[Severe small bowel involvement and chronic intestinal pseudo-obstruction in systemic sclerosis (scleroderma): Pathophysiological, diagnostic and therapeutic basis, including parenteral nutrition]. / Atteinte sévère de l'intestin grêle et pseudo-obstruction intestinale chronique au cours de la sclérodermie systémique : bases physiopathologiques, diagnostiques et thérapeutiques, dont la nutrition parentérale.

Gastrointestinal involvement in systemic sclerosis can be severe, reaching the critical point of chronic intestinal pseudo-obstruction, secondary to major disorders of small bowel motility. It is associated with some clinical and biological characteristics, in particular the positivity of anti-fibrillarin/U3RNP antibodies. Chronic intestinal pseudo-obstruction (CIPO) is complicated by a small intestinal bacterial overgrowth that requires cyclic antibiotic therapy. CIPO leads to a reduction of the food intake, due to painful symptoms, nausea and vomiting caused by meals, and ultimately to severe malnutrition. Meal splitting is often transiently effective and patients require exogenous nutritional support, mostly parenteral. Systemic sclerosis is not an obstacle to initiation and long-term continuation of parenteral nutrition and central venous catheter implantation is not associated with an increased risk of cutaneous or infectious complications. However, continuation of long-term parenteral nutrition requires monitoring in an expert nutrition center in order to adapt nutritional volumes and intakes and to limit potentially fatal cardiac and hepatobiliary complications. In addition to nutrition, prokinetic treatments, whose side effects must be known, can be associated. Invasive procedures, whose risk-benefit ratio must be carefully assessed, can also be used to treat symptoms exclusively.

[Infections in primary Sjögren's syndrome patients: "Real-life" study of 109 patients from Montpellier university hospital]. / Infections rapportées chez 109 patients avec syndrome de Gougerot-Sjögren primaire suivis au CHU de Montpellier.

INTRODUCTION: Infections are responsible for a part of the overall mortality in primary Sjögren's syndrome patients (pSS). Our retrospective monocentric study aimed at describing infections reported in a population of pSS hospitalized patients, along with the characteristics of their disease. METHODS: Patients with SS have been randomly selected from our hospital database claim, between 2009 and 2018. After careful analysis of their medical chart, only patients with pSS and fulfilling ACR/EULAR 2016 diagnosis criteria were included. We collected main clinical, biological and pathological characteristics of SS, along with all the reported infections during the follow-up. The characteristics of the disease were compared according to the presence of an infection in hospitalization. RESULTS: In total, 109 pSS patients were included (93% of women, mean age 53.6±14.3 years, mean follow-up 8.2±8.4 years). Fifty-one percent had been exposed to hydroxychloroquine (HCQ). Seventy-eight infections were recorded in 47 (43%) patients. Twenty-five infections were recorded in hospitalization (5 in critical care) in 20 (18%) patients, whom leading causes were urinary tract (28%), pulmonary (24%), ENT (16%), and intestinal (12%) infections. pSS patients with infections in hospitalization were older, exhibited more hypocomplementemia, and were less exposed to HCQ. We found no difference in immunosuppressive treatments exposure. CONCLUSIONS: The impact of HCQ exposure on infectious risk needs further investigations. Broad vaccination campaign and tight control of sicca syndrome could lead to a better control of infection risk.

Off-label use of biologics for the treatment of refractory and/or relapsing granulomatosis with polyangiitis.

OBJECTIVE: To describe the efficacy and safety of off-label use of biologics for refractory and/or relapsing granulomatosis with polyangiitis (GPA). METHODS: We conducted a French retrospective study including GPA patients who received off-label biologics for refractory and/or relapsing disease after failure of conventional immunosuppressive regimens. RESULTS: Among 26 patients included, 18 received infliximab (IFX), 2 adalimumab (ADA) and 6 abatacept (ABA). Biologics were initiated in median as 4th-line therapy (IQR 3-6) for relapsing and/or refractory disease in 23 (88%) and/or significant glucocorticoid-dependency in 8 cases (31%). At biologics initiation, median (IQR) BVAS and prednisone dose in anti- TNF-α and ABA recipients were 7 (3-8) and 2 (1-6), and 20 (13-30) mg/day and 20 (15-25) mg/day, respectively. Clinical manifestations requiring biologics were mainly pulmonary and ENT manifestations in 58% each. Anti-TNF-α and ABA were continued for a median duration of 8 months (IQR 6-13) and 11 months (IQR 6-18) respectively. Anti-TNF-α recipients showed remission, partial response and treatment failure in 10%, 30% and 60% at 6 months, and 25%, 20% and 55% at 12 months, respectively. ABA recipients showed remission, partial response and treatment failure in 17%, 33% and 50% at 6 months and 17%, 33% and 50% at 12 months. One patient treated with IFX experienced life-threatening reaction while one patient treated with ABA experienced a severe infection. CONCLUSION: This real-life study suggests that off-label use of anti-TNF-α and abatacept shows efficacy in less than 50% of refractory and/or relapsing GPA.

