Mesenteric inflammatory veno-occlusive disease of the spleen metasynchronous with two arterial thrombotic events in systemic lupus erythematosus.

Vasculitides, particularly those affecting small vessels, are known to complicate systemic lupus erythematosus (SLE); however, isolated venulitis of the mesenteric bed has rarely been reported. Here we relate the case of a 46-year-old woman with SLE who presented with acute abdominal pain due to artery thrombosis and extended splenic ischemia requiring splenectomy. The histological examination revealed diffuse venulitis in the absence of arterial vasculitis consistent with the definition of mesenteric inflammatory veno-occlusive disease (MIVOD). Furthermore, arterial wall thickening suggestive of uncomplicated atherosclerosis was observed. Two months later, the patient suffered of severe myocardial infarction (MI) resulting from thrombosis of the anterior interventricular coronary artery with otherwise no signs of coronary disease at coronarography. Extensive work-up to establish the cause of MI was negative, with the exception of marginal, isolated and transient elevation of cardiolipin IgG (14.5 GPL, n.v. 0-5 GPL). This patient's SLE history is dramatically marked by the previously non-described association of MIVOD and two arterial thrombotic events (splenic and coronary) occurring within a two months period, and stresses the need of better understanding and prevention of vascular complications in SLE.

[Lung involvement in systemic sclerosis]. / Manifestations pulmonaires de la sclérodermie systémique.

Systemic sclerosis (SSc) is a protean disorder in which prognosis and treatment are tailored on the basis of organ involvement. Among SSc lung manifestations, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) or the combination of both, are the first cause of SSc mortality and impact heavily on patient quality of life. ILD may begin early in disease and usually progresses slowly. However, approximately 10% of patients with ILD may reach terminal respiratory insufficiency. PAH may be an early or late complication of SSc in which increased blood pressure in pulmonary arteries leads to right heart failure. Current treatments provide some benefit, but both SSc-ILD and PAH still represent an enormous unmet need of more efficacious therapeutic strategies.

[Systemic vasculitides: novel nomenclature and novel therapeutic approaches]. / Vascularites systémiques: nouvelles nomenclature et approches thérapeutiques.

A novel nomenclature of systemic vasculitides is proposed by the 2012 Chapel Hill Consensus Conference. It aims at substituting established eponyms and introducing new terms and groups closer to our current understanding of vasculitis pathophysiology. In parallel, a therapeutic revolution is taking place partially based on the concept of re-induction of immune tolerance for ANCA-associated vasculitis (AAV). Two major multicentric randomized studies have shown that rituximab (RTX), monoclonal antibody capable of selectively killing B lymphocytes, is not inferior when compared to cyclophosphamide (CYC) to induce remission in AAV, and superior in the case of disease relapse. Thus, a hot debate is taking place whether or not to maintain CYC or use RTX in AAV. An individual-based choice may be wise for the moment being.

[Gastrointestinal features in systemic sclerosis]. / Manifestations digestives de la sclérodermie.

Systemic sclerosis (SSc) is a rare disorder associating vasculopathy, tissue fibrosis and autoimmunity. The gastro-intestinal tract (GIT) is frequently involved with any segment being potentially affected from mouth to anus. The esophagus is the most common localization resulting in reflux and its complications such as erosive esophagitis and Barrett's esophagus. Gastric involvement is less frequent but may be complicated by hemorrhage due to gastric antral vascular ectasia (GAVE or watermelon stomach). Intestinal involvement may lead to malabsorption, intestinal pseudo-obstruction or bacterial overgrowth. Anorectal involvement can cause fecal incontinence and rectal prolapse. GIT involvement greatly affects morbimortality in SSc and therapeutic approaches essentially aim at relieving the symptoms.

Rituximab in systemic lupus erythematosus: an updated systematic review and meta-analysis.

The wide spectrum of clinical manifestations and high relapse rate represent a therapeutic challenge in systemic lupus erythematosus (SLE). Observational studies suggested efficacy of rituximab (RTX), a B-cell-targeting antibody, to control the activity of SLE. Two randomized trials controlled by placebo did not prove the superiority of RTX when used in addition to conventional treatment in nonrenal (EXPLORER) and renal (LUNAR) lupus. A systematic review of studies exploring the efficacy of RTX in SLE patients was conducted. The pooled percentages of response were assessed. Thirty studies with 1243 patients were analyzed. In studies using the British Isles Lupus Assessment Group (BILAG), the complete response (CR) rate was 46.7% (95% CI 36.8%-56.8%) and the partial response (PR) was 37.9% (95% CI 30.6%-45.8%). With the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the CR was 56.6% (95% CI 32.4%-78.1%) and the PR was 30.9% (95% CI 8.9%-46%). In renal lupus the CR was 36.1% (95% CI 25.2%-48.6%); PR was 37.4% (95% CI 28.5%-47.3%). In EXPLORER, CR was 12.4% and PR was 17.2%; in LUNAR CR was 26.4% and PR was 30.6%, in both cases not different from controls. Assessment and standardization of SLE response to treatment remain a challenge. The discrepancy in the perceived efficacy of RTX between controlled and observational studies reflects the heterogeneity of lupus and stringency in criteria of response. Further randomized trials focusing on selected SLE manifestations and using composite response indices are warranted.

