Abstract Objective Heart involvement in systemic sclerosis (SSc) is a strong prognostic factor. Our aim was to examine left ventricle (LV) and right ventricle (RV) involvement. Methods We examined LV ...and RV, systolic and diastolic functions, using echocardiography and Tissue-Doppler echocardiography (TDE) indexes, in a cohort of 212 consecutive SSc patients seen during a 9-month period at 2 institutions (Paris, France and Los Angeles, USA). They were compared to 50 healthy controls. Results When compared to controls, SSc patients had consistently impaired RV indices that include reduced RV contractility ( p < 0.001), larger right atrial area ( p = 0.027) and overall RV diastolic dysfunction (25% of SSc patients versus 0% of controls; p < 0.001). Patients also exhibited alterations in LV contractility and diastolic function ( p < 0.001 each). In multivariate analysis, RV contractility as expressed by the TDE ST parameter was associated withT DE LV contractility SM ( p = 0.030), DLCO ( p = 0.013) whereas RV diastolic impairment was associated with systolic pulmonary artery pressure ( p = 0.015). A subgroup of 27 patients had proven pulmonary arterial hypertension (PAH); comparison between SSc-PAH versus SSc free of PAH patients revealed reduced LV diastolic function (transmitral E/A ratio, p = 0.045 and EA < 10 cm/s, p = 0.029), reduced overall RV contractility (21.5% versus 4.5%; p = 0.03) and reduced RV diastolic function (transtricuspid E/A ratio; p = 0.014 and 68% versus 29% with impaired function; p = 0.001). Conclusions Our data show that RV is commonly affected in SSc with predominant impaired diastolic function. Several factors, including primary heart, lung vascular disease and pulmonary hypertension, contribute to such impairment.
To evaluate the possible merit of endothelial markers for the prediction of ischaemic digital ulcers in patients with systemic sclerosis (SSc).
Circulating endothelial progenitor cells (EPC), ...circulating endothelial cells and serum levels of placental growth factor (PlGF), soluble vascular adhesion molecule and vascular endothelial growth factor were measured in a prospective cohort of 100 SSc patients. The primary outcome was the occurrence of one or more new ischaemic digital ulcers during a planned 3-year follow-up.
After the follow-up period, 17 patients developed new digital ulcers. By multivariate analysis focused on biomarkers, high PlGF serum levels and low EPC counts were identified as predictors of the occurrence of at least one new digital ulcer. In a secondary model including biomarkers together with clinical SSc characteristics all predictors of digital ulcers defined by p≤0.1 in univariate analysis, high PlGF serum levels (HR 7.26, 95% CI 1.92 to 27.41) and a history of digital ulcers (HR 9.32, 95% CI 1.51 to 59.83) were identified as independent predictors of a new digital ulcer. In an alternative model excluding patients with a history of digital ulcers at baseline, high PlGF serum levels (HR 13.46, 95% CI 1.58 to 114.73) and low EPC counts (HR 7.95, 95% CI 2.09 to 30.09) remained predictive of new digital ulcer occurrence during follow-up.
This study identified high PlGF serum levels and low circulating EPC counts as predictors of new digital ulcers in SSc. It highlights the critical role of angiogenesis in this vascular outcome. These markers may improve digital ulcer risk stratification and therefore allow earlier therapeutic intervention.
Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory ...rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10(-5) were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10(-8), OR = 0.69, 95% CI 0.60-0.79; rs6457617, P = 1.14×10(-7) and rs9275245, P = 1.39×10(-7). Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10(-5), OR = 1.36 1.18-1.56) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10(-5)) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10(-10), OR:1.25), TNIP1 (P = 4.68×10(-9), OR:1.31), and RHOB loci (P = 3.17×10(-6), OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis.
The excess of adipose tissue in obese individuals may have immunomodulating properties and pharmacokinetic consequences. The aim of this study was to determine whether body mass index (BMI) affects ...response to infliximab (IFX) in ankylosing spondylitis (AS) patients.
In 155 patients retrospectively included with active AS, the BMI was calculated before initiation of IFX treatment (5 mg/kg intravenously). After 6 months of treatment, changes from baseline in BASDAI, Visual Analogue Scale (VAS) pain, C-reactive protein (CRP) level, and total dose of nonsteroidal antiinflammatory drug (NSAID) were dichotomized with a threshold corresponding to a decrease of 50% of initial level of the measure, into binary variables assessing response to IFX (BASDAI50, VAS50, CRP50, NSAID50). Whether the BMI was predictive of the response to IFX therapy according to these definitions was assessed with logistic regression.
