RHEUMASEARCH

Evaluation of cardiovascular risk in patients with rheumatoid arthritis. Do cardiovascular biomarkers offer added predictive ability over established clinical risk scores?

Arthritis Care Res (Hoboken). 2012 Feb 2. doi: 10.1002/acr.21631. [Epub ahead of print]
 
Source
Division of Rheumatology, Department of Internal Medicine, Geneva, University Hospitals, Switzerland; Division of Clinical Epidemiology, University of Geneva, School of Medicine, Switzerland. axel.finckh@hcuge.ch.
Abstract
BACKGROUND:
Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular (CV) disease. CV risk can be estimated using established clinical risk scores; however traditional risk factors do not perform as well in RA patients. Reliable CV risk stratification remains an unmet clinical need in the RA population. It is unknown whether emergent biomarkers increase the predictive ability of clinical scores for CV risk in RA.

 
OBJECTIVE:
To determine whether adding C-reactive protein, anti-citrullinated peptide antibodies, rheumatoid factor, N-terminal pro-Brain Natriuretic peptide (NT-proBNP), oxidized LDL (oxLDL) or anti-apolipoprotein A-1 IgG (anti-apoA-1) to the 10 year-Framingham cardiovascular risk score (FRS) could improve its CV prognostic accuracy in RA.

 
METHODS:
We performed an ancillary study derived from a prospective single center cohort including 118 RA patients without cardiovascular disease at baseline. The FRS and the various biomarkers were assessed at enrollment and their prognostic accuracy was determined using receiver operating characteristic (ROC) curve analysis. The incremental predictive ability of biomarkers was assessed using the integrated discrimination improvement (IDI) statistics.

 
RESULTS:
During a median follow-up of 9 years, the incidence of CV events was 16%. Both the FRS and 3 of the biomarkers (NT-proBNP, oxLDL, anti-apoA-1) were significant predictors of subsequent CV events (area under the ROC curve (AUC) between 0.68 - 0.73). Anti-apoA-1 was the only biomarkers to improve significantly the FRS's prognostic ability, with AUCs increasing from 0.72 to 0.81 and the IDI improving by 175% (p<0.001).

 
CONCLUSION:
Among the biomarkers tested, only anti-apoA-1 significantly improved the FRS predictive ability. © 2012 by the American College of Rheumatology.

Differential drug retention between anti-TNF agents and alternative biological agents after inadequate response to an anti-TNF agent in rheumatoid arthritis patients.

Ann Rheum Dis. 2012 Jan 30. [Epub ahead of print]
 
Source
1Rheumatology, University Hospitals of Geneva, Geneva, Switzerland.
Abstract
BACKGROUND:
After inadequate response to an antitumour necrosis factor (aTNF) agent for treatment of rheumatoid arthritis (RA), rheumatologists can choose an alternative aTNF or a biological agent with another mode of action (non-aTNF biological (non-aTNF-Bio)).
 
OBJECTIVE:
To compare drug retention rates of non-aTNF-Bio with alternative aTNF.
 
METHODS:
All patients within the Swiss RA cohort (SCQM-RA) treated with an alternative biotherapy after a prior inadequate response to aTNF were analysed. The drug retention of alternative aTNF was compared with non-aTNF-Bio using Cox proportional hazards models, adjusted for potential confounders.
 
RESULTS:
1485 treatment courses after aTNF failure were available for analysis, 853 with alternative aTNF and 632 with non-aTNF-Bio. The median drug retention was 32 months (IQR 14-54) on non-aTNF-Bio versus 21 months (IQR 8-53) on alternative aTNF, or a 50% reduction drug discontinuation risk in favour of non-aTNF-Bio (adjusted hazard ratio (HR) for non-aTNF-Bio: 0.50 (95% CI 0.41 to 0.62)). This effect appears to be modified by the type of prior aTNF failure, with a larger difference in favour of non-aTNF-Bio in patients having experienced a primary failure with a previous aTNF (HR: 0.33 (95% CI 0.24 to 0.47), p<0.001).
 
CONCLUSION:
After inadequate response to aTNF, and particularly after primary failure, patients on a non-aTNF-Bio agent have significantly higher drug retention rates.
 

Articular inflammation is controlled by myeloid cell-derived interleukin 1 receptor antagonist during the acute phase of arthritis in mice.

Ann Rheum Dis. 2012 Feb;71(2):281-7. Epub 2011 Nov 9.
 
