Steroid hormones in systemic sclerosis: associations with disease characteristics and modifications during scleroderma renal crisis.

OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) and glucocorticoids (GCs) are involved in vascular remodeling and fibrosis, but have not been extensively studied in systemic sclerosis (SSc). Our aim was to investigate the RAAS and GC hormones in SSc patients. METHODS: Serum levels of renin (dosage and activity), aldosterone and its precursors (DOC, B, 18-OH-DOC, 18-OH-B), and GCs (cortisol, cortisone, 11-deoxycortisol, 18-OH-F) were assessed in 122 SSc patients and 52 healthy controls. After applying stringent inclusion criteria aimed at ensuring accurate hormone assessments (exclusion of interfering drugs, strict sampling conditions), we analyzed RAAS hormones in 61 patients, and GCs in 96 patients. Hormone levels were compared between patients and controls; and associations with disease characteristics were assessed in patients. RESULTS: Regarding RAAS hormones, SSc patients displayed significantly lower aldosterone levels (although within normal range), similar renin levels, and higher B levels than controls. Abnormal RAAS hormone levels were associated with a more severe SSc phenotype (lung and skin fibrosis, heart and pulmonary vascular involvements, inflammation). Regarding GC hormones, SSc patients had higher levels of cortisol, 11-desoxycortisol (precursor) and 18-OH-F (metabolite) but lower levels of cortisone (inactive counterpart) than controls.RAAS hormone levels were assessed in 5 SSc patients before and during scleroderma renal crisis (SRC): concentrations varied considerably between patients, but consistently included normal/increased aldosterone levels and elevated renin levels. CONCLUSION: RAAS and GC hormones are abnormally produced in SSc patients, especially in patients with severe SSc and during SRC. This could suggest a participation of these hormonal systems in SSc pathogenesis.

Evaluation of a self-questionnaire to screen for neurological complications associated with immunological checkpoint inhibitors: Are we missing something?

INTRODUCTION: Immunological checkpoint inhibitors (ICI) have led to a therapeutic revolution in the management of many cancers and indications are increasing. Neurological complications seem to have a profile quite distinct from that of toxicities related to chemotherapy, although it is possible that some manifestations remain under-reported or misdiagnosed. OBJECTIVES: (i) To evaluate the value of a self-questionnaire in screening for neurological ICI-related complications. (ii) To investigate whether, apart from the subacute complications described in the literature, neurological complications of more insidious onset might occur. METHOD: Patients followed in dermatology department for skin cancers treated with ICI, completed every infusion a neurological screening auto-questionnaire. Patients were selected for a neurological expertise based on the questionnaire's data. RESULTS: In total, 149 patients completed≥1 questionnaire, with a median delay of 174 days from the start of treatment. A total of 229 questionnaires were completed between July 2019 and December 2019. 38 patients were identified for a neurological consultation. None of these patients had a neurological event attributable to ICI. During the follow-up, only one patient had a neurological event related to ICI, which was not revealed by the questionnaire. DISCUSSION: Neurological signs in ICI-treated-skin-cancer context are more often due to tumoral progression. Neurological complications of ICI remain rare and unpredictable. The systematic neurological questionnaire has not been shown to be useful in this context. These results highlight the need to educate patients about possible subacute signs that should lead to contact the treating physicians and the need for a close cooperation between dermatologists/oncologists and neurologists.

Anticoagulation withdrawal in antiphospholipid syndrome: a retrospective matched-control study.