[Management of immune-related toxicities associated with immune checkpoints inhibitors: Data from the multidisciplinary meeting « ToxImmun ¼ in Eastern Occitania]. / Gestion des toxicités induites par les inhibiteurs de checkpoint immunologique : données de la réunion de concertation pluridisciplinaire « ToxImmun ¼ en Occitanie Est.

Immune checkpoint inhibitors (ICIs) can cause numerous and complex immune-related adverse events whose management need a multidisciplinary approach. Herein, we investigated 114 requests, mostly concerning patients suffering from lung cancer, that were submitted to the « ToxImmun ¼ multidisciplinary meeting in Eastern Occitania between December the 17th 2018 and January the 20th 2020. The leading reasons for the request concerned the putative causal link between immunotherapy and immune-toxicity and its management, followed by possible retreatment after temporary withdrawn because of adverse event, and finally the possibility to initiate ICIs in patients with pre-existing autoimmunity. Colitis, hepatitis and myocarditis were the most frequent immune-related adverse events (IRAEs), both all grade and grade 3-4. Sicca syndrome (with or without Sjogren criteria) was also frequent (26% of cases) and seems to be associated with severe toxicity and multi-toxicity. The mean time to first IRAE was 3.8 months, a time shortened with the use of anti-PD-L1 agents or ICI combination. A majority of requests came from initial evaluation by the internist confirming the early and main role of this specialty in the management of immunotoxicity. Expansion of this regional multidisciplinary meeting, coordinated by internists and medical oncologists, could improve management of immune-related adverse events for the patients' benefits.

[From fibrogenesis towards fibrosis: Pathophysiological mechanisms and clinical presentations]. / De la fibrogenèse à la fibrose : mécanismes physiopathologiques et présentations cliniques.

Fibrogenesis is a universal and ubiquitous process associated with tissue healing. The impairment of tissue homeostasis resulting from the deregulation of numerous cellular actors, under the effect of specific cytokine and pro-oxidative environments can lead to extensive tissue fibrosis, organ dysfunction and significant morbidity and mortality. This situation is frequent in internal medicine, since fibrosis is associated with most organ insufficiencies (i.e. cardiac, renal, or hepatic chronic failures), but also with cancer, a condition with common pathophysiological mechanisms. Finally, fibrosis is a hallmark of numerous systemic autoimmune diseases such as connective tissue disorders (in particular systemic sclerosis), vasculitides, granulomatoses, histiocytoses, and IgG4-associated disease. Although the process leading to tissue fibrosis may be in part irreversible, new pharmacological approaches or cell therapies bring hope in the field of fibrotic conditions.

[Diagnostic value of selective anorexia in pathological weight loss]. / Évaluation de l'apport diagnostique des anorexies sélectives au cours des amaigrissements pathologiques.

PURPOSE: The diagnostic value of selective anorexia is debated. Some authors have suggested an association between meat aversion and cancer, but most do not use it as a diagnostic tool. We aimed to characterize anorexia of different diseases to search for an association between selective aversions and diagnostic groups. METHODS: All the patients admitted to three departments of a teaching hospital were included consecutively for 22months if they had more than 10 % weight loss in less than one year. Patients were excluded if history taking was not reliable, or if they suffered from anorexia nervosa. We compiled diagnoses at discharge and validated them six months later. We used logistic regression to identify independent factors associated with selective anorexia. RESULTS: Inclusion criteria were met in 106patients (female 44 %, median age 65years). Most frequent diagnoses were: cancer (36 %), infection (35 %), digestive diseases (19 %), non organic diseases (21 %). Recent selective anorexia was found in 46 % of the cases. It was significantly associated with female gender (P=0.002), marginally with young age (P=0.069) and long duration of weight loss (P=0.079). Opioid use at admission was negatively associated with selective anorexia (P=0.001). No specific diagnostic category was found to be associated. CONCLUSION: Selective anorexia does not appear to be a useful symptom to investigate pathological weight loss. It behaves more like a non-specific reactivation by current disease of earlier latent personal food aversions.

