B. Imbert

The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France.

OBJECTIVE An algorithm for the detection of pulmonary arterial hypertension (PAH), based on the presence of dyspnea and the findings of Doppler echocardiographic evaluation of the velocity of tricuspid regurgitation (VTR) and right-sided heart catheterization (RHC), which was applied in a large multicenter systemic sclerosis (SSc) population, estimated the prevalence of PAH to be 7.85%. The aim of this observational study was to investigate the incidence of PAH and pulmonary hypertension (PH) during a 3-year followup of patients from the same cohort (the ItinérAIR-Sclérodermie Study). METHODS Patients with SSc and without evidence of PAH underwent evaluation for dyspnea and VTR at study entry and during subsequent visits. Patients in whom PAH was suspected because of a VTR of 2.8-3.0 meters/second and unexplained dyspnea or a VTR of >3.0 meters/second underwent RHC to confirm the diagnosis. RESULTS A total of 384 patients were followed up for a mean+/-SD of 41.03+/-5.66 months (median 40.92 months). At baseline, 86.7% of the patients were women, and the mean+/-SD age of the patients was 53.1+/-12.0 years. The mean+/-SD duration of SSc at study entry was 8.7+/-7.6 years. After RHC, PAH was diagnosed in 8 patients, postcapillary PH in 8 patients, and PH associated with severe pulmonary fibrosis in 2 patients. The incidence of PAH was estimated to be 0.61 cases per 100 patient-years. Two patients who exhibited a mean pulmonary artery pressure of 20-25 mm Hg at baseline subsequently developed PAH. CONCLUSION The estimated incidence of PAH among patients with SSc was 0.61 cases per 100 patient-years. The high incidence of postcapillary PH highlights the value of RHC in investigating suspected PAH.

Long‐term outcomes of the WEGENT trial on remission‐maintenance for granulomatosis with polyangiitis or microscopic polyangiitis

Findings from the WEGENT trial and other short‐term studies have suggested that azathioprine (AZA) or methotrexate (MTX) could effectively maintain remission of granulomatosis with polyangiitis (Wegeners) (GPA) or microscopic polyangiitis (MPA). This study was undertaken to examine whether differences in rates of relapse or adverse events would appear after discontinuation of these 2 maintenance regimens, when assessed over a longer followup period.

Cutaneous Iontophoresis of Treprostinil in Systemic Sclerosis: A Proof‐of‐Concept Study

Ischemic digital ulcer (DU) is a serious complication of systemic sclerosis (SSc). Intravenous prostanoids are the only approved treatment for active DUs, but they induce dose‐limiting side effects and require hospitalization. Our objective was to evaluate the effect of iontophoresis (a noninvasive drug delivery method) of treprostinil in SSc patients. Three studies were conducted: a pharmacokinetic study in 12 healthy volunteers showed that peak dermal concentration was reached at 2 hours, whereas plasma treprostinil was undetected. Then, a placebo‐controlled, double‐blind incremental dose study assessed the effect of treprostinil on digital skin blood flow in 22 healthy subjects. The effect of the highest dose was then compared with that of placebo in 12 SSc patients. Treprostinil significantly increased skin blood flow in healthy subjects (P = 0.006) and in SSc patients (P = 0.023). In conclusion, digital iontophoresis of treprostinil is feasible, is well tolerated, and increases digital skin perfusion. It could be tested as a treatment for SSc‐related DUs.

Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literature

BACKGROUND As intravenous immunoglobulins (IVIG) exhibit immunomodulatory and antifibrotic properties, they may be a relevant treatment for systemic sclerosis (SSc). The objectives of this work were thus to report on the efficacy and safety of IVIG in a population of SSc patients and to review the available literature. METHODS 46 patients from 19 French centers were retrospectively recruited. They were included if they had a diagnosis of SSc and received at least 1 IVIG infusion at a dosage >1g/kg/cycle. Relevant data collected at IVIG discontinuation were compared to those collected at IVIG initiation. A comprehensive literature review was performed. RESULTS We observed a significant improvement of muscle pain (74% vs. 20%, p<0.0001), muscle weakness (45% vs. 21%, p=0.01), joint pain (44% vs. 19%, p=0.02), CK levels (1069±1552UI vs. 288±449UI, p<0.0001) and CRP levels (13.1±17.6mg/L vs. 9.2±16.6mg/L, p=0.001). We also noted a trend for an improvement of gastro-esophageal reflux disease (68% vs. 53%, p=0.06) and bowel symptoms (42% vs. 27%, p=0.06). Skin and cardiorespiratory involvements remained stable. Finally, corticosteroid daily dose was significantly lower by the end of treatment (13.0±11.6mg/day vs. 8.9±10.4mg/day, p=0.01). Only two severe adverse events were reported (one case of deep vein thrombosis and one case of diffuse edematous syndrome). CONCLUSION Our work suggests that IVIG are a safe therapeutic option that may be effective in improving musculoskeletal involvement, systemic inflammation, digestive tract symptoms and could be corticosteroid sparing.