Background/Purpose Long-term anticoagulation is the standard treatment for thrombotic antiphospholipid syndrome (APS). However, in daily practice, the question of withdrawing anticoagulation may arise, without any evidence-based recommendations. This study aimed to assess outcomes in APS patients after anticoagulation withdrawal. Methods Thrombotic APS patients followed in our centre, whose anticoagulation was withdrawn after APS diagnosis, were retrospectively selected, and were match-controlled with patients under anticoagulation, based on sex, age, APS clinical phenotype and disease duration. Results Thirty cases with anticoagulation withdrawal were included. Median follow-up was 51 months (12-124). The risk of thrombotic relapse was higher in cases compared to controls (7.3% versus 1.5% patient-year ( p = 0.01); hazard ratio 4.8; 95% confidence interval (1.4-16.7)). Male gender, anti-ß2GP1 and triple positivity at inclusion were predictive factors for thrombotic relapse. Conversely, aspirin prescription was a protective factor against relapses. Persistence of LA, anti-ß2GP1 and triple positivity over time were associated with a higher risk of thrombosis and aPL disappearance with a lower risk. Conclusion In our study, anticoagulation withdrawal was associated with an increased risk of thrombotic relapse. Our findings emphasize the influence of anti-ß2GP1 and triple positivity persistence over time on the risk of relapse and the benefit of aspirin prescription when anticoagulation has been withdrawn.

Persistent triple antiphospholipid antibody positivity as a strong risk factor of first thrombosis, in a long-term follow-up study of patients without history of thrombosis or obstetrical morbidity.

Introduction The long-term risk of first thrombosis and benefit of prophylaxis in antiphospholipid antibody (aPL) carriers without history of thrombosis or obstetrical morbidity is poorly known. This study aimed to evaluate the long-term rate and risk factors associated with a first thrombosis in those patients. Patients and methods After a prior study ended in December 2005 and was already published, we extended the follow-up period of our cohort of aPL carriers. Results Ninety-eight of the 103 patients of the previous study were included. The annual first thrombosis rate was 2.3% per patient-year during a median of 13 years (6-17). None of the baseline characteristics was predictive of risk of first thrombosis, but persistent aPL over time were associated with an increased risk. The stronger association was found in triple aPL-positive carriers: OR 3.38 (95% CI: 1.24-9.22). Of note, conversely to our previous findings, no benefit of aspirin prophylaxis was observed. Conclusion The risk of first thrombosis in aPL carriers without history of thrombosis or obstetrical morbidity was significant, persisted linearly over time and was associated with persistent aPL. This risk was especially increased in triple aPL-positive carriers, in whom a close follow-up seems to be necessary. Nevertheless, the benefit of aspirin prophylaxis remained unclear.

Metastatic melanoma: spontaneous occurrence of auto antibodies is a good prognosis factor in a prospective cohort.

BACKGROUND: Melanoma is an immunogenic tumour type frequently associated with spontaneous auto-immune manifestations such as spontaneous regression, vitiligo-like reactions or auto-immune retinopathy, which seem to be associated with better prognosis. OBJECTIVES: The aim of this prospective study was to evaluate the correlation between spontaneous autoimmunity and survival in patients with stage IV melanoma. METHODS: From 2007 to 2008, 103 patients were studied with antithyroid and antinuclear auto antibody assays performed every 6 months. Any detectable occurrence of a spontaneous self antibody (SpSA) at the upper detection limit, at least for one assay, was considered to be a biological marker of autoimmunity. RESULTS: Univariate and multivariate analyses confirmed significantly longer survival in the absence of known primary melanoma (P = 0.044) and in the presence of marker of biologic autoimmunity, independently of previous immunotherapy (P = 0.045). CONCLUSIONS: This prospective and comparative study is, to our knowledge, the first to report the frequency of SpSA in stage IV melanoma. Our results suggest that spontaneous autoimmunity, through a rupture of self-tolerance, is a good prognostic factor in a subgroup of patients with stage IV melanoma.

[Singular, systemic, self-reactive IgG patterns related to age: relationship with cerebral malaria susceptibility in exposed subjects residing in an endemic area in Abidjan, Côte-d'Ivoire]. / Singularité des profils d'autoréactivité systémique en fonction de l'âge: relations avec la susceptibilité au neuropaludisme chez les sujets exposés en région endémique à Abidjan, Côte-d'Ivoire.

