	11.8 [7.4-15.9]	11 [7.2-14.9]	0.005
	Treatment
	Initial GC doses, mg/kg/day	0.87 [0.25-1.46]	0.75 [0.27-1.60]	0.03
	Duration of GC, months	42 [0-170]	28 [1-206]	0.16
	Use of a GC-sparing agent	7 (7)	19 (18)	0.01
	Outcomes
	Total follow-up, months	42 [0-170]	54 [1-211]	0.10
	Relapse	45 (43)	58 (56)	0.07
	GC-dependence	21 (20)	30 (29)	0.15
	Discontinuation of GC	50/86 a (58)	67/87 a (77)	0.008

Values are number (%) or median [range]; GCA: giant cell arteritis; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; GC: Glucocorticoids a Data was not available in all patients.

Table 2 . Characteristics of 104 GCA patients with ophthalmologic involvement at onset and according to their evolution after treatment Total (n=104)

 2

	Progressed	Visual	p
	to blindness	improvement
	(n=42)	(n=62)

.0001 Involvement of cranial nerve III and/or VI

		8 (8)	0 (0)	8 (14)	0.01
	Positive Histology	79 (76)	35 (83)	44 (71)	0.15
	Large vessel vasculitis on	8/55 (15)	4/22 (18)	4/33 (12)	0.53
	imaging
	Laboratory tests
	ESR, mm 63 [16-130]	68 [18-126]	51 [16-130]	0.19
	CRP, mg/L	54 [3-535]	86 [3-535]	44 [3-380]	0.09
	Delay between	2 [1-60]	1 [1-30]	3 [1-60]	0.06
	ophthalmologic signs and
	treatment, in days Pulses of IV	59/100 a (59)	32/41 (78)	27/59 (46)	0.001
	methylprednisolone
	Values are number (%) or median [range]; GCA: giant cell arteritis; ESR: erythrocyte
	sedimentation rate; CRP: C-reactive protein; IV: intravenous

a

In 4 patients, the information regarding IV pulse was lacking.

Table 3 . Variables associated with definite blindness or important visual damage in GCA patients with visual symptoms in a uni-and multivariable analysis Characteristics Univariate OR [95% CI] p Multivariate OR [95% CI] p

 3

	Age >79 a	2.33 [1.05-5.26]	0.03
	Delay of GC initiation	1.07 [1.01-1.16]	0.01
	AION and/or CRAO	33.42 [8.99-218.6]	<0.0001 33.42 [8.99-218.6]	<0.0001
	IV pulses of MP	4.21 [1.76-10.82]	0.001
	95% CI: 95% confidence interval; OR: odds ratio; GCA: giant cell arteritis; GC:
	glucocorticoids; AION: anterior ischemic optic neuropathy; CRAO: central retinal artery
	occlusion; IV: intravenous; MP: methylprednisolone
	a 79 is the median age of patients who kept a persisting blindness or important visual
	damage

  Au sein d'une cohorte monocentrique de 409 patients avec ACG, nous avons identifié 104 patients présentant une manifestation ophtalmologique au diagnostic. Ils ont été comparés à 104 patients témoins, appareillés selon l'âge et le sexe, sans atteinte ophtalmologique issus de cette même cohorte. Résultats: Comparés aux témoins, les patients présentant une atteinte ophtalmologique initiale présentaient moins de fièvre (p=0.0006), moins de pseudopolyarthrite rhizomélique (p=0.02) et un syndrome inflammatoire biologique moindre (p=0.004). Un flou visuel (chez 60% des patients), une amaurose fugace (chez 18%), une diplopie (chez 13%) et une cécité (chez 9%) étaient les 4 symptômes décrits au diagnostic. Une neuropathie optique ischémique antérieure (NOIA) a été retrouvée chez 47 (45%) des patients, suivi par l'occlusion de l'artère centrale de la rétine (OACR) pour 15 d'entre eux (15%). Le délais d'introduction de la corticothérapie ne différait pas dans les 2 groupes (p=0.06). Parmi les 60 patients avec NOIA et/ou OACR 39 (65%) ont gardé une cécité définitive ou un dommage visuel majeur en dépit du recours aux boli de corticoïdes pour 45 (75%) d'entre eux. 4% des patients avec atteinte ophtalmologique initiale ont présenté un nouvel événement ischémique (NOIA). Conclusion: Une atteinte ophtalmologique a été retrouvée chez 1/4 de nos patients avec ACG. La NOIA est toujours associée au pronostic visuel le plus péjoratif, et l'utilisation de boli de corticoïdes ne réduit pas le risque de cécité définitive dans notre cohorte.

	ANNEE DE SOUTENANCE : 2019
	NOM ET PRENOM DE L'AUTEUR : DUMONT Anaël
	TITRE DE LA THESE : Caractéristiques et évolution des manifestations
	ophtalmologiques dans l'artérite à cellules géantes : une étude cas-témoin.
	RESUME DE LA THESE EN FRANÇAIS :
	Objectif: Décrire les caractéristiques et l'évolution des manifestations ophtalmologiques au
	diagnostic dans l'artérite à cellules géantes (ACG).
	Méthode:

MOTS CLES : Artérite à cellules géantes ; manifestations ophtalmologiques, cécité, glucocorticoïdes, boli de méthylprednisolone. TITRE DE LA THESE EN ANGLAIS : Characteristics and outcomes of patients with ophthalmologic involvement in giant-cell arteritis: a case-control study.

Remerciements

Annexes « Par délibération de son Conseil en date du 10 Novembre 1972, l'Université n'entend donner aucune approbation ni improbation aux opinions émises dans les thèses ou mémoires. Ces opinions doivent être considérées comme propres à leurs auteurs ». VU, le Président de Thèse VU, le Doyen de la Faculté VU et permis d'imprimer en référence à la délibération du Conseil d'Université en date du 14 Décembre 1973 Pour le Président de l'Université de CAEN et P.O Le Doyen