Nat Clin Pract Rheum
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The identification of subgroups of patients from randomized clinical trials that are of specific interest for guiding clinical decisions can be an attractive idea; however, since such trials are designed for the comparison of groups of patients, performing subgroup analyses can result in misinterpretation of the data. Such analyses must, therefore, be performed and evaluated with caution: these should be pre-planned and included in the design of a suitably powered trial. ⋯ The caveats associated with this approach, such as the occurrence of false positive or false negative effects, chance differences in observed effects, lack of power to perform the analysis, floor or ceiling effects, issues relating to multiple statistical testing, and over-reporting and under-reporting are discussed in this review. Subgroup analyses can, however, provide valuable, albeit predominantly exploratory, information on which to base clinical decisions if they are performed in accordance with recommendations and guidelines, and do, therefore, have a legitimate place in rheumatology clinical trials.
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Nat Clin Pract Rheum · Jul 2007
ReviewMechanisms of disease: a 'DAMP' view of inflammatory arthritis.
Innate immunity achieves our primary host defense by recognizing invading microorganisms through pathogen-associated molecular patterns (PAMPs) and by reacting to tissue damage signals called damage-associated molecular patterns (DAMPs). DAMP molecules, including high mobility group box 1 protein (HMGB-1), heat-shock proteins (HSPs), uric acid, altered matrix proteins, and S100 proteins, represent important danger signals that mediate inflammatory responses through the receptor for advanced glycation end-products (RAGE, also known as AGER) and Toll-like receptors, after release from activated or necrotic cells. The terms 'alarmins' and 'endokines' have also been proposed for DAMP molecules. ⋯ They are rapidly secreted by activated monocytes or neutrophils, which are abundant in inflamed synovial tissue. HSPs are involved in the crosstalk between innate and adaptive immune systems, and primarily mediate immune regulatory functions. Multiple positive feedback loops between DAMPs and PAMPs and their overlapping receptors temporally and spatially drive these processes and may represent the molecular basis for the observation that infections, as well as nonspecific stress factors, can trigger flares in rheumatic diseases.