The impact of autoimmunity on malaria-infection evolution reported by various works has led us to compare reactive patterns of self-dependent systemic IgG from 54 patients aged less than 15 years old to those from 46 subjects older than 15 years. These subjects were divided into 34 Plasmodium falciparum asymptomatic carriers (ACs), 30 cases of uncomplicated malaria (UM), and 36 patients suffering from cerebral malaria (CM) living in the same endemic area. The reactivity of the plasma antibodies against human brain tissue extract was assessed by western blotting. Comparative analysis of reactive bands (linear discriminant analysis, LDA) revealed the existence of patterns that distinguish, among the more susceptible subjects aged less than 15 years old, the different clinical forms. In contrast, in less susceptible subjects aged more than 15 years old, the patterns are homogenous and do not allow the separation of these clinical forms. This self-reactive repertoire might be witnessed as an imprint of the clinical tolerance acquired during the years of living in endemic areas. The singularity of this profile under the age of 15 years might have a prognostic value.

Thrombotic events during long-term follow-up of obstetric antiphospholipid syndrome patients.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial and/or venous thromboses and/or pregnancy-associated morbidity. Some patients develop only obstetric complications (obstetric APS), but data on the frequency of thrombotic events during the follow-up of these patients are scarce. This study was undertaken to evaluate the rate of thrombotic events after obstetric APS diagnosis according to the 2006 revised criteria. In total, 32 obstetric APS patients were retrospectively studied, with mean follow-up of 50 ± 37 months. After delivery, aspirin was prescribed to all patients as primary thrombosis prevention. The thrombosis rate was 3.3/100 patient-years and was 4.6, 4.5 and 10/100 patient-years when we considered at least two antiphospholipid antibody positivities (among lupus anticoagulant, anticardiolipin and anti-ß2-glycoprotein-I), antinuclear antibody positivity or systemic lupus erythematosus-associated APS patients, respectively. The thrombosis rate was high after obstetric APS diagnosis, even for patients taking aspirin. Larger, prospective studies are needed to confirm this high frequency and determine the associated risk factors.

Interleukin 5 synthesis by eosinophils: association with granules and immunoglobulin-dependent secretion.

Interleukin 5 (IL-5) is the main factor that promotes the terminal differentiation of eosinophil progenitors (as indicated by colony formation assays), and enhances the effector capacity of mature eosinophils. IL-5 is produced by T lymphocytes, CD4-/CD8- and mast cells and recently, messenger (m)RNA of this cytokine has been identified in eosinophils from patients with coeliac disease, asthma, or eosinophilic heart diseases. In this study, IL-5 mRNA and immunoreactive IL-5 protein were detected in tissue and blood eosinophils from patients with eosinophilic cystitis or hypereosinophilic syndromes but not in Crohn's disease. By electron microscopy associated to immunogold staining, immunoreactive IL-5 was identified in eosinophilic granules. After stimulation with IgA-, IgE-, or IgG-immune complexes, blood eosinophils were shown, by immunocytochemistry and by enzyme-linked immunosorbent assay, to secrete IL-5. These observations demonstrate that eosinophils, under physiological stimulation, can release significant amounts of IL-5, which may contribute to local eosinophil recruitment and activation.

Role of B cells in the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is an orphan disease characterized by progressive fibrosis of the skin and internal organs. Aside from vasculopathy and fibrotic processes, its pathogenesis involves an aberrant activation of immune cells, among which B cells seem to play a significant role. Indeed, B cell homeostasis is disturbed during SSc: the memory subset is activated and displays an increased susceptibility to apoptosis, which is responsible for their decreased number. This chronic loss of B cells enhances bone marrow production of the naïve subset that accounts for their increased number in peripheral blood. This permanent activation state can be explained mainly by two mechanisms: a dysregulation of B cell receptor (BCR) signaling, and an overproduction of B cell survival signals, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). These disturbances of B cell homeostasis induce several functional anomalies that participate in the inflammatory and fibrotic events observed during SSc: autoantibody production (some being directly pathogenic); secretion of pro-inflammatory and pro-fibrotic cytokines (interleukin-6); direct cooperation with other SSc-involved cells [fibroblasts, through transforming growth factor-ß (TGF-ß) signaling, and T cells]. These data justify the evaluation of anti-B cell strategies as therapeutic options for SSc, such as B cell depletion or blockage of B cell survival signaling.