Source
Division of Rheumatology, University Hospitals of Geneva, Switzerland.
Abstract
OBJECTIVES:
To define the cell type (myeloid vs other cells) specific effect of interleukin 1 (IL-1) receptor antagonist (IL-1Ra) deficiency on the acute inflammatory phase of arthritis.
 
METHODS:
Arthritis was induced by K/BxN serum transfer in wild-type (WT), IL-1Ra-deficient (IL-1Ra(-/-)) and conditional knockout mice. In the latter, IL-1Ra production was specifically targeted in myeloid cells (IL-1Ra(?M)) or in both hepatocytes and myeloid cells (IL-1Ra(?H+M)). Arthritis severity was clinically evaluated and ankle sections were scored for synovial inflammation and cartilage erosion. Quantitative RT-PCR, western blot and immunohistochemical analyses measured expression, localisation and cellular sources of the different IL-1Ra isoforms in arthritic joints.
 
RESULTS:
Total and myeloid cell-specific IL-1Ra deficiency was associated with increased arthritis severity, although disease incidence was similar to that of WT mice. Increased clinical scores were associated with exacerbated synovial inflammation. All IL-1Ra isoforms, except for intracellular (ic)IL-1Ra2, were expressed in arthritic joints of WT mice. In contrast, production of secreted (s)IL-1Ra and icIL-1Ra3 isoforms was markedly decreased in arthritic joints of both IL-1Ra(?M) and IL-1Ra(?H+M) mice. Immunohistochemical and western blot analyses suggested that the icIL-1Ra1 isoform is produced primarily by synovial fibroblasts.
 
CONCLUSION:
Myeloid cell-derived IL-1Ra, including both sIL-1Ra and icIL-1Ra3 isoforms, controls articular inflammation during the acute phase of K/BxN serum transfer-induced arthritis.
 

The mouse interleukin (Il)33 gene is expressed in a cell type- and stimulus-dependent manner from two alternative promoters.

J Leukoc Biol. 2012 Jan;91(1):119-25. Epub 2011 Oct 19.
 
Source
Division of Rheumatology, University Hospital, and Department of Pathology and Immunology, University of Geneva School of Medicine, Geneva, Switzerland.
Abstract
GenBank entries for mouse Il33 reveal the existence of two transcripts, Il33a and Il33b, with different 5'UTRs but coding for the same protein. We investigated expression of these transcripts in different mouse organs and cell types in basal and inflammatory conditions. Il33a and Il33b mRNAs start with different noncoding first exons, transcribed from different promoter regions, which both contain a consensus TATA-like sequence. Constitutive Il33a mRNA expression was detected in mouse stomach, lung, spleen, and brain, whereas basal Il33b mRNA expression was observed only in the stomach. Expression of both transcripts increased after systemic LPS administration. In vitro, we observed high constitutive expression of Il33 transcripts in MEFs. Constitutive Il33a mRNA expression was observed also in BMDCs, where it was preferentially increased in response to poly(I:C), whereas LPS increased levels of Il33a and Il33b mRNA. In contrast, BMMs and Raw 264.7 cells did not express Il33 mRNA constitutively, and LPS stimulation selectively induced expression of Il33b mRNA in these cells. Our data indicate that the Il33 gene is expressed from two alternative promoters in the mouse and that the relative expression of Il33a and Il33b transcripts is cell type- and stimulus-dependent.

 

Adalimumab in acute sciatica reduces the long-term need for surgery: a 3-year follow-up of a randomised double-blind placebo-controlled trial.

Ann Rheum Dis. 2011 Oct 13. [Epub ahead of print]
 
Source
1Division of Rheumatology, University Hospitals of Geneva, Geneva, Switzerland. Abstract
IntroductionTwo subcutaneous injections of adalimumab in severe acute sciatica significantly reduced the number of back operations in a short-term randomised controlled clinical trial.
 
OBJECTIVE:
To determine in a 3-year follow-up study whether the short-term benefit of adalimumab in sciatica is sustained over a longer period of time.
 
METHODS:
The primary outcome of this analysis was incident discectomy. Three years after randomisation, information on surgery could be retrieved in 56/61 patients (92%).A multivariate Cox proportional hazard models, adjusted for potential confounders, was used to determine factors predisposing to surgery.
 
