Systemic sclerosis, silica exposure and cellular therapies: The sand in the gears?

Systemic sclerosis (SSc) is a chronic orphan autoimmune disease with the highest mortality rate among rheumatic diseases. SSc-related interstitial-lung disease (ILD) remains among the leading causes of SSc-related mortality with still few therapeutic effective strategies. In patients with crystallin silica exposure, SSc is recognized as an occupational disease according to the French social security system (Table 25A of the general insurance regimen). Lympho-ablative or myeloablative immunosuppression followed by autologous hematopoietic stem-cell transplantation (aHSCT) is the only therapeutic approach with demonstrated efficacy, improved survival with disease modifying effects on SSc-fibrotic manifestations (skin disease and ILD) and quality of life. A documented past and/or present occupational silica exposure, with extensive exposure and/or silica-related ILD and/or with persistent silica content in the broncho-alveolar lavage fluid are contra-indications to aHSCT in SSc patients, due to the risk of silica-related malignancy or of SSc relapse. This article aims to discuss alternative options in SSc patients with a history of silica exposure, and how innovative cellular therapies (mesenchymal stromal cells, CAR cells) could represent new therapeutic options for these patients.

Von Willebrand factor: a possible biomarker for disease activity in vasculitis.

OBJECTIVE: Inflammation markers, e.g. C- reactive protein (CRP) and sedimentation rate, can be normal despite active vasculitis. Von Willebrand factor (vWF) is secreted from endothelial cells in response to vascular damage. Some reports suggest increased vWF levels in vasculitis. This study aimed to evaluate vWF serum concentration in vasculitis patients as a possible biomarker of disease activity and to review the current literature. METHOD: Adult patients with systemic vasculitis were prospectively enrolled. Disease activity was recorded using the Birmingham Vasculitis Activity Score (BVAS) version 3. Blood group-adjusted vWF antigen serum level was evaluated at diagnosis and, when available, after treatment. RESULTS: Twenty-five vasculitis patients were compared to 15 healthy controls. The mean age of patients was 56 ± 17 years and 56% were women. Forty percent had anti-neutrophil cytoplasmic autoantibody-associated vasculitis, 20% giant cell arteritis, 16% polyarteritis nodosa, 8% Takayasu arteritis, and the rest had other vasculitides. The mean disease duration was 3.4 ± 4.8 years. Mean vWF was higher in patients with active vasculitis than in healthy controls (212 ± 81% vs 106 ± 26%, p < 0.001). vWF levels directly correlated with BVAS. In 13 patients with active vasculitis who reached remission or low disease activity after treatment, vWF level at follow-up decreased significantly. In three out of five patients who were treated with interleukin-6 inhibitors, vWF was elevated despite normal CRP levels, while vasculitis was clinically active. CONCLUSION: vWF antigen serum level is increased in active vasculitis and could potentially serve as a biomarker for active disease.

The role of regulatory T cells in familial Mediterranean fever (FMF).

The role of regulatory T cells (T-regs) in familial Mediterranean fever (FMF) was never evaluated. Preliminary studies that we have conducted suggested a rise in the number of regulatory T cells after FMF attacks reaching a maximal level at 7 days. The aim of this study was to evaluate the percentage and activity of regulatory T cells in FMF. Six patients with refractory FMF and six healthy controls were evaluated. The percentage of T-reg cells and forkhead box protein 3 (Foxp3) expression was evaluated and compared between four states: FMF in remission, FMF at the first day of an attack, FMF 7 days after the start of the attack, and healthy controls. Four females and two males were included. All patients had FMF with high severity score, 2.8 ± 0.4 (0-3). The mean age was 31.6 ± 6.2. The mean age at onset was 9.3 ± 9.3. The mean colchicine dose was 2.6 mg ± 0.4. The expression of Foxp3 7 days after the attacks was significantly higher than in FMF at the first day of the attack, FMF in remission, and healthy controls 10.08 ± 2.36 vs. 7.005 ± 0.3 vs. 5.3 ± 1.06 vs. 4.44 ± 1.8; p < 0.05 (Fig.1). The percentage of T-regs in peripheral blood was not statistically different between the four groups. Theexpression of Foxp3 by T-regs increases 7 days after attacks of FMF. Anti-inflammatory cytokines interleukin-10 and TGF-ß are known to activate T-regs and have been reported to increase in FMF attacks in line with the present findings. It is suggested that T-regs may have a role in terminating FMF attacks.