Multivariate analysis found that a higher BMI was associated with a lower response for BASDAI50 (P = 0.0003; OR, 0.87; 95% CI (0.81 to 0.94)), VAS50 (P < 0.0001; OR, 0.87; 95% CI (0.80 to 0.93)); CRP50 (P = 0.0279; OR, 0.93; 95% CI (0.88 to 0.99)), and NSAID50 (P = 0.0077; OR, 0.91; 95% CI (0.85 to 0.97)), criteria. According to the three WHO BMI categories, similar results were found for BASDAI50 (77.6%, 48.9%, and 26.5%; P < 0.0001), VAS50 (72.6%, 40.4%, and 16.7%; P < 0.0001); CRP50 (87.5%, 65.7%, and 38.5%; P = 0.0001), and NSAID50 (63.2%, 51.5%, and 34.6%; P = 0.06).
This study provides the first evidence that a high BMI negatively influences the response to IFX in AS. Further prospective studies, including assessment of the fat mass, pharmacokinetics, and adipokines dosages are mandatory to elucidate the role of obesity in AS IFX response.
Abstract Objective To compare mortality data obtained from randomized controlled trials for the 5 tumor necrosis factor-α (TNF-α) inhibitors used in the treatment of rheumatoid arthritis. Methods A ...systematic review of articles published up to November 2014 was performed using electronic databases. We included randomized, controlled trials, with a follow-up period of at least 24 weeks, comparing TNF-α inhibitors to placebo or disease-modifying antirheumatic drugs. The primary outcome was the occurrence of all-cause mortality. Results Twenty-three studies were selected. These articles included 6525 patients in the anti-TNF-α group and 3523 in the control group. The duration of patient follow-up ranged from 24 to 104 weeks. The risk of all-cause mortality in patients receiving TNF-α inhibitors was not significantly different from those receiving the comparator (odds ratio 1.32; 95% confidence interval, 0.76-2.29). Subgroup analyses with respect to the molecule used, the dose received, the use of TNF-α inhibitors as monotherapy or combination therapy, or the quality of the trial did not modify the findings. Conclusion This meta-analysis performed on a large number of patients and including the 5 TNF-α inhibitors currently available shows no increased risk of medium-term all-cause mortality in patients with rheumatoid arthritis.
Objective
To investigate ultrasonographic (US) hand features in systemic sclerosis (SSc) patients and their relationship with clinical, biologic, and radiographic data.
Methods
Fifty‐two consecutive ...SSc patients were included in a cross‐sectional observational study together with 24 rheumatoid arthritis (RA) patients enrolled as controls. All patients underwent clinical examination, including tender and swollen joint counts, measurement of disability indices, and hand/wrist radiographs. US was performed on the hand and wrist joints and was aimed at the detection of synovitis, tenosynovitis, and calcinosis.
Results
Synovitis and tenosynovitis were more frequently detected with US in SSc patients (46% and 27%, respectively) than with clinical examination (15% and 6%, respectively; P < 0.01 for both comparisons). Fifty‐seven percent of patients had inflammatory synovitis (mostly Doppler grade 1), and tenosynovitis was either inflammatory or fibrotic. Calcifications were observed using US and radiographs in 40% and 36% of SSc patients, respectively (P = 0.8). As compared to RA, US features specific to SSc were sclerosing tenosynovitis (P < 0.01) and soft tissue calcifications (P = 0.01).
Conclusion
Our study confirms that articular involvement in SSc is underestimated by a single clinical examination. It is characterized by mild inflammatory changes and the specific findings include sclerotic US aspects together with calcinosis. Further prospective studies are warranted to evaluate the predictive value of these findings and determine whether they should be considered for adapting a therapeutic strategy.
To investigate the contribution of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of dermal fibrosis on gene inactivation and targeted molecular strategies.
Human skin ...expression of DNAM-1 was determined by immunohistochemistry. Mice deficient for DNAM-1 (dnam1-/-) and wild-type controls (dnam1+/+) were injected with bleomycin or NaCl. Infiltrating leucocytes, T cells, B cells and monocytes were quantified and inflammatory cytokines were measured in lesional skin of dnam1-/- and dnam1+/+ mice. The anti-fibrotic potential of a DNAM-1 neutralising monoclonal antibody (mAb) was evaluated in the mouse model of bleomycin-induced dermal fibrosis.
Overexpression of DNAM-1 was detected in the skin of patients with SSc (systemic sclerosis). Dnam1-/- mice were protected from bleomycin-induced dermal fibrosis with reduction of dermal thickening (75±5%, p=0.03), hydroxyproline content (46±8%, p=0.04) and myofibroblast counts (39±5%, p=0.01). Moreover, the number of T cells was significantly decreased in lesional skin of dnam1-/- mice (69±15%, p=0.0007). Dnam1-/- mice also displayed decreased levels of TNF-α and IL-6 in lesional skin. Consistent with the gene inactivation strategy, treatment of mice with DNAM-1 neutralising mAb prevented dermal fibrosis induced by bleomycin with reduction of dermal thickness (64±6%, p=0.002), hydroxyproline content (61±8%, p=0.004) and myofibroblast counts (83±12%, p=0.002).
