Rheumatoid arthritis (RA) is a multisystem, chronic, T-cell-mediated disease in which immunological abnormalities result in symmetrical small joint inflammation, articular destruction due to ...synovitis, and extra-articular organ involvement. An important role in the pathogenesis of RA is attributed to a combination of genetic factors and environmental triggers. Literature data on the utility of circulating IL-1β, IL-6, IFN-γ, and sP-selectin concentration evaluation depending on the activity and advancement of RA seems to be inconclusive. The aim was a case-control study evaluating IL-1β, IL-6, IFN-γ, and sP-selectin concentrations in 77 RA patients dependent on the Steinbrocker classification as well as the disease activity score with examination of 28 joints (DAS28), and compared to 30 control subjects.
Serum IL-1β, IL-6, IFN-γ, and sP-selectin concentrations were measured using ELISA kits.
The concentrations of all molecules tested, except for IL-1β, were significantly different from the control group. Univariate logistic regression analysis indicated that their levels significantly influenced the likelihood of RA diagnosis. Differences between IL-1β, IL-6, IFN-γ, and sP-selectin concentrations dependent on the disease activity assessed on the basis of the DAS28 score, as well as the severity of the disease assessed based on the Steinbrocker classification, were not observed. IL-6 positively correlated with the DAS28 score.
Among the tested molecules, only IL-6 positively correlated with the DAS28 score. Thus, we postulate that next to C-reactive protein and the erythrocyte sedimentation rate, also IL-6 could be clinically relevant and possibly reflects RA activity. Because recently the IL-6 concentration can be determined in applied
diagnostic tests, it presents us with the possibility to test this protein as a marker of RA activity in routine laboratory practice.
To identify overall disease course, progression patterns and risk factors predictive for progressive interstitial lung disease (ILD) in patients with systemic sclerosis-associated ILD (SSc-ILD), ...using data from the European Scleroderma Trials And Research (EUSTAR) database over long-term follow-up.
Eligible patients with SSc-ILD were registered in the EUSTAR database and had measurements of forced vital capacity (FVC) at baseline and after 12±3 months. Long-term progressive ILD and progression patterns were assessed in patients with multiple FVC measurements. Potential predictors of ILD progression were analysed using multivariable mixed-effect models.
826 patients with SSc-ILD were included. Over 12±3 months, 219 (27%) showed progressive ILD: either moderate (FVC decline 5% to 10%) or significant (FVC decline >10%). A total of 535 (65%) patients had multiple FVC measurements available over mean 5-year follow-up. In each 12-month period, 23% to 27% of SSc-ILD patients showed progressive ILD, but only a minority of patients showed progression in consecutive periods. Most patients with progressive ILD (58%) had a pattern of slow lung function decline, with more periods of stability/improvement than decline, whereas only 8% showed rapid, continuously declining FVC; 178 (33%) experienced no episode of FVC decline. The strongest predictive factors for FVC decline over 5 years were male sex, higher modified Rodnan skin score and reflux/dysphagia symptoms.
SSc-ILD shows a heterogeneous and variable disease course, and thus monitoring all patients closely is important. Novel treatment concepts, with treatment initiation before FVC decline occurs, should aim for prevention of progression to avoid irreversible organ damage.
Summary Type B insulin resistance syndrome (TBIR) is characterised by the rapid onset of severe insulin resistance due to circulating anti-insulin receptor antibodies (AIRAs). Widespread acanthosis ...nigricans is normally seen, and co-occurrence with other autoimmune diseases is common. We report a 27-year-old Caucasian man with psoriasis and connective tissue disease who presented with unexplained rapid weight loss, severe acanthosis nigricans, and hyperglycaemia punctuated by fasting hypoglycaemia. Severe insulin resistance was confirmed by hyperinsulinaemic euglycaemic clamping, and immunoprecipitation assay demonstrated AIRAs, confirming TBIR. Treatment with corticosteroids, metformin and hydroxychloroquine allowed withdrawal of insulin therapy, with stabilisation of glycaemia and diminished signs of insulin resistance; however, morning fasting hypoglycaemic episodes persisted. Over three years of follow-up, metabolic control remained satisfactory on a regimen of metformin, hydroxychloroquine and methotrexate; however, psoriatic arthritis developed. This case illustrates TBIR as a rare but severe form of acquired insulin resistance and describes an effective multidisciplinary approach to treatment. Learning points: We describe an unusual case of type B insulin resistance syndrome (TBIR) in association with mixed connective tissue disease and psoriasis. Clinical evidence of severe insulin resistance was corroborated by euglycaemic hyperinsulinaemic clamp, and anti-insulin receptor autoantibodies were confirmed by immunoprecipitation assay. Treatment with metformin, hydroxychloroquine and methotrexate ameliorated extreme insulin resistance.
