While it is given that some or all of the biases involved in the design and the implementation of a trial are carried to the reporting, our concern in this talk is a list of biases more specific for ...this stage. I propose that the common denominator in this list is the “urge to prove” (1). One important outcome of this urge is the relative reluctance of the authors to acknowledge the limitations of their work. It is interesting to note that this reluctance is more pronounced in basic science (2) while it has even been said that the main purpose of the discussion sections should be authors discussing limitations of their work, naturally best known to them (3). Another manifestation of the same urge has to do with the pervasive mistaken or ill-use of the p values. As yet again brought up recently (4), the medical literature, for decades, has been replete with articles about this misconception. Physicians and investigators, with no apparent differences between the clinicians and the basic scientists, have singularly been reluctant to correctly understand and use the p value. The main elements of the said misconception seem to be a. Inadequacy in formal probabilistic thinking, the most common being that a p value represents the probability of our trial results being false positive while it actually represents the probability of obtaining the actual trial results had it been they were only due to chance; b. The power of a test is not only important in avoiding a Type II but also a Type I error; c. The information we get from any one p value much depends on the pre-test probabilities of what we try to measure in the study design in which we do this, i.e., an observational or a cross sectional study versus a placebo controlled randomized clinical trial (5). Publication bias traditionally referred to as the athors' and journal editors' propensity to publish positive or otherwise striking results. Recently this has been re-considered (6) and the proposal has been that a myriad of other biases, perhaps even including almost all items related to the “urge to prove” might also be included under this broader definition of a publication bias, and again perhaps now better called a 'dissemination bias'. Although much discussed this bias remains rather difficult to accurately identify and quantitate. Finally it has to be remembered, like all biases, the biases involved when reporting a trial can either be unintentional or intentional and this is equally difficult to differentiate and quantify.ReferencesYazici H. et al. Bull Hosp Jt Dis, 2013Yazici H et al. J Clin Epidemiol, 2014Puhan MA et al. Health Qual Life Outcomes, 2012Halsey LG et al. Nat Methods 2015Browner WS et al. JAMA, 1987Meerpohl et al. BMJ Open, 2015Disclosure of InterestNone declared
With an unknown etiology, pathogenesis and protean manifestations, Behçet's Syndrome (BS) remains a true construct – disease. As such, formulating disease criteria for BS is no easy task. This ...difficulty is compounded by the unfortunately much in vogue concept of formulating separate disease critera for classification and diagnosis (1). There are, however, specific and not so-specific elements of BS as a construct – disease and eye involvement is a specific element, as a well designed recent study underlined (2).Perhaps the more important contributions related to the understanding the pathogenesis within the past year were the papers related to the activations of the JAK-STAT and the NOTCH pathways in BS (3,4) with the upregulation SOCS proteins which negatively regulate the JAK-STAT pathway (5). HLA B51 remains the most prominent genetic association of BS and a recent work shed more light on its role in antigen recognition (6). Also in an important epigenetic study there were aberrations in the DNA methylation of genes related to cycoskletal function in BS and these tended to reverse with therapy (7).Some features of BS tend to cluster and vascular disease, a major cause of morbidity and mortality, is one such cluster. In a recent analysis we attempted to better define this cluster which involves dural sinus thrombi-pulmonary vascular disease-vena caval disease- peripheral deep vein thrombosis and finally superficial vein thrombosis (8). It is interesting to note that arterial disease, mainly on the form of anuerysms (excluding those in the pulmonary tree) is outside this cluster. We have also recently learned that the Budd-Chiari Syndrome, a relatively rare but a very serious complication of BS, can also present in milder forms, if specifically searched for (9).Our management know-how and capabilities are also improving. The precise role of colchicine in treatment and the use of anticoagulants in thrombotic disease in BS have, for years, been two important issues of debate. Within the past year two new observational studies provided additional useful data. Long term, 17 years, follow up of a group of patients from a double blind study of colchicine against placebo showed that the earlier use of colchicine did not have any affect on long term emergence of major morbidities as assessed by subsequent immunosuppresive use (10). For the role of anticoagulation, a retrospective reevaluation of management of vascular disease among 935 patients from 15 centers in Turkey revealed that the addition of anticoagulation to immunosuppresives was not effective in preventing recurrences (11). It is, however, to be underlined that a properly controlled randomized withdrawal study is still needed in the case of colchicine and a traditional randomized controlled trial in the case of the potential role of anticoagulants. Within the past year there were also a number of observational studies related to the successful use of biologics (12,13,14). Finally, a double blind, placebo controlled study with apremilast, an oral phosphodiesterase inhibitor, among patients with mainly skin-mucosa disease showed good effect of this agent in oral and, among the relatively small number of patients, in genital ulceration (15). Possible beneficial effects of apremilast on eye, vascular and central nervous disease remain to be seen.ReferencesYazici H et al. J Autoimmun, 2014.Tugal-Tutkun I et al. Ocul Immunol Inflamm, 2014.Tulunay A et al. Genes Immun, 2015.Qi J et al. Rheumatology (Oxford), 2014.Hamedi M et al. Scand J Immunol, 2014.Ombrello MJ et al. PNAS, 2014.Hughes T et al. Arthritis Rheum, 2014.Tascilar K et al. Rheumatology (Oxford), 2014.Seyahi E et al. Semin Arthritis Rheum, 2014.Hamuryudan V et al. J Rheumatol, 2014.Alibaz- Oner F et al. Medicine Baltimore), 2015.Papo M et al. Clin Exp Rheumatol, 2014.Salvarani C et al. Semin Arthritis Rheum, 2015.Feurer F et al. Rev Med Interne, 2014.Hatemi G et al. Arthritis Rheum (SI), 2014.Disclosure of InterestNone declared
Objectives:To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis.Methods:An expert group (10 rheumatologists, 3 nephrologists, 2 ...immunolgists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion.Results:Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures.Conclusions:On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.
