Clinical presentation, course, and prognosis of patients with mixed connective tissue disease: A multicenter retrospective cohort.

OBJECTIVES: The objective of this study is to better characterize the features and outcomes of a large population of patients with mixed connective tissue disease (MCTD). METHODS: We performed an observational retrospective multicenter cohort study in France. Patients who fulfilled at least one diagnostic criterion set for MCTD and none of the criteria for other differentiated CTD (dCTD) were included. RESULTS: Three hundred and thirty patients (88% females, median [interquartile range] age of 35 years [26-45]) were included. The diagnostic criteria of Sharp or Kasukawa were met by 97.3% and 93.3% of patients, respectively. None met other classification criteria without fulfilling Sharp or Kasukawa criteria. After a median follow-up of 8 (3-14) years, 149 (45.2%) patients achieved remission, 92 (27.9%) had interstitial lung disease, 25 (7.6%) had pulmonary hypertension, and 18 (5.6%) died. Eighty-five (25.8%) patients progressed to a dCTD, mainly systemic sclerosis (15.8%) or systemic lupus erythematosus (10.6%). Median duration between diagnosis and progression to a dCTD was 5 (2-11) years. The presence at MCTD diagnosis of an abnormal pattern on nailfold capillaroscopy (odds ratio [OR] = 2.44, 95% confidence interval [95%CI] [1.11-5.58]) and parotid swelling (OR = 3.86, 95%CI [1.31-11.4]) were statistically associated with progression to a dCTD. Patients who did not progress to a dCTD were more likely to achieve remission at the last follow-up (51.8% vs. 25.9%). CONCLUSIONS: This study shows that MCTD is a distinct entity that can be classified using either Kasukawa or Sharp criteria, and that only 25.8% of patients progress to a dCTD during follow-up.

Potential efficacy of T and B lymphocyte-targeted therapies on articular involvement of patients with rheumatoid arthritis and systemic sclerosis overlap syndrome. Results from a 2-centre series of 22 cases.

OBJECTIVES: To analyse in routine practice the efficacy of targeted therapies on joint involvement of patients with rheumatoid arthritis/systemic sclerosis (RA/SSc) overlap syndrome. METHODS: This was a retrospective analysis of medical records of two academic centres over a 10-year period. Joint response to targeted therapies was measured according to EULAR criteria based on Disease Activity Score (DAS)-28. In addition, changes in CRP level and glucocorticoid consumption were recorded. RESULTS: Nineteen patients were included. Methotrexate (n=11) and hydroxychloroquine (n=4) were the most used first-line treatments. Targeted therapies were frequently used (n=14). Tocilizumab was the most selected therapy (n=8), then rituximab (n=5), abatacept and anti-tumour necrosis factor (n=4). Twenty-one treatment sequences were assessed, including 18 with EULAR response criteria. Responses were "good" or "moderate" in 100% (4/4) of patients treated with abatacept, 80% (4/5) with rituximab, 40% (2/5) with tocilizumab, and 25% (1/4) with anti-TNF. T and B lymphocyte-targeted therapies (abatacept, rituximab) resulted more frequently in a "good" or "moderate" response compared to cytokine inhibitors (tocilizumab, etanercept, infliximab) with a significant decrease in DAS-28 at 6 months (-1.75; p=0.016) and a trend to a lower consumption of glucocorticoids. CCONCLUSIONS: In patients with RA/SSc overlap syndrome refractory to conventional synthetic-DMARDs, T and B lymphocyte-targeted therapies seem to be a promising therapeutic option to control joint activity.

Determination of four homogeneous subgroups of patients with antiphospholipid syndrome: a cluster analysis based on 509 cases.