[Physiological and pathological autoimmunity in neurological disease]. / Auto-immunité physiologique et pathologique dans les maladies neurologiques.

INTRODUCTION: Over the last years, the functions of the immune system have radically been revised. It has been illustrated how the different responses of the innate defense and the adaptative system were intimately intricated. STATE OF KNOWLEDGE: Innate immunity is an elaborate strategy, switched on by an invariant receptor-based response that is able to develop a specific defense against some pathogens. Moreover, this innate immunity governs T- and B-cell-dependent adaptive immune response, mediated via dendritic cells whose maturation is controlled by immune specificity. The concepts of autoreactivity have also strongly progressed and the functions of the physiological autoimmune response have been highlighted. The notion of T- and B-cell self-antigens not only shapes the immune repertoire, but also the self-recognition process which is a tool for the control of the immune response itself. PERSPECTIVE: New concepts of the pathophysiology of autoimmune diseases have emerged from a better understanding of the immune response, balancing between an intrinsic deregulation of the immune system and system deficiency to mount an effective response against an initial injury. CONCLUSION: Of course, therapeutic strategies are challenged by these data. We should expect that control of several autoimmune processes will be achieved in a few years, e.g. in rheumatoid arthritis or Crohn's disease controlled with biotherapies.

[The use of intravenous immunoglobulins in neurology]. / La place des immunoglobulines intraveineuses en neurologie.

INTRODUCTION: In the past decade, intravenous immunoglobulins (IVIG) have been widely used and their administration has grown throughout the world. The current indications of IVIG in neurological diseases are discussed on the basis of the passed and current trials. Unlike other immuomodulatory agents, IVIG are well tolerated and have very few side effects and a good viral safety. STATE OF ART: There is clinical evidence, based on controlled trials, for the effectiveness of IVIG in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal neuropathy with conduction blocks. In myasthenia gravis, the IVIG are effective especially in myasthenic crisis, but their synergistic effect with other treatments, the steroid sparing effect, and their long-term effect are unknown. These issues need to be addressed in further controlled clinical trials. In dermatoploymyositis, IVIG are reserved for steroid resistant patients. There is actually no support or no significant clinical benefit for the routine use of IVIG in other neurological diseases. PERSPECTIVES: Further controlled trials are warranted to assess the quality of life, the dose-finding effect and their long-term efficacy in order to improve clinical practices. CONCLUSION: Routine use of IVIG should be reserved for diseases in which positive controlled trials are available. For the remaining dysimmune diseases, IVIG should be assess in comparison with the other available therapies, taking into consideration the age of the patients, the safety of the IVIG and, in our country, the economic aspect.

Interleukin-5 messenger RNA and immunoreactive protein expression by activated eosinophils in lesional atopic dermatitis skin.

The main cellular sources of interleukin-5 (IL-5) are T lymphocytes and mast cells. Recently, IL-5 mRNA has been identified in eosinophils from patients with celiac disease, eosinophilic heart diseases, and asthma. In an attempt to determine whether IL-5 is generated by eosinophils in atopic dermatitis we have used i) in situ hybridization with 35S-labeled IL-5 RNA probe combined with immunohistochemistry using a monoclonal antibody (MoAb) (EG2) directed against the activated form of Eosinophil Cationic Protein (ECP) and ii) double-immunostaining with anti-IL-5 MoAb and polyclonal anti-ECP antibody. We found that dermal eosinophils from lesional atopic dermatitis skin express IL-5 mRNA and protein. Moreover, highly purified blood eosinophils were also labeled with anti-IL-5 antibodies. The expression of IL-5 by eosinophils in atopic dermatitis might suggest an autocrine pathway of eosinophil differentiation and activation.