[Serious clinical manifestations of vitamin deficiency after a "sleeve" gastrectomy: role of psychogenic anorexia]. / Anorexie psychogène et carences vitaminiques sévères dans les suites d'une gastrectomie longitudinale.

INTRODUCTION: Morbid obesity is an emerging condition in the general population. Bariatric surgery, which has demonstrated its effectiveness for weight loss, mortality and morbidity related to obesity, is required in some patients. However, it may be associated with various adverse effects, including vitamin deficiencies. CASE REPORT: We report a 33-year old man who presented central and peripheral neurological deficits and cardiac manifestations related to multiple vitamin deficiencies, following "sleeve" gastrectomy. The vitamin deficiencies were related to insufficient ingesta secondary to psychogenic anorexia. The patient improved with vitamins, antidepressant drugs and atypical neuroleptics. CONCLUSION: Post-operative complications of "sleeve" gastrectomy include vitamin deficiencies that can develop in the context of psychogenic anorexia and ingesta reduction, in the absence of any digestive malabsorption.

[Glycosylation of autoantibodies in autoimmunes diseases]. / Glycosylation des autoanticorps au cours des maladies auto-immunes.

Protein glycosylation is one of the most common post-translational modifications, involved in the well described protein biosynthesis process. Protein glycosylation seems to play a major role in the pathogenesis of auto-immune diseases. Herein are described the main alterations of autoantibody glycosylation associated with autoimmunes diseases such as rheumatoid arthritis, IgA glomerulonephritis, Schoenlein-Henoch purpura, Sjögren's syndrome, systemic scleroderma, systemic lupus erythematosus, myasthenia gravis and granulomatosis with polyangiitis (Wegener). Molecular identification of altered immunoglobulin glycosylation could lead to a better understanding of the pathogenesis of those diseases, might allow an evaluation of their biological activity and could even be a new therapeutic target.

[Pathogenic role of antimyeloperoxidase antibodies]. / Rôle pathogène des anticorps antimyéloperoxydase.

Antimyeloperoxidase antibodies are a variety of antineutrophil cytoplasm antibodies (Anca), which can be detected in systemic small-sized vessel vasculitides such as microscopic polyangiitis, Wegener's granulomatosis and Churg-Strauss syndrome. Antimyeloperoxidase antibodies have been also associated with the development of lung fibrosis. Their pathogenic role has been well established, both in vitro and in vivo. These autoantibodies can activate neutrophils and trigger their oxidative burst leading to the release of free oxygen species and cytotoxic proteins. The oxidative burst is deleterious for the endothelium. Another mechanism by which antimyeloperoxidase may act is the activation of myeloperoxydase leading to an increased production of hypochlorous acid, which is highly toxic for the endothelial cells. These mechanisms contribute to the development of vasculitis.

The oxidation induced by antimyeloperoxidase antibodies triggers fibrosis in microscopic polyangiitis.

Lung fibrosis is considered a severe manifestation of microscopic polyangiitis (MPA). Antimyeloperoxidase (anti-MPO) antibodies in MPA patients' sera can activate MPO and lead to the production of reactive oxygen species (ROS). While high levels of ROS are cytotoxic, low levels can induce fibroblast proliferation. Therefore, we hypothesised that the oxidative stress induced by anti-MPO antibodies could contribute to lung fibrosis. 24 MPA patients (45 sera) were enrolled in the study, including nine patients (22 sera) with lung fibrosis. Serum advanced oxidation protein products (AOPP), MPO-induced hypochlorous acid (HOCl) and serum-induced fibroblast proliferation were assayed. AOPP levels, MPO-induced HOCl production and serum-induced fibroblast proliferation were higher in patients than in healthy controls (p<0.0001, p=0.0001 and p=0.0005, respectively). Increased HOCl production was associated with active disease (p=0.002). Serum AOPP levels and serum-induced fibroblast proliferation were higher in patients with active MPA and lung fibrosis (p<0.0001). A significant linear relationship between fibroblast proliferation, AOPP levels and HOCl production was observed only in patients with lung fibrosis. Oxidative stress, in particular the production of HOCl through the interaction of MPO with anti-MPO antibodies, could trigger the fibrotic process observed in MPA.

