K. Ly

Risk factors for Visual loss in giant cell (temporal) arteritis : A prospective study of 174 patients

OBJECTIVE To determine the risk factors--especially the effects of thrombocytosis--for permanent visual loss in patients with temporal arteritis. METHODS One hundred seventy-four patients with temporal arteritis (147 biopsy proven) were prospectively observed for the development of permanent visual loss. We used multivariate logistic regression analysis to determine which of 17 pretreatment characteristics were associated with visual loss. RESULTS Visual ischemic manifestations occurred in 48 (28%) patients, including permanent visual loss in 23 (13%) patients. The independent predictors associated with an increased risk of permanent visual loss were a history of transient visual ischemic symptoms (odds ratio [OR] = 6.3; 95% confidence interval [CI]: 1.4 to 29; P = 0.02) and a higher platelet count (OR = 3.7 per SD; 95% CI: 1.8 to 7.9; P = 0.001). The presence of constitutional symptoms (OR = 0.14; 95% CI: 0.02 to 0.77, P = 0.01), polymyalgia rheumatica (OR = 0.04; 95% CI: 0.01 to 0.48, P = 0.02), and C-reactive protein level (OR = 0.35 per SD; 95% CI: 0.13 to 0.92, P = 0.03) were associated with a reduced risk. Upper limb artery involvement was excluded from the multivariate model, as no patients with that problem developed permanent visual loss. Of the 87 patients who presented with thrombocytosis (platelet count >400 x 10(9)/L), 32 (37%) developed ischemic visual symptoms, compared with 16 (18%) of those without thrombocytosis. CONCLUSIONS An elevated platelet count is a risk factor for permanent visual loss in temporal arteritis. The finding of thrombocytosis in a patient with suspected temporal arteritis should emphasize the need for urgent treatment, with consideration of using inhibitors of platelet aggregation or anticoagulation therapy.

Articular manifestations in primary Sjögren’s syndrome: clinical significance and prognosis of 188 patients

OBJECTIVES Articular manifestations (AMs) occurred in approximately 30-60% of patients with primary SS (pSS). We conducted the current study to describe clinical presentation, specific treatment and to report clinical outcome of pSS patients with AM in a large bicentric French cohort. METHODS Clinical, biological and immunological features of 419 consecutive patients with pSS were recorded in order to describe the clinical and immunological course of pSS AM and to point out the impact of those rheumatological features on pSS evolution. RESULTS A total of 188 patients with pSS (172 women, 16 men) exhibited AM. They preceded sicca symptoms in 32, were simultaneous to pSS diagnosis in 98 and followed diagnosis in 59 patients. Clinical presentation was polyarticular and concerned mostly peripheral joints (synovitis, n = 66). Symptoms responded readily to symptomatic treatment in 45 cases (24%). DMARDs or immunosuppressive treatments were introduced in 133 patients: HCQ (n = 111), corticosteroid (n = 53), MTX (n = 12), SSZ (n = 6), AZA (n = 3), LEF (n = 1), etanercept (n = 1) and allochrysine (n = 1). Only one case of RA was diagnosed during the evolution. Statistical analysis identified clinical and biological factors associated with AM (P < or = 0.05): RP, muscular manifestations, renal involvement, peripheral neuropathy, cutaneous vasculitis, and positivity of RF, anti-SSB antibodies and cryoglobulinaemia. Patients with AM at diagnosis were characterized by a multisystemic involvement at the end of the follow-up period (P < 0.001). CONCLUSION Although AMs are frequent and usually mild in pSS, these manifestations are associated with a pluri-systemic involvement of pSS.

Recovery of Adrenal Function after Long-Term Glucocorticoid Therapy for Giant Cell Arteritis: A Cohort Study

Objectives Giant cell arteritis (GCA) is a chronic systemic vasculitis of large and medium-sized arteries, for which long-term glucocorticoid (GC) treatment is needed. During GC withdrawal patients can suffer adrenal insufficiency. We sought to determine the time until recovery of adrenal function after long-term GC therapy, and to assess the prevalence and predictors for secondary adrenal insufficiency. Subjects and Design 150 patients meeting the ACR criteria for GCA between 1984 and 2012 were analyzed. All received the same GC treatment protocol. The low-dose ACTH stimulation test was repeated annually until adrenal recovery. Biographical, clinical and laboratory data were collected prospectively and compared. Results At the first ACTH test, 74 (49%) patients were non-responders: of these, the mean time until recovery of adrenal function was 14 months (max: 51 months). A normal test response occurred within 36 months in 85% of patients. However, adrenal function never recovered in 5% of patients. GC of >15 mg/day at 6 months, GC of >9.5 mg/day at 12 months, treatment duration of >19 months, a cumulative GC dose of >8.5 g, and a basal cortisol concentration of <386 nmol/L were all statistically associated with a negative response in the first ACTH test (p <0.05). Conclusion Adrenal insufficiency in patients with GCA, treated long-term with GC, was frequent but transitory. Thus, physicians’ vigilance should be increased and an ACTH test should be performed when GC causes the above associated statistical factors.