RESULTS:
Twenty-three (41%) patients had back surgery within 3 years, 8/29 (28%) in the adalimumab group and 15/27 (56%) in the placebo group, p=0.04. Adalimumab injections reduced the need for back surgery by 61% (HR)=0.39 (95% CI 0.17 to 0.92). In a multivariate model, treatment with a tumour necrosis factor-a antagonist remained the strongest protective factor (HR=0.17, p=0.002). Other significant predictors of surgery were a good correlation between symptoms and MRI findings (HR=11.6, p=0.04), baseline intensity of leg pain (HR=1.3, p=0.06), intensity of back pain (HR=1.4, p=0.03) and duration of sickness leave (HR=1.01 per day, p=0.03).
 
CONCLUSION:
A short course of adalimumab in patients with severe acute sciatica significantly reduces the need for back surgery.
 

IL-36R ligands are potent regulators of dendritic and T cells.

Blood. 2011 Nov 24;118(22):5813-23. Epub 2011 Aug 22.
 
Source
Division of Rheumatology and Department of Pathology-Immunology, University of Geneva School of Medicine, Geneva, Switzerland.
Abstract
IL-36a (IL-1F6), IL-36ß (IL-1F8), and IL-36? (IL-1F9) are members of the IL-1 family of cytokines. These cytokines bind to IL-36R (IL-1Rrp2) and IL-1RAcP, activating similar intracellular signals as IL-1, whereas IL-36Ra (IL-1F5) acts as an IL-36R antagonist (IL-36Ra). In this study, we show that both murine bone marrow-derived dendritic cells (BMDCs) and CD4(+) T lymphocytes constitutively express IL-36R and respond to IL-36a, IL-36ß, and IL-36?. IL-36 induced the production of proinflammatory cytokines, including IL-12, IL-1ß, IL-6, TNF-a, and IL-23 by BMDCs with a more potent stimulatory effect than that of other IL-1 cytokines. In addition, IL-36ß enhanced the expression of CD80, CD86, and MHC class II by BMDCs. IL-36 also induced the production of IFN-?, IL-4, and IL-17 by CD4(+) T cells and cultured splenocytes. These stimulatory effects were antagonized by IL-36Ra when used in 100- to 1000-fold molar excess. The immunization of mice with IL-36ß significantly and specifically promoted Th1 responses. Our data thus indicate a critical role of IL-36R ligands in the interface between innate and adaptive immunity, leading to the stimulation of T helper responses.
 

Autoimmunity and inflammation are independent of class II transactivator type PIV-dependent class II major histocompatibility complex expression in peripheral tissues during collagen-induced arthritis.

Arthritis Rheum. 2011 Nov;63(11):3354-63. doi: 10.1002/art.30522.
 
Source
University Medical Center and University of Geneva, Geneva, Switzerland. jean-marc.waldburger@hcuge.ch
Abstract
OBJECTIVE:
To determine the regulation of class II major histocompatibility complex (MHC) expression in fibroblast-like synoviocytes (FLS) in order to investigate their role as nonprofessional antigen-presenting cells in collagen-induced arthritis (CIA).
 
METHODS:
Expression of class II MHC, class II MHC transactivator (CIITA), and Ciita isoforms PI, PIII, and PIV was examined by real-time quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry in human synovial tissues, arthritic mouse joints, and human and murine FLS. CIA was induced in mice in which isoform PIV of Ciita was knocked out (PIV(-/-) ), in PIV(-/-) mice transgenic for CIITA in the thymus (K14 CIITA), and in their control littermates.
 
RESULTS:
HLA-DRA, total CIITA, and CIITA PIII messenger RNA levels were significantly increased in synovial tissue samples from patients with rheumatoid arthritis compared with the levels in tissue from patients with osteoarthritis. Human FLS expressed surface class II MHC via CIITA PIII and PIV, while class II MHC expression in murine FLS was entirely mediated by PIV. Mice with a targeted deletion of CIITA PIV lack CD4+ T cells and were protected against CIA. The expression of CIITA was restored in the thymus of PIV(-/-) K14 CIITA-transgenic mice, which had a normal CD4+ T cell repertoire and normal surface levels of class II MHC on professional antigen-presenting cells, but did not induce class II MHC on FLS. Synovial inflammation and immune responses against type II collagen were similar in PIV(-/-) K14 CIITA-transgenic mice and control mice with CIA, but bone erosion was significantly reduced in the absence of PIV.
 