Antifibroblast antibodies from systemic sclerosis patients bind to {alpha}-enolase and are associated with interstitial lung disease.

OBJECTIVE: To identify target antigens of antifibroblast antibodies (AFA) in systemic sclerosis (SSc) patients. PATIENTS AND METHODS: In the first part, sera from 24 SSc patients (12 with pulmonary arterial hypertension (PAH) and 12 without) and 36 idiopathic PAH patients, tested in pooled sera for groups of three, were compared with a sera pool from 14 healthy controls (HC). Serum IgG reactivity was analysed by the use of a two-dimensional electrophoresis and immunoblotting technique with normal human fibroblasts antigens. In the second part, serum IgG reactivity for two groups: 158 SSc, 67 idiopathic PAH and 100 HC; and 35 SSc and 50 HC was tested against alpha-enolase from Saccharomyces cerevisiae and recombinant human (rHu) alpha-enolase, respectively, on ELISA. RESULTS: In the first part, alpha-enolase was identified as a main target antigen of AFA from SSc patients. In the second part, 37/158 (23%) SSc patients, 6/67 (9%) idiopathic PAH patients and 4/100 (4%) HC (p<0.001) had anti-S cerevisiae alpha-enolase antibodies; 12/35 (34%) SSc patients and 3/50 (6%) HC had anti-rHu alpha-enolase antibodies (p = 0.001). In SSc, the presence of anti-S cerevisiae alpha-enolase antibodies was associated with interstitial lung disease (ILD), decreased total lung capacity (73.2% vs 89.7%; p<0.001) and diffusion capacity for carbon monoxide (47.4% vs 62.3%; p<0.001), and antitopoisomerase 1 antibodies (46% vs 21%; p = 0.005) but not anticentromere antibodies (11% vs 34%; p = 0.006). Results were similar with rHu alpha-enolase testing. CONCLUSION: In SSc, AFA recognise alpha-enolase and are associated with ILD and antitopoisomerase antibodies.

Impact of digital ulcers on disability and health-related quality of life in systemic sclerosis.

OBJECTIVE: To assess the impact of digital ulcers (DUs) on disability and health-related quality of life (HRQoL) in systemic sclerosis (SSc). METHODS: Two hundred and thirteen patients with SSc were evaluated at four annual meetings of a patient society between 2004 and 2007 (n = 177) or during hospital stay (n = 36). HRQoL was assessed by the SF-36, global disability by the health assessment questionnaire (HAQ), hand disability by the Cochin Hand Function Scale (CHFS) and global hand and wrist mobility by the Kapandji index. RESULTS: Sixty-seven patients (31.4%) had at least one DU at the time of evaluation. Patients with DUs showed significantly more pitting scars (p<0.001) and calcinosis (p<0.0001) than others. Patients with DU had significantly greater HAQ (mean (SD) 1.218 (0.723) vs 0.930 (0.717), p = 0.008), CHFS (mean (SD) 27.38 (20.68) vs 16.73 (18.19), p<0.0001) and aesthetic prejudice (mean (SD) 6.1 (2.2) vs 3.9 (2.5), p<0.0001) scores than others. Hand and wrist mobility were significantly diminished in patients with DU (mean (SD) Kapandji score 75.3 (22.8) vs 81.7 (19.2), p<0.0001). The presence of a DU did not significantly alter the physical component but influenced the mental component (mean (SD) 43.38 (12.53) vs 39.58 (9.54), p = 0.026) of the SF36. CONCLUSION: Patients with SSc with DUs have reduced wrist and hand mobility, increased global and hand disabilities and decreased mental component of HRQoL.

Impact of cardiac magnetic resonance imaging for assessment of Churg-Strauss syndrome: a cross-sectional study in 20 patients.

