Long-term corticosteroid use and dietary advice: a qualitative analysis of the difficulties encountered by patient.

BACKGROUND: Nearly 1% of the population is currently treated with long-term corticosteroid therapy. When corticosteroids are introduced, information concerning potential adverse effects and recommendations for lifestyle changes aimed at preventing such effects is provided to patients. However, studies have shown patients often do not fully comprehend the information provided and have difficulty implementing the recommended dietary and physical activity advice. In this study, we aim to highlight the difficulties encountered by patients in comprehending and implementing recommendations in the context of long-term corticosteroid use. Such information can be used to better optimize care, particularly concerning adherence to the treatment, the diet, and thus improve the quality of life of patients. METHODS: We recruited adult patients under long-term corticosteroid (≥ 3 months, ≥ 5 mg/day) treatment from both general medicine and rheumatology practices. We performed a qualitative analysis based on semi-structured interviews of these patients. Transcripts of these interviews were then compiled and analysed using a thematic approach. RESULTS: Sixteen patients were included. Analysis of the interviews revealed that patients' hope for effective corticosteroid treatment was counterbalanced by concerns over potential adverse effects. In some patients, the need to respect a strict and imposed diet induced psychological distress, potentially leading to eating disorders or fear of social exclusion. Furthermore, patient ambivalence toward the therapeutic education was highlighted, as well as the notion of filtering information, conscious or unconscious, as revealed by their lack of recall. The relationship with the physician also affected the treatment experience. CONCLUSION: Our analysis of the personal experience of patients regarding recommended lifestyle changes associated with long-term corticosteroid treatment highlights patient difficulties and suggests different ways of improving therapeutic education.

Remission-induction therapies for early rheumatoid arthritis: evidence to date and clinical implications.

Recent guidelines on rheumatoid arthritis (RA) point to the importance of achieving remission as soon as possible during the course of the disease. The appropriate use of antirheumatic drugs is critical, particularly in early RA patients, before 24 weeks, since this is a 'window of opportunity' for treatment to modify disease progression. A treat-to-target strategy added to an aggressive therapeutic approach increases the chance of early remission, particularly in early RA patients. We conducted an overview of current therapeutic strategies leading to remission in early RA patients. We also provide interesting predictive factors that can guide the RA management strategy with regard to disease-modifying treatment and/or drug-free remission.

Chest Low-Dose Computed Tomography for Early Lung Cancer Diagnosis as an Opportunity to Diagnose Vertebral Fractures in HIV-Infected Smokers, an ANRS EP48 HIV CHEST Substudy.

BACKGROUND: To estimate the prevalence of vertebral fractures on chest low-dose computed tomography (LDCT) in HIV-infected smokers. METHODS: Cross-sectional study of vertebral fractures visualized on chest LDCT from a multicenter prospective cohort evaluating feasibility of chest LDCT for early lung cancer diagnosis in HIV-infected subjects. Subjects were included if 40 years or older, had been active smokers within the last 3 years of at least 20 pack-years, and had a CD4 T-lymphocyte nadir cell count <350 per microliter and an actual CD4 T-cell count >100 cells per microliter. Spinal reconstructed sagittal planes obtained from chest axial native acquisitions were blindly read by a musculoskeletal imaging specialist. Assessment of the fractured vertebra used Genant semiquantitative method. The study end point was the prevalence of at least 1 vertebral fracture. RESULTS: Three hundred ninety-seven subjects were included. Median age was 49.5 years, median smoking history was 30 pack-years, median last CD4 count was 584 cells per microliter, and median CD4 nadir count was 168 cells per microliter; 90% of subjects had a viral load below 50 copies per milliliter. At least 1 fracture was visible in 46 (11.6%) subjects. In multivariate analysis, smoking ≥40 packs-years [OR = 2.5; 95% CI: (1.2 to 5.0)] was associated with an increased risk of vertebral fracture, while HIV viral load <200 copies per milliliter [OR = 0.3; 95% CI: (0.1 to 0.9)] was protective. CONCLUSIONS: Prevalence of vertebral fractures on chest LDCT was 11.6% in this high-risk population. Smoking cessation and early introduction of antiretroviral therapy for prevention of vertebral fractures could be beneficial. Chest LDCT is an opportunity to diagnose vertebral fractures.

