[Inflammatory syndrome of unknown origin and PET/CT: Economic and iatrogenic impacts of false positive]. / Syndrome inflammatoire inexpliqué et TEP/CT : impacts économiques et iatrogènes des faux positifs.

INTRODUCTION: PET/CT is regularly used to investigate inflammatory syndrome of unknown origin (IUO), but hypermetabolisms found are not always consistent with the final diagnosis. The objective of the study was to assess the cost attributed to the diagnostic work-up for these false positives. MATERIALS AND METHODS: We conducted an ancillary study on a previous retrospective cohort from the internal medicine department at Amiens university hospital in patients who had a PET/CT scan between October 2004 and April 2017. Patients were included if PET/CT had been prescribed to investigate IUO. Among the 763 PET/CT performed, 144 met the inclusion criteria and a false-positive rate of 17.4% (n=25) was reported. RESULTS: Among these 25 patients, 21 underwent further investigations. The most frequently found hypermetabolic territories were digestive (n=12, mean SUVmax 8 [±4.33]) and osteoarticular (n=11, mean SUVmax 4.33 [±1.15]). The total cost of the 13 prescribed consultations was €390, the total cost of the 40 additional tests was €4,476 (mainly digestive endoscopies and radiological tests) and the total cost of medical transport was €572. The total cost of the 35 days of hospitalization specifically required to investigate these false positives was €22,952. In 23.8% (n=5), these investigations led to the incidental discovery of tumor lesions. CONCLUSION: The economic impact of false-positive PET/CT results does not appear to be negligible and merits a genuine prospective medico-economic study.

[Platypnea-orthodeoxia syndrome secondary to pneumonia: Two cases]. / Syndrome platypnée-orthodéoxie secondaire à une pneumopathie : à propos de deux cas.

INTRODUCTION: The platypnea-orthodeoxia syndrome is a rare situation characterized by the appearance of dyspnea and/or hypoxemia during the transition to orthostatism. OBSERVATIONS: We report the case of two patients, who presented with a platypnea-orthodeoxia syndrome following pneumocystis pneumonia and COVID-19, revealing an intracardiac communication with a right-left shunt on contrast ultrasound. CONCLUSION: This syndrome can be detected easily at the bedside with positional maneuvers and the shunt demonstrated by a hyperoxia test. Non-reversible situations may require correction of the anatomical anomaly by transcatheter intervention or surgery.

Prevalence of anti-S100A10 antibodies in antiphospholipid syndrome patients.

INTRODUCTION: Annexin A2 (ANXA2), an endothelial cell receptor for plasminogen and tissue plasminogen activator, has been identified as a new autoantigen in antiphospholipid syndrome (APS). ANXA2 can exist as a monomer or a heterotetrameric complex with S100A10 protein. This S100A10 subunit also plays a pivotal role in the regulation of fibrinolysis. The aim of this study was to evaluate the prevalence of autoantibodies directed against S100A10 protein in patients with APS. METHODS: Patients with primary antiphospholipid syndrome (PAPS), patients with systemic lupus erythematosus (SLE) and patients with unexplained thrombosis were retrospectively included in this study. Patients were followed in the department of Internal Medicine of Amiens University Hospital, Amiens, France. IgG and IgM anti-S100A10 antibodies were detected in the serum of patients by enzyme-linked immunosorbent assay. The cut-off value for positivity was defined as 3 standard deviations above the mean optical density (OD) obtained in the sera of 116 healthy blood donors. RESULTS: The study group consisted of 116 healthy individuals and 106 patients: 42 APS patients (26 patients with PAPS and 16 patients with secondary SLE-related APS), 43 SLE patients without APS and 21 patients with unexplained thrombosis. The median age of APS patients, SLE patients without APS, patients with unexplained thrombosis and healthy individuals was 47, 38, 53 and 42 years, respectively. Anti-S100A10 antibodies were detected in 11.9% of APS patients and this prevalence was statistically higher than that observed in healthy individuals (1.7%) (p = 0.0148). Highest levels of anti-S100A10 were observed in the serum of one PAPS patient with venous thrombosis and one SLE patient with APS with a history of stroke and recurrent miscarriage. CONCLUSION: S100A10 protein, the binding partner of ANXA2, was identified as a target of autoantibodies in sera from patients with APS. Further studies involving a large cohort of APS patients are required to determine whether these antibodies could play a role in thrombogenic mechanisms of APS and to determine their diagnostic value in discriminating clinical subgroups of patients with APS, particularly those with seronegative APS.