The prevalence of Sjögren syndrome in patients with primary progressive multiple sclerosis.

OBJECTIVE: To assess the prevalence of Sjögren syndrome (SS) in patients with primary progressive MS (PPMS). BACKGROUND: SS may be considered in the differential diagnosis of MS. Age at onset and clinical presentation are similar in SS and PPMS. However, occurrence of SS in definite cases of PPMS has been recently reported. METHODS: Proposed clinical and laboratory diagnostic criteria for SS were systematically assessed in 60 consecutive patients with PPMS. The authors questioned all patients about xerophthalmia and xerostomia, biopsied minor salivary glands, and performed a Schirmer test, a salivary gland scintigraphy, and anti-Ro (SSa) and anti-La (SSb) serologies. RESULTS: Ten patients (16.6%) met four or more criteria for SS. This prevalence is higher than in the general population (1 to 5%) and implies that SS can mimic PPMS. CONCLUSIONS: The authors propose that SS should be screened for systematically in patients with PPMS.

Interferon beta in multiple sclerosis: relationship between sustained serum IgG levels and clinical outcome.

We investigated the effects of interferon beta-1a (IFN beta-1a) on specific response towards two immunodominant MBP peptides and on global production of IgG. We evaluated 54 sera from multiple sclerosis (MS) patients at baseline and 1 year after treatment. We did not observe any modification of immune response to the MBP peptides but we noted a significant decrease in mean IgG concentrations in patients with progression of the disease but not in stable patients. These results suggest that IFN beta1a restores or maintains a beneficial immune response.

IgG reactivity against citrullinated myelin basic protein in multiple sclerosis.

An increased level of citrullinated myelin basic protein (MBP-C8) has been reported in the brains of multiple sclerosis (MS) patients. However, the involvement of the immune response to post-translational modified MBP in the pathophysiology of MS remains speculative. The aim of this study was to compare the levels of immunoglobulin G antibodies to several MBP epitopes, before and after citrullination, in the cerebrospinal fluid (CSF) and sera of MS patients using enzyme-linked immunosorbent assay (ELISA). We analyzed antibody reactivity against various MBP-peptides in the CSF and sera of 60 MS patients, and 30 patients with other neurological diseases (OND) as controls. The peptides tested were: MBP(75-98) (peptide 1), native (peptide 2) and citrullinated (peptide 3) MBP(108-126) (ARG(122)-->Cit(122)), and native (peptide 4) and citrullinated (peptide 5) MBP(151-170) (ARG(159, 170)-->Cit(159, 170)). All selected peptides could support an immune reactivity in CSF and sera of MS and OND patients. A higher reactivity against peptide 4 was found in the CSF of MS patients compared with OND patients (P<0.0001), but not against citrullinated peptides (peptides 3 and 5). However, we observed that the citrullination state of peptide 2 modified the patterns of immune reactivity more markedly in MS patients (P<0.0001) than in OND patients (P<0.02). Although some MBP epitopes could be a potential target in MS, our data did not demonstrate any difference of antibody response to MBP peptides in their citrullinated forms.

CD28+ intraepithelial lymphocytes with long telomeres are recruited within the inflamed ileal mucosa in Crohn disease.