Involvement and prognosis value of CD8(+) T cells in giant cell arteritis.

CD8(+) T cells participate in the pathogenesis of some vasculitides. However, little is known about their role in Giant Cell Arteritis (GCA). This study was conducted to investigate CD8(+) T cell involvement in the pathogenesis of GCA. Analyses were performed at diagnosis and after 3 months of glucocorticoid treatment in 34 GCA patients and 26 age-matched healthy volunteers. Percentages of CD8(+) T-cell subsets, spectratype analysis of the TCR Vβ families of CD8(+) T cells, levels of cytokines and chemokines and immunohistochemistry of temporal artery biopsies (TAB) were assessed. Among total CD8(+) T cells, percentages of circulating cytotoxic CD8 T lymphocytes (CTL, CD3(+)CD8(+)perforin(+)granzymeB(+)), Tc17 (CD3(+)CD8(+)IL-17(+)), CD63(+)CD8(+) T cells and levels of soluble granzymes A and B were higher in patients than in controls, whereas the percentage of Tc1 cells (CD3(+)CD8(+)IFN-γ(+)) was similar. Moreover, CD8(+) T cells displayed a restricted TCR repertoire in GCA patients. Percentages of circulating CTL, Tc17 and soluble levels of granzymes A and B decreased after treatment. CXCR3 expression on CD8(+) T cells and its serum ligands (CXCL9, -10, -11) were higher in patients. Analyses of TAB revealed high expression of CXCL9 and -10 associated with infiltration by CXCR3(+)CD8(+) T cells expressing granzyme B and TiA1. The intensity of the CD8 T-cell infiltrate in TAB was predictive of the severity of the disease. This study demonstrates the implication and the prognostic value of CD8(+) T-cells in GCA and suggests that CD8(+) T-cells are recruited within the vascular wall through an interaction between CXCR3 and its ligands.

Neurotrophins are expressed in giant cell arteritis lesions and may contribute to vascular remodeling

IntroductionGiant cell arteritis (GCA) is characterized by intimal hyperplasia leading to ischaemic manifestations that involve large vessels. Neurotrophins (NTs) and their receptors (NTRs) are protein factors for growth, differentiation and survival of neurons. They are also involved in the migration of vascular smooth muscle cells (VSMCs). Our aim was to investigate whether NTs and NTRs are involved in vascular remodelling of GCA.MethodsWe included consecutive patients who underwent a temporal artery biopsy for suspected GCA. We developed an enzymatic digestion method to obtain VSMCs from smooth muscle cells in GCA patients and controls. Neurotrophin protein and gene expression and functional assays were studied from these VSMCs. Neurotrophin expression was also analysed by immunohistochemistry in GCA patients and controls.ResultsWhereas temporal arteries of both GCA patients (n = 22) and controls (n = 21) expressed nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and sortilin, immunostaining was more intense in GCA patients, especially in the media and intima, while neurotrophin-3 (NT-3) and P75 receptor (P75NTR) were only detected in TA from GCA patients. Expression of TrkB, a BDNF receptor, was higher in GCA patients with ischaemic complications. Serum NGF was significantly higher in GCA patients (n = 28) vs. controls (n = 48), whereas no significant difference was found for BDNF and NT-3. NGF and BDNF enhanced GCA-derived temporal artery VSMC proliferation and BDNF facilitated migration of temporal artery VSMCs in patients with GCA compared to controls.ConclusionsOur results suggest that NTs and NTRs are involved in vascular remodelling of GCA. In GCA-derived temporal artery VSMC, NGF promoted proliferation and BDNF enhanced migration by binding to TrkB and p75NTR receptors. Further experiments are needed on a larger number of VSMC samples to confirm these results.

