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Duru N.,University Utrecht | Van Der Goes M.C.,University Utrecht | Jacobs J.W.G.,University Utrecht | Andrews T.,EULAR Social Leagues Patients Representative | And 12 more authors.
Annals of the Rheumatic Diseases | Year: 2013

To develop recommendations for the management of medium to high-dose (ie, >7.5 mg but 7le;100 mg prednisone equivalent daily) systemic glucocorticoid (GC) therapy in rheumatic diseases. A multidisciplinary EULAR task force was formed, including rheumatic patients. After discussing the results of a general initial search on risks of GC therapy, each participant contributed 10 propositions on key clinical topics concerning the safe use of medium to high-dose GCs. The final recommendations were selected via a Delphi consensus approach. A systematic literature search of PubMed, EMBASE and Cochrane Library was used to identify evidence concerning each of the propositions. The strength of recommendation was given according to research evidence, clinical expertise and patient preference. The 10 propositions regarded patient education and informing general practitioners, preventive measures for osteoporosis, optimal GC starting dosages, risk-benefit ratio of GC treatment, GC sparing therapy, screening for comorbidity, and monitoring for adverse effects. In general, evidence supporting the recommendations proved to be surprisingly weak. One of the recommendations was rejected, because of conflicting literature data. Nine final recommendations for the management of medium to high-dose systemic GC therapy in rheumatic diseases were selected and evaluated with their strengths of recommendations. Robust evidence was often lacking; a research agenda was created.


Imrich R.,Slovak Academy of Sciences | Rovensky J.,National Institute of Rheumatic Diseases
Rheumatic Disease Clinics of North America | Year: 2010

The hypothalamic-pituitary-adrenal (HPA) system is a powerful neuroendocrine control mechanism involved in many core body functions including metabolic and energy homeostasis. The HPA axis has been considered an important immune modulator primarily in view of potent anti-inflammatory effects of cortisol in high physiologic and pharmacologic doses. This article describes HPA's role in rheumatoid arthritis. © 2010 Elsevier Inc.


Rovensky J.,National Institute of Rheumatic Diseases | Imrich R.,Slovak Academy of Sciences | Lazurova I.,Pavol Jozef Safarik University | Payer J.,Comenius University
Annals of the New York Academy of Sciences | Year: 2010

The article summarizes reports on the concurrence of Klinefelter's syndrome (KS) with inflammatory rheumatic diseases, rheumatoid arthritis (RA), juvenile idiopathic arthritis, psoriatic arthritis, polymyositis/dermatomyositis, systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, the antiphospholipid syndrome, and ankylosing spondylitis. These include two case reports of patients with KS concurrently associated with RA or antisynthetase syndrome, respectively, previously reported by the author and his coworkers. Attention is paid to the pathogenesis and the course of the disease in patients with KS. The importance of early diagnosis of the syndrome, when occurring simultaneously with other diseases of connective tissue, is emphasized. © 2010 New York Academy of Sciences.


Sieper J.,Rheumatology | Srinivasan S.,Merck And Co. | Srinivasan S.,Celgene | Zamani O.,Rheuma Zentrum Favoriten | And 15 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objective To determine which of two referral strategies, when used by referring physicians for patients with chronic back pain (CBP), is superior for diagnosing axial spondyloarthritis (SpA) by rheumatologists across several countries. Methods Primary care referral sites in 16 countries were randomised (1 : 1) to refer patients with CBP lasting >3 months and onset before age 45 years to a rheumatologist using either strategy 1 (any of inflammatory back pain (IBP), HLA-B27 or sacroiliitis on imaging) or strategy 2 (two of the following: IBP, HLAB27, sacroiliitis, family history of axial SpA, good response to non-steroidal anti-inflammatory drugs, extraarticular manifestations). The rheumatologist established the diagnosis. The primary analysis compared the proportion of patients diagnosed with definite axial SpA by referral strategy. Results Patients (N=1072) were referred by 278 sites to 64 rheumatologists: 504 patients by strategy 1 and 568 patients by strategy 2. Axial SpA was diagnosed in 35.6% and 39.8% of patients referred by these respective strategies (between-group difference 4.40%; 95% CI -7.09% to 15.89%; p=0.447). IBP was the most frequently used referral criterion (94.7% of cases), showing high concordance (85.4%) with rheumatologists' assessments, and having sensitivity and a negative predictive value of >85% but a positive predictive value and specificity of <50%. Combining IBP with other criteria (eg, sacroiliitis, HLA-B27) increased the likelihood for diagnosing axial SpA. Conclusions A referral strategy based on three criteria leads to a diagnosis of axial SpA in approximately 35% of patients with CBP and is applicable across countries and geographical locales with presumably different levels of expertise in axial SpA.


Stark K.,University of Regensburg | Straub R.H.,University of Regensburg | Rovensky J.,National Institute of Rheumatic Diseases | Blazickova S.,National Institute of Rheumatic Diseases | And 3 more authors.
Arthritis Research and Therapy | Year: 2015

Introduction: Rheumatoid arthritis (RA) is characterized by decreased androgen levels, which was the first hormonal abnormality described. Several studies indicated that steroidogenesis is directed towards endogenous glucocorticoids at the expense of androgens. The decisive step governing androgen synthesis is the 17,20-lyase activity of the CYP17A1 gene-encoded enzyme cytochrome P450 17A1. Here, we focused on the role in RA of the critical cofactor for 17,20-lyase activity, cytochrome b5, encoded by the CYB5A gene. Methods: Data sets of two genome wide RA association studies (GWAS) were screened for single nucleotide polymorphisms (SNP) in the CYB5A gene. Candidate SNPs in CYB5A were studied in a case-control study population of Slovakia. Expression analyses were done in synovial fibroblasts from RA patients by quantitative real-time polymerase chain reaction, and cytochrome b5-expression was detected by immunohistochemistry. Real-life androgen production after steroid conversion was measured using radiolabeled substrates. Results: The study identified the RA-associated intronic SNP rs1790834 in the CYB5A gene in one GWAS and confirmed the same SNP in our study. The minor allele reduced RA risk selectively in women (P = 4.1*10-3; OR = 0.63, 95% CI [0.46-0.86]). The protective effect was confined to rheumatoid factor-positive (OR = 0.53, [0.37-0.75]) and anti-cyclic citrullinated peptide-positive (OR = 0.58, [0.41-0.83]) cases, respectively. The protective allele doubles CYB5A mRNA-expression resulting in 2-3fold activation of steroid 17,20-lyase activity, and protective allele was accompanied by a higher density of cytochrome b5-positive cells in synovial tissue. Conclusions: CYB5A is the first RA susceptibility gene involved in androgen synthesis. Our functional analysis of SNP rs1790834 indicates that it contributes to the sex bias observed in RA. © Stark et al.; licensee BioMed Central.

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