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Smolen J.S.,Medical University of Vienna | Smolen J.S.,Hietzing Hospital Vienna | Landewe R.,University of Amsterdam | Landewe R.,Atrium Medical | And 38 more authors.
Annals of the Rheumatic Diseases | Year: 2014

In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.

Smolen J.S.,Medical University of Vienna | Smolen J.S.,Hietzing Hospital Vienna | Braun J.,Rheumazentrum Ruhrgebiet | Dougados M.,University of Paris Descartes | And 30 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Background Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA). Objective To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy. Methods Based on results of a systematic literature review and expert opinion, a task force of expert physicians and patients developed recommendations which were broadly discussed and voted upon in a Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by respective means. The commonalities between axial SpA, peripheral SpA and PsA were discussed in detail. Results Although the literature review did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated the development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of these recommendations related commonly to the whole spectrum of SpA and PsA, and only 2 were designed separately for axial SpA, peripheral SpA and PsA. The main treatment target, which should be based on a shared decision with the patient, was defined as remission, with the alternative target of low disease activity. Follow-up examinations at regular intervals that depend on the patient's status should safeguard the evolution of disease activity towards the targeted goal. Additional recommendations relate to extra-articular and extramusculoskeletal aspects and other important factors, such as comorbidity. While the level of evidence was generally quite low, the mean strength of recommendation was 9-10 (10: maximum agreement) for all recommendations. A research agenda was formulated. Conclusions The task force defined the treatment target as remission or, alternatively, low disease activity, being aware that the evidence base is not strong and needs to be expanded by future research. These recommendations can inform the various stakeholders about expert opinion that aims for reaching optimal outcomes of SpA.

Nam J.L.,University of Leeds | Ramiro S.,University of Amsterdam | Ramiro S.,Hospital Garcia Of Orta | Gaujoux-Viala C.,University of Nimes | And 11 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objectives To update the evidence for the efficacy of biological disease-modifying antirheumatic drugs (bDMARD) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism (EULAR) Task Force treatment recommendations. Methods Medline, Embase and Cochrane databases were searched for articles published between January 2009 and February 2013 on infliximab, etanercept, adalimumab, certolizumab-pegol, golimumab, anakinra, abatacept, rituximab, tocilizumab and biosimilar DMARDs (bsDMARDs) in phase 3 development. Abstracts from 2011 to 2012 American College of Rheumatology (ACR) and 2011-2013 EULAR conferences were obtained. Results Fifty-one full papers, and 57 abstracts were identified. The randomised controlled trials (RCT) confirmed the efficacy of bDMARD+conventional synthetic DMARDs (csDMARDs) versus csDMARDs alone (level 1B evidence). There was some additional evidence for the use of bDMARD monotherapy, however bDMARD and MTX combination therapy for all bDMARD classes was more efficacious (1B). Clinical and radiographic responses were high with treat-to-target strategies. Earlier improvement in signs and symptoms were seen with more intensive initial treatment strategies, but outcomes were similar upon addition of bDMARDs in patients with insufficient response to MTX. In general, radiographic progression was lower with bDMARD use, mainly due to initial treatment effects. Although patients may achieve bDMARD- and drug-free remission, maintenance of clinical responses was higher with bDMARD continuation (1B), but bDMARD dose reduction could be applied (1B). There was still no RCT data for bDMARD switching. Conclusions The systematic literature review confirms efficacy of biological DMARDs in RA. It addresses different treatment strategies with the potential for reduction in therapy, particularly with early disease control, and highlights emerging therapies.

Ramiro S.,University of Amsterdam | Ramiro S.,Hospital Garcia Of Orta | Gaujoux-Viala C.,University of Nimes | Nam J.L.,University of Leeds | And 10 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objectives To update the evidence for the safety of synthetic disease-modifying antirheumatic drugs (sDMARDs), glucocorticoids (GC) and biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism (EULAR) recommendations for the management of RA. Methods Systematic literature review (SLR) of observational studies (including registries). Interventions were any bDMARD (anakinra, infliximab, etanercept, adalimumab, rituximab, abatacept, tocilizumab, golimumab or certolizumab pegol) or sDMARD (methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, gold/auranofin, azathioprine, chlorambucil, chloroquine, cyclosporin, cyclophosphamide, mycophenolate, minocycline, penicillamine, tacrolimus or tofacitinib) and a comparator was required. Information on GCs was collected from the included studies. All safety outcomes were included. Results Forty-nine observational studies addressing diverse safety outcomes of therapy with bDMARDs met eligibility criteria. Substantial heterogeneity precluded meta-analysis of any of the outcomes. Patients on tumour necrosis factor inhibitors (TNFi) compared to patients on conventional sDMARDs had a higher risk of serious infections (adjusted HR (aHR) 1.1-1.8), a higher risk of tuberculosis, and an increased risk of infection by herpes zoster cannot be excluded. Patients on TNFi did not have an increased risk for malignancies in general, lymphoma or non-melanoma skin cancer, but the risk of melanoma may be slightly increased (aHR 1.5). From the studies identified on conventional sDMARDs, no new safety signals were found. Conclusions The findings from this SLR confirm the known safety pattern of sDMARDs and bDMARDs for the treatment of RA.