PROGNOSIS OF ACQUIRED HEMOPHILIA IN OLDER PEOPLE

To the Editor: We read with great interest the letter by Lambotte et al., published in a recent issue of the Journal. These authors reported a case series of 17 elderly patients (median age 82.5) with acquired hemophilia (AH) admitted to a national reference center for the treatment of hemophilia between 1994 and 2007. Although intensive care was proposed for 82% of the patients, yielding eight complete responses (CR) and two partial responses, overall mortality rate was 76% within a mean follow-up of 12 months (median 3 months). Inhibitor-related deaths represented 77% of deaths, consisting of bleeding (n 5 3, 23%) and iatrogenic complications (n 5 7, 54%), including five deaths from infection related to immunosuppressive treatment. Owing to the paucity of specific data regarding management and prognosis of AH in this population, Lambotte et al. concluded, from their disappointing personal results, that older people with AH have a poor prognosis even with intensive therapy. This definitive conclusion compelled us to present similarly a case series of older patients with AH. Of 18 consecutive patients admitted to Dupuytren University Hospital with AH between 1989 and 2007, 13 (72.2%), including eight men, were aged 70 and older (mean age 82.3, range 72–92). Of these, three cases histories have been published previously. Clinical data were retrospectively collected from the medical charts and included medical history, comorbid conditions, clinical course at admission, full blood cell counts, activated partial thromboplastin time, factor VIII (FVIII), and levels of antibodies directed to human FVIII. We also recorded in detail each patient’s treatment and clinical course. Patients were managed in a collaborative way in the intensive care unit of the Department of Internal Medicine or the Hematology Department. Treatment strategy was adjusted individually, based on severity of bleeding and estimated degree of frailty. All the patients were followed until recovery, death, or lasting stabilization. Complete response, partial response to treatment, and recovery from AH were defined as in Lambotte et al.’s report. Search for an underlying condition was not standardized. Inhibitors were regarded as idiopathic in the absence of identifiable cause or commonly associated condition at the onset of clotting disorder and after at least 6 months of follow-up. As depicted in Table 1, all the patients except one had one or more comorbidities; seven had an underlying condition, mainly a malignancy or an autoimmune disease, and all presented with large, superficial bruising, often associated with intramuscular hematomas, hematuria, or gastrointestinal bleeding. Although retroperitoneal hemorrhage was observed only once, a 7.5 g/dL mean nadir of blood hemoglobin level (range 5.2–12.2) attested to the overall severity of AH in our patients, with 11 patients requiring repeated red cell transfusions, a mean FVIII level of 2.2% (range 0–7%) of normal values, and a mean inhibitor titer of 69 (range 2–330) Bethesda units. Eleven patients were treated symptomatically; eight received activated prothrombin complex concentrates (FEIBA, Baxter, Maurepas, France) or recombinant human activated FVII, which controlled bleeding in seven with excellent tolerance. Four patients received intravenous immunoglobulin, which appeared effective in one. All of the patients received inhibitor suppression, based in seven patients on various combinations of oral prednisone and cyclophosphamide and in six recent cases on a short corticosteroid course associated with four weekly courses of rituximab (375 mg/m). Treatment toxicity, mainly infections and hematological toxicity, was observed in five of seven patients receiving a classical immunosuppression regimen and two of six patients receiving a rituximab-based regimen. The time to complete control of bleeding averaged 23 days (range 2–50) in six assessable patients treated classically and 19 days (range 2– 55) in five assessable patients treated with rituximab. After a mean 16-month (range 1–34) follow-up, AH status in 11 assessable patients was complete response in eight (average 5.7 months) including three of four who received rituximab treatment (average 5.3 months), partial response in two, and no response in one, whereas inhibitor titers were gradually declining in two ongoing cases. In all, four patients (31%) died, after a mean time of 10.6 months (range 1–31), two deaths being unrelated to bleeding or treatment toxicity. Patients included in this study had a consistently better prognosis than patients described by Lambotte et al. (overall survival 69% vs 24%), despite a similar mean age and mean duration of follow-up. As the authors suggested, a bias in their population, compared with our regional, unbiased population, can best explain such a difference. Patients referred to Bicètre Hospital seemingly had a higher frequency of severe comorbidities and poorer physical status than our patients. The higher frequency of retroperitoneal hematoma in the series by Lambotte et al. than in our series (35.3% vs 7.7%), may point to a referral bias toward more-severe AH or more-delayed patient referral to Bicètre Hospital than to regional centers. AH occurs overwhelmingly in patients aged 65 and older, which seems to represent an independent risk factor for death. The present study and the study by Lambotte et al. highlight the utmost importance of diagnosing AH in a timely manner and accurately selecting older subjects who will truly benefit from intensive care. In this regard, we agree with Lambotte et al. that rituximab, although expensive, could be the first choice in frail older patients with AH, especially those with high-titer FIII inhibitor, because of its good safety profile and often rapid efficacy.

Serum neurotrophin profile in systemic sclerosis.

