Treatment of adult-onset Still's disease: a review

Adult-onset Still's disease (AOSD) is a rare inflammatory disorder that has been recently classified as a polygenic autoinflammatory disorder. The former classification, based on the disease course, seems to be quite dated. Indeed, there is accumulating evidence that AOSD can be divided into two distinct phenotypes based on cytokine profile, clinical presentation, and outcome, ie, a "systemic" pattern and an "articular" pattern. The first part of this review deals with the treatments that are currently available for AOSD. We then present the different strategies based on the characteristics of the disease according to clinical presentation. To do so, we focus on the two subsets of the disease. Finally, we discuss the management of life-threatening complications of AOSD, along with the therapeutic options during pregnancy

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity.

Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1β. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R-dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavir-mediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity

A proximity-dependent biotinylation (BioID) approach flags the p62/sequestosome-1 protein as a caspase-1 substrate.

The inflammasome is a major component of the innate immune system, and its main function is to activate caspase-1, a cysteine protease that promotes inflammation by inducing interleukin-1β (IL-1β) maturation and release into the extracellular milieu. To prevent uncontrolled inflammation, this complex is highly regulated. When it is assembled, the inflammasome is insoluble, which has long precluded the analysis of its interactions with other proteins. Here we used the proximity-dependent biotinylation assay (BioID) to identify proteins associated with caspase-1 during inflammasome activation. Using the BioID in a cell-free system in which the inflammasome had been activated, we found that a caspase-1-biotin ligase fusion protein selectively labeled 111 candidates, including the p62/sequestosome-1 protein (p62). Using co-immunoprecipitation experiments, we demonstrated that p62 interacts with caspase-1. This interaction promoted caspase-1-mediated cleavage of p62 at Asp-329. Mechanistic and functional analyses revealed that caspase-1-mediated cleavage of p62 leads to loss of its interaction with the autophagosomal protein microtubule-associated protein 1 light chain 3 β (LC3B). Strikingly, overexpression of a p62 N-terminal fragment generated upon caspase-1 cleavage decreased IL-1β release, whereas overexpression of p62's C-terminal portion enhanced IL-1β release, by regulating pro-IL1β levels. Overall, the overexpression of both fragments together decreased IL-1β release. Taken together, our results indicate that caspase-1-mediated p62 cleavage plays a complex role in balancing caspase-1-induced inflammation

Les inflammasomes et les maladies humaines

The understanding of the innate immunity, the first line of the host defence, was significantly modified following the sequential discovery of innate immune receptors such as the Toll-like receptors (TLRs) and the NOD-like receptors (NLRs). In response to recognition of microbial patterns or danger signals, some NLRs assemble a multimolecular platform termed as the inflammasome. Inflammasome assembly leads to the activation of the proinflammatory caspase-1. Consequently, an inflammatory immune response is mounted along with a programmed cell death, called pyroptosis. This review summarizes recent advances in the knowledge of the inflammasome and its role in auto-inflammatory diseases, autoimmune diseases, and most common metabolic, cardiovascular or rheumatic diseases

Commentary

International audienc

Le temps est venu de réconcilier l’arthrite juvénile idiopathique systémique et la maladie de Still de l’adulte

no abstract availabl

Treatment of Progressive Multifocal Leukoencephalopathy With Mirtazapine

International audienceBACKGROUND AND OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) is a rare, JC-virus-mediated, demyelinating disease with a high mortality rate. As no recommended treatment exists, mirtazapine, a potential blocker of virus entry into cells, has been empirically used. METHODS: We analysed existing data on mirtazapine's efficacy to treat PML by systematically reviewing the literature since 2005, when it was first used. RESULTS: Searches in PubMed, EBSCO, SCOPUS and Google Scholar between January 2005 and December 2015, identified five cohort studies and 74 case reports. No statistically significant effect of mirtazapine on PML outcome was observed in the cohort studies. From studying the case reports, mortality rate for PML was associated with the underlying circumstances, such as an older age, the use of an immunosuppressant, or PML occurring in patients with a haematological malignancy or a transplant. CONCLUSIONS: Except for natalizumab-associated PML, we did not highlight any potential benefit of mirtazapine on disease outcomes. Further interventional studies are needed to confirm that 5-HT2AR inhibition is relevant to treat PM

Refractory Sarcoidosis: A Review

Thomas El Jammal,1 Yvan Jamilloux,1 Mathieu Gerfaud-Valentin,1 Dominique Valeyre,2 Pascal Sève1,3 1Department of Internal Medicine, Lyon University Hospital, Lyon, France; 2Department of Pneumology, Assistance Publique - Hôpitaux de Paris, Hôpital Avicenne et Université Paris 13, Sorbonne Paris Cité, Bobigny, France; 3Hospices Civils de Lyon, Pôle IMER, Lyon, F-69003, France, University Claude Bernard Lyon 1, HESPER EA 7425, Lyon F-69008, FranceCorrespondence: Pascal SèveService de Médecine Interne, Groupement Hospitalier Nord, 103 Grande rue de la Croix-Rousse, Lyon F-69004, FranceTel +33 426 732 636Fax +33 426 732 637Email [email protected]: Sarcoidosis is a multi-system disease of unknown etiology characterized by granuloma formation in various organs (especially lung and mediastinohilar lymph nodes). In more than half of patients, the disease resolves spontaneously. When indicated, it usually responds to corticosteroids, the first-line treatment, but some patients may not respond or tolerate them. An absence of treatment response is rare and urges for verifying the absence of a diagnosis error, the good adherence of the treatment, the presence of active lesions susceptible to respond since fibrotic lesions are irreversible. That is when second-line treatments, immunosuppressants (methotrexate, leflunomide, azathioprine, mycophenolate mofetil, hydroxychloroquine), should be considered. Methotrexate is the only first-line immunosuppressant validated by a randomized controlled trial. Refractory sarcoidosis is not yet a well-defined condition, but it remains a real challenge for the physicians. Herein, we considered refractory sarcoidosis as a disease in which second-line treatments are not sufficient to achieve satisfying disease control or satisfying corticosteroids tapering. Tumor necrosis alpha inhibitors, third-line treatments, have been validated through randomized controlled trials. There are currently no guidelines or recommendations regarding refractory sarcoidosis. Moreover, criteria defining non-response to treatment need to be clearly specified. The delay to achieve response to organ involvement and drugs also should be defined. In the past ten years, the efficacy of several immunosuppressants beforehand used in other autoimmune or inflammatory diseases was reported in refractory cases series. Among them, anti-CD20 antibodies (rituximab), repository corticotrophin injection, and anti-JAK therapy anti-interleukin-6 receptor monoclonal antibody (tocilizumab) were the main reported. Unfortunately, no clinical trial is available to validate their use in the case of sarcoidosis. Currently, other immunosuppressants such as JAK inhibitors are on trial to assess their efficacy in sarcoidosis. In this review, we propose to summarize the state of the art regarding the use of immunosuppressants and their management in the case of refractory or multidrug-resistant sarcoidosis.Keywords: refractory sarcoidosis, JAK inhibitors, anti-TN