[Smoking cessation in secondary prevention of acute coronary syndrome: The role of the electronic cigarette]. / Sevrage tabagique en prévention secondaire d'un syndrome coronarien aigu : la place de la cigarette électronique.

OBJECTIVES: To study the use, efficiency and wishes for a "medicalization" of the electronic cigarette (EC) for smoking cessation in secondary prevention of acute coronary syndrome (ACS). PATIENTS AND METHOD: Prospective epidemiological study with inclusion of smoker patients hospitalized from 1st June 2015 to 31st March 2016 at the St Quentin Hospital (Picardy, France) for an ACS (except unstable angina), interviewed 1 year after their ACS, excluding patients over 75 years or with personal history of ACS. RESULTS: Eighty-one patients were included. 59 questionnaires (73%) were returned and analyzed. The average age was 53.3 years. There were 45 men (76.3%) and 14 women (23.7%). 11 patients (18.6%) had used the EC at least once before their ACS and 11 (18.6%) had used it after. That was the second most used smoking cessation method after the nicotine patches. One year after their SCA, 39 patients (66.1%) had stopped smoking: 63.6% (7/11) of EC users after the ACS against 66.7% (32/48) of non-users (P=0.848). After multivariate analysis, only cessation without help was associated with ceasing (P=0.013). CE users were significantly younger, were smoking more before their ACS, and had started smoking earlier. 50% of CE users would have appreciated to be better informed by their general practitioner and 53.3% expressed themselves in favor of a sale in pharmacies. CONCLUSION: EC is the second most common means of smoking cessation after an ACS. Further comparative studies are essential to know more about its efficiency and safety.

Interstitial lung disease in primary Sjögren's syndrome.

Interstitial lung disease (ILD) has been reported in 3 to 11% of patients with primary Sjögren's syndrome (pSS). The aims of this retrospective multicenter study were to: 1) analyze characteristics and outcome of ILD in pSS; and 2) evaluate predictive factors associated with ILD onset and deterioration. Twenty-one of 263 patients with pSS (8%) developed ILD. ILD onset preceded pSS diagnosis (n=5), was concurrently identified in association with pSS (n=6) and developed after pSS onset (n=9). Presenting ILD manifestations were: acute/subacute (n=11) onset of ILD, symptomatic progressive onset of ILD (n=5), and asymptomatic patients exhibiting abnormalities consistent with ILD on PFTs and HRCT-scan (n=5). ILD therapy included: steroids (n=21), cyclophosphamide (n=1), azathioprine (n=4) and rituximab (n=1). The course of ILD was as follows: improvement (15.8%), stabilization (47.4%) or deterioration (36.8%). Predictive parameters of ILD onset were: older age (p=0.044), Raynaud's phenomenon (p=0.001) and esophageal involvement (p=0.001). Factors associated with ILD deterioration were: older age (p=0.038) and esophageal involvement (p=0.038). Thus, this study underscores the poor outcome of ILD during pSS; thus, systematic screening of pulmonary involvement is required in pSS patients, resulting in both diagnosis and management at early stage of ILD. We also suggest that patients presenting predictive factors of ILD deterioration may need a closer follow-up and a more aggressive therapy.

Antibodies directed against annexin A2 and obstetric morbidity.