Smolen J.S.,Medical University of Vienna | Smolen J.S.,Hietzing Hospital Vienna | Van Der Heijde D.,Leiden University | MacHold K.P.,Medical University of Vienna | And 3 more authors.
Annals of the Rheumatic Diseases | Year: 2014

In light of the recent emergence of new therapeutics for rheumatoid arthritis, such as kinase inhibitors and biosimilars, a new nomenclature for disease-modifying antirheumatic drugs (DMARDs), which are currently often classified as synthetic (or chemical) DMARDs (sDMARDS) and biological DMARDs (bDMARDs), may be needed. We propose to divide the latter into biological original and biosimilar DMARDs (boDMARDs and bsDMARDs, respectively, such as abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab or tocilizumab, but also emerging ones like clazakizumab, ixekizumab, sarilumab, secukinumab or sirukumab) and the former into conventional synthetic and targeted synthetic DMARDs (csDMARDs and tsDMARDs, respectively). tsDMARDs would then constitute only those that were specifically developed to target a particular molecular structure (such as tofacitinib, fostamatinib, baricitinib or apremilast, or agents not focused primarily on rheumatic diseases, such as imatinib or ibrutinib), while csDMARDs would comprise the traditional drugs (such as methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, gold salts and others). The proposed nomenclature may provide means to group and distinguish the different types of DMARDs in clinical studies and review articles.

Gaujoux-Viala C.,University of Nimes | Nam J.,University of Leeds | Nam J.,Leeds Teaching Hospitals NHS Trust | Ramiro S.,University of Amsterdam | And 7 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objectives To update a previous systematic review assessing the efficacy of conventional synthetic diseasemodifying antirheumatic drugs (csDMARDs) in rheumatoid arthritis (RA). Methods Two systematic reviews of the literature using PubMed, Embase and the Cochrane library were performed from 2009 until January 2013 to assess the efficacy of csDMARDs (as monotherapy or combination therapy) in adults with RA, and the efficacy of glucocorticoids in early RA. A third systematic review was performed until March 2013 to assess the efficacy of tofacitinib by meta-analysis. Results For glucocorticoids, of 222 hits, five publications relating to four new trials were analysed for efficacy, confirming that initial treatment of RA with lowdose prednisone plus methotrexate (MTX) results in better clinical and structural outcomes at 1 and 2 years than treatment with MTX alone. For csDMARDs, of 498 studies, only two new studies were randomised controlled trials comparing MTX monotherapy with MTX in combination with another csDMARD without differences in glucocorticoid usage. Using tight control principles, clinical outcomes were no better with immediate triple therapy than with 'step-up' therapy. For tofacitinib, the pooled analysis of 10 trials showed that tofacitinib was more efficacious on signs and symptoms, disability and appeared to be more efficacious on structural damage than control treatment with placebo (OR (95% CI) - American College of Rheumatology 20% (ACR20) response: 2.44 (1.97 to 3.02)) or treatment with MTX (ACR20 response: 2.38 (1.66 to 3.43)). Conclusions Addition of low-dose glucocorticoids to csDMARD therapy produces benefits in early RA. Under tight control conditions, combination therapy with csDMARDs is no better than MTX monotherapy. Tofacitinib is a new DMARD with proven efficacy.

Huelsmann M.,Medical University of Vienna | Neuhold S.,Medical University of Vienna | Resl M.,Medical University of Vienna | Strunk G.,Complexity Research | And 7 more authors.
Journal of the American College of Cardiology | Year: 2013

Objectives The study sought to assess the primary preventive effect of neurohumoral therapy in high-risk diabetic patients selected by N-terminal pro-B-type natriuretic peptide (NT-proBNP). Background Few clinical trials have successfully demonstrated the prevention of cardiac events in patients with diabetes. One reason for this might be an inaccurate selection of patients. NT-proBNP has not been assessed in this context. Methods A total of 300 patients with type 2 diabetes, elevated NT-proBNP (>125 pg/ml) but free of cardiac disease were randomized. The "control" group was cared for at 4 diabetes care units; the "intensified" group was additionally treated at a cardiac outpatient clinic for the up-titration of renin-angiotensin system (RAS) antagonists and beta-blockers. The primary endpoint was hospitalization/death due to cardiac disease after 2 years. Results At baseline, the mean age of the patients was 67.5 ± 9 years, duration of diabetes was 15 ± 12 years, 37% were male, HbA1c was 7 ± 1.1%, blood pressure was 151 ± 22 mm Hg, heart rate was 72 ± 11 beats/min, median NT-proBNP was 265.5 pg/ml (interquartile range: 180.8 to 401.8 pg/ml). After 12 months there was a significant difference between the number of patients treated with a RAS antagonist/beta-blocker and the dosage reached between groups (p < 0.0001). Blood pressure was significantly reduced in both (p < 0.05); heart rate was only reduced in the intensified group (p = 0.004). A significant reduction of the primary endpoint (hazard ratio: 0.351; 95% confidence interval: 0.127 to 0.975, p = 0.044) was visible in the intensified group. The same was true for other endpoints: all-cause hospitalization, unplanned cardiovascular hospitalizations/death (p < 0.05 for all). Conclusions Accelerated up-titration of RAS antagonists and beta-blockers to maximum tolerated dosages is an effective and safe intervention for the primary prevention of cardiac events for diabetic patients pre-selected using NT-proBNP. (Nt-proBNP Guided Primary Prevention of CV Events in Diabetic Patients [PONTIAC]; NCT00562952). © 2013 by the American College of Cardiology Foundation.