An inactivation gene strategy showed that DNAM-1 exerts profibrotic effects by controlling T cell activation and cytokine release. A molecular targeted strategy confirmed that DNAM-1 neutralising mAb has potent antifibrotic properties, supporting the hypothesis that inhibition of DNAM-1 might be a promising new approach for the treatment of SSc and potentially other related fibrotic diseases.
Objective
To elucidate the role of gene candidates involved in pulmonary hypertension (PH) associated with systemic sclerosis (SSc).
Methods
Gene candidates were identified through microarray ...experiments performed on Affymetrix GeneChip Human Exon 1.0 ST arrays in endothelial progenitor cell (EPC)–derived endothelial cells (ECs) obtained from patients with SSc‐associated PH, patients with SSc without PH, and healthy control subjects. Expression of identified gene candidates was assessed by quantitative sandwich enzyme‐linked immunosorbent assay in the serum, and by immunohistochemistry in lesional lung tissue. The functional importance of the identified gene candidates was then evaluated in fos‐related antigen 2–transgenic (Fra‐2–Tg) mice that spontaneously develop SSc‐like features associated with an intense pulmonary vascular remodeling.
Results
Microarray experiments revealed that the matrix metalloproteinase 10 (MMP‐10) gene was the top up‐regulated gene in SSc‐associated PH EPC‐derived ECs. Circulating serum proMMP10 concentrations were markedly increased in patients with SSc‐associated PH compared to SSc patients without PH and healthy controls. Consistent with these observations, a strong MMP10 staining of the thickened wall of distal pulmonary arteries was found both in the lungs of patients with SSc‐associated PH and in the lungs of Fra‐2–Tg mice. Daily treatment of Fra‐2–Tg mice with neutralizing anti‐MMP10 antibodies did not significantly affect the development and severity of pulmonary fibrosis, but did reverse established PH and markedly reduced pulmonary vascular remodeling by reducing cell proliferation, cell survival, and the platelet‐derived growth factor signaling axis.
Conclusion
Gene expression profiling of EPC‐derived ECs identified MMP10 as a novel candidate gene in SSc‐associated PH. MMP10 is overexpressed in the serum and pulmonary arteries of patients with SSc‐associated PH, and its blockade alleviates PH in the Fra‐2–Tg mouse model. MMP10 appears to be a prospective treatment target for this devastating disorder.
Systemic sclerosis: an update in 2008 Allanore, Yannick; Avouac, Jérôme; Kahan, André
Joint, bone, spine : revue du rhumatisme,
12/2008, Volume:
75, Issue:
6
Journal Article
Peer reviewed
Abstract The pathogenic process of systemic sclerosis targets the skin and internal organs, and involves sequential or concomitant abnormalities in blood vessel function, in immunity and ...inflammation, and in subsequent fibroblast activation. These characteristics are disease-specific and may partly explain the unresolved therapeutic strategies. These latter must take into account not only the broad biological abnormalities but also the complexities of the disturbances throughout the duration of the disease. However, recent epidemiological data have suggested a decrease in excess mortality, which may be mostly due to the use of cardiovascular drugs. Indeed, the prognoses of the kidney, heart and pulmonary vascular involvements have been improved. Nevertheless and despite several trials, pulmonary fibrosis remains a challenge with no clear efficacy of the regimen of immunosuppressors that have been investigated. This article deals with current and possible future therapeutic options.
Whipple disease is a rare infection caused by Tropheryma whipplei. Although patients commonly complain of osteoarticular involvement, musculoskeletal manifestations have been poorly described. We ...report cases of Whipple disease with rheumatic symptoms and describe their clinical presentation, modes of diagnosis, and outcomes.
This retrospective multicenter study included patients with Whipple disease diagnosed and referenced between 1977 and 2011 in 10 rheumatology centers in France and Italy.
Twenty-nine patients were included. The median age was 55 years. The median time to diagnosis from first symptoms was 5 years. Polyarthritis was the most frequent presentation (20/29), and was most often chronic, intermittent (19/29), seronegative (22/23), and nonerosive (22/29). In all cases, the symptoms had led to incorrect diagnosis of inflammatory rheumatic disease and immunosuppressants, including biotherapy, were prescribed in most cases (24/29) without success. The diagnosis of Whipple disease was made by histological analysis, molecular biology tests, or both in 21%, 36%, and 43% of the cases, respectively. Duodenal biopsies were performed in most cases (86%). Synovial biopsies were performed in 18% of cases, but all contributed to diagnosis. The clinical outcomes after antibiotic therapy were good for all patients.
Polyarthritis is the main feature observed in cases of Whipple disease; it is seronegative and associated with general and gastrointestinal symptoms. The molecular analysis of duodenal tissue and/or other tissues remains the method of choice to confirm the diagnosis. Reducing the time to diagnosis is important because severe late systemic and fatal forms of the disease may occur.
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