Background Neurotrophins (NTs) are able to activate lymphocytes and fibroblasts; they can modulate angiogenesis and sympathic vascular function. Thus, they can be implicated in the three pathogenic processes of systemic sclerosis (SSc). The aims of this study are to determine blood levels of Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT-3) in SSc and to correlate them with clinical and biological data. Methods Serum samples were obtained from 55 SSc patients and 32 control subjects to measure NTs levels by ELISA and to determine their relationships with SSc profiles. Findings Serum NGF levels were higher in SSc patients (288.26±170.34 pg/mL) than in control subjects (170.34±50.8 pg/mL, p<0.001) and correlated with gammaglobulins levels and the presence of both anti-cardiolipin and anti-Scl-70 antibodies (p<0.05). In contrast, BDNF levels were lower in SSc patients than in controls (1121.9±158.1 vs 1372.9±190.9 pg/mL, p<0.0001), especially in pulmonary arterial hypertension and diffuse SSc as compared to limited forms (all p<0.05). NT-3 levels were similar in SSc and in the control group (2657.2±2296 vs 2959.3±2555 pg/mL, NS). BDNF levels correlated negatively with increased NGF levels in the SSc group (and not in controls). Conclusion Low BDNF serum levels were not previously documented in SSc, particularly in the diffuse SSc subset and in patients with pulmonary hypertension or anti-Scl-70 antibodies. The negative correlation between NGF and BDNF levels observed in SSc and not in healthy controls could be implicated in sympathic vascular dysfunction in SSc.

No evidence for a putative involvement of platelet-activating factor in systemic lupus erythematosus without active nephritis.

BACKGROUND: Platelet-activating factor (PAF) seems to be implicated in systemic lupus erythematosus (SLE) patients with associated renal diseases. AIMS: In this study, we ensured the role of PAF in SLE patients without renal complications. METHODS: Blood PAF and acetylhydrolase activity, plasma soluble phospholipase A(2), and the presence of antibodies against PAF were investigated in 17 SLE patients without active nephritis and in 17 healthy controls. RESULTS: Blood PAF levels were not different (p=0.45) between SLE patients (6.7+/-2.8 pg/ml) and healthy subjects (9.6+/-3.1 pg/ml). Plasma acetylhydrolase activity (the PAF-degrading enzyme) was significantly (p=0.03) elevated in SLE patients (57.8+/-6.4 nmol/min/ml) as compared with controls (37.9+/-2.6 nmol/min/ml). Plasma soluble phospholipase A(2) (the key enzyme for PAF formation) was not different (p=0.6) between SLE patients (59.1+/-5.1 U/ml) and controls (54.7+/-2.4 U/ml). Antibodies against PAF were detected only in 3/17 SLE patients. Flow cytometry analysis did not highlight PAF receptors on circulating leukocytes of SLE patients. CONCLUSION: This clinical study highlights no evidence for a putative important role of PAF in SLE patients without active nephritis.

An uncommon case of dyspnea with unilateral laryngeal paralysis in acromegaly

A 61-year-old man with obstructive sleep apnea syndrome and normal BMI complained of dyspnea. Nasofibroscopy revealed a global and major oedema of the glottis and supraglottis and also a paralysis of the left vocal fold. CT-scan pointed out a spontaneous hyperdensity of the left arytenoid cartilage. A tracheostomy was performed. Clinical examination revealed large hands and macroglossy with high IGF1 rate. MRI confirmed a supracentimetric pituitary adenoma. To our knowledge, this is the first description of a case of acute respiratory distress due to unilateral larynx paralysis leading to acromegaly diagnosis. This is due to submucosal hypertrophy and vocal cord immobility.

Les neurotrophines sont impliquées dans le remodelage vasculaire de l’artérite à cellules géantes

Resultats.– Les parametres hemodynamiques (frequence cardiaque, pression arterielle) et l’indice de masse corporelle etaient similaires chez les patients ScS et les temoins. Le diametre de l’artere brachiale etait comparable dans les deux groupes, ainsi que l’epaisseur intima-media carotidienne. Les patients ScS presentaient une reduction significative de la FMD et de l’hyperhemie post-ischemique par rapport aux sujets temoins. En revanche, les valeurs de FMD indexees a l’augmentation des forces de cisaillement etaient similaires dans les deux groupes, temoignant d’une fonctionendotheliale endothelium-dependantepreservee au niveau de l’artere brachiale chez les patients ScS. En analysant le profil des flux Doppler, nous avons observe que l’indice de resistance etait similaire dans les deux groupes au repos,mais qu’il etait significativement augmente lors de la levee de l’ischemie dans le groupeScS, temoignantd’une reductionde la vasodilatation induite par l’ischemie en aval de l’artere brachiale. Discussion.– La vasodilatation de l’artere brachiale induite par le flux (endothelium-dependante) est preservee au cours de la ScS. La mesure de la dilatation de l’artere brachiale dependante de l’endothelium chez les patients ScS est sous estimee du fait de la faible hyperhemie reactionnelle observee ; l’importance de cette dilatation etant directement liee a l’augmentation des forces de cisaillement lors de la levee de l’ischemie. La limitation de la vasodilatation induite par l’ischemie chez les patients ScS en est probablement a l’origine. Conclusion.– Au total, cette etude suggere une atteinte microcirculatoire exclusive dans la vasculopathie liee a la ScS. Reference [1] Rossi P, et al. Clin Physiol Funct Imaging 2010;30:453–9.