Summary
Natural killer (NK) cells have been implicated in tumour surveillance and in the early control of several microbial infections. In autoimmune disease their involvement in these processes has ...been evaluated in animal models, with conflicting results. Both a disease‐controlling and a disease‐promoting role have been suggested. In human autoimmune disease only a few studies, mainly descriptive, have demonstrated qualitative and quantitative modification of NK cells. These changes were observed on blood‐ or tissue‐infiltrating NK cells. Taken together with our expanding knowledge of the genetical variability of NK cell receptors and NK cell physiology, these findings pave the way for the dissection of the role of NK cells in human autoimmune diseases. NK cells may be directly involved in these diseases through their potential autoreactivity or through their interaction with dendritic cells, macrophages or T lymphocytes, thereby inducing excessive inflammation or favouring the adaptive autoimmune response. Thus, NK cells may be implicated in the onset, the maintenance or the progression of autoimmune diseases. Some reports also suggest the involvement of NK cells in the treatment of human autoimmune disease by biotherapies. All these observations suggest that NK cells are involved in the complex processes of autoimmune diseases. Nevertheless, further careful analysis of NK cells at different steps of these diseases, in different tissues and through combined genetical and functional studies will contribute to a better understanding of their role in autoimmune diseases. This knowledge might allow the development of new therapeutic strategies based on NK cells for the treatment of some autoimmune diseases.
Although oesophageal motor disorders (OMDs) are frequent in systemic sclerosis (SSc), the frequency of associated endoscopic lesions is unknown. We aimed at assessing the presence of endoscopic ...lesions in SSc patients with OMD. The secondary objective was to identify the clinical and serological profile of such patients.
This retrospective study included SSc patients suffering from OMD diagnosed by oesophageal high-resolution manometry (OHRM) and with recent upper gastro-intestinal endoscopy (UGIE). Clinical data collected were age, gender, body mass index, SSc disease duration, tobacco, SSc cutaneous type, non-digestive SSc visceral disorders, oesophageal symptoms, serological profile (autoantibodies), proton pump inhibitor use, time between SSc diagnosis and UGIE.
53 selected patients from 210 SSc patients investigated by OHRM in our department were included. Among these patients, 25 (47.2%) had endoscopic lesions: 18 (34.6%) had oesophagitis and 7 (13.5%) had Barrett's oesophagus. The only two parameters significantly associated with endoscopic lesions were a shorter disease duration (6 vs. 11 years; p = .002) and a shorter delay between SSc diagnosis and UGIE (3 vs. 8.5 years; p = .002). No other clinical or biological parameters could help identify the patients at risk of endoscopic lesion.
In our study, only a shorter disease duration and a shorter delay between SSc diagnosis and UGIE were significantly associated with the presence of endoscopic lesions in patients with OMD, but no other parameters were identified. This study highlights the need to perform UGIE in SSc patients with OMD whatever their clinical symptoms.
In patients with systemic sclerosis (scleroderma, SSc), impaired hand function greatly contributes to disability and reduced quality of life, and is insufficiently relieved by currently available ...therapies. Adipose tissue-derived stromal vascular fraction (SVF) is increasingly recognised as an easily accessible source of regenerative cells with therapeutic potential in ischaemic or autoimmune diseases. We aimed to measure for the first time the safety, tolerability and potential efficacy of autologous SVF cells local injections in patients with SSc with hand disability.
We did an open-label, single arm, at one study site with 6-month follow-up among 12 female SSc patients with Cochin Hand Function Scale score >20/90. Autologous SVF was obtained from lipoaspirates, using an automated processing system, and subsequently injected into the subcutaneous tissue of each finger in contact with neurovascular pedicles. Primary outcome was the number and the severity of adverse events related to SVF-based therapy. Secondary endpoints were changes in hand disability and fibrosis, vascular manifestations, pain and quality of life from baseline to 2 and 6 months after cell therapy.
All enrolled patients had surgery, and there were no dropouts or patients lost to follow-up. No severe adverse events occurred during the procedure and follow-up. Four minor adverse events were reported and resolved spontaneously. A significant improvement in hand disability and pain, Raynaud's phenomenon, finger oedema and quality of life was observed.
This study outlines the safety of the autologous SVF cells injection in the hands of patients with SSc. Preliminary assessments at 6 months suggest potential efficacy needing confirmation in a randomised placebo-controlled trial on a larger population.
GFRS (Groupe Francophone de Recherche sur la Sclérodermie).
NCT01813279.