Outcome of hepatitis E virus infection in patients with inflammatory arthritides treated with immunosuppressants: a French retrospective multicenter study.

The clinical presentation and outcome of hepatitis E virus (HEV) infection in inflammatory rheumatic diseases are unknown. We aimed to investigate the severity of acute HEV infection and the risk of chronic viral replication in patients with inflammatory arthritides treated with immunosuppressive drugs. All rheumatology and internal medicine practitioners belonging to the Club Rhumatismes et Inflammation in France were sent newsletters asking for reports of HEV infection and inflammatory arthritides. Baseline characteristics of patients and the course of HEV infection were retrospectively assessed by use of a standardized questionnaire. From January 2010 to August 2013, we obtained reports of 23 cases of HEV infection in patients with rheumatoid arthritis (n = 11), axial spondyloarthritis (n = 5), psoriatic arthritis (n = 4), other types of arthritides (n = 3). Patients received methotrexate (n = 16), antitumor necrosis factor α agents (n = 10), rituximab (n = 4), abatacept (n = 2), tocilizumab (n = 2), and corticosteroids (n = 10, median dose 6 mg/d, range 2-20). All had acute hepatitis: median aspartate and alanine aminotransferase levels were 679 and 1300 U/L, respectively. Eleven patients were asymptomatic, 4 had jaundice. The HEV infection diagnosis relied on positive PCR results for HEV RNA (n = 14 patients) or anti-HEV IgM positivity (n = 9). Median follow-up was 29 months (range 3-55). Treatment included discontinuation of immunosuppressants for 20 patients and ribavirin treatment for 5. Liver enzyme levels normalized and immunosuppressant therapy could be reinitiated in all patients. No chronic infection was observed. Acute HEV infection should be considered in patients with inflammatory rheumatism and elevated liver enzyme values. The outcome of HEV infection seems favorable, with no evolution to chronic hepatitis or fulminant liver failure.

Circulating miRNA-125b is a potential biomarker predicting response to rituximab in rheumatoid arthritis.

Although biologic therapies have changed the course of rheumatoid arthritis (RA), today's major challenge remains to identify biomarkers to target treatments to selected patient groups. Circulating micro(mi)RNAs represent a novel class of molecular biomarkers whose expression is altered in RA. Our study aimed at quantifying miR-125b in blood and serum samples from RA patients, comparing healthy controls and patients with other forms of rheumatic diseases and arthritis, and evaluating its predictive value as biomarker for response to rituximab. Detectable levels of miR-125b were measured in total blood and serum samples and were significantly elevated in RA patients compared to osteoarthritic and healthy donors. The increase was however also found in patients with other forms of chronic inflammatory arthritis. Importantly, high serum levels of miR-125b at disease flare were associated with good clinical response to treatment with rituximab three months later (P = 0.002). This predictive value was not limited to RA as it was also found in patients with B lymphomas. Our results identify circulating miR-125b as a novel miRNA over expressed in RA and suggest that serum level of miR-125b is potential predictive biomarker of response to rituximab treatment.

TGF beta1 polymorphisms are candidate predictors of the clinical response to rituximab in rheumatoid arthritis.

OBJECTIVE: To evaluate the association between several candidate single-nucleotide polymorphisms (SNPs) and responsiveness to rituximab in patients with rheumatoid arthritis (RA). METHODS: Sixty-three RA patients were included. Nine genes (13 SNPs) were subsequently analyzed, including those coding for cytokines involved in synovitis (IL10, LTA, TGFß1, TNF-α, TNF receptor II) and genes associated with RA susceptibility (-C5 TRAF1, STAT4, TNFAIP3 and PTPN22). RESULTS: Forty-four patients were defined as responders and 19 as nonresponders. TGFß1 Codon 10 and TGFß1 Codon 25 SNPs were both associated with clinical response (probability to respond to treatment with the Codon 10C/T genotype: OR = 1.6; P = 0.002, and with the Codon 25 G/C genotype: OR = 1.6; P = 0.025). The probability to be a responder when the TGFß Codon10 C/T and TGFß Codon 25 G/C genotypes were co-inherited, doubled (OR = 2.6; P = 0.008). CONCLUSION: The TGFß1 SNPs are associated with a good response to rituximab therapy and as such could be useful genetic biomarkers in predicting therapy outcome.