Acquired and inherited thrombophilia have both been reported to be associated with an increased risk of obstetric complications in early or later stages of pregnancy. Annexin A2 (ANXA2) is strongly expressed in vascular and placental tissues and plays a crucial role in fibrinolysis. The aim of the present study was to evaluate the prevalence of antibodies directed against ANXA2 in patients with recurrent miscarriage or obstetric complications. Anti-ANXA2 antibodies (aANXA2) were detected by ELISA in the sera from 46 women with obstetric morbidity, mainly recurrent miscarriage. The cut-off value for positivity was defined as 3 standard deviations above the mean optical density (OD) obtained in the sera from 42 female blood donors. The prevalence of aANXA2 in patients and healthy individuals was 15.2% and 2.3%, respectively. A statistically significant difference was observed between the 2 groups in terms of aANXA2 IgG titers (p=0.01). The highest aANXA2 levels were observed in sera from 2 patients with recurrent miscarriage and one patient with preeclampsia. aANXA2 could play a role in thrombotic mechanisms leading to recurrent pregnancy loss and placental vascular disease. Further studies are needed to determine whether ANXA2 is critical for maintenance of placental integrity.

Incidence of Severe Infections and Infection-Related Mortality During the Course of Giant Cell Arteritis: A Multicenter, Prospective, Double-Cohort Study.

OBJECTIVE: To assess the incidence of infections leading to hospitalization, the mortality rate related to infections, and the determinants of these factors in patients with giant cell arteritis (GCA). METHODS: In total, 486 patients with GCA (75% women) were enrolled at the time of diagnosis. All patients fulfilled the American College of Rheumatology criteria for GCA. As controls, age- and sex-matched subjects were randomly selected from the general population and matched to patients at the time of diagnosis of GCA. Both groups were prospectively followed up over a 5-year period. RESULTS: Severe infections were more frequent among patients with GCA during the first year after diagnosis, compared to general population controls (incidence rate ratio 2.1, 95% confidence interval [95% CI] 1.2-3.4; incidence rate 11.1/100 patient-years [95% CI 8.3-14.6] in patients with GCA versus 5.9/100 patient-years [95% CI 4-8.4] in controls). Specifically, septic shock and infectious colitis were more frequent among the patients with GCA. Mortality caused by infections was higher in patients with GCA compared to controls (P < 0.0001 by log rank test). In analyses adjusted for age, among patients with GCA, a diagnosis of diabetes (hazard ratio [HR] 3.3, 95% CI 1.4-7.7) and a corticosteroid dosage that was >10 mg/day after 12 months of treatment (HR 4.61, 95% CI 1.38-15.36) were associated with death attributed to severe infection. The observed overall incidence of mortality was increased in patients with GCA during the early period of enrollment in the study (before 1997) (P = 0.0001 by log rank test), but thereafter was the same as that in the general population controls. CONCLUSION: Frequencies of severe infections and rates of infection-related mortality are increased during the first year after the diagnosis of GCA. The risk of infection increases in GCA patients with older age or in the presence of diabetes, or is greater when the dosage of corticosteroids has been increased to >10 mg/day after 12 months of treatment.

[Aortitis in giant cell arteritis]. / Atteinte aortique dans la maladie de Horton.

Aortitis is a frequent complication of giant cell arteritis. Imaging techniques can reveal the inflammation of the aortic wall. CT-scan can show circumferential aortic wall thickening, or TEP-scan can show aortic FDG-uptake. Aortic aneurysm and dissection is a feared but probably rare complication of the inflammation of the aortic wall during GCA. Screening for aortitis could be proposed for patients with symptoms of aortic involvement, for patients with signs of large vessels involvement (limb claudication, bruit) or for patients with incomplete response to treatment. The best follow-up and treatment are to be determined for the patients with aortitis related to GCA.

Vascular expression of annexin A2 in lupus nephritis.

