[High anti-topoisomerase-1 autoantibodies levels are associated with the extension of skin fibrosis and vascular progression in patients with systemic sclerosis]. / Des taux élevés d'auto-anticorps anti-topo-isomérase-1 sont associés à l'extension de la fibrose cutanée et à la progression vasculaire chez les patients atteints de sclérodermie systémique.

BACKGROUND: Anti-centromere antibodies, anti-topoisomerase-1 antibodies (ATA), and anti-RNA-polymerase III antibodies are three Systemic Sclerosis (SSc)-specific autoantibodies. Their detection is helpful in determining the prognosis. We aimed to evaluate whether ATA levels were associated with disease severity at diagnosis or disease progression during follow-up in ATA positive patients. METHODS: We conducted a single-centre French retrospective observational study, between 2014 and 2021. ATA positive patients fulfilling the ACR/EULAR 2013 classification criteria for SSc with a minimal follow-up of 1 year and 2 ATA dosages were included. SSc patients with high IgG ATA levels at baseline (>240IU/mL) were compared with SSc patients with low levels (≤240IU/mL), at inclusion and at 1 and 3 years. A variation of at least 30 % of ATA levels was considered significant. RESULTS: Fifty-nine SSc patients were included and analysed. There was a predominance of women and of patients with diffuse interstitial lung disease. Patients with high ATA levels exhibited a higher skin sclerosis assessed by the modified Rodnan skin score (P=0.0480). They had a lower carbon monoxide transfer coefficient (P=0.0457), a lower forced vital capacity (FVC) (P=0.0427) and more frequently had a FVC under 80 %, when compared to patients with low ATA levels (P=0.0423). Initial high ATA levels were associated with vascular progression at one year (21.95 % vs. 0 %; P=0.0495). CONCLUSION: ATA levels are associated with skin sclerosis and vascular progression in SSc. Beyond the detection of ATA, quantifying this autoantibody might be of interest in predicting disease severity and prognosis in SSc.

French recommendations for the management of non-infectious chronic uveitis.

This French National Diagnostic and Care Protocol (NDPC) includes both pediatric and adult patients with non-infectious chronic uveitis (NICU) or non-infectious recurrent uveitis (NIRU). NICU is defined as uveitis that persists for at least 3 months or with frequent relapses occurring less than 3 months after cessation of treatment. NIRU is repeated episodes of uveitis separated by periods of inactivity of at least 3 months in the absence of treatment. Some of these NICU and NIRU are isolated. Others are associated with diseases that may affect various organs, such as uveitis associated with certain types of juvenile idiopathic arthritis, adult spondyloarthropathies or systemic diseases in children and adults such as Behçet's disease, granulomatoses or multiple sclerosis. The differential diagnoses of pseudo-uveitis, sometimes related to neoplasia, and uveitis of infectious origin are discussed, as well as the different forms of uveitis according to their main anatomical location (anterior, intermediate, posterior or panuveitis). We also describe the symptoms, known physiopathological mechanisms, useful complementary ophthalmological and extra-ophthalmological examinations, therapeutic management, monitoring and useful information on the risks associated with the disease or treatment. Finally, this protocol presents more general information on the care pathway, the professionals involved, patient associations, adaptations in the school or professional environment and other measures that may be implemented to manage the repercussions of these chronic diseases. Because local or systemic corticosteroids are usually necessary, these treatments and the risks associated with their prolonged use are the subject of particular attention and specific recommendations. The same information is provided for systemic immunomodulatory treatments, immunosuppressive drugs, sometimes including anti-TNFα antibodies or other biotherapies. Certain particularly important recommendations for patient management are highlighted in summary tables.

[Hospitalization for infection in patients treated for giant cell arteritis: A single-centre retrospective study]. / Hospitalisation pour infection chez les patients suivis pour une artérite à cellules géantes : étude monocentrique rétrospective.