CONCLUSION:
Overexpression of class II MHC is tightly correlated with CIITA expression in arthritic synovium and in FLS. Selective targeting of Ciita PIV in peripheral tissues abrogates class II MHC expression by murine FLS but does not protect against inflammation and autoimmune responses in CIA.
 

Interleukin-33 biology with potential insights into human diseases.

Nat Rev Rheumatol. 2011 Jun;7(6):321-9. Epub 2011 Apr 26.
 
Source
Division of Rheumatology, University Hospitals of Geneva & Department of Pathology-Immunology, University of Geneva School of Medicine, 26 avenue Beau-Séjour, 1211 Geneva 14, Switzerland.
Abstract
Interleukin (IL)-33 is a member of the IL-1 family of cytokines. IL-33 is a nuclear protein that is also released into the extracellular space, and thus acts as a dual-function molecule, as does IL-1a. Extracellular IL-33 binds to the cell-surface receptor ST2, leading to the activation of intracellular signaling pathways similar to those used by IL-1. Unlike conventional cytokines, IL-33 might be secreted via unconventional pathways, and can be released upon cell injury as an alarmin. IL-33 is expressed in cells that are in contact with the environment, and acts as an early inducer of inflammation. Its production is then upregulated in inflamed tissues, thus contributing to the further amplification of inflammatory responses. Studies of IL-33-deficient mice will provide more information on intracellular functions of this cytokine. A large body of evidence supports the pathogenic role of IL-33 in asthma and possibly other inflammatory airway conditions. Furthermore, IL-33 has been shown to be involved in experimental models of arthritis and potentially has a pathogenic role in ulcerative colitis and fibrotic conditions, suggesting that IL-33 antagonists might be of interest for the treatment of asthma, rheumatoid arthritis and ulcerative colitis. However, IL-33 also appears to exert important functions in host defense against pathogens and to display cardioprotective properties, which might have implications for the clinical use of IL-33 blockade.

 

Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis.

Joint Bone Spine. 2012 Jan;79(1):32-7. Epub 2011 Mar 26.
 
Source
Division of Rheumatology, University Hospital, Geneva, Switzerland; Department of Pathology and Immunology, University of Geneva School of Medicine, 1, rue Michel-Servet, 1211 Geneva 4, Switzerland.
Abstract
OBJECTIVES:
Recent evidence suggests a role for interleukin (IL)-33 and its receptor ST2 in arthritis. In this study, we quantified IL-33 and soluble (s)ST2 levels in serum and synovial fluid (SF), and assessed synovial IL-33 expression levels and pattern in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or osteoarthritis (OA).
 
METHODS:
Serum and SF IL-33 and sST2 levels were assessed by ELISA. IL-33 mRNA was quantified by RT-qPCR. Synovial IL-33 protein expression pattern was examined by immunohistochemistry.
 
RESULTS:
Serum and SF IL-33 levels tended to be higher in RA than in OA patients. In contrast to RA, IL-33 was not detectable in PsA serum and SF. Serum sST2 levels were higher in RA than in OA. There was a wide variation of synovial tissue IL-33 mRNA expression within each disease group and IL-33 mRNA levels were not significantly different between the groups. A similar IL-33 protein expression pattern was observed in RA, PsA and OA synovium, with strong nuclear expression of IL-33 in endothelial cells and, in a subset of RA, PsA and OA patients, in cells morphologically consistent with synovial fibroblasts.
 
DISCUSSION/CONCLUSIONS:
This study confirms increased circulating IL-33 levels in RA. In addition, we report that IL-33 is undetectable in the serum or SF of PsA patients. Local expression of IL-33 in the synovium was observed at similar variable levels in RA, PsA and OA, suggesting that inflamed joints do not represent the primary source of elevated serum and SF levels of IL-33 in RA.
 

Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to the AS03-adjuvanted pandemic influenza vaccine: a prospective, open-label, parallel-cohort, single-center study.

Arthritis Rheum. 2011 Jun;63(6):1486-96. doi: 10.1002/art.30325.
 
Source
University Hospitals of Geneva and University of Geneva, Geneva, Switzerland. cem.gabay@hcuge.ch
Abstract
OBJECTIVE:
To identify the determinants of antibody responses to adjuvanted split influenza A (H1N1) vaccines in patients with inflammatory rheumatic diseases.
 
