National Institute for Rheumatic Diseases

Piešťany, Slovakia

National Institute for Rheumatic Diseases

Piešťany, Slovakia
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Van Vollenhoven R.F.,Unit for Clinical Therapy Research | Van Vollenhoven R.F.,Karolinska Institutet | Mosca M.,University of Pisa | Bertsias G.,University of Crete | And 35 more authors.
Annals of the Rheumatic Diseases | Year: 2014

The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treatto- target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.

PubMed | New York University, Center for Rheumatology and Spine Diseases, Medical University of Graz, Corporal Michael escenz Va Medical Center Philadelphia and 45 more.
Type: | Journal: Annals of the rheumatic diseases | Year: 2016

Treat-to-target recommendations have identified remission as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE.An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%.The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1.Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by . (reference to symptoms, signs, routine labs).2.For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physicians global assessment.3.Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone 5mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life.The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.

Distler J.H.W.,Friedrich - Alexander - University, Erlangen - Nuremberg | Jordan S.,University of Zürich | Airo P.,Unit of Rheumatology and Clinical Immunology | Alegre-Sancho J.J.,Hospital Universitario Dr Peset Valencia | And 32 more authors.
Clinical and Experimental Rheumatology | Year: 2011

Objective: To obtain experiences and expert opinion on treatment of SSc patients with TNF-α antagonists. Methods: An investigation was carried out among the EUSTAR centres into their expertise on use of TNF-α antagonists. Assessment forms on the frequency of TNF-α inhibitor use were distributed to EULAR Scleroderma Trials and Research Group (EUSTAR) centres. Afterwards, a three round Delphi exercise was performed to obtain expert consensus on the use of TNF-α inhibitors in SSc. Results: Seventy-nine centres returned information on use of TNF-α antagonists in SSc patients. A total of 65 patients were treated with TNF-a inhibitors in 14 different centres. Forty-eight of the 65 patients treated with TNF-α inhibitors improved. Improvement was mainly seen in patients with arthritis, whereas the effects on fibrosis varied. In the first round of the subsequent Delphi approach, 71 out of 79 experts stated that they would use TNF-α antagonists in SSc. Arthritis was suggested as an indication for TNFa antagonists by 75% of the experts. However, after the third stage of the Delphi exercise, the acceptance for the off-label use of TNF-a antagonists decreased and 59% recommended that TNF-α antagonists should not be used or only used in clinical trials in SSc patients, while 38% of the experts suggested the use of TNF-a antagonists for arthritis associated with SSc. Conclusions: Most of the experts do not recommend the routine use of TNF-a antagonists in systemic sclerosis. Arthritis might be a potential indication in SSc, although controlled clinical trials with TNF-α antagonists are needed before general recommendations can be given. © Copyright Clinical and Experimental Rheumatology 2011.

Rauova L.,Children's Hospital of Philadelphia | Rauova L.,National Institute for Rheumatic Diseases | Rauova L.,University of Pennsylvania | Hirsch J.D.,Children's Hospital of Philadelphia | And 8 more authors.
Blood | Year: 2010

Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening thrombotic disorder that develops after exposure to heparin, often in the setting of inflammation. We have shown previously that HIT is associated with antibodies to complexes that form between platelet factor 4 and glycosaminoglycan (GAG) side chains on the surface of platelets. However, thrombosis can occur in the absence of thrombocytopenia.We now show that platelet factor 4 binds to monocytes and forms antigenic complexes with their surface GAG side chains more efficiently than on platelets likely due to differences in GAG composition. Binding to monocytes is enhanced when the cells are activated by endotoxin. Monocyte accumulation within developing arteriolar thrombi was visualized by situ microscopy. Monocyte depletion or inactivation in vivo attenuates thrombus formation induced by photochemical injury of the carotid artery in a modified murine model of HIT while paradoxically exacerbating thrombocytopenia. These studies demonstrate a previously unappreciated role for monocytes in the pathogenesis of arterial thrombosis in HIT and suggest that therapies targeting these cells might provide an alternative approach to help limit thrombosis in this and possibly other thrombotic disorders that occur in the setting of inflammation. © 2010 by The American Society of Hematology.

Sachais B.S.,University of Pennsylvania | Litvinov R.I.,University of Pennsylvania | Yarovoi S.V.,University of Pennsylvania | Rauova L.,Children's Hospital of Philadelphia | And 8 more authors.
Blood | Year: 2012

Rapid laboratory assessment of heparin-induced thrombocytopenia (HIT) is important for disease recognition and management. The utility of contemporary immunoassays to detect antiplatelet factor 4 (PF4)/heparin antibodies is hindered by detection of antibodies unassociated with disease. To begin to distinguish properties of pathogenic anti-PF4/heparin antibodies, we compared isotype-matched monoclonal antibodies that bind to different epitopes: KKO causes thrombocytopenia in an in vivo model of HIT, whereas RTO does not. KKO binding to PF4 and heparin is specifically inhibited by human HIT antibodies that activate platelets, whereas inhibition of RTO binding is not differentially affected. Heparin increased the avidity of KKO binding to PF4 without affecting RTO, but it did not increase total binding or binding to nontetrameric PF4 K50E. Single-molecule forced unbinding demonstrated KKO was 8-fold more reactive toward PF4 tetramers and formed stronger complexes than RTO, but not to PF4 K50E dimers. KKO, but not RTO, promoted oligomerization of PF4 but not PF4 K50E. This study reveals differences in the properties of anti-PF4 antibodies that cause thrombocytopenia not revealed by ELISA that correlate with oligomerization of PF4 and sustained high-avidity interactions that may simulate transient antibody-antigen interactions in vivo. These differences suggest the potential importance of epitope specificity in the pathogenesis of HIT. © 2012 by The American Society of Hematology.

