Serum IL-15 in patients with early systemic sclerosis: a potential novel marker of lung disease

The pathogenesis of systemic sclerosis (SSc) is characterized by autoimmunity, vasculopathy and fibrosis. IL-15 is a pleiotropic cytokine that has impact on immune, vascular and connective tissue cells. We therefore investigated IL-15 in the circulation of patients with early SSc and explored possible associations of serum IL-15 with vasculopathy and fibrosis. Serum levels of IL-15 were analysed in 63 consecutive patients with SSc of disease duration less than 4 years and without disease-modifying treatment. Thirty-three age-matched healthy control individuals were enrolled. Serum IL-15 levels were increased in the sera of SSc patients compared with that of healthy control individuals (P < 0.01). Serum IL-15 levels correlated with impaired lung function, assessed both by the vital capacity (P < 0.05) and by the carbon monoxide diffusion capacity (P < 0.05). The association between IL-15 and the vital capacity remained after multiple linear regression analysis. Patients with intermediate serum IL-15 levels had a higher prevalence of increased systolic pulmonary pressure compared with patients with either low or high serum IL-15 levels (P < 0.05). Moreover, increased serum IL-15 levels were associated with a reduced nailfold capillary density in multivariable logistic regression analysis (P < 0.01). Serum IL-15 levels also correlated inversely with the systolic blood pressure (P < 0.01). We conclude that IL-15 is associated with fibrotic as well as vascular lung disease and vasculopathy in early SSc. IL-15 may contribute to the pathogenesis of SSc. IL-15 could also be a candidate biomarker for pulmonary involvement and a target for therapy in SSc

Specific autoantibody profiles and disease subgroups correlate with circulating micro-RNA in systemic sclerosis.

To evaluate the expression profiles of cell-free plasma miRNAs in SSc and to characterize their correlation with disease subgroups (lcSSc and dcSSc) and with autoantibody profiles

The Pronounced Th17 Profile in Systemic Sclerosis (SSc) Together with Intracellular Expression of TGFβ and IFNγ Distinguishes SSc Phenotypes

Contains fulltext : 81194.pdf (publisher's version ) (Open Access)BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease where controversy on Th1/Th2 balance dominates. We investigated whether the recently discovered Th17 pattern was present in SSc. METHODOLOGY AND PRINCIPAL FINDINGS: Patients were subdivided as having limited cutaneous SSc (lcSSc, n = 12) or diffuse cutaneous SSc (dcSSc, n = 24). A further arbitrary subdivision was made between early dcSSc (n = 11) and late dcSSc (n = 13) based upon the duration of disease. As a comparator group 14 healthy controls were studied. CD3+ cells were isolated using FACS and subsequently studied for the expression of CD4, CD8, CD25, CD45Ro, CD45Ra, IL-23, GITR, CD69 and intracellular expression of IL-17, TGFbeta and IFNgamma using flow cytometry. Levels of IL-17, IL-6, IL-1alpha and IL-23 were measured using Bioplex assays. SSc patients had more and more activated CD4+ cells. In addition, CD4, CD45Ro and CD45Ra cells from all SSc patients highly expressed the IL23R, which was associated with a higher IL-17 expression as well. In contrast, IFNgamma and TGFbeta were selectively up regulated in SSc subsets. In line with these observation, circulating levels of IL-17 inducing cytokines IL-6, IL-23 and IL-1alpha were increased in all or subsets of SSc patients. CONCLUSION AND SIGNIFICANCE: The combination of IL-17, IFNgamma and TGFbeta levels in CD45Ro and CD45Ra cells from SSc patients is useful to distinguish between lSSc, ldSSc or edSSc. Blocking Th17 inducing cytokines such as IL-6 and IL-23 may provide a useful tool to intervene in the progression of SSc

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P &lt; 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P &lt; 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P &lt; 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P &lt; 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P &lt; 0.001; OR(BP) = 2.4, P &lt; 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P &lt; 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P &lt; 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Cellular immunity and inflammation in atherosclerosis