METHODS:
One hundred seventy-three patients (82 with rheumatoid arthritis, 45 with spondylarthritis, and 46 with other inflammatory rheumatic diseases) and 138 control subjects were enrolled in this prospective single-center study. Controls received 1 dose of adjuvanted influenza A/09/H1N1 vaccine, and patients received 2 doses of the vaccine. Antibody responses were measured by hemagglutination inhibition assay before and 3-4 weeks after each dose. Geometric mean titers (GMTs) and rates of seroprotection (GMT=40) were calculated. A comprehensive medical questionnaire was used to identify the determinants of vaccine responses and adverse events.
 
RESULTS:
Baseline influenza A/09/H1N1 antibody levels were low in patients and controls (seroprotection rates 14.8% and 14.2%, respectively). A significant response to dose 1 was observed in both groups. However, the GMT and the seroprotection rate remained significantly lower in patients (GMT 146 versus 340, seroprotection rate 74.6% versus 87%; both P<0.001). The second dose markedly increased antibody titers in patients, with achievement of a similar GMT and seroprotection rate as elicited with a single dose in healthy controls. By multivariate regression analysis, increasing age, use of disease-modifying antirheumatic drugs (DMARDs) (except hydroxychloroquine and sulfasalazine), and recent (within 3 months) B cell depletion treatment were identified as the main determinants of vaccine responses; tumor necrosis factor a antagonist treatment was not identified as a major determinant. Immunization was well tolerated, without any adverse effect on disease activity.
 
CONCLUSION:
DMARDs exert distinct influences on influenza vaccine responses in patients with inflammatory rheumatic diseases. Two doses of adjuvanted vaccine were necessary and sufficient to elicit responses in patients similar to those achieved with 1 dose in healthy controls.
 

Absence of up-regulation for a proliferation-inducing ligand in Sjögren's sialadenitis lesions.

Rheumatology (Oxford). 2011 Jul;50(7):1211-5. Epub 2011 Feb 16.
 
Source
Laboratory of Oral Histopathology, Division of Stomatology, Faculty of Medicine, Department of Pathology-Immunology, Geneva, Switzerland.
Abstract
OBJECTIVE:
To determine whether a proliferation-inducing ligand (APRIL) has a role in the survival of plasma cells infiltrating salivary glands from SS patients.
 
METHODS:
We performed immunological staining for APRIL in minor salivary glands from SS with a pair of antibodies specifically recognizing APRIL-producing cells and secreted APRIL.
 
RESULTS:
Despite high leucocyte infiltration, APRIL-producing cells, identified as neutrophils, were rare in SS salivary glands. Keratinocytes from the adjacent oral epithelium also produced APRIL, but we never detected significant levels of secreted APRIL in SS salivary glands. We obtained similar results with B-cell lymphomas associated with SS. In fact, there was no significant difference in APRIL production and the level of secreted APRIL in these pathological samples compared with normal corresponding tissues.
 
CONCLUSION:
The combined observation that APRIL production is not up-regulated in lesions from SS patients, and that secreted APRIL is not retained in these lesions, indicates that plasma cells frequently present in SS lesions may not rely on APRIL for survival, as they do in other rheumatic diseases.
 

Spontaneous secretion of interleukin-17 and -22 by human cervical cells in Chlamydia trachomatis infection.

Microbes Infect. 2011 Feb;13(2):167-78. Epub 2010 Oct 27.
 
Source
Institute of Pathology-ICMR, Safdarjung Hospital Campus, New Delhi, India.
Abstract
To investigate whether IL-17A (IL-17) and IL-22 are produced in response to Chlamydia trachomatis infection, the cervical washes of 27 women with C. trachomatis infection and 17 C. trachomatis negative controls were collected. The levels of cytokines were determined in the cervical wash and in the supernatant of cervical and systemic cell cultures upon C. trachomatis antigen stimulation. C. trachomatis infection appeared to activate local IL-17 and IL-22 production more efficiently than IFN-? production. In the cervical wash of infected women, median concentrations of IL-17 and -22 were 5- and 3-fold higher, respectively, than in negative controls. The spontaneous intracellular expression of these cytokines was analysed by flow cytometry in blood and cervical cells and 26% of cervical mononuclear cells from infected women were shown to produce IL-22 and 12% to coproduce IL-17 and IL-22. In addition, it was demonstrated that 20-25% of IL-22 producing and IL-17-IL-22 coproducing cervical CD4+ T cells expressed the mucosal homing receptor CCR6. These results suggest that CCR6 is involved in the migration of these cells to the cervix and that IL-17 and IL-22 might play a role in the immune response at the site of C. trachomatis infection.