OBJECTIVE: To examine the diagnostic contributions of cardiac magnetic resonance imaging (CMRI) with delayed-enhancement (DE) in patients with Churg-Strauss syndrome (CSS). METHODS: We consecutively recruited 14 men and 6 women (mean age: 50+/-14 years) with CSS (mean disease duration: 4.5+/-3.6 years) and investigated them independently of the presence/absence of cardiac manifestations. Cardiac manifestations included heart failure in 6 patients, angina pectoris in 1, isolated ECG abnormality in 1, and isolated echocardiography and ECG abnormalities in 1. T1-weighted sequences were recorded after gadolinium injection to study myocardial DE. RESULTS: CMRI abnormalities were found in 13/20 patients, including all 9 patients with myocardial manifestations, and 4 of the 11 asymptomatic patients. DE was centromyocardial in 6 patients, subepicardial in 4, and subendocardial in 3. Most enhanced lesions were in the anteroseptal or lateral walls. Patients with myocardial symptoms and DE had higher transmyocardial wall DE scores (mean: 9.4 vs. 3.7, respectively; p=0.01) and lower left ventricular ejection fractions (mean: 42% vs. 59%; p=0.001) than asymptomatic patients with DE. CONCLUSION: CMRI with DE enabled the detection of myocardial involvement in CSS patients with or without clinical symptoms. The clinical relevance of CMRI abnormalities in patients without clinical, echocardiographic and ECG signs of cardiac involvement remains unknown and needs to be evaluated in future studies. It seems premature to intensify treatment or to prescribe systematically steroids and cytotoxic agents based on the presence of isolated CMRI anomalies.

High frequency of venous thromboembolic events in Churg-Strauss syndrome, Wegener's granulomatosis and microscopic polyangiitis but not polyarteritis nodosa: a systematic retrospective study on 1130 patients.

OBJECTIVE: To determine the frequency and risk factors of venous thromboembolic events (VTE) in Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and, the so far unstudied, Churg-Strauss syndrome (CSS) and polyarteritis nodosa (PAN). METHODS: Retrospective, systematic analysis and comparisons were made between the characteristics of patients in the VTE group and non-VTE group. 1130 patients with WG, MPA, CSS or PAN were identified from the French Vasculitis Study Group cohort. RESULTS: During a mean follow-up of 58.4 (45.8) months, 83 VTE occurred in 74 (6.5%) patients, with a median vasculitis-VTE diagnosis interval of 5.8 months (-3 to +156). VTE occurred in seven of 285 (2.5%) patients with PAN, 19 of 232 (8.2%) with CSS, 30 of 377 (8%) with WG and 18 of 236 (7.6%) with MPA. Multivariate analysis retained age, male sex or previous VTE or stroke with motor deficit as being associated with a higher VTE risk. The adjusted odds ratio (95% confidence interval) for VTE was 2.88 (1.27 to 6.50) for patients with WG, MPA or CSS compared with PAN (p = 0.01). CONCLUSIONS: Our results suggest that, like WG and MPA, patients with CSS are at a greater risk of VTE, than those with PAN. The reasons for this difference remain to be elucidated.

Infections, connective tissue diseases and vasculitis.

In genetically predisposed individuals, viruses, bacteria, or parasitic infectious agents are suspected of inducing autoimmunity and/or exacerbating autoimmune rheumatic diseases (ARD) once self-tolerance is broken. Although direct evidence for this association is still lacking, numerous data from animal models as well as from humans support the hypothesis of a direct contribution of pathogens to the induction of several ARD. This review focuses on the possible role of infectious agents as triggers of autoimmunity in systemic lupus erythematosus, polymyositis-dermatomyositis, antiphospholipid antibody syndrome, and primary vasculitis. Indeed, vasculitis may be a clinical manifestation of an infectious disease (secondary vasculitis). In addition, immune response abnormalities and immunosuppressive medications may be responsible for the high percentage of infectious complications in ARD patients. Recent therapeutic approaches aimed at lowering doses of cytotoxic agents and shortening duration of treatment with the most toxic drugs, have proved to be as effective as conventional regimens. New drugs and strategies aimed at preventing infections could further improve the outcome of ARD patients.

Osteomalacia revealing celiac disease and primary biliary cirrhosis-related Fanconi syndrome in a patient with systemic sclerosis.

Systemic sclerosis (SSc) may affect the gastrointestinal tract and cause very rarely malabsorption syndrome related to bacterial overgrowth. Malabsorption syndrome may be responsible for weight loss, diarrhea, osteomalacia, and iron and vitamins deficiency. We report the case of a SSc patient who developed osteomalacia caused by the combination of two exceptional conditions in the setting of SSc: celiac disease (CD) and primary biliary cirrhosis (PBC)-related Fanconi syndrome. Oral prednisone with angiotensin-converting enzyme inhibitors, was initiated because of active lesions of tubulitis, and led to the complete regression of bone pains, and by the improvement of renal function and regression of the features of proximal tubulopathy. Thus, in the presence of vitamin deficiencies in a patient with SSc, together with a search for malabsorption syndrome secondary to bacterial overgrowth, CD and/or PBC-associated Fanconi syndrome should be investigated.