OBJECTIVE: APS is a heterogeneous disease with different phenotypes. Using an unsupervised hierarchical cluster analysis, we aimed to determine distinct homogeneous phenotypes among APS patients. METHODS: We performed an observational, retrospective study of APS patients enrolled in the French multicentre 'APS and SLE' registry who met the Sydney classification criteria. The clustering process involved an unsupervised multiple correspondence analysis followed by a hierarchical ascendant clustering analysis; it used 27 variables selected to cover a broad range of APS clinical and laboratory manifestations. RESULTS: These analyses included 509 patients, mainly women (77.8%). Mean (s.d.) age at APS diagnosis was 36.2 (14.6) years, and mean follow-up since diagnosis 10.3 (8.5) years. This hierarchical classification cluster analysis yielded four homogeneous groups of patients: cluster 1, mostly with venous thromboembolism without any associated autoimmune disease; cluster 2, older, lowest proportion of women, history of arterial events, and/or with migraines, arterial hypertension, diabetes mellitus, or dyslipidaemia; cluster 3, younger, highest proportion of women, associated SLE or other autoimmune diseases, and a history of venous thromboembolism or pregnancy morbidity; and cluster 4, mainly with a history of catastrophic antiphospholipid syndrome, aPL-associated nephropathy, and pregnancy morbidity, with frequent triple positivity and more deaths (16.7%). CONCLUSIONS: Our study applied an unsupervised clustering method to distinguish four homogeneous APS patient subgroups that were predominantly venous; arterial; associated with SLE or another autoimmune disease; and arterial microthrombotic. Heterogeneous pathophysiological mechanisms may explain these findings.

In-depth characterization of pulmonary arterial hypertension in mixed connective tissue disease: a French national multicentre study.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a leading cause of death in MCTD. We aimed to describe PAH in well-characterized MCTD patients. METHODS: MCTD patients enrolled in the French Pulmonary Hypertension Registry with a PAH diagnosis confirmed by right heart catheterization were included in the study and compared with matched controls: MCTD patients without PAH, SLE patients with PAH and SSc patients with PAH. Survival rates were estimated by the Kaplan-Meier method and risk factors for PAH in MCTD patients and risk factors for mortality in MCTD-PAH were sought using multivariate analyses. RESULTS: Thirty-six patients with MCTD-PAH were included in the study. Comparison with MCTD patients without PAH and multivariate analysis revealed that pericarditis, polyarthritis, thrombocytopenia, interstitial lung disease (ILD) and anti-Sm antibodies were independent predictive factors of PAH/PH in MCTD. Estimated survival rates at 1, 5 and 10 years following PAH diagnosis were 83%, 67% and 56%, respectively. MCTD-PAH presentation and survival did not differ from SLE-PAH and SSc-PAH. Multivariate analysis revealed that tobacco exposure was an independent factor predictive of mortality in MCTD-PAH. CONCLUSION: PAH is a rare and severe complication of MCTD associated with a 56% 10-year survival. We identified ILD, pericarditis, thrombocytopenia and anti-Sm antibodies as risk factors for PAH in MCTD and tobacco exposure as a predictor of mortality in MCTD-PAH.

The IgG-degrading enzyme, Imlifidase, restores the therapeutic activity of FVIII in inhibitor-positive hemophilia A mice.

Neutralizing anti-factor VIII (FVIII) antibodies, known as FVIII inhibitors, represent a major drawback of replacement therapy in persons with congenital hemophilia A (PwHA), rendering further infusions of FVIII ineffective. FVIII inhibitors can also appear in non-hemophilic individuals causing acquired hemophilia A (AHA). The use of non-FVIII bypassing agents in cases of bleeds or surgery in inhibitor-positive patients is complicated by the lack of reliable biological monitoring and increased thrombotic risk. Imlifidase (IdeS) is an endopeptidase that degrades human immunoglobulin G (IgG); it was recently approved for hyperimmune patients undergoing renal transplants. Here we investigated the ability of IdeS to eliminate FVIII inhibitors in vitro and in a model of inhibitor-positive HA mice. IdeS cleaved anti-FVIII plasma IgG from PwHA and AHA patients, and hydrolyzed recombinant human anti-FVIII IgG independently from their subclass or specificity for the A2, A3, C1 or C2 domains of FVIII. In HA mice passively immunized with recombinant human anti-FVIII IgG, IdeS restored the hemostatic efficacy of FVIII, as evidenced by the correction of the bleeding tendency. Our results provide the proof of concept for the transient removal of FVIII inhibitors by IdeS, thereby opening a therapeutic window for efficient FVIII replacement therapy in inhibitor-positive patients.