[Dysimmune neuromuscular disorders: diagnostic challenges and new ways of management]. / Maladies auto-immunes neuromusculaires: diagnostic et prise en charge.

This review describes some dysimmune neuromuscular disorders and their recent management: syndrome of peripheral nerve hyperexcitability (treatment of cramps, immunosuppressors); Guillain-Barré syndrome (new mechanisms and consensus treatment); chronic inflammatory demyelinating polyradiculoneuropathy (new indication for the use of pulse dexamethasone, new scores of activity); importance of subcutaneous immunoglobulin in multifocal motor neuropathy and of infusions of rituximab in myasthenia gravis; new entities in myositis and their treatment.

Association of the CD226 Ser(307) variant with systemic sclerosis: evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis.

OBJECTIVE: The nonsynonymous polymorphism rs763361 of the CD226 gene, which encodes DNAX accessory molecule 1, which is involved in T cell costimulation pathways, has recently been identified as a genetic risk factor for autoimmunity. The purpose of this study was to test for association of the CD226 rs763361 polymorphism with systemic sclerosis (SSc) in European Caucasian populations. METHODS: CD226 rs763361 was genotyped in 3,632 individuals, consisting of a discovery sample (991 SSc patients and 1,008 controls) and a replication sample (999 SSc patients and 634 controls). All study subjects were of European Caucasian origin. Expression of CD226 was assessed on peripheral blood mononuclear cells obtained from 21 healthy donors genotyped for CD226 rs763361. RESULTS: The CD226 rs763361 T allele was found to be associated with SSc in both the discovery and the replication samples, showing the following results in the combined populations: odds ratio (OR) 1.22 (95% confidence interval [95% CI] 1.10-1.34), P = 5.69 × 10(-5) . The CD226 T allele was also associated with various SSc subsets, highlighting a potential contribution to disease severity. The most remarkable associations of the CD226 TT risk genotype were observed with the diffuse cutaneous SSc subtype, the anti-topoisomerase I antibody-positive, and SSc-related fibrosing alveolitis subsets: OR 1.86 (95% CI 1.42-2.43), P = 5.15 × 10(-6) , OR 1.82 (95% CI 1.38-2.40), P = 2.16 × 10(-5) , and OR 1.61 (95% CI 1.25-2.08), P = 2.73 × 10(-4) , respectively. CD226 expression was not significantly influenced by CD226 rs763361 genotypes whatever the T cell subtype investigated. CONCLUSION: Our results establish CD226 as a new SSc genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of SSc. Further work is nevertheless needed to define the causal variant at the CD226 locus as well as the functional consequences.

[Allergo-immunology. Clinical immunology]. / Allergo-immunologie. 2. Immunologie clinique.

The past year has been characterized by significant novelties from the point of view of the clinical immunologist. With the BLISS 52 study showing that belimumab has the ability to decrease the activity of systemic lupus erythematosus (SLE) resistant to conventional therapy an important step towards the control of this difficult disease has been carried forward. In addition, the long-term results of the ALMS study have demonstrated that mycophenolate mofetil is superior to azathioprine in maintaining the remission in patients with severe lupus nephritis. Furthermore, the results of the RAVE and RITUXVASC studies have documented that rituximab is a valid alternative to cyclophosphamide in the control of ANCA associated vasculitis.

[Cardiovascular risk in autoimmune and inflammatory disorders]. / Le risque cardiovasculaire dans les maladies auto-immunes systémiques.

Atherosclerosis (ATS) is characterized by an inflammatory process initiated by oxidized LDL in the vessel wall, where activation of cells of the innate and adaptive immune system takes place. ATS is accelerated with an increased risk of cardiovascular (CV) events in systemic autoimmune disorders (AID) such as systemic lupus erythematosus or rheumatoid arthritis (RA). In addition to the traditional CV risk factors, which are over-represented in AID, the underlying chronic inflammation and dysregulation of the immune system play an amplifying role in ATS. Although certain drugs used in AID can increase the CV risk, the control of the disease as permitted by TNF-blocking agents in RA, reduces this risk. The strategies specific to AID to reduce the CV risk remain to be better defined.

Antimalarial immunity in Saimiri monkeys. Immunization with surface components of asexual blood stages.