INTRODUCTION: Infections are associated with morbimortality of patients with giant cell arteritis (GCA). The aim of this work was twofold: the identification of factors predisposing to the risk of infection and the description of patients hospitalized with an infection occurring during the treatment period of CAG. METHODS: A monocentric retrospective study was conducted in GCA patients, comparing patients hospitalized for infection with patients without infection. The analysis included 21/144 (14.6%) patients with 26 infections (cases) and 42 control matched on sex, age, and diagnosis of GCA. RESULTS: Both groups were similar except for a higher frequency of seritis in cases (15% vs. 0%, p=0.03). Relapses of GCA were less common in cases (23.8% vs 50.0%, p=0.041). Hypogammaglobulinemia was present during infection. More than half of the infections (53.8%) occurred in the first year of follow-up with an average dose of 15mg/day of corticosteroids. Infections were mainly pulmonary (46.2%) and cutaneous (26.9%). CONCLUSION: Factors associated with infectious risk were identified. This preliminary monocentric work will continue with a national multicentre study.

[Endothelial dysfunction in thrombotic thrombocytopenic purpura: therapeutic perspectives]. / Dysfonction endothéliale au cours du Purpura Thrombotique Thrombocytopénique : un nouvel axe de prise en charge ?

Immune Thrombotic Thrombocytopenic Purpura (iTTP) is a rare but severe disease with a mortality rate of almost 100 % in the absence of adequate treatment. iTTP is caused by a severe deficiency in ADAMTS13 activity due to the production of inhibitory antibodies. Age has been shown to be a major prognostic factor. iTTP patients in the elderly (60yo and over) have more frequent organ involvement, especially heart and kidney failures compared with younger patients. They also have non-specific neurologic symptoms leading to a delayed diagnosis. Factors influencing this impaired survival among older patients remain unknown so far. Alteration of the functional capacity of involved organs could be part of the explanation as could be the consequences of vascular aging. In fact, severe ADAMTS13 deficiency is necessary but likely not sufficient for iTTP physiopathology. A second hit leading to endothelial activation is thought to play a central role in iTTP. Interestingly, the mechanisms involved in endothelial activation may share common features with those involved in vascular aging, potentially leading to endothelial dysfunction. It could thus be interesting to better investigate the causes of mid- and long-term mortality among older iTTP patients to confirm whether inflammation and endothelial activation really impact vascular aging and long-term mortality in those patients, in addition to their presumed role at iTTP acute phase. If so, further insights into the mechanisms involved could lead to new therapeutic targets.

[Immunosuppressive therapy in severe or chronic pediatric uveitis: Review of the literature]. / Les immunosuppresseurs dans les uvéites pédiatriques sévères ou chroniques : revue de la littérature.

Immunosuppressants are prescribed for pediatric uveitis in cases of severe involvement affecting the prognosis for vision or life, in cases of recurrent or chronic uveitis to achieve corticosteroid sparing, or in cases of corticosteroid resistance. Immunosuppressants used in children include antimetabolites (methotrexate, mycophenolate mofetil, azathioprine), cyclosporine, tacrolimus, and biologics, including infliximab, adalimumab, anakinra, canakinumab, and tocilizumab. The mechanisms of action and indications of the various immunosuppressants are described in this review.

Characteristics of Systemic Sclerosis patients with positive anti-Th/To antibodies: About 6 patients and literature review.

Among the antibodies described in Systemic Sclerosis (SSc), anti-Th/To antibodies (anti-Th/To) are rare and have been poorly studied. Thus, little is known about the profile of anti-Th/To positive patients. From our local Biobank (Marseille, France), we retrospectively selected data for 6 patients positive for anti-Th/To with an Immunodot assay. All of them suffered from SSc, sharing clinical and biological common features such as a limited cutaneous form of SSc, a decreased lung diffusing capacity and a speckled nuclear nucleolar immunofluorescence pattern of antinuclear antibodies screening on HEp-2 cells. In order to further characterize patients positive for anti-Th/To, we performed a thorough literature review. From 402 studied patients positive for anti-Th/To, we confirmed that these antibodies are associated with the limited cutaneous form of the disease (88% of the patients), and with an SSc related-pulmonary involvement (50%). The review analysis pointed out the rarity of the anti-Th/To with an estimated mean frequency of 3.4% of all SSc patients worldwide, their usual exclusivity with respect to the specific antibodies of scleroderma, and their high specificity (around 98%) for the diagnosis of SSc.

