Fabienne Coury

Langerhans cell histiocytosis reveals a new IL-17A- dependent pathway of dendritic cell fusion

IL-17A is a T cell–specific cytokine that is involved in chronic inflammations, such as Mycobacterium infection, Crohns disease, rheumatoid arthritis and multiple sclerosis. Mouse models have explained the molecular basis of IL-17A production and have shown that IL-17A has a positive effect not only on granuloma formation and neurodegeneration through unknown mechanisms, but also on bone resorption through Receptor activator of NF-κB ligand (RANKL) induction in osteoblasts. Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology, lacking an animal model, that cumulates symptoms that are found separately in various IL-17A–related diseases, such as aggressive chronic granuloma formation, bone resorption and soft tissue lesions with occasional neurodegeneration. We examined IL-17A in the context of LCH and found that there were high serum levels of IL-17A during active LCH and unexpected IL-17A synthesis by dendritic cells (DCs), the major cell type in LCH lesions. We also found an IL-17A–dependent pathway for DC fusion, which was highly potentiated by IFN-γ and led to giant cells expressing three major tissue-destructive enzymes: tartrate resistant acidic phosphatase and matrix metalloproteinases 9 and 12. IFN-γ expression has been previously documented in LCH and observed in IL-17A–related diseases. Notably, serum IL-17A–dependent fusion activity correlates with LCH activity. Thus, IL-17A and IL-17A–stimulated DCs represent targets that may have clinical value in the treatment of LCH and other IL-17A–related inflammatory disorders.

Infliximab therapy in rheumatoid arthritis and ankylosing spondylitis-induced specific antinuclear and antiphospholipid autoantibodies without autoimmune clinical manifestations: a two-year prospective study

Treatment of rheumatoid arthritis (RA) with infliximab (Remicade®) has been associated with the induction of antinuclear autoantibodies (ANA) and anti-double-stranded DNA (anti-dsDNA) autoantibodies. In the present study we investigated the humoral immune response induced by infliximab against organ-specific or non-organ-specific antigens not only in RA patients but also in patients with ankylosing spondylitis (AS) during a two-year followup. The association between the presence of autoantibodies and clinical manifestations was then examined. The occurrence of the various autoantibodies was analyzed in 24 RA and 15 AS patients all treated with infliximab and in 30 RA patients receiving methotrexate but not infliximab, using the appropriate methods of detection. Infliximab led to a significant induction of ANA and anti-dsDNA autoantibodies in 86.7% and 57% of RA patients and in 85% and 31% of AS patients, respectively. The incidence of antiphospholipid (aPL) autoantibodies was significantly higher in both RA patients (21%) and AS patients (27%) than in the control group. Most anti-dsDNA and aPL autoantibodies were of IgM isotype and were not associated with infusion side effects, lupus-like manifestations or infectious disease. No other autoantibodies were shown to be induced by the treatment. Our results confirmed the occurrence of ANA and anti-dsDNA autoantibodies and demonstrated that the induction of ANA, anti-dsDNA and aPL autoantibodies is related to infliximab treatment in both RA and AS, with no significant relationship to clinical manifestations.

Rheumatoid Arthritis and Fibromyalgia: A Frequent Unrelated Association Complicating Disease Management

Objective To assess the value of the 28-joint Disease Activity Score (DAS28) in evaluating disease activity in rheumatoid arthritis (RA) associated with fibromyalgia (FM). In this situation, because of the weight of the subjective measures included in the DAS28 equation, the patient’s status may be overestimated, leading to inappropriate treatment. We analyze the relationship between RA and FM and discuss whether the association is random or a marker of poor prognosis. Methods A questionnaire, developed when biologic therapies were introduced, was administered and the results analyzed in a consecutive, female outpatient population including 105 patients with RA, 49 with RA and FM (RAF), and 28 with FM. Psychosocial characteristics, disease presentation, and radiographic joint destruction evaluation were compared in the 3 populations. Results The presentation of RA was the same in patients with RA and RAF, but the 2 populations differed by socioprofessional characteristics, significantly higher disease activity in patients with RAF, and significantly more severe joint destruction in patients with RA. The RAF group was similar to the FM control population in socioprofessional and some physical characteristics. Regression analysis using the DAS28 measures differed significantly in the weight allowed to 28-joint counts for pain and swelling, but the constant factor was higher in patients with RAF. Conclusion DAS28 overestimated objective RA severity in patients who also had FM. The association between RA and FM does not appear to be a marker of worse prognosis, but rather a fortuitous association between the 2 diseases and one that may afford these patients some protection against joint destruction.

Murine dendritic cell transdifferentiation into osteoclasts is differentially regulated by innate and adaptive cytokines

Dendritic cells (DC) are the mononuclear cells that initiate adaptive immune responses. Osteoclasts (OC) are the multinucleated giant cells that resorb bone. As previously described for human conventional DC (cDC), we demonstrate that murine cDC, either in vitro generated from Fms‐like tyrosine kinase 3 (Flt3)+ bone marrow progenitors or ex vivo purified from spleen, are able to develop into OC in response to M‐CSF and receptor activator of NF‐κB ligand (RANKL) in vitro. This transdifferentiation is driven by the immune environment that controls cDC maturation, cell fusion, tartrate‐resistant acid phosphatase (TRAP) and bone resorption activities. Only immature cDC have the capacity to become OC since mature cDC or plasmacytoid DC do not. Additions of the pro‐inflammatory cytokines, such as IL‐1β and TNF‐α, or human rheumatoid synovial fluid, increase murine cDC transdifferentiation into OC, whereas IFN‐α inhibits it. The adaptive cytokine, IFN‐γ, inhibits cDC fusion while IL‐4 increases it. IL‐2, IFN‐γ and IL‐4 inhibit TRAP and bone resorption activities contrary to IL‐10, which enhances both activities. A putative new “immune multinucleated giant cell” unable to resorb bone, which is formed owing to IL‐4, is underlined. The future analysis of cDC transdifferentiation into OC in murine models of inflammatory arthritis will give us the quantitative importance of this phenomenon in vivo.