Adipose tissue-derived stromal vascular fraction for treating hands of patients with systemic sclerosis: a multicentre randomized trial Autologous AD-SVF versus placebo in systemic sclerosis.

OBJECTIVE: To assess the superiority of adipose tissue-derived stromal vascular fraction (AD-SVF) injection into the fingers vs placebo in reducing hand disability in systemic sclerosis (SSc) patients. METHODS: We performed a double-blind, multicentre, phase II trial from October 2015 to January 2018 in France. SSc patients with a Cochin Hand Function Scale (CHFS) ≥20/90 were randomized 1:1 to receive injection of AD-SVF or placebo. AD-SVF was obtained using the automated processing Celution 800/CRS system. The placebo was lactated Ringer's solution. The primary efficacy end point was the change of the CHFS score from baseline to 3 months. Secondary efficacy endpoints included the CHFS score at 6 months, hand function, vasculopathy, hand pain, skin fibrosis, sensitivity of the finger pulps, Scleroderma Health Assessment Questionnaire, patients and physician satisfaction, and safety. RESULTS: Forty patients were randomized. The AD-SVF and placebo groups were comparable for age, sex ratio, disease duration, skin fibrosis of the hands and main cause of hand disability. After 3 months' follow-up, hand function significantly improved in both groups with no between-group difference of CHFS (mean change of -9.2 [12.2] in the AD-SVF group vs -7.6 [13.2] in the placebo group). At 6 months, hand function improved in both groups. CONCLUSION: This study showed an improvement of hand function in both groups over time, with no superiority of the AD-SVF. Considering the limits of this trial, studies on a larger population of patients with homogeneous phenotype and hand handicap should be encouraged to accurately assess the benefit of AD-SVF therapy. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02558543. Registered on September 24, 2015.

Potential Benefit of Rituximab in Rhupus Patients From a Single-Center: A Series of 16 Cases.

BACKGROUND: Rhupus syndrome is better characterized, but uncertainties remain, and therapeutic management must be defined. The objective was to analyze therapeutic procedures with a focus on biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: This 10-year medical records review was based on diagnosis codes (rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE]) and biological data (anti-CCP testing, anti-dsDNA, and anti-RNP antibodies). Patients fulfilling 2010 ACR/EULAR and 2012 SLICC and/or 2019 ACR/EULAR classification criteria for RA and SLE, respectively, were included. RESULTS: Sixteen patients were identified. Rheumatoid arthritis most often preceded rhupus, with predominant articular pattern; 11 of them had erosive arthropathy. Skin involvement was the most frequent associated manifestation (n = 12). Serious events were reported, including active glomerulonephritis (n = 3), ischemic stroke (n = 1), and myocardial infarction (n = 1). Immunological profiles showed positivity for antinuclear (n = 16), anti-dsDNA (n = 9), and anti-CCP (n = 9). Ten patients required bDMARDs. All types of RA-approved bDMARDs were used. Abatacept was considered effective in 3 of the 4 patients, with 1 primary failure, 1 secondary escape, and 2 therapeutic maintenances, whereas primary or secondary failure was observed under tocilizimub and TNF-blocking agents. Rituximab was the most prescribed (n = 9) and the most effective with a sustained response in 6 patients. CONCLUSIONS: In rhupus refractory to conventional treatment, T or B lymphocytes targeted therapies, and particularly rituximab, seem to be a relevant therapeutic option unlike anticytokine biologics.