[Witches saints and other diseases].

Salem, was the site at which Massachusetts was established in 1632, however, it is more famous for the witch-hunt that took place there 60 years later by some riotous puritans. Several teenaged girls that were struck by delirious fits and seizures captured the center of the stage. The local physicians, who could not come up with a medical solution, explained the strange phenomenon as witchcraft. The new world's moral code was brought to trial along with 20 innocent men who were accused, convicted and executed for the crime of practicing witchcraft. In this article we will try to acquit these men by introducing historical, medical and circumstantial evidence that ergot and alkaloids substances, produced by a mold called Claviceps purpura, may have been responsible for an intoxication that could account for the events of Salem 1692. Furthermore, we will try to explain how this ergot intoxication, also referred to as Saint Anthony's fire, has had a crucial influence on modern history including the Black Death plague that struck Europe since the 14th century.

Nosocomial multi-drug resistant Acinetobacter baumannii bloodstream infection: risk factors and outcome with ampicillin-sulbactam treatment.

The emergence of multidrug-resistant (MDR) Acinetobacter baumannii poses a therapeutic problem. The aim of this study was to assess the risk factors for nosocomial MDR-A. baumannii bloodstream infection (BSI) and the efficacy of ampicillin-sulbactam (A/S) in its treatment. Of 94 nosocomial A. baumannii BSI during the year 2000, 54% involved MDR strains, 81% of which were genetically related. Various risk factors for MDR-A. baumannii were found, of which intensive-care unit admission and prior aminoglycoside therapy were independently associated with MDR-A. baumannii acquisition on multivariate analysis. Of MDR-A. baumannii BSI cases, 65% received A/S and 35% inadequate antibiotic therapy, whereas of 43 non-MDR cases, 86% were treated according to susceptibility and 14% inappropriately with antibiotics to which these organisms were resistant. Crude mortality was comparable in the adequately treated groups. Respective mortalities among patients treated adequately and inadequately were 41.4 and 91.7% (p<0.001). Among severely ill patients, A/S therapy significantly decreased the risk of death (P=0.02 OR=7.64). MDR-A. baumannii has become highly endemic in our institution. A/S appears to be one of the last effective and safe empirical resorts for treatment of MDR A. baumannii BSI.

Improved prognosis of patients presenting with clinical markers of spontaneous reperfusion during acute myocardial infarction.

OBJECTIVE: To describe the clinical features, management, and prognosis of patients presenting with clinical markers of spontaneous reperfusion (SR) during acute myocardial infarction (AMI). DESIGN: Cohort study. SETTING: National registry of 26 coronary care units. PATIENTS: 2382 consecutive patients with AMI. MAIN OUTCOME MEASURES: Patient characteristics, management, and mortality. RESULTS: The incidence of SR was 4% of patients (n = 98) compared with thrombolytic treatment (n = 1163, 49%), primary angioplasty (n = 102, 4%), and non-reperfusion (n = 1019, 43%). SR patients were more likely to develop less or no myocardial damage as indicated by a higher percentage of non-Q wave AMI (58% v 32%, 47%, and 44%, respectively, p < 0.0001), aborted AMI (25% v 9%, 8%, and 12%, p < 0.001), and lower peak creatine kinase (503 v 1384, 1519, and 751 IU, p < 0.0001). SR patients, however, were more likely to develop recurrent ischaemic events (35% v 17%, 12%, and 16%, respectively; p < 0.001) and subsequently were more likely to be referred to coronary angiography (67%), angioplasty (41%), or bypass surgery (16%, p < 0.001). Mortality at 30 days (1% v 8%, 7%, and 13%, respectively, p < 0.0001) and one year (6% v 11%, 12%, and 19%, p < 0.0001) was significantly lower for SR patients than for the other subgroups. By multivariate analysis, SR remained a strong determinant of 30 day survival (odds ratio (OR) 0.16, 95% confidence interval (CI) 0.01 to 0.74). At one year, the association between SR and survival decreased (OR 0.49, 95% CI 0.18 to 1.13). CONCLUSIONS: Clinical markers of SR are associated with greater myocardial salvage and favourable prognosis. The vulnerability of SR patients to recurrent ischaemic events suggests that they need close surveillance and may benefit from early intervention.