Objectives:To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis.Methods:An expert group (consisting of 10 rheumatologists, 3 ...nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion.Results:In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures.Conclusions:On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.
Objective: To formulate EULAR recommendations for the management of early arthritis. Methods: In accordance with EULAR’s “standardised operating procedures”, the task force pursued an evidence based ...approach and an approach based on expert opinion. A steering group comprised of 14 rheumatologists representing 10 European countries. The group defined the focus of the process, the target population, and formulated an operational definition of “management”. Each participant was invited to propose issues of interest regarding the management of early arthritis or early rheumatoid arthritis. Fifteen issues for further research were selected by use of a modified Delphi technique. A systematic literature search was carried out. Evidence was categorised according to usual guidelines. A set of draft recommendations was proposed on the basis of the research questions and the results of the literature search.. The strength of the recommendations was based on the category of evidence and expert opinion. Results: 15 research questions, covering the entire spectrum of “management of early arthritis”, were formulated for further research; and 284 studies were identified and evaluated. Twelve recommendations for the management of early arthritis were selected and presented with short sentences. The selected statements included recognition of arthritis, referral, diagnosis, prognosis, classification, and treatment of early arthritis (information, education, non-pharmacological interventions, pharmacological treatments, and monitoring of the disease process). On the basis of expert opinion, 11 items were identified as being important for future research. Conclusions: 12 key recommendations for the management of early arthritis or early rheumatoid arthritis were developed, based on evidence in the literature and expert consensus.
Objectives:We undertook a systematic literature review as a background to the European League Against Rheumatism (EULAR) recommendations for conducting clinical trials in anti-neutrophil cytoplasm ...antibody associated vasculitis (AAV), and to assess the quality of evidence for outcome measures in AAV.Methods:Using a systematic Medline search, we categorised the identified studies according to diagnoses. Factors affecting remission, relapse, renal function and overall survival were identified.Results:A total of 44 papers were reviewed from 502 identified by our search criteria. There was considerable inconsistency in definitions of end points. Remission rates varied from 30% to 93% in Wegener granulomatosis (WG), 75% to 89% in microscopic polyangiitis (MPA) and 81% to 91% in Churg–Strauss syndrome (CSS). The 5-year survival for WG, MPA and CSS was 74–91%, 45–76% and 60–97%. Relapse (variably defined) was common in the first 2 years but the frequency varied: 18% to 60% in WG, 8% in MPA, and 35% in CSS. The rate of renal survival in WG varied from 23% at 15 months to 23% at 120 months. Methods used to assess morbidity varied between studies. Ignoring the variations in definitions of the stage of disease, factors influencing remission, relapse, renal and overall survival included immunosuppressive therapy used, type of organ involvement, presence of ANCA, older age and male gender.Conclusions:Factors influencing remission, relapse, renal and overall survival include the type of immunosuppressive therapy used, pattern of organ involvement, presence of ANCA, older age and male gender. Methodological variations between studies highlight the need for a consensus on terminology and definitions for future conduct of clinical studies in AAV.
Behçet Syndrome: Is It One Condition? Yazici, H.; Ugurlu, S.; Seyahi, E.