AIMS: To evaluate vascular expression of annexin A2 (ANXA2) and its subunit S100A10 in lupus nephritis (LN). METHODS: The present histological study included 14 patients with LN and 11 controls (patients with non-lupus kidney diseases). Kidney biopsies from patients with lupus were scored for lupus glomerulonephritis (according to the International Society of Nephrology/Renal Pathology Society 2003 classification) and vascular lesions (such as microthrombi and antiphospholipid syndrome nephropathy (APSN)). ANXA2 and S100A10 expression in glomerular and peritubular capillaries was evaluated by immunohistochemistry on tissue sections. The staining intensity score ranged from 0 (no expression) to 4 (intense expression). RESULTS: In patients with LN, the median age (range) at first kidney biopsy was 36 (18-49). Vascular lesions were observed in six patients (including two with APSN). We observed intense expression of ANXA2 in glomerular and peritubular capillaries while expression of S100A10 was weaker. However, one of the patients with APSN showed strong S100A10 expression. Patients with LN and controls differed significantly in terms of S100A10 expression in peritubular capillaries. We also observed a statistical difference between patients who had LN with renal vascular lesions and those without renal vascular lesions in terms of ANXA2 expression in peritubular capillaries. CONCLUSIONS: The presence of vascular lesions in LN appears to be associated with significant differences in the vascular expression of ANXA2. Vascular expression of ANXA2 was somewhat higher in LN. Vascular expression of S100A10 was somewhat lower in LN (except one of the two patients with APSN). Further studies of ANXA2's putative value as a biomarker of active LN or of vascular lesions in LN are required.

[Early cardiotoxicity of Hydroxychloroquine]. / Cardiotoxicité précoce de l'hydroxychloroquine.

INTRODUCTION: Hydroxychloroquine (HCQ) is most frequently used in the treatment of systemic inflammatory diseases. Cardiac complications of anti-malarial drugs are uncommon, and most of the time are the result of a long-term exposition. In this case, cardiotoxicity is the consequence of the lysosomal dysfunction and the result of intracytoplasmic granular material inclusions. CASE REPORT: We report a 77-year-old woman who presented a very early and reversible cardiotoxicity, probably related to the quinidine like effect of the HCQ, 10 days after initiation of therapy for Whipple endocarditis. CONCLUSION: We discuss the different mechanisms of cardiotoxicity of anti-malarial drugs and their clinical manifestations.

Gastrointestinal mucosal abnormalities using videocapsule endoscopy in systemic sclerosis.

BACKGROUND: To date, there are no large studies on videocapsule endoscopy in systemic sclerosis (SSc). Consequently, the prevalence and features of gastrointestinal mucosal abnormalities in SSc have not been determined. AIMS: To determine both prevalence and characteristics of gastrointestinal mucosal abnormalities in unselected patients with SSc, using videocapsule endoscopy. To predict which SSc patients are at risk of developing potentially bleeding gastrointestinal vascular mucosal abnormalities. METHODS: Videocapsule endoscopy was performed on 50 patients with SSc. RESULTS: Prevalence of gastrointestinal mucosal abnormalities was 52%. Potentially bleeding vascular mucosal lesions were predominant, including: watermelon stomach (34.6%), gastric and/or small intestinal telangiectasia (26.9%) and gastric and/or small intestinal angiodysplasia (38.5%). SSc patients with gastrointestinal vascular mucosal lesions more often exhibited: limited cutaneous SSc (P = 0.06), digital ulcers (P = 0.05), higher score of nailfold videocapillaroscopy (P = 0.0009), anaemia (P = 0.02), lower levels of ferritin (P < 0.0001) and anti-centromere antibody. CONCLUSIONS: Our study identifies a high frequency of gastrointestinal mucosal abnormalities in SSc, with a marked predominance of vascular mucosal damage. Furthermore, our study shows a strong correlation between gastrointestinal vascular mucosal lesions and presence of severe extra-digestive vasculopathy (digital ulcers and higher nailfold videocapillaroscopy scores). This latter supports the theory that SSc-related diffuse vasculopathy is responsible for both cutaneous and digestive vascular lesions. Therefore, we suggest that nailfold videocapillaroscopy may be a helpful test for managing SSc patients. In fact, nailfold videocapillaroscopy score should be calculated routinely, as it may result in identification of SSc patients at higher risk of developing potentially bleeding gastrointestinal vascular mucosal lesions.