Resl M.,Medical University of Vienna | Clodi M.,Medical University of Vienna | Neuhold S.,Medical University of Vienna | Kromoser H.,Medical University of Vienna | And 7 more authors.
Diabetic Medicine | Year: 2012

Background Hyperuricemia is a risk factor for cardiovascular events and renal insufficiency. It correlates to intima-media thickness and microalbuminuria. In this study we evaluated uric acid as an independent marker for cardiac events in patients with diabetes. Methods In a prospective observational study we recruited 494 patients with diabetes. Patients were then followed for 12.8months (mean follow-up) and hospitalizations as a result of cardiac events (ischaemic heart disease, arrhythmias, heart failure) were recorded. Results The median duration of diabetes was 11±10.35years. Patients were in the mean 60±13years old and mean HbA 1c was 62±13mmol/mol (7.8±3.3%). At baseline, mean uric acid was 321.2±101.1μmol/l (range 101.1-743.5μmol/l), median N-terminal pro-B-type natriuretic peptide was 92±412pg/ml and median urinary albumin to creatinine ratio was 8±361mg/g; Uric acid significantly correlated to N-terminal pro-B-type natriuretic peptide (r=0.237, P<0.001) and urinary albumin:creatinine ratio (r=0.198, P<0.001). In a Cox regression model, including age, estimated glomerular filtration rate, gender, systolic blood pressure, smoking and alcohol consumption, uric acid was the best predictor of cardiac events (hazard ratio1.331, confidence interval 1.095-1.616, P=0.04). However, uric acid lost its prognostic value when the natural logarithm of N-terminal pro-B-type natriuretic peptide was added to the model. Conclusion Serum uric acid is a predictor of cardiac events and correlates to N-terminal pro-B-type natriuretic peptide and albuminuria, underscoring the importance of uric acid as a cardiovascular risk marker in patients with diabetes. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

Smolen J.S.,Medical University of Vienna | Smolen J.S.,Hietzing Hospital Vienna | Aletaha D.,Medical University of Vienna | McInnes I.B.,University of Glasgow
The Lancet | Year: 2016

Rheumatoid arthritis is a chronic inflammatory joint disease, which can cause cartilage and bone damage as well as disability. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterised risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and use of conventional, biological, and new non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favourable, many still do not respond to current therapies. Accordingly, new therapies are urgently required. In this Seminar, we describe current insights into genetics and aetiology, pathophysiology, epidemiology, assessment, therapeutic agents, and treatment strategies together with unmet needs of patients with rheumatoid arthritis. © 2016 Elsevier Ltd.

Aust S.,Medical University of Vienna | Horak P.,Medical University of Vienna | Pils D.,Medical University of Vienna | Pils S.,Medical University of Vienna | And 7 more authors.
BMC Cancer | Year: 2013

Background: Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), a coregulator of the estrogen receptors (ERs) alpha and beta, is a potential proto-oncogene in hormone dependent gynecological malignancies. To better understand the role of PELP1 in epithelial ovarian cancer (EOC), the protein expression and prognostic significance of PELP1 was evaluated together with ERalpha and ERbeta in EOC tissues.Methods: The expression of PELP1, ERalpha, and ERbeta was characterized in tumor tissues of 63 EOC patients. The prognostic value was calculated performing log-rank tests and multivariate Cox-Regression analysis. In a second step, validation analysis in an independent set of 86 serous EOC patients was performed.Results: Nuclear PELP1 expression was present in 76.2% of the samples. Prevalence of PELP1 expression in mucinous tumors was significantly lower (37.5%) compared to serous (85.7%) and endometrioid tumors (86.7%). A significant association between PELP1 expression and nuclear ERbeta staining was found (p=0.01). Positive PELP1 expression was associated with better disease-free survival (DFS) (p=0.004) and overall survival (OS) (p=0.04). The combined expression of ERbeta+/PELP1+ revealed an independent association with better DFS (HR 0.3 [0.1-0.7], p=0.004) and OS (HR 0.3 [0.1-0.7], p=0.005). In the validation set, the combined expression of ERbeta+/PELP1+ was not associated with DFS (HR 0.7 [0.4-1.3], p=0.3) and OS (HR 0.7 [0.3-1.4], p=0.3).Conclusion: Positive immunohistochemical staining for the ER coregulator PELP1, alone and in combination with ERbeta, might be of prognostic relevance in EOC. © 2013 Aust et al.; licensee BioMed Central Ltd.

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