Cardiac involvement during systemic lupus erythematosus (SLE) may include the pericardium, myocardium, valvular tissue, and coronary arteries. The aim of this study was to describe the clinical, ...biological, and radiological presentation of lupus myocarditis (LM) as well as the treatment response and longterm outcomes.
We conducted a multicentric retrospective study of LM from January 2000 to May 2014.
Twenty-nine patients (3 men and 26 women) fulfilled the inclusion criteria (median age at the diagnosis of SLE: 30 yrs, range 16-57). Myocarditis was the first sign of SLE in 17/29 cases (58.6%). Troponin was elevated in 20/25 cases. Electrocardiogram results were abnormal in 25/28 cases. Echocardiography revealed low (≤ 45%) left ventricular ejection fraction (LVEF; 19/29, 66%) and pericardium effusion (20/29, 69%). Cardiac magnetic resonance imaging revealed delayed gadolinium enhancement in 9/13 patients (69%). Patients were treated with corticosteroids (n = 28), cyclophosphamide (CYC; n = 16), intravenous immunoglobulins (n = 8), and/or mycophenolate mofetil (n = 2). The median followup was 37 months. One month after the beginning of the treatment, 10/23 patients (43%) who had undergone echocardiography had an LVEF ≥ 55%. At the end of followup, 21/26 patients (81%) exhibited an LVEF ≥ 55%. Three patients died during followup, and 2 died from LM.
LM is a severe manifestation of SLE. It can be the first manifestation of the disease or it can occur during followup, in particular in untreated patients. However, the longterm prognosis is typically positive. Patients with less severe disease exhibited good LVEF recovery without CYC.
Objective. Scleroderma renal crisis (SRC) is a severe manifestation of SSc, whose prognosis remains severe, despite treatment with angiotensin-converting-enzyme inhibitor and dialysis. This study was ...undertaken to describe SRC characteristics, prognosis and outcome, and evaluate the responsibility of CSs in its occurrence.
Methods. Analysis concerned 91 SSc patients with SRC who were compared with 427 non-SRC-SSc patients taken as controls.
Results. Among the 91 SRC patients, 71 (78.0%) had high blood pressure, 53 (58.2%) hypertensive encephalopathy and 51 (56.0%) thrombotic microangiopathy; 64 (70.3%) had received CSs before or concomitantly with SRC vs 156 (36.5%) non-SRC-SSc patients (P < 0.001). Treated SRC patients also received more prednisone 29.3 (28.4) vs 3.6 (9.9) mg than controls (P < 0.001). SRC clinical outcomes were poor: 49 (53.8%) patients required dialysis, which was definitive for 38. Thirty-seven (40.7%) SRC patients died vs 10.8% of the controls (P < 0.001). Death was most frequent among dialysed patients who never recovered renal function (22 vs 2) and 13 never-dialysed SRC patients died.
Conclusions. Although SRC prognosis has improved markedly, SRC remains a severe manifestation of SSc, despite treatment with angiotensin-converting enzyme inhibitor and dialysis. CSs contributed significantly to SRC occurrence.
Epistaxis is the most frequent and disabling manifestation of hereditary hemorrhagic telangiectasia (HHT). The efficacy of intravenous bevacizumab (an anti-vascular endothelial growth factor ...monoclonal antibody) for epistaxis has been shown. However, the efficacy of intranasal bevacizumab has yet to be evaluated.
To evaluate the efficacy of 3 different doses of bevacizumab administered as a nasal spray in a repeated manner for the duration of nosebleeds in patients with HHT.
Randomized, multicenter, placebo-controlled, phase 2/3 clinical trial with dose selection at an intermediate analysis and prespecified stopping rules (nonbinding stopping for futility). Patients aged 18 years or older with a diagnosis of HHT were recruited from 5 French centers from April 2014 to January 2015 with a 6-month follow-up after the end of treatment. Participants had a history of self-reported nosebleeds with a monthly duration of more than 20 minutes in at least the 3 months prior to inclusion corroborated by epistaxis grids completed during the same preinclusion period.
Eighty consecutive HHT patients were randomized and treated in the phase 2 study, with 4 parallel groups in a 1:1:1:1 ratio. One group received placebo (n = 21); the other 3 received bevacizumab nasal spray. Each bevacizumab group received a different dose of the drug (25 mg n = 20, 50 mg n = 20, or 75 mg n = 19 per treatment) in 3 doses 14 days apart for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, and 225 mg in each treatment group.
Mean monthly epistaxis duration for 3 consecutive months immediately after the end of the treatment.