Plasmodium falciparum polypeptides of 200 and 140 K mol wt exposed at the surface of merozoites and/or schizonts were purified by affinity chromatography and by electroelution from sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Monkeys were separated into three groups of four and immunized either with one of the two polypeptides or with saline (control). After intravenous challenge with 2.5 X 10(7) P. falciparum asexual blood stages, two monkeys of the control group had to be treated and two recovered spontaneously after peak parasitemia of 9 and 11%. The four monkeys immunized with the 140 K polypeptide recovered without treatment after peak parasitemia between 1.5 and 4.5%. Monkeys immunized with the 200 K polypeptide had similar peak parasitemia except one monkey who suffered from a large skin excoriation and who recovered spontaneously after a peak parasitemia of 11%. Prechallenge sera of the immunized monkeys reacted only with the polypeptide used for immunization except for one serum of the 140 K group, which precipitated an additional polypeptide of 39 K, and a polypeptide of 31 K weakly precipitated by the four sera of monkeys immunized with the 200 K polypeptide. The relatedness between the 200 and 140 K polypeptides was investigated using tryptic digestion and reverse phase chromatography. No clear analogy was found between the two polypeptides, which suggests that immunization with either of two independent surface components of P. falciparum asexual blood stages is able to induce at least a partial protective immunity in immunized hosts.

[Progress in allergy/immunology in 2009]. / Allergo-immunologie.

Progresses in allergy in 2009 were particularly noticeable in the field of diagnosis with an increased use of recombinant food allergens; tolerance induction protocols, in particular for egg and milk allergy show promising results for the future; and interesting new possibilities for treatment of mastocytosis with anti-IgE antibodies are reported. Clinical immunology has witnessed advances along two main axes. The first aiming at defining new efficacious therapeutic strategies less toxic compared to those currently in use to control SLE and ANCA-related vasculitis. The second highlights a novel response index appears to be a major advancement toward our understanding of SLE.

No association of complement mannose-binding lectin deficiency with cardiovascular disease in patients with Systemic Lupus Erythematosus.

Cardiovascular (CV) morbidity is the major cause of death in patients with Systemic Lupus Erythematosus (SLE). Previous studies on mannose-binding lectin (MBL) gene polymorphisms in SLE patients suggest that low levels of complement MBL are associated with cardiovascular disease (CVD). However, as large studies on MBL deficiency based on resulting MBL plasma concentrations are lacking, the aim of our study was to analyze the association of MBL concentrations with CVD in SLE patients. Plasma MBL levels SLE patients included in the Swiss SLE Cohort Study were quantified by ELISA. Five different CV organ manifestations were documented. Of 373 included patients (85.5% female) 62 patients had at least one CV manifestation. Patients with MBL deficiency (levels below 500 ng/ml or 1000 ng/ml) had no significantly increased frequency of CVD (19.4% vs. 15.2%, P = 0.3 or 17.7% vs. 15.7%, P = 0.7). After adjustment for traditional CV risk factors, MBL levels and positive antiphospholipid serology (APL+) a significant association of CVD with age, hypertension, disease duration and APL+ was demonstrated. In our study of a large cohort of patients with SLE, we could not confirm previous studies suggesting MBL deficiency to be associated with an increased risk for CVD.

Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus.

LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(TFH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications.

Immunization with a Plasmodium falciparum merozoite surface antigen induces a partial immunity in monkeys.

Saimiri monkeys immunized with a Plasmodium falciparum merozoite polypeptide of 41 kD mol wt are resistant to a blood challenge infection that induces a fulminant infection in control monkeys. The sera of the immunized monkeys reacted, as shown by the indirect immunofluorescence technique, with the apical part of the merozoites from five isolates or clones of P. falciparum. Whether the immunogen was dissolved in nonionic detergent (NP-40) or in sodium dodecyl sulfate (SDS) had a marked influence on the level of protection in immunized monkeys. Thus, monkeys immunized with the antigen solubilized in a nonionic detergent developed much lower parasitemia than monkeys immunized with denatured antigen (antigen eluted from SDS polyacrylamide gel electrophoresis).

Anti-fibroblast antibodies detected by cell-based ELISA in systemic sclerosis enhance the collagenolytic activity and matrix metalloproteinase-1 production in dermal fibroblasts.