Antibodies against the N-terminal domain of annexin A2 in antiphospholipid syndrome.

Annexin A2 (ANXA2, an endothelial cell receptor for plasminogen and tissue plasminogen activator) has been identified as a new autoantigen in antiphospholipid syndrome (APS). The aim of the present study was to evaluate the presence of antibodies against the N-terminal domain of annexin A2 (ANXA2) in primary APS (PAPS). By using a synthetic peptide corresponding to the 31N-terminal amino acids of ANXA2 (ANXA2(N31)) as an antigen, we performed an enzyme-linked immunosorbent assay (ELISA) to measure anti-ANXA2(N31) IgG and IgM antibodies in the serum of PAPS patients (n=19), systemic lupus erythematosus (SLE) patients (n=50) and healthy blood donors (n=106). We did not find any statistically differences between the three groups in terms of IgG and IgM anti-ANXA2(N31) titres. Elevated IgG anti-ANXA2(N31) titres were not observed in the serum of PAPS or SLE patients who had previously tested positive for anti-ANXA2 antibodies. Thus, the ANXA2 N-terminal domain does not appear to be the target antigen for anti-ANXA2 antibodies in APS.

Serum procalcitonin does not differentiate between infection and disease flare in patients with systemic lupus erythematosus.

Systemic erythematosus lupus (SLE) is a common autoimmune disease. Disease flares may mimic infection with fever, inflammatory syndrome and chills, sometimes resulting in a difficult differential diagnosis. Elevated serum procalcitonin (PCT) levels have been reported to be predictive of bacterial infections, but with conflicting results. The value of serum procalcitonin has not been assessed in large series of SLE. We aimed to describe the distribution of PCT levels in SLE patients with and without flares, to assess the factors associated with increased PCT levels, and to determine the positive and negative predictive values of increased PCT for bacterial infection in SLE patients. Hospitalized SLE patients were included in a retrospective study. Serum PCT had been assayed, or a serum sample had been frozen on admission, before treatment modification. Serum PCT, measured by an automated immunofluorometric assay, and SLEDAI were assessed at the same time. Some 53 women (median age: 33.7 years, range 16-76) and seven men (median age: 52.5 years ± 19) were included. The median SLEDAI for patients with flare (n = 16, 28%) was 2 (range: 0-29). Five patients (8%) had systemic infection. Only one patient had increased PCT levels. Men had significantly higher PCT levels than women (0.196 ± 0.23 versus 0.066 ± 0.03, p < 0.01) and a significant correlation was observed between PCT, age, erythrocyte sedimentation rate, and C-reactive protein. We conclude that PCT levels were within the normal range in infected and non-infected SLE patients and there was no ability to differentiate SLE patients with or without bacterial infection.

Pathological features of temporal arteries in patients with giant cell arteritis presenting with permanent visual loss.

BACKGROUND: Permanent visual loss (PVL) is the most feared complication of giant cell arteritis (GCA), and its risk factors are still unclear. OBJECTIVES: The aim of our study was to assess the pathological features predictive of PVL on temporal artery biopsy (TAB) specimens in patients with GCA. METHODS: The slides of 391 TAB specimens from patients with GCA were reviewed by two pathologists without clinical information. RESULTS: A total of 29 patients (26 females and 3 males, mean age 78.3 years) presented with unilateral PVL at the onset of the disease, and 362 patients (258 females, 104 males, mean age 74.7 years), did not. The pathological features strongly predictive for PVL were the presence (p = 0.003), number (p = 0.001) and aggregates of giant cells (p = 0.001), presence of plasmocytes (p = 0.002), thickened intima (p = 0.007), neoangiogenesis (p = 0.001) and degree of arterial occlusion (p = 0.006). Presence of neutrophils, eosinophils, parietal necrosis, calcification in the arterial wall and disruption of the internal elastic membrane were similar in both groups. Total obstruction of the arterial lumen by a thrombus, intensity of the inflammatory cells infiltration and inflammation of small vessels, nerves and veins surrounding the temporal artery were not associated with blindness. In multivariate analysis, only giant cells remained significantly associated with PVL. CONCLUSION: Giant cells are strongly associated with PVL, with a significant gradient between great risk and large number of giant cells. However, PVL was neither associated with the intensity of the inflammatory infiltrate, nor with the presence of arterial thrombosis.

