Mathilde Versini

Unraveling the Hygiene Hypothesis of helminthes and autoimmunity: origins, pathophysiology, and clinical applications

BackgroundThe Hygiene Hypothesis (HH) attributes the dramatic increase in autoimmune and allergic diseases observed in recent decades in Western countries to the reduced exposure to diverse immunoregulatory infectious agents. This theory has since largely been supported by strong epidemiological and experimental evidence.DiscussionThe analysis of these data along with the evolution of the Western world’s microbiome enable us to obtain greater insight into microorganisms involved in the HH, as well as their regulatory mechanisms on the immune system. Helminthes and their derivatives were shown to have a protective role. Helminthes’ broad immunomodulatory properties have already begun to be exploited in clinical trials of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and type-1 diabetes.SummaryIn this review, we will dissect the microbial actors thought to be involved in the HH as well as their immunomodulatory mechanisms as emphasized by experimental studies, with a particular attention on parasites. Thereafter, we will review the early clinical trials using helminthes’ derivatives focusing on autoimmune diseases.

Smoke and autoimmunity: The fire behind the disease.

The association between smoke habit and autoimmunity has been hypothesized a long time ago. Smoke has been found to play a pathogenic role in certain autoimmune disease as it may trigger the development of autoantibodies and act on pathogenic mechanism possibly related with an imbalance of the immune system. Indeed, both epidemiological studies and animal models have showed the potential deleterious effect caused by smoke. For instance, smoke, by provoking oxidative stress, may contribute to lupus disease by dysregulating DNA demethylation, upregulating immune genes, thereby leading to autoreactivity. Moreover, it can alter the lung microenvironment, facilitating infections, which, in turn, may trigger the development of an autoimmune condition. This, in turn, may result in a dysregulation of immune system leading to autoimmune phenomena. Not only cigarette smoke but also air pollution has been reported as being responsible for the development of autoimmunity. Large epidemiological studies are needed to further explore the accountability of smoking effect in the pathogenesis of autoimmune diseases.

Smoking and obesity in systemic lupus erythematosus: a cross-sectional study

Both smoking and obesity have been demonstrated as risk factors in several autoimmune diseases. Little is known about the relationship between systemic lupus erythematosus (SLE) and both smoking and obesity.

Treating prolactinoma can prevent autoimmune diseases.

Prolactin (PRL) is a pleiotropic hormone; in addition to a wide variety of endocrine effects, PRL also exhibits immunostimulating effects. Therefore, there is increasing evidence linking PRL with a large number of systemic and organ specific autoimmune diseases. Herein, we report the case of an adolescent girl diagnosed with multiple sclerosis (MS) occurring in the context of untreated prolactinoma evolving since childhood. This raises the exciting question of the involvement of PRL in the pathogenesis of MS. It is likely that early treatment of hyperprolactinemia in this case would have significantly reduced the risk of developing MS or even prevented its occurrence.

Biologics in myelodysplastic syndrome-related systemic inflammatory and autoimmune diseases: French multicenter retrospective study of 29 patients.

BACKGROUND Systemic inflammatory and autoimmune diseases (SIADs) associated with myelodysplastic syndromes are often difficult to treat. Corticosteroids are efficient but only usually at high doses. The use of biologics needs to be specified. METHODS In a French multicenter retrospective study, we analyzed the efficacy and safety of biologics (tumor necrosis factor-α [TNF-α] antagonists, tocilizumab, rituximab and anakinra) for SIADs associated with myelodysplastic syndromes (MDSs). Clinical, biological and overall treatment responses were evaluated. When several lines of treatment were used, data were analyzed before and at the end of each treatment line and were pooled to compare overall response among steroids, disease-modifying anti-rheumatic drugs (DMARDs) and biologics. RESULTS We included 29 patients (median age 67years [interquartile range 62-76], 83% males) with MDS-related SIADs treated with at least one biologic. The MDSs were predominantly refractory anemia with excess blasts 1 (38%) and refractory cytopenia with multilineage dysplasia (21%). The SIADs were mainly arthritis (n=6; 20%), relapsing polychondritis (n=8; 30%) and vasculitis (n=10; 34%). During a 3-year median follow-up (IQR 1.3-4.5), a total of 114 lines of treatments were used for all patients: steroids alone (22%), DMARDs (23%), TNF-α antagonists (14%), anakinra (10%), rituximab (10%), tocilizumab (7%) and azacytidine (9%). Considering all 114 lines, overall response (complete and partial) was shown in 54% cases. Overall response was more frequent with steroids (78%) and rituximab (66%) than DMARDs (45%) and other biologics (33%) (p<0.05). Rituximab had better response in vasculitis and TNF-α antagonists in arthritis. During follow-up, 20 patients (71%) presented at least one severe infection. CONCLUSION This nationwide study demonstrates the efficacy of steroids for SIAD-associated MDSs but a high frequency of steroid dependence. The response to biologics seems low, but rituximab and azacytidine seem promising.