The digital thermal hyperemia pattern is associated with the onset of digital ulcerations in systemic sclerosis during 3 years of follow-up

OBJECTIVES One of the most important skin complications in systemic sclerosis (SSc) is digital ulceration. Local thermal hyperemia (LTH) in the skin is a biphasic response to local heating involving both neurovascular and endothelial responses. Since LTH is abnormal in SSc patients, we aimed at testing whether LTH could be a prognostic tool for the onset of digital ulcers. METHODS We prospectively enrolled 51 patients with SSc. Nailfold capillaroscopy and LTH were recorded at baseline, and patients were followed for 3 years. RESULTS No patient with a LTH peak/plateau ratio ≥1 (n=19) developed digital ulcerations during the 3 year follow-up (100% negative predictive value), while 6 out of 32 patients with a LTH peak/plateau ratio <1 at enrolment presented with finger pad ulcerations within 3 years (p=0.05). In contrast, when lidocaine/prilocaine was applied to the finger pad, no relationship between thermal hyperemia and digital ulcerations was observed. CONCLUSIONS A LTH peak/plateau ratio on the finger pad greater than 1, which can easily be determined in routine clinical practice, could be used to reassure patients, whatever the subtype of SSc, about the low probability of future digital ulceration. However, the prognostic value of this parameter should be confirmed in a larger cohort.

Abnormal amplitude and kinetics of digital postocclusive reactive hyperemia in systemic sclerosis

OBJECTIVES Postocclusive reactive hyperemia is mediated by two major mediators: sensory nerves and endothelium-derived hyperpolarizing factors. We hypothesized that the skin microvascular response to 5 min ischemia would differ depending upon the hand location in patients with systemic sclerosis (SSc), primary Raynauds phenomenon (PRP) and healthy controls. METHODS Fifteen patients with SSc, 15 sex- and age-matched patients with PRP and healthy controls were enrolled. Their right hands were subjected to 5 min ischemia followed by a postocclusive hyperemia test, with local microcirculation monitoring by laser speckle contrast imaging on the dorsal face of the hand. RESULTS Postocclusive reactive hyperemia was abnormal in terms of peak and area under the curve (AUC) on all fingers except the thumb in patients with SSc and PRP compared with controls. In contrast, the kinetics of the response was longer only in SSc patients, with mean (SD) time to peak on the index, middle and ring finger were respectively 72 (58), 73 (51) and 67 (47) s for SSc; 40 (20), 40 (20) and 36 (19) s for PRP; and 34 (30), 34 (30) and 29 (24) s for controls (P=0.009 for interaction). CONCLUSIONS We observed decreased distal digital microvascular perfusion following 5 min of ischemia in patients presenting with PRP or SSc, while the kinetics was prolonged only in SSc. A dynamic assessment of digital skin blood flow using laser speckle contrast imaging following 5 min ischemia could be used as a tool to assess microvascular abnormalities in patients with Raynauds phenomenon secondary to SSc.

Reproducibility of the scleroderma pattern assessed by wide-field capillaroscopy in subjects suffering from Raynaud’s phenomenon

Objectives The aim of this work was to study inter- and intra-observer agreement for the diagnosis of scleroderma pattern by wide-field capillaroscopy. Methods Images were taken from 50 patients known to have SSc and 50 controls consulting for RP who did not have SSc. These images were rated simultaneously by 11 experienced vascular medicine physicians as scleroderma pattern or not. Two weeks later, 7 of the 11 observers again rated the same images. Results Inter-observer agreement was almost perfect between the 11 observers (κ 0.86 ± 0.01), and the proportion of concordant observations was 79% (70-87). When each observer was compared with the reference, agreement was also almost perfect: κ coefficient 0.92 ± 0.03 and proportion of concordant observations 79% (70-87). Intra-observer agreement was also almost perfect: median κ coefficient 0.94 (0.78-0.96) and median proportion of concordant observations 97% (89-98). Conclusion Excellent inter- and intra-observer agreement was obtained in experienced vascular physicians for the diagnosis of capillaroscopic landscape by wide-field nailfold capillary microscopy.