Gene therapy for rheumatoid arthritis: current status and future prospects.

Rheumatoid arthritis (RA) was one of the earliest targets for gene therapy. Since the first clinical trial involving gene therapy in RA was initiated in 1996, eight clinical trials have been conducted assessing gene therapy in RA. Gene therapy has benefited from advances in biologics in terms of the increasing choice of novel, efficient targets to treat RA and also from the optimization of the delivery systems. Several strategies are possible; one of particular interest is local gene therapy directed to rheumatic joints, which avoids systemic vector diffusion. In this review, we discuss (i) gene therapeutic approaches that have been attempted for patients with RA, and (ii) novel strategies that are in development for delivery into patients. We analyze the advantages and disadvantages of the various approaches and how best to optimize them with regard to choosing the most promising vectors and strategies to allow for efficient, long-term, safe delivery of gene therapy in RA.

[Pharmacological approaches in immuno-rhumatology]. / Approches pharmacologiques en immuno-rhumatologie.

Biologics have proven to be an effective treatment option for adults with rheumatoid arthritis but their use in clinical practice may be limited by concerns over severe side effects and cost. Pharmacology and development of biomarkers could help to optimize the use of biologics in clinical practice. Biomarkers are surrogate markers and include all diagnostic tests, imaging and technologies and any other objective measure of a person's health status and all pharmacodiagnostic tests. Several studies evaluated interest of biomarkers in RA patients treated with biologics: 1- to optimize doses and frequency of drug administration; 2- to predict response to treatment; 3- to predict tolerance of biologics; 4- to monitor patient who stopped treatment and are in remission, and predict new RA flare.

Isolation of functional autologous collagen-II specific IL-10 producing Tr1 cell clones from rheumatoid arthritis blood.

IL-10 producing regulatory type 1 (Tr1) cells represents a subpopulation of CD4+ regulatory cells able to prevent in vitro bystander T-cell proliferation and to inhibit a wide range of inflammatory diseases in mice. Our aim was to evaluate the frequency and function of joint specific Tr1 cells in the peripheral blood of severe Rheumatoid Arthritis (RA) patients. The collagen II protein was chosen to isolate Tr1 cells specific for a joint antigen. We successfully isolated Tr1 clones from 9 out of 11 RA patients. We showed that cells from patients display the same phenotype and surface marker regulation as previously shown for human Tr1 cells, characterized by expression of markers of regulation (FoxP3, CD25) at the activated but not at the resting state. Importantly, cells from patients showed Tr1 cytokine secretion (IL-10 and IFN-γ) and immunosuppressive action on bystander T cell proliferation. Based on these results, we demonstrated that collagen II specific Tr1 cells can be isolated from the blood of severe refractory patients and that these cells are not altered in their phenotype and function.

Adeno-associated virus type 5-mediated intraarticular administration of tumor necrosis factor small interfering RNA improves collagen-induced arthritis.