Of the 80 patients who were randomized (mean age, 60.47 SD, 10.61 years; 37 women 46.25%), 75 completed the study. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 59 patients receiving bevacizumab in comparison with the placebo group (P = .57) or between the bevacizumab groups. The mean monthly epistaxis duration was 259.2 minutes (95% CI, 82.1-436.3 minutes) in the 25-mg group, 244.0 minutes (95% CI, 81.8-406.2 minutes) in the 50-mg group, 215.0 minutes (95% CI, 102.8-327.2 minutes) in the 75-mg group, and 200.4 minutes (95% CI, 109.3-291.5 minutes) in the placebo group. Toxicity was low and no severe adverse events were reported. This study was terminated prior to phase 3 for treatment futility after interim analysis on the recommendations of an independent data monitoring committee.
In patients with HHT, a bevacizumab nasal spray treatment of 3 administrations at 14-day intervals with doses of 25 mg, 50 mg, or 75 mg per spray, compared with a placebo, did not reduce monthly epistaxis duration in the 3 consecutive months immediately after the end of treatment.
clinicaltrials.gov Identifier: NCT02106520.
Abstract Inflammatory myopathy is a major clinical manifestation of the antisynthetase syndrome. Patients with anti Jo-1 antibodies can also present with other clinical manifestations as arthritis, ...mechanic's hands and lung fibrosis. As in dermatomyositis, polymyositis and overlap myopathies proximal muscle of the limbs are preferentialy involved. Associated fascia edema on magnetic resonance imagery studies with histological proven fasciitis has been reported. However peripheral limb involvement, reported here in two patients, as the isolated initial manifestation is unusual.
Abstract
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.
Background: Recently, metagenomic studies have identified viable Pepper mild mottle virus (PMMoV), a plant virus, in the stool of healthy subjects. However, its source and role as pathogen have not ...been determined. Methods and Findings: 21 commercialized food products containing peppers, 357 stool samples from 304 adults and 208 stool samples from 137 children were tested for PMMoV using real-time PCR, sequencing, and electron microscopy. Anti-PMMoV IgM antibody testing was concurrently performed. A case-control study tested the association of biological and clinical symptoms with the presence of PMMoV in the stool. Twelve (57%) food products were positive for PMMoV RNA sequencing. Stool samples from twenty-two (7.2%) adults and one child (0.7%) were positive for PMMoV by real-time PCR. Positive cases were significantly more likely to have been sampled in Dermatology Units (p<10−6), to be seropositive for anti-PMMoV IgM antibodies (p=0.026) and to be patients who exhibited fever, abdominal pains, and pruritus (p=0.045, 0.038 and 0.046, respectively). Conclusions: Our study identified a local source of PMMoV and linked the presence of PMMoV RNA in stool with a specific immune response and clinical symptoms. Although clinical symptoms may be imputable to another cofactor, including spicy food, our data suggest the possibility of a direct or indirect pathogenic role of plant viruses in humans.
Objectives
We aimed to assess the clinical significance of Krebs von den Lungen-6 (KL-6) in the diagnosis and severity of interstitial lung disease (ILD) in a French cohort of patients with systemic ...sclerosis (SSc).
Methods
Serum KL-6 concentrations were measured with chemiluminescent enzyme immunoassay (CLEIA) in 75 SSc patients. Patients were divided into two groups according to the presence of interstitial lung disease (SSc-ILD versus SSc-without ILD) on chest High-Resolution Computed Tomography. Pulmonary function tests, main manifestations and severity of the lung disease (Medsger’s severity scale) were collected.
Results
KL-6 serum concentrations were significantly higher in SSc-ILD patients than in those without ILD (
p
< 10
−4
) and were inversely correlated with forced vital capacity, total lung capacity and diffuse lung capacity of carbon monoxide. Serum KL-6 level superior to 872 U/ml appeared as the optimal cut-off value associated with ILD. Patients with a restrictive pulmonary syndrome and dyspnoea had significant higher KL-6 serum concentrations. SSc patients with anti-topoisomerase 1 antibodies had higher KL-6 serum levels than patients with anti-centromere antibodies (
p
< 10
− 4
). ILD and anti-topoisomerase 1 antibodies were independent factors associated with KL-6 in multivariate analysis. Interestingly, KL-6 serum concentrations positively increased with the patient lung severity.
Conclusions
Our study confirms that KL-6 is an accurate biomarker for the diagnosis of SSc-ILD in a French cohort of patients. High KL-6 levels should prompt physicians to assess ILD with pulmonary imaging and pulmonary functions tests. Prospective clinical studies are still required to determine whether levels of KL-6 might predict progression of ILD as well as its usefulness in the timing of therapeutic intervention.
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