[Characteristics of giant cell arteritis patients under and over 75-years-old: A comparative study on 164 patients]. / Caractéristiques des patients de moins et de plus de 75 ans atteints d'artérite à cellules géantes : étude comparative de 164 patients.

PURPOSE: Giant cell arteritis (GCA) is the most common vasculitis of the elderly. In order to assess the impact of age at diagnosis, we compared the characteristics of patients of less than 75 years (<75 years), to those of the 75 years and over (≥75 years). PATIENTS AND METHODS: We conducted a retrospective study on 164 patients with GCA diagnosed from 2005 to 2017. All patients had at least 3/5 of the ACR criteria and had a CT-scan at diagnosis. The mean age was of 73±9.6 years. The age was<75 years for 84 patients (59 women) and≥75 years for 80 patients (53 women). RESULTS: Patients≥75 years had more cardiovascular underlying diseases (P=0.026), a higher rate of hypertension (P=0.005) and more ophthalmic complications (P=0.02). They had less large vessel involvement (P<0.001), showed lower biological inflammatory reaction and had a more frequently positive temporal artery histology (P=0.04). The oral initial dose of corticosteroids did not differ between the groups. Corticosteroids pulse therapy was more frequent in patients≥75 years (P=0.01). The frequency of anti-platelet agents use was similar in the two groups. Relapse rate, corticodependance and the rate of corticosteroids weaning were similar in both groups. CONCLUSION: Patients≥75 years at diagnosis of GCA were at lower risk of aortitis but were more likely to suffer from ophthalmic complications and to receive corticosteroid pulse therapy.

[Retinal vasculitis and systemic diseases]. / Vascularites rétiniennes et maladies systémiques.

Retinal vasculitis (RV) is an inflammation of retinal blood vessels that can be associated with uveitis or be isolated, and can induce vascular occlusion and retinal ischemia. Visual acuity can be severely affected in case of macular involvement or neovessel formation. The diagnosis relies on fundoscopy and fluorescein angiography. Systemic diseases may be associated with RV, the most frequently encountered are Behçet's disease, sarcoidosis or multiple sclerosis, all predominantly associated with venous involvement, whereas systemic lupus erythematosus and necrotizing vasculitis are less frequently observed and predominantly associated with arterial or mixed vasculitis. Treatments are usually aggressive in order to preserve a good visual acuity and to reduce retinal inflammation and chronic ischemia. Steroids, immunosuppressive drugs, retinal laser photocoagulation, intravitreal anti-VEGF injections are usual treatments and more recently, anti-TNFalpha monoclonal therapeutic antibodies have been shown to be very successful.

[Therapeutic strategy for the treatment of non-infectious uveitis proposed by an expert panel]. / Avis d'experts pour le traitement des uvéites non infectieuses.

Conventional immunosuppressive drugs, anti-TNF alpha and other biotherapies used in clinical practice are capable of controlling non-infectious anterior uveitis, posterior uveitis and panuveitis. The present work has been led by a multidisciplinary panel of experts, internists, rheumatologists and ophthalmologists and is based on a review of the literature. In case of corticodependency or sight-threatening disease, conventional immunosuppressive drugs (methotrexate, azathioprine and mycophenolate mofetil) and/or anti-TNF alpha (adalimumab, infliximab) are used to achieve and maintain remission. Interferon is an efficient immunomodulatory treatment, as a second-line therapy, for some therapeutic indications (refractory macular edema, Behçet's vascularitis). Other biologics, especially tocilizumab, are showing promising results. Local treatments (corticosteroids, sirolimus etc.) are adjuvant therapies in case of unilateral inflammatory relapse. Therapeutic response must be evaluated precisely by clinical examination and repeated complementary investigations (laser flare photometry, multimodal imaging, perimetry, electroretinography measures).