Ischémie subaiguë d'un membre inférieur et toxicité artérielle périphérique de la cocaïne chez une patiente présentant une artériopathie juvénile

Resume Une patiente de 35 ans etait hospitalisee pour ischemie subaigue de la jambe gauche compliquant une claudication de survenue recente. Il existait egalement une pâleur et une froideur des mains avec abolition des pouls radiaux. Les facteurs de risque vasculaires etaient representes par un tabagisme actif. Le bilan morphologique mettait en evidence un thrombus arteriel poplite gauche associe a des axes jambiers greles et aux membres superieurs une stenose de l’artere radiale gauche et une thrombose distale de l’artere radiale droite. Le bilan a la recherche d’une cause embolique, metabolique ou d’une thrombophilie s’averait negatif. La reprise de l’interrogatoire decelait la consommation de cannabis et la consommation recente de cocaine par prise nasale. L’evolution etait favorable sous heparinotherapie malgre la persistance plusieurs mois apres d’une ischemie d’effort des membres superieurs et d’un phenomene de Raynaud severe. Cette observation attire l’attention sur la toxicite arterielle combinee de drogues souvent consommees en association par le toxicomane. L’association tabac-cannabis est frequemment retrouvee dans les arteriopathies juveniles de type Buerger et la cocaine peut donner des lesions thrombotiques arterielles peripheriques par embole ou thrombose in situ. L’interrogatoire d’un patient porteur d’une maladie arterielle de type Buerger doit s’efforcer de rechercher la consommation d’autres toxiques associes au tabac. (J Mal Vasc 2006 ; 31 : 76-78).

Thromboses aortiques « isolées » : analyse rétrospective de 10 observations

Resume Introduction Les thromboses aortiques sont le plus souvent liees a la presence de lesions atheromateuses au sein de la paroi aortique chez des patients avec des facteurs de risques cardio-vasculaires. De rares cas surviennent sur artere saine et sont alors consideres comme « isoles ». Methodologie Nous presentons une analyse retrospective de dix cas de thromboses aortiques isolees observees entre 1995 et 2004 au CHU de Grenoble. Nous avons analyse l’âge de survenue de la thrombose, le sexe des patients, les facteurs de risque cardio-vasculaire, le mode de revelation de la thrombose aortique, la localisation anatomique du thrombus et les elements du bilan etiologique effectue. Etaient exclus tous les patients avec des lesions atheromateuses de l’aorte. Resultats Le mode de revelation clinique de la thrombose etait une ischemie aigue de membre dans 8 cas sur 10. Le diagnostic etait confirme dans tous les cas par un scanner thoraco-abdominal injecte, excepte un cas ou l’echo-Doppler arteriel a permis le diagnostic initial. Dans 7 cas, la recherche d’une thombophilie pouvait etre consideree comme exhaustive, dans 8 cas avec la recherche d’un syndrome des anticorps anti-phospholipides. Deux diagnostics etiologiques ont pu etre poses : le premier cas revelait lors de la thrombose aortique une neoplasie de type adenocarcinome sans primitif retrouve, et le deuxieme etait une thrombocytemie essentielle diagnostiquee un an apres la thrombose. Huit cas sur 10 sont restes « isoles », avec un suivi moyen de 2,5 ans. Discussion On denombre dans la litterature moins d’une centaine d’observations de thrombus aortiques. Les cas survenant sur artere saine sont difficiles a denombrer et le terme de thrombus « isole » est peut-etre employe par defaut. L’hypothese d’une lesion atheromateuse focale isolee induisant un thrombus, ou des pathologies inflammatoires diagnostiquees sur l’examen anatomopathologique du thrombus l’illustrent. Les explorations morphologiques et biologiques doivent etre exhaustives, meme si elles ne suffisent pas dans la plupart des cas a poser un diagnostic. La therapeutique fait appel aux anticoagulants mais n’est pas codifiee. Le suivi clinique nous apparait comme capital devant la possible revelation de pathologies posterieurement a la survenue de la thrombose, et afin d’affiner la conduite a tenir notamment en ce qui concerne les anti-coagulants au long cours. (J Mal Vasc 2005 ; 30 : 280-90)

Thromboses veineuses à répétition et syndrome myéloprolifératif : positivité secondaire d’une mutation JAK2 cinq ans après l’événement initial

JAK 2 mutation is the molecular event responsible for 95% of polycythemia cases and 50% of thrombocythemia vera and myelofibrosis cases. It can be used as a tool for the diagnosis of myeloproliferative disorders. We report a case illustrating the fact that a negative result does not definitively eliminate the diagnosis. A 40-year old woman, with a medical history of familial deep vein thrombosis, developed thrombosis of the inferior vena cava with extension to the suprahepatic veins and pulmonary embolism. No constitutional or acquired thrombophilia was diagnosed; search for JAK 2 mutation was negative. The patient was treated with fluindione. Five years later, she relapsed with popliteo-femoral and vena cava deep vein thrombosis. The etiological work-up included a PET scan which revealed diffuse uptake in bones and suspected neoplasic bone marrow invasion. Progenitor cell cultures were positive and JAK 2 mutation was confirmed. The bone marrow aspirate had the cytologic appearance of a myeloproliferative disorder. This case illustrates the fact that JAK 2 mutation can be identified several years after onset of a latent myeloproliferative disorder. Cases with a high clinical likelihood should lead to renewed search for this mutation. Secondary discovery of this mutation can be explained by a higher proportion of mutation expressing clones.