Pulmonary involvement is common in patients with connective tissue diseases (CTDs), and significantly contributes to morbidity and mortality in this patient population. There are different forms of ...lung pathology in CTDs, which include primary involvement such as interstitial lung disease or pulmonary hemorrhage, and pulmonary complications resulting from other CTD-related organ involvement including aspiration pneumonia due to muscle weakness or esophageal fibrosis. Moreover, iatrogenic lung disease, such as medication-induced hypersensitivity pneumonitis or opportunistic infections due to immunosuppression, may develop. Appropriate treatment of pulmonary complications in patients with CTDs requires careful diagnostic workup because different forms of lung involvement may overlap, causing similar clinical manifestations and similar radiological or functional impairment. Moreover, in view of the broad variability of clinical course of CTD-related interstitial lung disease, identification of biomarkers helpful in predicting prognosis becomes of key importance. In addition to radiological assessment and functional testing that provide information regarding localization and severity of lung disease, bronchoalveolar lavage (BAL) appears helpful in revealing the nature of lung pathology and intensity of lung inflammation through sampling of cells and fluid from the lower respiratory tract. The aim of this article is to critically review available data concerning the evaluation of BAL cytology in different forms of lung disease associated with CTDs.
The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the ...previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.
To determine the causes of death and risk factors in systemic sclerosis (SSc).
Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. ...Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation.
We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile.
Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival.
Objective
To investigate the role of microRNA (miRNA) as posttranscriptional regulators of profibrotic genes in systemic sclerosis (SSc).
Methods
MicroRNA, which target collagens, were identified by ...in silico analysis. Expression of miRNA‐29 (miR‐29) was determined by TaqMan real‐time polymerase chain reaction analysis of skin biopsy and fibroblast samples from SSc patients and healthy controls as well as in the mouse model of bleomycin‐induced skin fibrosis. Cells were transfected with precursor miRNA (pre‐miRNA)/anti‐miRNA of miR‐29 using Lipofectamine. Collagen gene expression was also studied in luciferase reporter gene assays. For stimulation, recombinant transforming growth factor β (TGFβ), platelet‐derived growth factor B (PDGF‐B), or interleukin‐4 (IL‐4) was used. The effects of inhibiting PDGF‐B and TGFβ signaling on the levels of miR‐29 were studied in vitro and in the bleomycin model.
Results
We found that miR‐29a was strongly down‐regulated in SSc fibroblasts and skin sections as compared with the healthy controls. Overexpression in SSc fibroblasts significantly decreased, and accordingly, knockdown in normal fibroblasts increased, the levels of messenger RNA and protein for type I and type III collagen. In the reporter gene assay, cotransfection with pre‐miR‐29a significantly decreased the relative luciferase activity, which suggests a direct regulation of collagen by miR‐29a. TGFβ, PDGF‐B, or IL‐4 reduced the levels of miR‐29a in normal fibroblasts to those seen in SSc fibroblasts. Similar to human SSc, the expression of miR‐29a was reduced in the bleomycin model of skin fibrosis. Inhibition of PDGF‐B and TGFβ pathways by treatment with imatinib restored the levels of miR‐29a in vitro and in the bleomycin model in vivo.
Conclusion
These data add the posttranscriptional regulation of collagens by miR‐29a as a novel aspect to the fibrogenesis of SSc and suggest miR‐29a as a potential therapeutic target.
Introduction: Systemic sclerosis (SSc) is a multisystem connective tissue disease, characterized by chronic inflammation and vascular changes that result in esophageal smooth muscle atrophy and ...fibrosis. Subsequent progressive loss of peristalsis in the distal esophagus and loss of lower esophageal sphincter function lead to problems with the protective barrier and exposure of sensitive tissues to the gastroduodenal contents, a disorder called reflux disease.
Areas covered: Depending on the range, nature and symptoms of the disease, the term 'reflux disease' may refer to gastroesophageal reflux, laryngopharyngeal reflux, microaspiration into the airways and silent reflux. Despite the links between these visceral complications, this connection remains controversial. This is due to a lack of complete understanding, the asymptomatic nature of the disease and the limited diagnostic accuracy of tests, which can delay diagnosis. Such delays are problematic, given that the early detection of GERD in SSc patients, the timing of assessment, the treatment of the organs involved are critical aspects of patient prognosis and disease outcome.
Expert commentary: This review summarizes the most recent knowledge about the pathophysiology, diagnosis and prospective treatment of GERD in SSc patients and highlights how innovative technologies applied through an integrative, interdisciplinary approach may soon lead to effective treatment strategies.
The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee ...of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc.
Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc.
It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc.
The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
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