Cardiac involvement in adult-onset Still's disease: Manifestations, treatments and outcomes in a retrospective study of 28 patients.

OBJECTIVE: Adult-onset Still's disease (AOSD) is a rare inflammatory disease that may be life-threatening if complicated by cardiac problems. We performed a retrospective multicenter study to describe the manifestations, treatments and outcomes of cardiac involvement in AOSD. METHODS: We reviewed the medical databases of eight centers. All AOSD patients identified as fulfilling Yamagushi's or Fautrel's criteria were included in the study. Cardiac involvement, clinical manifestations, laboratory features, the course of the disease and treatments were evaluated. RESULTS: We included 96 AOSD patients in this study: 28 (29%) had documented cardiac involvement (AOSD + C group) and 68 (71%) had no cardiac involvement (control group). Cardiac complications were observed at diagnosis in 89% of cases. It were pericarditis (n = 17), tamponade (n = 5), myocarditis (n = 5) and non-infectious endocarditis (n = 1). Levels of leukocytes, neutrophils and C-reactive protein were significantly higher (p = 0.02, p = 0.02 and p = 0.002, respectively in the AOSD + C group than in the control group. Admission to intensive care, and the use of biotherapy were more frequent during follow-up in the AOSD + C group than the control group (p = 0.0001 and p = 0.03 respectively). Cardiac involvement was associated with refractory form in multivariate analyzed (p = 0.01). Corticosteroids were effective with or without methotrexate in 71% of patients but not in severe involvement as myocarditis or tamponade. CONCLUSION: Cardiac complications are frequent, inaugural, can be life-threatening and predictive of a refractory course in patients with AOSD. Systematic cardiac screening should be proposed at diagnosis and biotherapy early use should be considered especially in myocarditis.

TRIM33 gene somatic mutations identified by next generation sequencing in neoplasms of patients with anti-TIF1γ positive cancer-associated dermatomyositis.

OBJECTIVE: To deep sequence the TRIM33 gene in tumours from patients with cancer-associated anti-TIF1γ autoantibody-positive dermatomyositis (DM) as TRIM33 somatic mutations in tumours may trigger this auto-immune disease. METHODS: Next generation sequencing of tumour DNA samples from patients with cancer-associated anti-TIF1γ autoantibody-positive DM. Fourteen tumours from 13 anti-TIF1γ autoantibody-positive DM individuals were sequenced along with two control tumours from non-DM individuals. RESULTS: Fourteen probable somatic variants from four tumours were identified in the TRIM33 gene. CONCLUSION: These results are in accordance with the previous report of Pinal-Fernandez et al. and support the hypothesis of a role of TRIM33 gene mutations in the pathophysiology of anti-TIF1γ autoantibody-positive DM.

Comparison of conventional immunosuppressive drugs versus anti-TNF-α agents in non-infectious non-anterior uveitis.

OBJECTIVE: To compare the efficacy and safety of Disease-modifying antirheumatic drugs (DMARDs) and anti-TNF-α agents in patients with non-infectious non-anterior uveitis. METHODS: Single center retrospective study including adult patients with non-infectious intermediate, posterior or pan-uveitis. Outcomes were compared between patients treated with DMARDs or anti-TNF-α agents. The primary outcome was treatment failure or occurrence of serious adverse events. Treatment failure was determined by ophthalmologic criteria. RESULTS: Seventy-three patients were included, mostly female (52%). Among them, 39 were treated with DMARDs and 34 with anti-TNF-α agents. The main uveitis causes were idiopathic (30%), birdshot chorio-retinopathy (25%), sarcoidosis (16%) and Behçet's disease (14%). The primary outcome was observed in 56% of patients treated with anti-TNF-α agents versus 59% of patients treated with DMARDs (p = 0.82). Median time to observe the primary outcome was 16 months (anti-TNF-α group) versus 21 months (p = 0.52). There was no significant difference between the two groups in terms of treatment failure, corticosteroid sparing effect, visual acuity improvement or adverse events. Earlier control of ocular inflammation was achieved with anti-TNF-α agents than with DMARDs (p = 0.006). In relapsing patients, anti-TNF-α agents allowed better corticosteroid sparing (p = 0.06). CONCLUSION: DMARDs could still be used as first-line therapy for non-infectious non-anterior uveitis after corticosteroid therapy. However, anti-TNF-α agents could be proposed as an alternative in cases of severe inflammation or initial high level of steroid dependency.