[Scleritis and systemic diseases: What should know the internist?] / Sclérites et maladies systémiques : que doit savoir l'interniste ?

Scleritis is an inflammatory disease of the sclera; outer tunic of the eye on which the oculomotor muscles are inserted. It can be associated with a systemic disease up to one time out of 3. These associated diseases are mainly rheumatoid arthritis, vasculitis, including granulomatosis with polyangiitis in the first line and spondyloarthropathies. Before mentioning such an etiology, it is necessary to eliminate an infectious cause, mainly herpetic, which is regularly underestimated. The classification of scleritis is clinical. We distinguish between anterior scleritis and posterior scleritis. Anterior scleritis is diffuse or nodular, usually of good prognosis. Anterior necrotizing scleritis with inflammation is often associated with an autoimmune disease, necrotizing scleritis without inflammation usually reflects advanced rheumatoid arthritis. The treatment of these conditions requires close collaboration between internists and ophthalmologists to decide on the use of corticosteroid therapy with or without immunosuppressors or biotherapies.

[Uveitis: Diagnostic work-up. Recommendations from an expert committee]. / Prise en charge diagnostique des uvéites : recommandations d'un groupe d'experts.

INTRODUCTION: Diagnostic work-up of uveitis involves many uncertainties. Search for an etiology should take into account the epidemiology of uveitis and focus on the most severe diseases or those, which can be treated. This work was undertaken to establish recommendations for the diagnosis work-up of uveitis. METHODS: Recommendations were developed by a multidisciplinary panel of 15 experts, including internists, ophthalmologists and a rheumatologist and are based on a review of the literature with regard to effectiveness of investigations and the results of the ULISSE study, which is the first prospective study assessing the efficiency of a standardized strategy for the etiological diagnosis of uveitis. Children, immunocompromised patients, severe retinal vasculitis and specific ophthalmological entities are excluded from these recommendations. RESULTS: Investigations should be first guided by the history and physical examination. Serological screening for syphilis is the only test appropriate in all forms of uveitis. If no diagnosis is made after this stage, we propose investigations guided by the anatomic characteristics of uveitis. It includes HLA B27 testing (in unilateral acute anterior non-granulomatous uveitis), serum angiotensin converting enzyme, interferon-gamma release assay and chest CT (chronic uveitis), cerebral MRI and anterior chamber tap with IL10 analysis (intermediate or posterior uveitis in patients over 40 years). Investigations ordered in the absence of orientation are almost always unhelpful. CONCLUSIONS: We propose a strategy for the etiologic diagnosis of uveitis. The recommendations should be updated regularly. The efficiency of more invasive investigations has yet to be evaluated.

[Reached multifocal secondary syphilis: A case presentation]. / Atteinte plurifocale de syphilis secondaire: présentation d'un cas.

INTRODUCTION: Syphilis is a sexually transmitted infection (STI) related to Treponema pallidum. Secondary syphilis is the blood-borne systemic spread of Treponema. OBSERVATION: We report the case of secondary syphilis in a patient without risk of STIs factor. The clinical picture began with a genital affection followed by oral erosions and ulcers and an anterior and then posterior uveitis. Serology established the diagnosis and intravenous penicillin G treatment allowed for healing. DISCUSSION: Called the "great pretender" because of its clinical polymorphism, secondary syphilis can lead to formidable neurological and ophthalmological complications. Serological diagnosis is based on the use of treponemal and a nontreponemal tests. Penicillin G remains the treatment of choice and must be adapted according to the clinical damage.

Circulating endothelial cells and progenitors as prognostic factors during autoimmune thrombotic thrombocytopenic purpura: results of a prospective multicenter French study.