Sarcoidosis: an underestimated and potentially severe side effect of anti-TNF-alpha therapy.

Joint Bone Spine - In Press.Proof corrected by the author Available online since vendredi 10 aout 2012

Gene expression profiling in peripheral blood cells of patients with rheumatoid arthritis in response to anti-TNF-α treatments

The efficacy of anti-TNF-α therapies highlights the role of TNF-α in the pathogenesis of rheumatoid arthritis (RA). However, the mechanism of action of these agents is poorly understood at the molecular level. The aim of this study was to characterize the effects of anti-TNF-α treatment on the global gene expression profile in peripheral blood mononuclear cells (PBMCs) of responder RA patients. Changes in gene expression were determined using oligonucleotide microarrays (25,341 genes) in PBMCs obtained before and after 12 wk of treatment with either etanercept or adalimumab from responder RA patients. Two hundred fifty-one genes displayed significant changes (false discovery rate < 0.1%) in expression level (178 upregulations with mean fold change = 1.5 and 73 downregulations with mean fold change = -1.50) after 12 wk of treatment. Importantly, the expression of several genes, including those coding for the calcium binding proteins S100A12 and A8, CD14 antigen, Selectin P, or ribosomal protein L39, reported to be upregulated in RA patients, were found to be decreased after anti-TNF-α treatment. Globally, inflammation, immune response, apoptosis, protein synthesis, and mitochondrial oxido-reduction were the most affected pathways in response to anti-TNF-α treatment. The obtained gene expression signature in PBMCs provides new information to better understand the mechanisms of action of anti-TNF-α treatment in RA patients.

Fibromyalgia in Spondyloarthritis: Effect on Disease Activity Assessment in Clinical Practice

Objective. Spondyloarthritis (SpA) is the second most frequent inflammatory rheumatic disease, characterized by spinal involvement, peripheral arthritis, or enthesitis with marked pain, stiffness, and fatigue. Fibromyalgia (FM) may be associated with SpA, and shares some common symptoms. We aimed to determine how FM influences assessment of SpA disease activity, which is mainly dependent on patient-based outcome measures such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) or the Ankylosing Spondylitis Disease Activity Score (ASDAS). Methods. This single-center cross-sectional study included consecutive patients with SpA according to the Assessment of SpondyloArthritis International Society criteria. FM was diagnosed according to the 1990 American College of Rheumatology criteria. Patient characteristics, BASDAI, ASDAS/C-reactive protein (CRP), Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index, and the Medical Outcomes Study Short Form-36 questionnaire were recorded and compared. Results. The study included 103 patients with SpA; 81 with axial and 22 with peripheral forms. Eighteen patients presented with concomitant FM, of whom 12 had axial SpA and 6 peripheral SpA. Demographic characteristics did not differ except for sex, with a female predominance in the FM group that was more marked in peripheral forms. BASDAI was higher in patients with FM [median (IQR): 4.2 (4.2) vs 2.2 (3.1); p = 0.0068], whereas ASDAS-CRP was not significantly different [median (IQR): 2.7 (2) vs 2 (1.3); p = 0.1264]. Nevertheless, median ASDAS-CRP corresponded to high disease activity in patients with SpA or FM compared with moderate activity in non-FM patients. Conclusion. FM is a frequent comorbidity in patients with SpA, especially in peripheral forms. In patients with SpA-FM, disease activity may be overestimated when measured by BASDAI and to a lesser extent by ASDAS-CRP, and this overestimation could lead to inappropriate treatment escalation.

A bicentre retrospective study of features and outcomes of patients with reactive arthritis

OBJECTIVE Reactive arthritis (ReA) is a sterile arthritis following an extra-articular infection, usually of the gastrointestinal or genitourinary tract. The aim of this study was to assess the incidence and the clinical and therapeutic characteristics of ReA and to compare them with those of a historical cohort. We hypothesised that improved hygiene together with prevention and treatment of sexually transmitted infections may have decreased the incidence of ReA. METHODS All patients with ReA diagnosed in the University Hospital Centres of Lyon Sud and Besançon from January 2002 to December 2012 were included in the study retrospectively and were compared with ReA patients diagnosed from January 1986 to December 1996 in the same two hospitals. Medical records were reviewed, clinical features, treatments and outcomes were analysed and diagnoses were compared with international diagnostic criteria. RESULTS Twenty-seven patients were included between 2002 and 2012 compared with 31 between 1986 and 1996. The overall incidence of ReA in patients hospitalised in the rheumatology department did not change, although the current evolution is more severe with development of chronic disease in the form of more frequent spondyloarthritis. While the incidence of Chlamydiae trachomatis has decreased, new microbes are now found to be involved. CONCLUSIONS ReA still exists and its incidence has been stable over the last 30 years. However, ReA currently more often progress to spondyloarthritis. Our study also highlights the need for diagnostic criteria that accurately detect ReA.

Posterior epidural migration of herniated lumbar disc fragment

Joint Bone Spine - In Press.Proof corrected by the author Available online since samedi 28 janvier 2017

Early treatment of reactive arthritis with etanercept and 2 years follow-up

Joint Bone Spine - In Press.Proof corrected by the author Available online since lundi 6 juin 2016