Workload, well-being and career satisfaction among French internal medicine physicians and residents in 2018.

OBJECTIVES: This work aimed to study the prevalence and risk factors associated with well-being and career satisfaction among French internal medicine physicians and residents. METHODS: A total of 1689 French internal medicine physicians or trainees were surveyed to evaluate their workload, well-being and career satisfaction during February 2018. RESULTS: The response rate was 620/1689 (37%). The mean age of the participants was 37 years (±12); 49% of the participants were female, 27% worked in the Paris area, 74% worked in a university hospital and 49% were residents. Sixty-six per cent of the responders were satisfied with their work, and 66% would choose the internal medicine specialty again. However, 71% of the responders worked more than 50 hours a week, 21% worked more than 60 hours a week and 70% believed that they did not have enough time for personal/family activities. Twenty-five per cent of the responders had at least one sign of burnout (19% of the physicians in practice and 32% of the residents). Compared with the graduate physicians in practice, the residents worked more hours a week, had more activities at night, spent more time on administrative tasks, had a worse global appreciation of their work and felt that their work was less meaningful. In multivariate analysis, the factors associated with global satisfaction at work were autonomy and meaningful work. CONCLUSIONS: French internal medicine physicians have a high rate of career satisfaction. However, residents have a higher workload, less time for personal/family activities and feel that their work is less meaningful.

Nail involvement in systemic sclerosis.

BACKGROUND: Nail involvement has rarely been recognized in systemic sclerosis (SSc). Indeed, only a few small series have assessed nail changes in SSc, most of which are case reports. OBJECTIVE: The aims of the current case-control study were to: (1) determine the prevalence of fingernail changes in SSc; and (2) evaluate the correlation between fingernail changes and other features of SSc. METHODS: In all, 129 patients with SSc and 80 healthy control subjects underwent routine fingernail examination. RESULTS: The prevalence of fingernail changes was 80.6% in SSc. Patients with SSc more frequently exhibited: trachyonychia (P = .006), scleronychia (P < .0001), thickened nails (P < .0001), brachyonychia (P = .0004), parrot beaking (P < .0001), pterygium inversum unguis (P < .0001), splinter hemorrhages (P < .0001), and cuticle abnormalities (P < .0001) than healthy control subjects. The presence of fingernail changes was associated with digital ulcers (P < .0001), calcinosis cutis (P = .004), and higher values of mean nailfold videocapillaroscopy score (P = .0009). LIMITATIONS: The cohort originated from a single center. CONCLUSION: This study underlines that fingernail changes are correlated with more severe forms of SSc characterized by digital microangiopathy, including digital ulcers and calcinosis cutis. Nail changes should be systematically checked in all patients with SSc, and may be included in the American College of Rheumatology/European League Against Rheumatism classification criteria for SSc.

Angioedema Triggered by Medication Blocking the Renin/Angiotensin System: Retrospective Study Using the French National Pharmacovigilance Database.