OBJECTIVES: Antibodies binding to the surface of fibroblasts (anti-fibroblast antibodies: AFA) have been described in systemic sclerosis (SSc). We aimed to assess the effect of AFA on extracellular matrix (ECM) turnover and whether AFA were associated with anti-topoisomerase-I antibody. METHODS: IgG were purified from AFA-positive and AFA-negative sera selected within 20 SSc and 20 healthy individuals, and tested on normal dermal fibroblasts, at protein and mRNA level, for their capacity to induce collagen deposition or degradation. RESULTS: Fibroblasts stimulated with AFA-positive but not with AFA-negative and control IgG showed an increased capacity to digest collagen matrix and produce metalloproteinase-1 (MMP-1) while their production of total collagen, type I collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) was unaffected. The steady-state mRNA levels of MMP-1, COL1A1 and TIMP-1 paralleled the protein levels. AFA-positive IgG did not induce Smad 2/3 phosphorylation, indicating that this transforming growth factor-beta signalling pathway was not involved. IL-1 and tumour necrosis factor (TNF) neutralization did not reverse the enhanced production of MMP-1, suggesting a direct effect of AFA on fibroblasts. Finally, anti-topoisomerase-I antibodies were present in 11 of 12 AFA-negative IgG, and an anti-topoisomerase-I monoclonal antibody failed to enhance MMP-1 production, thus indicating a lack of correlation between AFA and anti-topoisomerase-I antibody. CONCLUSIONS: These results indicate that SSc antibodies binding to fibroblasts enhance matrix degradation and MMP production events that may favour inflammation but do not directly impact on fibrosis development.

Epilepsy and cerebellar ataxia associated with anti-glutamic acid decarboxylase antibodies.

Anti-glutamic acid decarboxylase (GAD) antibodies are described in stiff-person syndrome and also in other neurological syndromes, including cerebellar ataxia and epilepsy. This paper reports the case of a patient who had chronic focal epilepsy, upbeat nystagmus and cerebellar ataxia, associated with a polyautoimmune response including anti-GAD antibodies. Both gait and nystagmus improved markedly after immunosuppressive treatment with corticosteroids and azathioprine. After the introduction of benzodiazepines, previously refractory seizures were completely controlled. Anti-GAD antibodies should be actively sought out in pharmacoresistant epilepsy, particularly if other neurological abnormalities are present. Combined treatment with immunosuppressants and gammahydroxybutyric acidergic agents may be highly effective.

Role of cellular immunity in the pathogenesis of autoimmune skin diseases.

The pathomechanism of most autoimmune skin diseases is still elusive; however, recent clinical and basic research is leading novel insights into the cellular and molecular biological underlying pathways. Several types of infectious skin diseases are infiltrated by significant number of gamma/delta T cells and similar observations have been made in selected immune-mediated skin conditions. In particular, a role for gamma/delta T cells has been suggested in discoid lupus erythematosus, contact dermatitis, herpetiformis dermatitis, necrotizing cutaneous vasculitis, and cutaneous lesions of systemic sclerosis. The pathogenesis of these diseases is different and this may suggest multiple potential functions of this subset of T cells in the immune system of the skin. Furthermore, most T cells infiltrating tissue and organs undergoing fibrosis have the potential to produce high levels of interleukin 4. This is particularly true for the CD8+ or CD4+ CD8+ double positive T-cell subsets. Furthermore, leukocyte recruitment is a key event in immunity and a better understanding of the signals involved in autoimmune diseases constitutes a valuable basis for the development of new strategies, which control leukocyte migration and function under pathological conditions.

[Diagnosis and follow-up of vasculitis: usefulness of imaging]. / Diagnostic et suivi des vascularites: apport de l'imagerie.

Vasculitides are due to inflammation of the vessel wall. There is a definite advantage in visualizing the inflammatory process within blood vessels without resorting to invasive procedures. A variety of non-invasive imaging techniques is now becoming available to investigate patients with vasculitis. These include ultrasonography, MRI coupled to angiographic sequences, PET, single photon emission computed tomography (SPECT). Their role is being evaluated and their characteristics exploited to address issues specific to each vasculitis. Thus, cardiac IRM should be considered in patients with ANCA-negative Churg-Strauss syndrome. Moreover, PET could be useful from investigate a subgroup of patients suffering from giant-cell arteritis. However, to validate these techniques, prospective studies in large cohorts of patients are needed.

[Pathogenic mechanisms in systemic sclerosis and their therapeutical consequences. Part 1: pathogenesis]. / Mécanismes pathogéniques de la sclérodermie et leurs conséquences thérapeutiques. 1ère partie: pathogénie.

Systemic sclerosis I(cleroderma) is a connective tissue disease caracterized by an aberrant immune activation, a vasculopathy and a fibrosis of skin and multiple internal organs (lung, kidneys, gut, among others). At present no unifying pathogenetic hypothesis exists to explain all aspects of this disease. The current hypothesis is that in patients with a favourable genetic background, certain environmental factors could produce alterations of cellular and humoral immunity and alterations of the microcirculation resulting in excessive fibrosis. A crucial component in systemic sclerosis pathogenesis is the persistent and unregulated activation of genes encoding the various extracellular matrix proteins. This is in correlation with different cytokines and growth factors produced mainly by T lymphocytes.