I. Marie

Esophageal involvement and pulmonary manifestations in systemic sclerosis.

OBJECTIVE To assess whether esophageal manometric motor disturbances are associated with abnormalities consistent with interstitial lung disease (ILD) on both pulmonary function tests (PFT) and high resolution computerized tomography (HRCT) scans in patients with systemic sclerosis (SSc), during initial evaluation and at 2 years followup. METHODS Esophageal manometry, PFT, and HRCT scans were performed in 43 consecutive SSc patients. PFT and HRCT scan parameters were compared between patients with severe esophageal motor dysfunction (i.e., aperistalsis and decreased low esophageal sphincter pressure), patients with moderate esophageal motor dysfunction (hypoperistalsis), and patients without esophageal motor dysfunction on manometry. RESULTS During initial evaluation of SSc, patients with severe esophageal motor impairment, compared with those with moderate and without esophageal dysmotility, exhibited significantly decreased median values of diffusing capacity for carbon monoxide (DLco) (68% vs. 94% vs. 104%) and exhibited higher prevalence of evidence for ILD on HRCT scan (57% vs. 27% vs. 18%). At 2 years followup of SSc, patients with severe esophageal motor disturbances, compared with those without, had faster deterioration of DLco median values (-16% vs. +1%) and higher frequency of ILD on HRCT scan (70% vs. 25%). CONCLUSION Our series underscores a correlation between the degree of esophageal manometric motor disturbances and evidence for ILD on PFT and HRCT scan in SSc patients, suggesting that gastroesophageal reflux (GER) may be one of the contributing factors of ILD in SSc. Our findings further indicate that patients with severe esophageal impairment may require closer followup of lung parameters. In turn, it suggests that aggressive therapy of GER should be initiated in these SSc patients, as it may result in decreased deterioration of pulmonary function.

Transcriptional Regulation of β-Secretase by p25/cdk5 Leads to Enhanced Amyloidogenic Processing

Cyclin-dependent kinase 5 (cdk5) has been implicated in Alzheimers disease (AD) pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription (STAT1/3) was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis.

Review: Enhancement and Diversification of IFN Induction by IRF-7-Mediated Positive Feedback

Interferons (IFN) are potent components of the innate immune response to microbial infection. The genes for type I IFN (IFN-alpha and IFN-beta) are rapidly induced in response to viral infection through a mechanism that involves latent cellular transcription factors that are activated in response to innate recognition of viral components. IFN regulatory factor (IRF) proteins are key to this regulation, and their conversion from latent to active involves virus-induced serine phosphorylation. Differential utilization of distinct IRF proteins by different members of the type I IFN gene family produces a graded induction of gene expression, resulting in tight control of these cytokines through a positive feedback mechanism. Early response to virus causes secretion of a subset of IFN genes through the action of IRF-3 in conjunction with additional transcription factors, such as NF-kappaB and activator protein-1 (AP-1) (c-jun/ATF). This early IFN acts in an autocrine manner to stimulate production of IRF-7, a transcription factor capable of activating the many additional members of the IFN-alpha gene family. The dependence of IRF-7 on virus-induced phosphorylation for its activity insures that IFN production is limited to virus-infected cells. Characterization of the cellular components involved in viral detection and IRF activation will further delineate this vital mechanism of innate immune response.

Influence of age on characteristics of polymyositis and dermatomyositis in adults.

In a retrospective study of 79 consecutive patients, we evaluated characteristics of polymyositis (PM) and dermatomyositis (DM) and compared clinical presentation, biochemical findings, histologic changes, evolution, complications, and mortality rate of elderly patients (aged > or = 65 yr) and younger patients (aged < or = 64 yr) at the onset of PM/DM. We found a high prevalence of PM/DM in elderly patients: 23 patients (29%) were aged 65 years or over. We also found that esophageal involvement (34.8% versus 16.1%, respectively) and bacterial pneumonia related to both ventilatory insufficiency and esophageal impairment (21.7% versus 5.4%, respectively) were more common in elderly patients compared with younger patients, resulting in increased morbidity and mortality rates. Moreover, malignancy frequency was higher in elderly patients compared with younger patients (47.8% versus 9.1%, respectively, p = 0.0001), particularly patients with DM (10/11). Fifty percent of malignancies were colon malignancies in elderly patients. Erythrocyte sedimentation rate, C-reactive protein, fibrinogen, and ferritin levels were also higher in the elderly patient group compared with the younger group, and the presence of serum hypoprotidemia, hypoalbuminemia, and anemia was more frequent. Finally, PM/DM complete remission was less frequent (13.6% versus 41.1%) and the mortality rate (47.8% versus 7.3%) was higher in elderly patients than in younger patients. The main causes of death in elderly patients were bacterial pneumonia, due to ventilatory insufficiency and esophageal impairment, and malignancies. Our findings therefore indicate that PM/DM-related esophageal and lung involvement should be systematically searched for in elderly patients. Esophageal manometry and pulmonary function tests should become an integral part of initial evaluation in elderly patients for early detection of impairment. Moreover, as we observed a marked overrepresentation of colon cancer in elderly patients with DM, we suggest that the search for malignancies in elderly patients with DM should include lower gastrointestinal tract investigations.