INTRODUCTION: Bradykinin-mediated angioedema (AE) is a rare side effect of some medications, including angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). In France, side-effects to treatments are reported to the national pharmacovigilance database. METHODS: The national MedDRA database was searched using the term "angioedema". Patients were included if they met the clinical criteria corresponding to bradykinin-mediated AE, if their C1-inhibitor levels were normal, and if they were treated with an ACEi or an ARB. RESULTS: 7998 cases of AE were reported between 1994 and 2013. Among these, 112 met the criteria for bradykinin-mediated AE with normal C1-inhibitor levels. On the 112 drug-AE, patients were treated with an ARB in 21% of cases (24 patients), or an ACEi in 77% of cases (88 patients), in combination with another treatment in 17 cases (mTORi for 3 patients, iDPP-4 for 1 patient, hormonal treatment for 7 patients). ENT involvement was reported in 90% of cases (tongue: 48.2%, larynx: 23.2%). The median duration of treatment before the first attack was 720 days, and the mean duration of attacks was 36.6 h. Forty-one percent (19/46) of patients relapsed after discontinuing treatment. CONCLUSION: Angioedema triggered by medication blocking the renin/angiotensin system is rare but potentially severe, with a high risk of recurrence despite cessation of the causative drug.

Association of occupational exposure with features of systemic sclerosis.

BACKGROUND: Occupational exposure is reported as playing a substantial causative role in systemic sclerosis (SSc). OBJECTIVE: We sought to compare the characteristics of SSc in patients with and without occupational exposure to crystalline silica/solvents. METHODS: In all, 142 patients with SSc were enrolled in this prospective study. An expert committee performed blind evaluation of occupational exposure to crystalline silica/solvents. RESULTS: Patients exposed to crystalline silica more often exhibited: diffuse cutaneous SSc (P = .02), digital ulcers (P = .05), interstitial lung disease (P = .0004), myocardial dysfunction (P = .006), and cancer (P = .06). Patients exposed to solvents more frequently developed: diffuse cutaneous SSc (P = .001), digital ulcers (P = .01), interstitial lung disease (P = .02), myocardial dysfunction (P = .04), and cancer (P = .003); in addition, these patients were more frequently anti-Scl 70 positive and anticentromere negative. Under multivariate analysis, significant factors for SSc associated with exposure to silica/solvents were: male gender (odds ratio 19.31, 95% confidence interval 15.34-69.86), cancer (odds ratio 5.97, 95% confidence interval 1.55-23.01), and digital ulcers (odds ratio 2.42, 95% confidence interval 1.05-5.56). LIMITATIONS: The cohort originated from a single geographic region. CONCLUSION: Occupational exposure to crystalline silica/solvents is correlated with more severe forms of SSc characterized by: diffuse cutaneous involvement, interstitial lung disease, general microangiopathy (digital ulcers and myocardial dysfunction), and association with cancer. Occupational exposure should be systematically checked in all patients with SSc, as exposed patients seem to develop more severe forms of SSc.

Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry.

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

Detection of microcirculatory impairment by transcutaneous oxymetry monitoring during hemodialysis: an observational study.

BACKGROUND: Little is known about the effects of intermittent hemodialysis on microcirculatory perfusion. The aim of this study is to assess the effects of hemodialysis on microvascular perfusion using transcutaneous oxymetry (TCPO2). METHODS: In this observational study, hourly TCPO2 measurements were performed during hemodialysis sessions. Ankle brachial index (ABI) was carried out to classify patients according their vascular condition. RESULTS: 50 patients (mean age 70 ± 8 years old) were enrolled. Mean TCPO2 decreased significantly on average 23.9% between start and finish of hemodialysis. Severe ischemia (TCPO2 < 30 mmHg) and critical ischemia (TCPO2 < 10 mmHg) occurred during dialysis in 47.1% and 15.5% respectively. Critical ischemia occurred only in limbs with ABI < 0.9 (8.3%) or > 1.3 (28%). Patients with critical ischemia experienced a significantly larger decline in mean blood pressure (32.4 ± 26.1 mmHg vs 12.7 ± 10.7 mmHg; P = 0.007) and a more pronounced ultrafiltration (45.55 ± 16.9 ml/kg vs 35.17 ± 18.2 ml/kg; P = 0.04) compared to patients without ischemia. Clinical outcomes (death or vascular procedures) were five times more frequent in patients who had developed critical ischemia (55.7% vs 10.1% P = 0.01). The elevated age of patients, the low basal value of TCPO2, and the occurrence of critical ischemia were more frequently associated with clinical outcome (P = 0.03, P = 0.048, P = 0.01 respectively). CONCLUSIONS: This study demonstrates that hemodialysis induces microcirculatory injury, dependent on blood pressure reduction, peripheral vascular state and ultrafiltration. The occurrence of critical ischemia is associated to pejorative patient outcome and therefore, TCPO2 seems to be useful to avoid potential distal tissue damage during hemodialysis.

