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MD Consult: Books: Goldman: Cecil Medicine: Chapter 278 – LABORATORY TESTING IN THE RHEUMATIC DISEASES

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 278 – LABORATORY TESTING IN THE RHEUMATIC DISEASES

David S. Pisetsky

The rheumatic diseases are a heterogeneous group of conditions that result from diverse pathophysiologic mechanisms and involve the musculoskeletal system as well as other organs. These conditions range from mild, diffuse joint and muscle pain to severe life-threatening kidney failure and stroke. Although the rheumatic diseases have many origins, immune disturbances resulting in local and systemic inflammation are frequently the underlying cause. The approach to diagnosis therefore entails a wide variety of laboratory tests to assess functional disturbances of individual organs and their relationship to inflammation and autoimmunity.

Laboratory testing in patients with rheumatic disease has two main purposes. The first is diagnostic, and the second is prognostic. Some tests are useful in both contexts, but others have different performance characteristics related to their specificity and pattern of expression during disease. Prognostic tests provide critical information to help distinguish activity that is reversible from damage that is fixed and irreversible. In general, the assessment of damage relies on specific tests of end-organ function or structure rather than process markers. Distinguishing activity from damage is very important in the management of rheumatic diseases, especially with respect to the use of therapies associated with toxicity.

MARKERS OF INFLAMMATION

For many patients, the initial goal of evaluation is to determine the presence of inflammation. Inflammation is the body’s response to injury and is characterized by a cascade of cellular and molecular events that arise irrespective of stimulus or locale. The immediate response to inflammatory stimuli is termed the acute phase response and comprises a set of proteins produced primarily in the liver in response to cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1. These cytokines are produced by macrophages and dendritic cells after stimulation of pattern recognition receptors called toll-like receptors (TLRs); TLRs recognize bacterial and viral products as well as molecules from damaged cells and trigger innate immunity. Many proteins in the acute phase response show dramatic increases in concentration, although some show a reduction. Because the levels of these proteins can increase hundreds to thousands of times in magnitude, they provide a sensitive and powerful set of markers for inflammation, whether induced by infection, trauma, or autoimmunity.

Of the proteins stimulated during the acute phase response, C-reactive protein (CRP) has received the most attention as a marker of inflammation in both rheumatic and nonrheumatic disease. CRP is a member of the pentraxin family; although its function is not fully known, its ability to bind to phosphocholine suggests a scavenger function to eliminate bacterial products or damaged cells and attenuate the consequences of infection or tissue injury. Other molecules, such as serum amyloid protein (SAP), fibrinogen, and complement, also show marked elevations during the acute phase response, signifying a broad-based effort at host defense.

The CRP level provides a very useful measure of inflammation and can convey information for categorization of a clinical process (e.g., inflammatory versus noninflammatory arthritis) as well as assessment of disease activity or prognosis (e.g., activity of rheumatoid arthritis [RA] or likelihood of erosion). The advantage of measuring CRP in the blood, rather than cytokines, is that the protein levels are much higher. Furthermore, CRP levels remain elevated for a longer period (days) than cytokines do; the latter may appear only transiently in the blood and thereby evade detection.

Another simple laboratory text reflecting the acute phase response is the erythrocyte sedimentation rate (ESR). In this test, commonly called the sed rate, anticoagulated blood is drawn into a long, thin tube and allowed to settle under the influence of gravity for 1 hour. The distance the blood falls depends on a number of factors, including the concentration of serum proteins such as immunoglobulins and fibrinogen, an acute phase reactant. The sedimentation rate is nonspecific with respect to disease association and also depends on age and gender. The upper limits of normal vary between women and men.

Other simple laboratory tests point to an acute phase response. For example, patients with inflammation frequently have a leukocytosis or thrombocytosis, most likely reflecting the action of cytokines and other mediators, including glucocorticoids, during this process. With chronic inflammation, anemia of chronic disease can also occur, with the hematocrit in conjunction with the white blood cell and platelet counts pointing to the presence of an inflammatory process. In systemic lupus erythematosus (SLE), lymphopenia, thrombocytopenia, and low CRP values often characterize active disease, with the discordance between laboratory and clinical findings a clue to diagnosis.

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