OBJECTIVE: RNA interference (RNAi) is a powerful tool for sequence-specific gene silencing, and interest in its application in human diseases is growing. Given the success of recent strategies for administering gene therapy in rheumatoid arthritis using recombinant vectors such as adeno-associated virus type 5 (rAAV5) for optimized intraarticular gene transfer, we undertook the present study to determine the feasibility of using rAAV5-mediated RNAi-based therapy in arthritis. METHODS: We developed rAAV5 vectors expressing short hairpin small interfering RNA (shRNA) against tumor necrosis factor alpha (TNFalpha) under H1 promoter, and carrying the enhanced green fluorescent protein (eGFP) reporter gene under cytomegalovirus promoter (rAAV5-shTNF). TNFalpha gene silencing was validated in vitro with mouse macrophages. Mice with collagen-induced arthritis were injected in the ankle and knee joints, at disease onset, with either rAAV5-shTNF or control rAAV5-eGFP vectors (5 x 10(9) particles). Arthritis severity was assessed clinically and histologically, and immunologic response was examined. Local and systemic transgene expression was monitored using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemical analysis, and enzyme-linked immunosorbent assay. RESULTS: After a single injection of rAAV5-shTNF into inflamed joints, local TNFalpha gene silencing provided rapid and long-term suppression of arthritis progression and reduced joint damage compared with that observed in control groups. Treatment with rAAV5-shTNF was associated with decreased proliferation and interferon-gamma production by antigen-stimulated T cells from draining lymph nodes, and the potency of this treatment was similar to that observed with other treatment strategies targeting TNFalpha at the protein level, either locally or systemically. CONCLUSION: Our data present the first proof-of-concept for the application of rAAV5-mediated RNAi-based gene therapy for local blockade of inflammation in experimental arthritis.

Peripheral blood T4 cell surface CCR5 density as a marker of activity in rheumatoid arthritis treated with anti-CD20 monoclonal antibody.

The chemokine (C-C motif) receptor CCR5 and its ligand CCL5 play key roles in the intra-articular recruitment of peripheral blood mononuclear cells (PBMC) in rheumatoid arthritis (RA). Therefore, using quantitative cytofluorometry, we followed T4 cell surface CCR5 density in 27 subjects with RA before and after treatment with the anti-CD20 monoclonal antibody rituximab. We observed low T4 cell surface CCR5 densities before treatment, which correlated positively with disease activity, as determined using a disease activity score evaluated on 28 joints (DAS 28), and negatively with CCL5 mRNA concentrations in PBMC, contrasting with a high proportion of intracellular CCR5 molecules, a pattern compatible with ligand-induced CCR5 internalization. At 3 months post-treatment, CCL5 mRNA expression in PBMC declined, whereas T4 cell surface CCR5 densities increased proportionally to the decrease in DAS 28. Thus, peripheral blood T4 cell surface CCR5 density is a good surrogate marker of RA activity and of the efficiency of anti-CD20 therapy.

Inflammatory cytokine regulation of transgene expression in human fibroblast-like synoviocytes infected with adeno-associated virus.

OBJECTIVE: An ideal gene transfer vector for chronic inflammatory diseases such as rheumatoid arthritis (RA) would provide local transgene expression only when the disease is active. To determine whether adeno-associated virus (AAV) possesses this ability, the effects of inflammatory cytokines on transgene expression were evaluated in human RA fibroblast-like synoviocytes (FLS). METHODS: Human FLS were infected with AAV in the presence or absence of inflammatory cytokines or synovial fluid obtained from patients with RA. Transgene expression was monitored by either enzyme-linked immunosorbent assay or flow cytometry. Transgene messenger RNA (mRNA) was measured by real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Inflammatory cytokines increased transgene expression in FLS by up to 60-fold. Synovial fluid from patients with RA, but not from patients without arthritis, was also able to increase expression in synoviocytes. Protein expression correlated with transgene mRNA levels. The enhanced expression required the continued presence of cytokines because, upon removal, transgene expression returned to baseline levels. Expression could be repeatedly reinduced by reexposure to cytokines. The effect was not promoter specific and was demonstrated to be phosphatidylinositol 3-kinase-dependent. CONCLUSION: These results suggest that expression of a therapeutic transgene can be controlled by the presence of inflammation following AAV gene transfer, making it an attractive vector for chronic inflammatory diseases such as RA.

Complexation of dimethylmagnesium with alpha-diimines; structural and EPR characterisation of single electron and alkyl transfer products.