BACKGROUND: Autoimmune thrombotic thrombocytopenic purpura (AI-TTP) is characterized by an excess of circulating ultralarge von Willebrand factor (VWF) caused by anti-ADAMTS-13 autoantibodies. Animal studies, however, have shown that endothelial cell activation may also be an important trigger of AI-TTP. OBJECTIVES: To prospectively study circulating biomarkers of endothelial lesion and activation, such as circulating endothelial cells (CECs), soluble P-selectin (sP-selectin), or VWF, and of endothelial repair, such as circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs), in AI-TTP, in relation to disease severity and prognosis. RESULTS: Twenty-two patients were included in this study. CEC (P < 0.01), VWF (P < 0.05) and sP-selectin (P < 0.01) levels were significantly increased during crisis, and returned to baseline levels during remission. Both CEC (P < 0.05) and sP-selectin (P < 0.05) levels were significantly higher in patients who died or developed neurologic sequelae. CPC levels were substantially increased during the acute phase of the disease (P < 0.001), and returned to baseline levels during remission. Among CPCs, EPC levels were also increased during crisis (P < 0.05) and significantly decreased during remission. Patients who received < 16 plasma exchanges (PEs) had significantly higher EPC counts (P < 0.05) than those who needed more numerous PEs to obtain remission, suggesting that initial EPC counts may be associated with faster endothelial repair. CONCLUSION: The profile of circulating endothelial markers shows massive endothelial activation and repair/remodeling during AI-TTP, and suggests that CECs and EPCs may be promising prognostic biomarkers of the disease.

[Clinical, laboratory, radiological features, and outcome in 26 patients with aortic involvement amongst a case series of 63 patients with giant cell arteritis]. / Caractéristiques cliniques, paracliniques et profil évolutif de l'atteinte aortique de la maladie de Horton : à propos de 26 cas d'aortite parmi 63 cas de maladie de Horton.

PURPOSE: Aortic involvement that occurs in temporal arteritis is probably underestimated because it is usually asymptomatic. The characteristics of giant cell arteritis with aortic involvement are still poorly described and the relationship between aortitis and vascular outcome of the disease has not been clearly delineated. The objective of this retrospective study of 63 patients with giant cell arteritis, including 26 with aortic involvement, was to compare the features of patients with and without aortitis, and to assess the contribution of CT-scan and FDG-PET-scan in screening for vascular disease, monitoring, and therapeutic management of patients. METHODS: This retrospective study was conducted in the internal medicine department of the university hospital in Marseille, France, from January 1, 2005 to September 30, 2011. Patients had at least three out of the five American College of Rheumatology criteria for temporal arteritis and aortic involvement was investigated in all patients using CT-scan. Aortic wall thickness greater or equal to 3mm was considered to be abnormal. RESULTS: Of 63 patients diagnosed with giant cell arteritis, 26 (41.3%) had aortic involvement diagnosed by aortic CT-scan. Age at diagnosis was significantly younger (66.8 vs 73.8 years; P=0.002) in the group with aortitis. Inflammatory dorsal and low back pain, signs of vascular disease of the upper limbs (P=0.009), and higher level of acute phase reactants were associated with aortitis. Aneurysmal lesions of the aorta were significantly more frequent in the group with aortitis. Twenty patients had both aortic CT-scan and FDG-PET-scan. For patients in whom aortic involvement was not demonstrated with CT-scan, FDG-PET-scan was always non-contributive. With corticosteroids, aortitis resolved within 6 months in all patients as evaluated by aortic CT-scan. However, aortitis persisted in 80% of cases at 6 months when evaluated with FDG-PET-scan, and in 66% of cases at 12 months, without influencing the treatment. CONCLUSION: This case series shows no specific features of aorta and its main roots involvement in giant cell arteritis, justifying a systematic screening by CT-scan. The high frequency of this arterial involvement could help physicians in the diagnosis of giant cell arteritis. Aortitis seems to be associated with vascular complications as highlighted by the frequency of aortic aneurysm and a case of early aortic dissection. Finally, the role of PET-CT-scan for screening vascular disease and therapeutic monitoring remains to be clarified.

