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Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier


The most common presentation of musculoskeletal disease is pain in and around a joint in association with functional impairment. Collectively, diseases causing joint symptoms are called arthritis, implying inflammation. The extent of inflammation in these diseases varies markedly, however, with some forms such as osteoarthritis showing scant evidence of inflammation either locally or systemically.

Arthritis results from many different diseases and occurs in various patterns defined by the number and size of joints affected, symmetry, and involvement of the axial as well as peripheral joints. For each pattern (e.g., chronic polyarthritis), a key issue in diagnosis concerns its place in the spectrum of inflammatory versus noninflammatory arthritis. Furthermore, although many diseases can cause arthritis, their prevalence varies enormously, with osteoarthritis or degenerative joint disease being the most common form of noninflammatory arthritis and RA the most common form of inflammatory arthritis.

The differential diagnosis of arthritis is based on a comprehensive history and physical examination to assess symptoms suggesting inflammation (e.g., morning stiffness and fatigue), the presence of synovitis, and results of laboratory tests indicative of an inflammatory process. Of these tests, the ESR and CRP are nonspecific indicators of inflammation. Two autoantibody tests, rheumatoid factor (RF) and antibodies to citrullinated proteins, provide more specific diagnostic information. Given the demographics of inflammatory arthritis, testing for antinuclear antibodies is often part of this evaluation as well.

Rheumatoid Factor

RF comprises a family of specificities that bind to the immunoglobulin G (IgG) molecule. These RFs target primarily the constant region or Fc portion of IgG, reacting with antigenic determinants that are most likely conformational in origin. IgM RFs are the most abundant of these antibodies and have been easiest to measure, using agglutination assays with red blood cells or latex beads coated with IgG. More recently, enzyme-linked immunosorbent assays (ELISA) and nephelometry have been used to detect RFs.

RFs occur in approximately 80% of patients with RA and represent a criterion for the classification or diagnosis of this disease. Furthermore, high levels of RFs are often associated with a worse prognosis, the occurrence of erosion as measured by radiographs, and deformity. Despite these associations, RFs occur in sera of patients with a wide range of autoimmune and inflammatory diseases as well as in normal individuals, especially with age. The frequent occurrence of RFs may reflect their etiology and role in innate immune responses to promote the binding of IgG antigen by Fc cross-linking.

Antibodies to Citrullinated Proteins

Antibodies to citrullinated proteins are another set of autoantibody specificities that are important in the diagnosis of RA. Citrulline is a post-translational modification of the amino acid arginine that results from deimidation. This chemical reaction is catalyzed by the enzyme peptidylarginine deiminase (PAD) and may occur in the setting of inflammation; the function of this modification is unknown. Citrullination can affect many different proteins, creating antigenic sites on proteins that include keratin, fibrinogen, and filaggrin. This antibody system can be detected by Western blotting, ELISA, or cellular immunofluorescence.

Although antibodies are directed to citrullinated residues on intact proteins, they can be conveniently measured using synthetic peptides containing citrulline. Among these synthetic antigens, a citrulline-containing protein with a cyclic structure provides sensitive and specific assays in an ELISA format. Antibodies directed to this type of antigen are known as anti-CCP (cyclic citrullinated peptide) and can be formally distinguished from antibodies to the citrullinated proteins themselves (ACPA, or anti-citrullinated protein antibodies). The term anti-CCP is commonly used for these specificities, although it is formally synonymous with ACPA.

Anti-CCP antibodies are highly associated with RA. They occur in 60 to 70% of patients with RA and uncommonly in those with other forms of inflammatory arthritis, making their presence important in diagnosis. Significantly, anti-CCP antibodies can occur before the onset of other signs and symptoms of RA, suggesting utility for screening of at-risk patients and for diagnosis in the earliest stage of disease to allow initiation of therapy.

Joint Fluid Analysis

Analysis of joint fluid can provide decisive data in the evaluation of arthritis and, in some instances, a definitive diagnosis. This analysis is essential in the setting of acute monoarthritis to investigate the possibility of infection; for chronic forms of arthritis, joint fluid should be analyzed if there is uncertainty about the diagnosis and involvement of one joint out of proportion to others. Joint aspiration is a sterile procedure performed with a local anesthetic. Although fluid can be analyzed by tests to assess viscosity and mucin content, the cell count, examination of crystals, and stains and cultures to evaluate infection are the most informative.

On the basis of cell counts, joint fluids can be categorized into four main types: noninflammatory, inflammatory, septic, and hemorrhagic. A noninflammatory fluid has fewer than 2000 cells/mm3 with mononuclear cell predominance. An inflammatory fluid has more than 2000 cells/mm3, with 50,000 cells/mm3 frequently used as the upper limit for this type of fluid. In an inflammatory fluid, polymorphonuclear cells predominate. A septic fluid is an inflammatory fluid in which culture or staining for microorganisms demonstrates infection. Suspicion of infection is especially high for fluids with cell counts greater than 50,000/mm3. However, crystal-induced arthritis can produce cell counts of this magnitude, and an infected fluid can have counts below this level. Hemorrhagic fluids have red cell predominance that can approximate that of blood.

In the setting of an acute monoarthritis, crystal-induced disease is much more common than infection, with the presence of crystals demonstrated by polarization microscopy. With this technique, monosodium urate crystals in gout appear needle-shaped and are negatively birefringent. In contrast, calcium pyrophosphate dihydrate crystals in pseudogout are rhomboidal in shape and are weakly positively birefringent. Infection can coexist with crystal-induced disease, necessitating microbiologic evaluation even when crystals are found. Hemorrhagic fluids can also result from infection, although their presence suggests malignancy or trauma. Figure 278-1 provides an algorithm for the analysis of joint fluid.

FIGURE 278-1  Algorithm for analysis of joint fluid. Examples of inflammatory arthritis are indicated, although many conditions can produce these findings. AS = ankylosing spondylitis; PsA = psoriatic arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; TB = tuberculosis.

Depending on the clinical findings and the results of initial laboratory testing, other studies may be performed to investigate less common diagnostic possibilities such as metabolic disease or malignancy. The laboratory evaluation of inflammatory arthritis may also include serologic tests for infections such as Lyme disease, human immunodeficiency virus (HIV) infection, or hepatitis.

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