[Pathogenesis of primary large vessel arteritis]. / Immunopathologie des artérites primitives des gros vaisseaux.

Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are the two primary large-vessel arteritides. Recent advances in cellular immunology have allowed better understanding of pathogenesis of these diseases. In GCA and TA, resident adventitial dendritic cells are activated by unidentified stimuli. This activation induces chemokine synthesis which enhances recruitment of inflammatory cells. T-cells infiltrate the vascular wall and specifically recognize one or a few antigens presented by shared epitopes associated with specific HLA molecules on dendritic cells. Activated T-cells produce IFNgamma stimulating two distinct populations of macrophages. Macrophages located in the intima produce pro-inflammatory cytokines (IL-1, IL-6). Macrophages located in the media differentiate into giant cells and/or produce reactive oxygen species, nitric oxide and matrix metallo-proteinases. Macrophages of the media also produce VEGF, which leads to neovascularization and PDGF, which induces intimal hyperplasia and vascular occlusion. In TA, cytotoxic T cells infiltrate the vascular wall and induce apoptosis of the vascular cells. Better understanding of the pathogenesis of large-vessel arteritis may lead to development of immunosuppressive drugs specifically targeting the immunological mechanisms implicated in GCA and TA.

Procalcitonin at the onset of giant cell arteritis and polymyalgia rheumatica: the GRACG prospective study.

OBJECTIVES: An epidemic pattern has been reported for GCA and PMR. Immunological studies have shown that an unknown antigen activates the dendritic cells of the adventitia and the type 4 toll-like receptors. Procalcitonin (PCT) is an early marker of bacterial infection. The goal of the study was to assess the level of PCT in GCA and PMR at the onset of the disease. METHODS: Patients diagnosed during the 2002-06 period were randomly selected. All the 46 patients fulfilled the ACR or the Hunder criteria, and all blood samples were taken before steroid therapy. RESULTS: PCT was normal in all patients. PCT was slightly increased in men (0.087 +/- 0.023 microg/l) compared with women (0.066 +/- 0.027 microg/l) (P = 0.009), and in PMR (0.092 +/- 0.027 microg/l) compared with GCA (0.068 +/- 0.026 microg/l) (P = 0.018). There was no significant correlation with inflammation markers. CONCLUSIONS: These results are not in favour of a bacterial trigger for GCA or PMR. Increased PCT levels in patients with inflammatory syndrome, GCA-PMR symptoms and negative temporal artery biopsy may rule out the diagnosis of GCA and PMR.

[Haematopoietic stem cell transplantation in the treatment of autoimmune diseases]. / Intensification thérapeutique dans les maladies auto-immunes.

PURPOSE: During the past ten years, more than 1000 patients suffering from severe autoimmune disease have received an autologous haematopoietic stem cell transplant. These new therapeutic have been used in systemic sclerosis (scleroderma), multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis and systemic lupus erythematosus. CURRENT KNOWLEDGE AND KEY POINTS: Autologous haematopoietic stem cell transplantation has become a curative option for condition with very poor prognosis as severe systemic sclerosis, lupus erythematosus or other systemic diseases. This review summarizes the current experience in the phase I and II clinical trials in Europe and North America. We describe the main results and the limits of stem cell transplantation in systemic diseases. FUTURE PROSPECTS AND PROJECTS: Autologous haematopoietic stem cell transplant in the treatment of autoimmune disease has evolved from a experimental concept to a clinically feasible and powerful therapy for selected patients with severe disease.