Diplorickettsia massiliensis as a human pathogen.

Diplorickettsia massiliensis has been recently isolated from Ixodes ricinus ticks. We screened 13,872 serum samples from patients in France with suspected tick-borne diseases and found three cases that had serological evidence of D. massiliensis infection; for one of these three cases, we obtained molecular evidence of an infection as well.

Cardiovascular risk and lupus disease.

AIM: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). The aim of this study was to evaluate subclinical atherosclerosis and to determine the prevalence of risk factors for CVD in SLE patients. METHODS: One hundred fifty-three patients (149 women and 4 men), aged (37±11.6) years with a definite diagnosis of SLE according to the revised criteria of the American College of Rheumatology (ACR), underwent physical examination, carotid and leg arteries B-mode ultrasound with a measure of ankle-brachial pressure index (ABPI); 94 patients had myocardial tomoscintigraphy. The laboratory check-up was: total cholesterol (TC), HDLc, LDLc, homocystein, glycemia, vascular cell adhesion molecules (VCAM-I). All patients had a normal renal function at the time of the study. RESULTS: The mean age is 37 years. Cardiovascular events were noticed in 15 patients (6 angina, 2 myocardial infarction and 7 strokes). Cardiovascular risk factors (CVRF) were: dyslipidemia (62.8%), moderate homocysteinemia (55%), BMI>25 (39%) and hypertension (35%) which is associated with a stroke (P<0.0006). The cumulative prednisone dose per patient was 45.5g. V.C.A.M-I level was high in 86.2 % of cases.95% of our patients had at least two CVRF. Myocardial perfusion stress scanning showed abnormalities in 21 patients (22.3%). Perfusion defects were linked with a stroke (P<0.01) and coronary events (P<0.02). Carotid atheroma was present in 32 patients (20.9%). Carotid plaques were associated with age (P<0.01), total cholesterol (TC)(P<0.05), and steroid dose (P<0.01). Intima-media-thickness was correlated with age (P<0.0003), TC (P<0.0007), LDLc (P<0.002), and homocysteine (P<0.03). 70% patients had a mediacalcinosis in femoral and popliteal arteries. The ABPI was correlated with V.C.A.M-I (P<0.0005). CONCLUSION: In Algeria, as elsewhere, young women with SLE have subclinical atherosclerosis which must be detected and they are at high risk of a vascular event.

Normalization of serum-free light chains in patients with systemic lupus erythematosus upon rituximab treatment and correlation with biological disease activity.

Increased free light chain (FLC) levels have been reported as useful in various autoimmune conditions. We investigated how FLC concentrations change upon B cell targeted therapy in systemic lupus erythematosus (SLE) patients and if they correlate with disease activity. We retrospectively studied 11 SLE patients without renal failure, whom were treated with rituximab. Quantitative determination of IgG, IgA, IgM, and serum FLC was performed before and after rituximab. At baseline, 70% had abnormal serum FLC levels, including increased kappa and lambda levels, while the kappa/lambda ratio was normal for all. A strong correlation was observed between complement C3 fraction and kappa levels (r = -0.929, P < 0.001) or lambda levels (r = -0.854, P = 0.003), but not with IgG, IgA, or IgM levels. After rituximab treatment, kappa and lambda FLC concentrations decreased significantly whilst total concentrations of IgG, IgA, and IgM also decreased but remained within the normal range. There was a strong correlation only between kappa FLC levels and complement C3 fraction consumption (r = -0.543, P = 0.003). In SLE patients without renal failure, increased FLC levels (mainly kappa) with normal kappa/lambda ratios are a common feature, and in contrast to total IgG levels, FLC concentrations correlate with biological disease activity.