Tendinous disorders attributed to statins: A study on ninety-six spontaneous reports in the period 1990–2005 and review of the literature

OBJECTIVE To date, statins have more often been considered a safe medication. However, with the wider use of statins, severe side effects have also been reported to occur in statin-treated patients, especially myositis and rhabdomyolysis. Currently, however, statin-associated tendon impairment has only been described anecdotally. The aim of this retrospective study was to evaluate tendon manifestations occurring in statin-treated patients. METHODS All reports in which a statin was listed spontaneously as a causative suspect medication of tendon complications in the network of the 31 French Pharmacovigilance Centers from 1990-2005 were included in this study. Data collection included patient characteristics and tendon adverse effects (time to onset of adverse effects, pattern, site of injury, and outcome). The percentage of the reports was further calculated for each statin. RESULTS Data were collected from 96 patients with a median age of 56 years; patients exhibited tendinitis (n = 63) and tendon rupture (n = 33). Tendinopathy more often occurred within the first year after statin initiation (59%). Tendon manifestations were related to atorvastatin (n = 35), simvastatin (n = 30), pravastatin (n = 21), fluvastatin (n = 5), and rosuvastatin (n = 5). Statin was reinitiated in 7 patients, resulting in recurrence of tendinopathy in all cases. CONCLUSION Our series suggests that statin-attributed tendinous complications are rare, considering the huge number of statin prescriptions. We suggest that prescribers should be aware of tendinous complications related to statins, particularly in risky situations, including physical exertion and association with medications known to increase the toxicity of statins.

Induction and function of type I and III interferon in response to viral infection

The type I and III interferon (IFN) families consist of cytokines rapidly induced during viral infection that confer antiviral protection on target cells and are critical components of innate immune responses and the transition to effective adaptive immunity. The regulation of their expression involves an intricate and stringently regulated signaling cascade, initiated by recognition most often of viral nucleic acid in cytoplasmic and endosomal compartments and involving a series of protein conformational rearrangements and interactions regulated by helicase action, ubiquitin modification, and protein aggregation, culminating in kinase activation and phosphorylation of critical transcription factors and their regulators. The many IFN subtypes induced by viruses confer amplification, diversification, and cell-type specificity to the host response to infection, providing fertile ground for development of antiviral therapeutics and vaccines.

Gastric involvement in systemic sclerosis: a prospective study

OBJECTIVES:This study aims to assess the prevalence of gastric electrical activity dysfunction with cutaneous electrogastrography (EGG), disturbances of gastric emptying function using radiopaque pellets, and gastric endoscopic abnormalities in patients with systemic sclerosis (SSc). We also investigate for an association between EGG and gastric-emptying data with clinical manifestations and esophageal motor disturbances.METHODS:Fasting and postprandial gastric electrical activity was studied in 22 consecutive patients with SSc (17 with and 5 without clinical gastric manifestations) and 22 age- and sex-matched healthy subjects. Gastric emptying of radiopaque pellets and gastroscopy were also performed in SSc patients.RESULTS:The prevalence of EGG disturbances was as high as 81.82% in SSc patients. SSc patients exhibited, compared with controls, higher median percentage of dominant frequency in bradygastria during the fasting period and lower median values for postprandial electrical power and postprandial to fasting ratio for electrical power. Gastric emptying of radiopaque pellets was delayed in 11 SSc patients, and gastroscopy demonstrated “watermelon stomach” in 3 SSc patients. No correlation was found between the severity of gastric impairment and clinical presentation, SSc duration and subsets, and esophageal manometric impairment.CONCLUSIONS:Our study underlines the high frequency of gastric dysfunction in SSc patients. It suggests the usefulness of EGG in SSc in noninvasively detecting disorders of gastric electrical activity at an early stage and symptomatic patients with gastroparesis (because there was a correlation between values of postprandial to fasting ratio for electrical power of < 1 on EGG and delayed gastric emptying). Gastric-emptying evaluation of radiopaque pellets may further be a helpful method to depict symptomatic SSc patients with gastroparesis. Finally, our series confirms that watermelon stomach diagnosis should be excluded in SSc patients presenting with gastrointestinal hemorrhage or with anemia related to iron deficiency.

Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-α–producing and partially matured phenotype

Plasmacytoid DCs (pDCs) are innate immune cells that are specialized to produce IFN-α and to activate adaptive immune responses. Although IFN-α inhibits HIV-1 replication in vitro, the production of IFN-α by HIV-activated pDCs in vivo may contribute more to HIV pathogenesis than to protection. We have now shown that HIV-stimulated human pDCs allow for persistent IFN-α production upon repeated stimulation, express low levels of maturation molecules, and stimulate weak T cell responses. Persistent IFN-α production by HIV-stimulated pDCs correlated with increased levels of IRF7 and was dependent upon the autocrine IFN-α/β receptor feedback loop. Because it has been shown that early endosomal trafficking of TLR9 agonists causes strong activation of the IFN-α pathway but weak activation of the NF-κB pathway, we sought to investigate whether early endosomal trafficking of HIV, a TLR7 agonist, leads to the IFN-α-producing phenotype we observed. We demonstrated that HIV preferentially traffics to the early endosome in human pDCs and therefore skews pDCs toward a partially matured, persistently IFN-α-secreting phenotype.

Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey

Data on the clinical spectrum and therapeutic management of noninfectious mixed cryoglobulinemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. We analyzed data from 242 patients with noninfectious mixed CryoVas included in the French multicenter CryoVas survey. Baseline manifestations were purpura (75%), peripheral neuropathy (52%), arthralgia or arthritis (44%), glomerulonephritis (35%), cutaneous ulcers (16%), and cutaneous necrosis (14%). A connective tissue disease was diagnosed in 30% and B-cell non-Hodgkin lymphoma in 22%, whereas the CryoVas was considered to be essential in 48%. With the use of Cox-marginal structural models, rituximab plus corticosteroids showed the greater therapeutic efficacy compared with corticosteroids alone and alkylating agents plus corticosteroids to achieve complete clinical, renal, and immunologic responses and a prednisone dosage < 10 mg/d at 6 months. However, this regimen was also associated with severe infections, particularly when high doses of corticosteroids were used, whereas death rates did not differ between the therapeutic regimens. The role of each of these strategies remains to be defined in well-designed randomized controlled trials.

Small intestinal bacterial overgrowth in systemic sclerosis

OBJECTIVES The aims of this study were to: (i) determine the prevalence of small intestinal bacterial overgrowth (SIBO) in unselected patients with SSc; (ii) assess both clinical presentation and outcome of SIBO; and (iii) make predictions about which SSc patients are at risk for SIBO. METHODS Fifty-one consecutive patients with SSc underwent glucose hydrogen and methane (H(2)/CH(4)) breath test. All SSc patients also completed a questionnaire for intestinal symptoms, and a global symptomatic score (GSS) was calculated. SSc patients with SIBO were given rotating courses of antibiotics (norfloxacin/metronidazole) for 3 months; glucose H(2)/CH(4) breath test was performed at 3-month follow-up. RESULTS The prevalence of SIBO was 43.1% in our SSc patients. After logistic regression, we identified the following risk factors for SIBO: presence of diarrhoea and constipation. Interestingly, we observed a marked correlation between values of GSS of digestive symptoms (> or =5) and the presence of SIBO (P = 10(-6)); indeed, both sensitivity and specificity of GSS > or =5 to predict SIBO were as high as 0.909 and 0.862, respectively. Finally, eradication of SIBO was obtained in 52.4% of the SSc patients with a significant improvement of intestinal symptoms. CONCLUSION Our study underscores that SIBO often occurs in SSc patients. We further suggest that GSS may be systematically performed in SSc patients; since we found a correlation between GSS of digestive symptoms > or =5 and SIBO, we suggest that glucose H(2)/CH(4) breath test may be performed in the subgroup of SSc patients exhibiting GSS > or =5.