Atherosclerosis, the major cause of death and disability in western countries, is nowadays recognized as an inflammatory disease. Low density lipoprotein (LDL), the major carrier of cholesterol in plasma, is trapped in the subendothelial space, where compounds inside of LDL are chemically modified through lipid peroxidation. The oxidized LDL (oxLDL) is believed to initiate the inflammatory reaction in atherosclerosis. By activation of the endothelial cell layer, cells of the immune system (monocytes and T lymphocytes, T cells) are recruited to developing atherosclerotic lesions. Monocytes differentiated into macrophages, which engulf oxLDL through specialized scavenger receptors leading to accumulation of cholesterol in the vessel wall, so-called foam cell formation. Macrophages may also activate T cells, which in turn secrete cytokines. Previous data have shown that oxLDL can activate T cells, but the molecular mechanisms have not been identified. Oxidation of fatty acids in LDL generates reactive aldehydes that modify proteins. Two important aldehydes are malondialdehyde (MDA) and 4-hydroxynonenal, which can form covalent adducts on proteins. To analyze the mechanisms for the activation of T cells by aldehyde-modified proteins, T cells that were activated by MDA- or HNE-modified self-proteins were established in a mouse model. MDA modified self- proteins triggered T cells that directly recognized the MDA adduct with their T cell receptors. This finding demonstrates that lipid peroxidation derived aldehydes may turn selfproteins into antigens that can initiate a T cell mediated inflammatory reaction. These T cells may also activate B cells to secrete antibodies that are directed either towards the modifications or towards unmodified sequences of altered proteins. To study the inflammatory response during atherosclerotic plaque development gene expression array technology was applied in a mouse model of atherosclerosis. The expression of previously known atherosclerosis related genes, e.g. the expression of adhesion molecules and markers of blood derived inflammatory cells, were used to validate the experimental procedure. The gene array analysis revealed that the cytokine interleukin-15 (IL-15) was expressed in the vessel wall and upregulated in atherosclerotic plaques. IL- 15 expression could be identified in macrophage rich areas of the lesions supporting the hypothesis that IL-15 may be involved in the recruitment of T cells to the atherosclerotic lesion. The gene array analysis identified the expression of cellular retinoic acid binging protein-II, a gene that is regulated by vitamin A signaling pathways. This finding led us to study effects of vitamin A on foam cell formation. The vitamin A derivative all-trans retinoic acid was shown to upregulate the expression scavenger receptor CD36 through retinoic acid receptor (RAR) signaling path in the human monocytic cell line THP-1. The RAR signaling path was identified in human atherosclerotic lesion associated with infiltrating leukocytes. This suggests that RAR-signaling may contribute to the inflammation in the vessel wall and promote atherosclerosis

Scleroderma renal crisis in a Swedish systemic sclerosis cohort: survival, renal outcome, and RNA polymerase III antibodies as a risk factor.

Objectives: To study survival, renal outcome, and RNA polymerase III antibodies (RNAP Abs) as a risk factor for scleroderma renal crisis (SRC) in a Swedish cohort of systemic sclerosis (SSc) patients. Methods: SRC was diagnosed in 16 SSc patients during the period from 1982 to 2010. For comparison, 112 (seven for each SRC patient) SSc patients without SRC were included. RNAP Abs were detected by a fully automated fluoroenzymeimmunoassay (EliA). Values greater than 15 μg/L were considered positive. Frozen serum samples from the time of diagnosis of SSc were used. Results: The 5- and 10-year survival rates were, respectively, 58% and 40% for SRC patients and 90% and 76% for patients without SRC (p < 0.001). The odds ratio (OR) for mortality was 4.39 [95% confidence interval (CI) 2.10-9.16, p < 0.001] in patients with SRC compared to those without SRC. Renal outcome was good in three patients. Haemodialysis was started in 10 patients and peritoneal dialysis in three. Renal function improved in three patients and dialysis was terminated. Four patients underwent renal transplantation. Seven SRC patients and nine without SRC were positive for RNAP Abs. Anti-RNAP Abs was a strong predictor of SRC. The sensitivity and specificity for development of SRC were 0.44 and 0.92, respectively. The OR for development of SRC was 8.90 (95% CI 2.68-29.6, p = 0.001) in RNAP-positive patients. Conclusions: RNAP positivity is a strong risk factor for SRC. Renal outcome was variable and survival is still notably decreased

The modified hand mobility in scleroderma test and skin involvement - A followup study