Bauerova K.,Slovak Academy of Sciences | Paulovicova E.,Slovak Academy of Sciences | Mihalova D.,Slovak Academy of Sciences | Drafi F.,Slovak Academy of Sciences | And 7 more authors.
Acta Biochimica Polonica | Year: 2010

Rheumatoid arthritis is a common severe joint disease that affects all age groups, it is thus of great importance to develop new strategies for its treatment. The aim of the present study was to examine the combined effect of coenzyme Q10 (CoQ10) and methotrexate (MTX) on the progression of adjuvant-induced arthritis in rats. Adjuvant arthritis (AA) was induced by a single intradermal injection of heat-inactivated Mycobacterium butyricum in incomplete Freund's adjuvant. The experiments included healthy animals, arthritic animals not treated, arthritic animals treated with CoQ10, with methotrexate, and with a combination of CoQ10 and methotrexate. The two latter groups received a daily oral dose of 20 mg/kg b.w. of CoQ10, either alone or with methotrexate in an oral dose of 0.3 mg/kg b.w. twice a week. We found that CoQ10 potentiated both the antiarthritic (decrease of hind paw volume) and the antioxidant effect of methotrexate on the level of oxidation of proteins (suppression of protein carbonyl level in plasma) as well as lipoperoxidation (suppression of levels of HNE-adducts and MDA-adducts to plasma proteins). The same effect was observed for plasmatic levels of CoQ9 and IL-1α, and partially also for γ-glutamyltransferase activity assessed in joints and spleen. Moreover, the combination therapy improved the functionality of peripheral blood neutrophils in AA, with a balancing effect on the immunosuppression caused by MTX monotherapy. In summary, combined administration of CoQ10 and methotrexate suppressed arthritic progression in rats more effectively than did MTX alone. This finding may help improve treatment of rheumatoid arthritis.

Ponist S.,Slovak Academy of Sciences | Mihalova D.,Slovak Academy of Sciences | Jancinova V.,Slovak Academy of Sciences | Snirc V.,Slovak Academy of Sciences | And 6 more authors.
Acta Biochimica Polonica | Year: 2010

The aim of this study was to evaluate the therapeutic potential of oxidative stress (OS) reduction by using pyridoindole (PI) antioxidants in adjuvant arthritis (AA). The substances tested were stobadine dipalmitate (STB) and SMe1. AA was used as animal model. The experiments included healthy animals, control arthritic animals and arthritic animals with administration of PI in the oral daily dose of 15 mg/kg b.m during 28 experimental days. The rats were sacrificed on day 28. Clinical and biochemical parameters were determined. The effect of PI administration was evaluated on the basis of the following parameters: (a) arthritis (volume of hind paws - HPW, change of animal body mass - CBM), (b) OS (chemiluminescence of whole blood - CWB, levels of thiobarbituric acid reacting substance - TBARS and of HNE- and MDA-protein adducts in plasma and activity of γ-glutamyltransferase (GGT) in hind paw joint homogenates). The PI studied significantly increased the CBM of animals and corrected the HPW. STB also significantly decreased the activity of GGT in joint homogenates. SMe1 was more effective in decreasing plasmatic TBARS levels, but STB was more effective in reducing plasmatic HNE- and MDA-protein adducts. The assay for HNE- and MDA-adducts in plasma as a function of time was applied for the first time in AA. STB markedly decreased spontaneous and PMA-stimulated CWB and reduced neutrophil count. In summary, STB was more effective than SMe1 in reducing OS in AA. Our results showed that the reduction of OS in arthritis also corrected the clinical manifestations of the disease.

Jimenez-Boj E.,Medical University of Vienna | Stamm T.A.,Medical University of Vienna | Sadlonova M.,Medical University of Vienna | Rovensky J.,National Institute for Rheumatic Diseases | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Background/objective: Current therapies for psoriatic arthritis (PsA) comprise synthetic drugs and tumour necrosis factor inhibitors. In contrast, other biologicals including rituximab (RTX) are available for treating rheumatoid arthritis (RA). RTX is effective in autoantibody positive RA patients, although some efficacy has been reported in seronegative individuals. RTX has not yet been assessed in PsA. Therefore, an open label study of RTX in PsA was performed. Patients and methods: Nine patients with PsA and 14 with RA received RTX at 1000 mg twice within 14 days and were evaluated over 6 months. Results: A PsA response criteria response was attained in 56% of patients. DAS28 improved from 6.2 to 4.9 (medians) in PsA and 6.4 to 5.2 in RA, and Health Assessment Questionnaire from 1.5 to 1.0 and from 2.1 to 1.4, respectively (all p≤0.05). Disease Activity index for PSoriatic Arthritis changed from 52.0 to 32.5 (p<0.05); C reactive protein and Psoriasis Area and Severity Index did not change significantly. RTX was tolerated well. Conclusions: In this exploratory open study, RTX exhibited significant efficacy in PsA patients with long-standing disease. Thus, RTX may have efficacy in PsA warranting a randomised controlled clinical trial.

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