Treatment of dimethylmagnesium with the alpha-diimine ligands Ar'N=C(R)C(R)=NAr' [R = naphth-1,8-diyl (1), H (2), CH3 (3); Ar' = 2,6-diisopropylphenyl] in diethyl ether provides the neutral methyl-bridged dimeric complexes [(alpha-diimine-.)Mg+(mu-CH3)]2 via single electron transfer (SET) to the coordinated diimine and elimination of a methyl radical. These biradical species have been characterised by EPR spectroscopy and, for the ligand , X-ray crystallography. In the presence of THF the reaction of ligand proceeds to the diamagnetic [(ene-1,2-diamide)Mg(THF)3] complex in which the diimine ligand has been doubly reduced to an ene-diamide by two successive SET processes. Comparison of the structural data for the free ligand with that obtained for the alpha-diimine radical anion and ene-diamide complexes shows the expected increases in C-N, and decreases in C-C, bond lengths within the N-C-C-N unit consistent with the progressive reduction of the ligand. In the case of ligand , reaction at low temperature provides the complex [Mg(mu2-Me){Ar'NC(Me)2C(Me)NAr'}]2 in which methyl transfer to a ligand imine carbon atom has occurred. This species has also been structurally characterised. This contrasts with the formation of the radical species at room temperature, and indicates the involvement of an intermediate in which the radical products of the SET process are held in close proximity by the solvent cage. Two competing processes of methyl radical escape and methyl transfer to the ligand account for the formation of the observed products at different temperatures.

Primary cutaneous Nocardia otitidiscaviarum infection in a patient with rheumatoid arthritis treated with infliximab.

Anti-tumor necrosis factor-a (anti-TNF-a) therapy strategies result in significant clinical benefits in patients with rheumatoid arthritis, but with an increased rate of serious infectious diseases. We describe a patient receiving infliximab who developed a primary cutaneous Nocardia otitidiscaviarum infection after a skin injury.

Structural and EPR characterisation of single electron and alkyl transfer products from reaction of dimethyl magnesium with bulky alpha-diimine ligands.

Treatment of dimethylmagnesium with bulky alpha-diimine ligands provides either the biradical methyl-bridged complexes [(alpha-diimine-.)Mg+(mu-CH3)]2 via single electron transfer (SET), or the product of methyl transfer to an imine carbon atom depending upon conditions.

The first structural characterisation of a group 2 metal alkylperoxide complex: comments on the cleavage of dioxygen by magnesium alkyl complexes.

A new high-yield synthesis of [(PhCH(2))(2)Mg(thf)(2)] and [[(PhCH(2))CH(3)Mg(thf)](2)] via benzylpotassium has allowed a simple entry into benzylmagnesium coordination chemistry. The syntheses and X-ray crystal structures of both [(eta(2)-Me(2)NCH(2)CH(2)NMe(2))Mg(CH(2)Ph)(2)] and [eta(2)-HC[C(CH(3))NAr'](2)Mg(CH(2)Ph)(thf)] (Ar'=2,6-diisopropylphenyl) are reported. The latter beta-diketiminate complex reacts with dioxygen to provide a 1:2 mixture of dimeric benzylperoxo and benzyloxo complexes. The benzylperoxo complex [[eta(2)-HC[C(CH(3))NAr'](2)Mg(mu-eta(2):eta(1)-OOCH(2)Ph)](2)] is the first example of a structurally characterised Group 2 metal-alkylperoxo complex and contains the benzylperoxo ligands in an unusual mu-eta(2):eta(1)-coordination mode, linking the two five-coordinate magnesium centres. The O[bond]O separation in the benzylperoxo ligands is 1.44(2) A. Reaction of the benzylperoxo/benzyloxo complex mixture with further [eta(2)-HC[C(CH(3))NAr'](2)Mg(CH(2)Ph)(thf)] results in complete conversion of the benzylperoxo species into the benzyloxo complex. This reaction, therefore, establishes the cleavage of dioxygen by this system as a two-step process that involves initial oxygen insertion into the Mg[bond]CH(2)Ph bond followed by O[bond]O/Mg[bond]C sigma-bond metathesis of the resulting benzylperoxo ligand with a second Mg[bond]CH(2)Ph bond. The formation of a 1:2 mixture of the benzylperoxo and benzyloxo species indicates that the rate of the insertion is faster than that of the metathesis, and this is shown to be consistent with a radical mechanism for the insertion process.