Proteolytic antibodies activate factor IX in patients with acquired hemophilia.

Acquired hemophilia is a rare bleeding disorder characterized by the spontaneous occurrence of inhibitory antibodies against endogenous factor VIII (FVIII). IgG from some patients with acquired hemophilia hydrolyze FVIII. Because of the complex etiology of the disease, no clinical parameter, including the presence of FVIII-hydrolyzing IgG, has been associated with patient's survival or death. Here, we demonstrate the presence of anti-FIX antibodies in acquired hemophilia patients. IgG from some patients were found to hydrolyze FIX. In most cases, IgG-mediated FIX-hydrolysis resulted in FIX activation. IgG-mediated hydrolysis of FIX thus led to the significant generation of activated FIX in 25 of 65 patients. Based on the estimated kinetic parameters, patients' IgG activated up to 0.3nM FIX in 24 hours, an amount that restored thrombin generation in vitro provided the presence of more than or equal to 3% residual FVIII activity in plasma. This work identifies proteolytic IgG as novel molecules able to activate FIX under pathologic conditions. IgG-mediated FIX activation is a prevalent phenomenon among acquired hemophilia patients. The presence of FIX-activating IgG may partly compensate for the antibody-mediated inhibition of endogenous FVIII in restoring thrombin generation. This clinical trial was registered at www.clinicaltrials.gov as #NCT00213473.

Delayed gastric emptying determined using the 13C-octanoic acid breath test in patients with systemic sclerosis.

OBJECTIVE: To determine the prevalence of delayed gastric emptying using the 13C-octanoic acid breath test in unselected patients with systemic sclerosis (SSc), to evaluate whether findings of the 13C-octanoic acid breath test are associated with clinical digestive manifestations, gastric mucosal abnormalities detected by gastroscopy, motor activity dysfunction detected by antroduodenal manometry, and esophageal motor impairment and extradigestive manifestations of SSc, and to develop a risk prediction score of gastric emptying in SSc. METHODS: Consecutive patients with SSc (n=57) underwent the 13C-octanoic acid breath test. All of the patients with SSc completed a questionnaire on digestive symptoms, and a global symptom score (GSS) was calculated. RESULTS: The prevalence of delayed gastric emptying was 47.4% in patients with SSc. A marked correlation was observed between a GSS of digestive symptoms≥5 and the presence of delayed gastric emptying (P<0.00001). The sensitivity of a GSS≥5 for predicting delayed gastric emptying was as high as 0.93, while the specificity was 0.73. Moreover, a GSS≥5, mucosal gastric abnormalities, severe esophageal motor impairment, and interstitial lung disease were factors that were independently associated with the presence of delayed gastric emptying, and these variables were used to create a risk prediction score. The area under the receiver operating characteristic curve for the risk prediction score was 0.90; the sensitivity of this score for the prediction of delayed gastric emptying was 0.93, while the specificity was 0.77. CONCLUSION: The results indicate that delayed gastric emptying occurs often in patients with SSc. Interestingly, using risk models with routine clinical characteristics, a simple risk prediction score can be calculated, allowing prediction of the occurrence of delayed gastric emptying in patients with SSc.