Clinical reviews in allergy & immunology,
12/2012, Letnik:
43, Številka:
3
Journal Article
Recenzirano
Behçet's syndrome (BS) is a disease of unknown etiology, and as such, there have been efforts to classify BS within the popular nosological identities of the times such as seronegative ...spondarthritides, autoimmune, and more recently autoinflammatory diseases. Current evidence suggests that BS does not easily fit into any one of these lumps, while on occasion, it might be impossible to tell BS from Crohn's disease, especially when the main clinical presentation is intestinal ulceration. There are distinct regional differences in disease expression of BS with fewer cases of intestinal disease in the Mediterranean basin and less severe eye disease and less frequent skin pathergy among patients reported from northern Europe or America. The clustering of symptoms, especially with the recently described increased frequency of the acne/arthritis cluster in familial cases, suggests that more than one pathological pathway is involved in what we call BS today. Supportive evidence for this contention also comes from the observations that (a) the genetic component is very complex with perhaps different genetic modes of inheritance in the adult and in the pediatric patients; and (b) there are differing organ responses to one same drug. For example, the anti-TNF agents successfully control the oral ulcers while they have no effect on the pathergy reaction.
Objectives:To develop evidence-based European League Against Rheumatism (EULAR) recommendations for the management of Behçet disease (BD) supplemented where necessary by expert opinion.Methods:The ...multidisciplinary expert committee, a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), consisted of nine rheumatologists (one who was also a clinical epidemiologist and one also a Rehabilitation Medicine doctor), three ophthalmologists, one internist, one dermatologist and one neurologist, representing six European countries plus Tunisia and Korea. A patient representative was also present. Problem areas and related keywords for systematic literature research were identified. Systematic literature research was performed using Medline and the Cochrane Library databases from 1966 through to December 2006. A total of 40 initial statements were generated based on the systematic literature research. These yielded the final recommendations developed from two blind Delphi rounds of voting.Results:Nine recommendations were developed for the management of different aspects of BD. The strength of each recommendation was determined by the level of evidence and the experts’ opinions. The level of agreement for each recommendation was determined using a visual analogue scale for the whole committee and for each individual aspect by the subgroups, who consider themselves experts in that field of BD. There was excellent concordance between the level of agreement of the whole group and the “experts in the field”.Conclusion:Recommendations related to the eye, skin–mucosa disease and arthritis are mainly evidence based, but recommendations on vascular disease, neurological and gastrointestinal involvement are based largely on expert opinion and uncontrolled evidence from open trials and observational studies. The need for further properly designed controlled clinical trials is apparent.
Objectives:To present and analyse the literature sources regarding the management of Behçet disease (BD) identified during the systematic literature research, which formed the basis for the European ...League Against Rheumatism (EULAR) evidence-based recommendations for the management of BD.Methods:Problem areas and related keywords regarding the management of BD were determined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A systematic literature research was performed using MedLine and Cochrane Library resources through to December 2006. Meta-analyses, systematic reviews, randomised controlled trials (RCTs), open studies, observational studies, case control studies and case series’ involving ⩾5 patients were included. For each intervention the effect size and number needed to treat were calculated for efficacy. Odds ratios and numbers needed to harm were calculated for safety issues of different treatment modalities where possible.Results:The literature research yielded 137 articles that met the inclusion criteria; 20 of these were RCTs. There was good evidence supporting the use of azathioprine and ciclosporin A in eye involvement and interferon (IFN)α in mucocutaneous involvement. There were no RCTs with IFNα or tumour necrosis factor (TNF)α antagonists in eye involvement. Similarly controlled data for the management of vascular, gastrointestinal and neurological involvement is lacking.Conclusion:Properly designed, controlled studies (new and confirmatory) are still needed to guide us in managing BD.
Objectives: To develop the European League Against Rheumatism (EULAR) recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis. Methods: An expert consensus group ...was formed consisting of rheumatologists, nephrologists and specialists in internal medicine representing five European countries and the USA, a clinical epidemiologist and representatives from regulatory agencies. Using an evidence-based and expert opinion-based approach in accordance with the standardised EULAR operating procedures, the group identified nine topics for a systematic literature search through a modified Delphi technique. On the basis of research questions posed by the group, recommendations were derived for conducting clinical studies and/or clinical trials in systemic vasculitis. Results: Based on the results of the literature research, the expert committee concluded that sufficient evidence to formulate guidelines on conducting clinical trials was available only for anti-neutrophil cytoplasm antibody-associated vasculitides (AAV). It was therefore decided to focus the recommendations on these diseases. Recommendations for conducting clinical trials in AAV were elaborated and are presented in this summary document. It was decided to consider vasculitis-specific issues rather than general issues of trial methodology. The recommendations deal with the following areas related to clinical studies of vasculitis: definitions of disease, activity states, outcome measures, eligibility criteria, trial design including relevant end points, and biomarkers. A number of aspects of trial methodology were deemed important for future research. Conclusions: On the basis of expert opinion, recommendations for conducting clinical trials in AAV were formulated. Furthermore, the expert committee identified a strong need for well-designed research in non-AAV systemic vasculitides.
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