Crohn disease is a chronic inflammatory bowel disease that involves all the intestine but predominantly alters the ileum. The disease largely depends on T cells, but the biologic role of intestinal intraepithelial lymphocytes (IEL) in transmural inflammation remains poorly characterized. To address this issue, a comparison of IEL and lamina propria lymphocytes (LPL) isolated from the uninvolved and the inflamed ileal mucosa of Crohn disease patients was performed. More CD8+ IEL (26% versus 8%) from the inflamed ileal mucosa expressed the CD28 receptor and the CD11a integrin than IEL from the uninvolved ileal mucosa, which were mostly CD28-. IEL had longer telomeres in the inflamed than in the uninvolved areas and a TCR Vbeta repertoire more similar to circulating T cells, suggesting that the increased proportion of CD28+ TCRalphabeta+ IEL within the inflamed mucosa is more likely due to recruited lymphocytes from the periphery that populate the epithelial layer than to the acquisition of the CD28 molecule by activated resident lymphocytes. In the uninvolved ileal mucosa, IEL from Crohn disease patients had shorter telomeric lengths than IEL from control patients, suggesting that they have been chronically stimulated. Such perturbation of the IEL population within the ileal mucosa could contribute to the inflammation in Crohn disease.

[Systemic lupus erythematosus presenting with recurrent psychiatric disturbances]. / Troubles psychiatriques itératifs révélateurs d'un lupus érythémateux disséminé.

INTRODUCTION: There is a wide range of non-specific symptoms that can reveal neurolupus, sometimes making diagnosis difficult. OBSERVATION: A 29-year-old man presented, from 1996 to 2002, three episodes of mood disorders with hetero-aggression, preceded by seizures, which resolved completely. Repeated investigations were negative except for lymphopenia, an inflammatory cerebrospinal fluid and some rare non-specific areas of high intensity signals in the white matter on the brain MRI. After a six-year course, the patient was considered to have a severe mood disorder related to a schizoid personality. A new dot-blot search for antinuclear antibodies detected anti-Sm antibodies was positive, leading to the diagnosis of neuropsychiatric lupus since the patient's symptoms fulfilling four of the American Rheumatism Association criteria (neuropsychiatric events, lymphopenia, antinuclear and anti-Sm antibodies). The patient was given monthly pulses of cyclophosphamide and remained symptom free one year after the last flare up. CONCLUSIONS: Lupus can rarely be revealed by long-standing isolated psychiatric disorders. Search for auto-antibodies, using highly specialized techniques (western blot, dot blot) should be a routine practice since antibody titres fluctuate during the course of the disease; elevated titres may correlate with exacerbations. Considering the prominence and severity of these behavior disorders, systemic diseases may often be misdiagnosed.

[Relevance of anti-tissue transglutaminase antibodies in coeliac disease diagnosis]. / Intérêt des anticorps anti-transglutaminase tissulaire dans le diagnostic de la maladie coeliaque.

Coeliac disease is precipitated upon exposure to the dietary wheat gluten. Definitive diagnosis relies on intestinal biopsy and regression of clinical and histological disorders with adherence to a gluten-free diet. Coeliac disease is usually associated with a malabsorption syndrome. However, both atypical and silent clinical forms have been recently described and prevalence of the disease may be under-estimated. Serological tests have been developed in order to select candidates for intestinal biopsy, but these biological parameters are not suitable for screening in the general population. Indeed, antigliadin IgG antibodies have a poor specificity. antigliadin IgA antibodies a poor sensitivity. The detection of antiendomysial IgA antibodies (EmA) by immunofluorescence, although considered as the "gold standard" of serological coeliac disease markers, could not be automated, depends on a subjective fluorescence display, and may be limited by the degree of training of the observer. In year 1997, tissue transglutaminase (tTg) has been identified as the main autoantigen recognized by EmA. On this basis, solid-phase enzyme-linked immunosorbent assays (Elisa) have been developed in order to potentially replace the EmA assay. Several commercial kits are now available but their diagnostic performances have not yet been compared. We selected 75 sera, including sera from 26 patients with coeliac disease in order to evaluate five commercial anti-tTG Elisa kits. For all patients, treated or not, detection of anti-tTG antibodies with four of the five tested kits correlates with EmA test. Kits using human tTG have the highest specificity, equivalent to the value of EMA test, and widely better than antigliadin antibodies. Anti-tTG Elisa kits using human tTG may be used as an alternative way to the EmA assay in the next future, and may supplant IgA anti-gliadin antibodies for coeliac disease screening.