Objective. To study the change in the modified Hand Mobility in Scleroderma (mHAMIS) test from early to advanced stages of systemic sclerosis (SSc), and the relationship between mHAMIS and skin involvement during followup. Methods. This retrospective study includes 65 patients with baseline disease duration of . 3 years who were assessed with the mHAMIS test at baseline and at 1 or 2 predefined followup points (3.1.5 yrs and 5.1.9 yrs after disease onset). Studied measures were the modified Rodnan skin score (mRSS), mRSS of the hand, serum cartilage oligomeric matrix protein, and digital vascular lesions. Results. The mHAMIS and the mRSS hand changed synchronously during the first 5 years after disease onset (rs = 0.44, p = 0.001). In the group with high mHAMIS at baseline, both mHAMIS and mRSS hand improved significantly at the first followup (p <0.05), and the improvement sustained during the followup in the mRSS hand. Patients with antitopoisomerase I and anti-RNA polymerase III antibodies had significantly higher mHAMIS at baseline (p = 0.003) and at the second followup (p = 0.030) compared to patients with anticentromere antibodies. Patients with digital vascular lesions at baseline had significantly higher mHAMIS during the followup (p <0.05) compared to patients without. The mHAMIS improved significantly during the followup in patients with immunosuppressive treatment in early disease (p <0.05), but not in patients without this treatment. Conclusion. The mHAMIS reflects disease activity in fibrosis in early stages of SSc. In later stages it can be regarded as a measure of damage arising from fibrotic and vascular involvement, making it suitable as an endpoint in followup examinations

Validation of the Swedish version of PROMIS-29v2 and FACIT-Dyspnea Index in patients with systemic sclerosis

Purpose: To evaluate the reliability, internal consistency, and construct validity of the Swedish versions of PROMIS-29 and Functional Assessment of Chronic Illness Therapy-Dyspnea (FACIT-Dyspnea) instruments in patients with systemic sclerosis (SSc). Methods: In a cross-sectional study, consecutive SSc patients completed a paper-based survey. Internal consistency was assessed using Cronbach’s alpha. Test–retest reliability was tested employing weighted Kappa (K w) and intra-class correlation coefficient (ICC). Construct validity was evaluated by hypotheses testing using RAND-36, MRC Dyspnea score, Scleroderma Health Assessment Questionnaire (SHAQ) and clinical measurements. Results: Forty-nine patients (86% female; 73% limited cutaneous SSc) completed the survey. The mean disease duration was 11 years and mean SHAQ was 0.5. Internal consistency and test–retest reliability were good with the exception of PROMIS-29 anxiety. PROMIS-29, FACIT-Dyspnea, and Functional limitation showed strong correlations to corresponding RAND-36 domains (|r s|=0.67 to −0.85). Relevant PROMIS-29 domains, FACIT-Dyspnea and Functional limitation correlated strongly to SHAQ and VAS overall disease severity (|r s|=0.60 to −0.75). Ceiling effects (>15%) were found in six PROMIS-29 domains and in both FACIT-Dyspnea and Functional limitations. Four (4/5) hypotheses were confirmed. Conclusions: PROMIS-29 and FACIT-Dyspnea meet the requirements for reliability and have adequate construct validity in Swedish patients with SSc.Implications for rehabilitation PROMIS-29v2 and Functional Assessment of Chronic Illness Therapy-Dyspnea (FACIT-Dyspnea) Index are patient outcome measures that gain increasing interest for the evaluation of patient with rheumatologic diseases. PROMIS-29v2 and FACIT-Dyspnea Index meet the requirements for reliability and have adequate construct validity compared to legacy measures in Swedish patients with systemic sclerosis. Translation and validation of PROMs is important for studies of rare diseases in multi-center collaborations

Renal function is mostly preserved in patients with systemic sclerosis.

Objective: Chronic renal disease other than scleroderma renal crisis (SRC) is not well documented in systemic sclerosis (SSc). We examined the occurrence of decreased glomerular filtration rate (GFR) in a large consecutive SSc cohort and analysed whether it was related to SSc or could be related to other causes. Methods: During 1983-2004 GFR was measured by chromium-51-ethylenediaminetetraacetic acid (51Cr-EDTA) or iohexol clearance in 461 patients with SSc according to the American College of Rheumatology (ACR) criteria [356 with limited cutaneous SSc (lcSSc) and 105 with diffuse cutaneous SSc (dcSSc)] and the measurements were repeated once a year. Decreased GFR was defined as GFR/=4 years and no progress was seen in 11/15. Conclusions: A minority of patients with SSc develop renal dysfunction other than SRC. Decreased GFR was associated with other manifestations such as hypertension and cardiac involvement indicating possible pre-renal causes