Introduction to the special issue on the 9th International Congress on Autoimmunity

It is a great pleasure to introduce this special issue of Immunologic Research on the 9th International Congress on Autoimmunity held in Nice, France, on March 26–30, 2014. This special edition highlights a broad spectrum of emerging issues in the field of autoimmune diseases, both through original studies, reviews and case reports. Nice area and most particularly Grasse (France) might be the sweetest smelling city in Europe, widely known as the perfume capital in the world. While a superior olfactory sense, like that of Jean Baptiste Grenouille, the antihero of Patrick Süskind’s novel Perfume, may lead to addiction and psychiatric diseases, some olfactory function has been found to be impaired in patients affected by variety of autoimmune diseases. Recently, several studies have reported olfactory disorders in various immune-mediated diseases [1] including systemic lupus erythematosus (SLE) [2]. In this issue, two articles evaluate for the first time olfactory function in patients with idiopathic inflammatory myopathies (IIM) [3], fibromyalgia (FM) and systemic sclerosis (SSc) [4]. Thus, Iaccarino et al. [3] performed a case–control study in 60 patients with IIM using the Sniffin’ Sticks test, based on threshold, discrimination and identification (TDI) of odors. TDI score was found to be significantly lower in IIM patients when compared to ageand sex-matched healthy control individuals. Similarly, Amital et al. [4] investigated olfactory function in 24 patients with FM compared to 20 SSc and age-matched healthy controls. They demonstrated that TDI score was significantly decreased in FM and SSc compared with controls, the sense of smell being more deeply altered in patients with FM. The mechanisms of smell system damage in patients with autoimmune diseases are still elusive and are though to result from a complex interplay between genetic, environmental and hormonal factors [1]. In both articles, the role of depression as a potential confounding factor is still unclear. Unfortunately, none of these studies explored potential pathophysiological processes. Whether olfactory function may parallel disease activity or outcome should also be explored. Many women report a heightened sense of smell during pregnancy. Accounts of these anecdotes have existed for over 100 years, but scientific evidence has been sparse and inconclusive. A recent review [5] examined the literature on olfactory perception during pregnancy, showing no support for a general decrease in olfactory thresholds. This special issue examined more conventional aspects of pregnancy in the context of autoimmunity. Two authors have questioned predictive factors of SLE flares as well as of obstetric and fetal complications during pregnancy [6, 7]. Despite considerable progress in the identification of pre-conception, per pregnancy and puerperium risk factors for lupus flare, summarized by Jara et al. [7], it appears that predictive factors in pregnancy have not been systematically and fully elucidated. However, by prospectively following 132 pregnancies in 96 SLE patients, Borella et al. [6] reported that the number of flares before conception best predicted the risk of lupus flares during pregnancy. Moreover, manifestations during flares were even best predicted by the same features occurred before conception, illustrating Thucydides’ quote ‘‘History eternally repeats itself.’’ E. Rosenthal (&) M. Versini P.-Y. Jeandel Department of Internal Medicine, Centre Hospitalier Universitaire de Nice, Université de Nice Sophia Antipolis, 06200 Nice, France e-mail: rosenthal.e@chu-nice.fr

HIBISCUS: HYDROXYCHLOROQUINE FOR THE SECONDARY PREVENTION OF THROMBOTIC AND OBSTETRICAL EVENTS IN PRIMARY ANTIPHOSPHOLIPID SYNDROME

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%-21% at 5 years in thrombotic APS and 20-28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4-16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.