Infected synovium exhibits a chronic synovitis marked by synoviocyte hyperplasia, fibrin deposition, mononuclear cell infiltrates (especially CD4+ T cells), and onionskin thickening of arterial walls. The morphology in severe cases can closely resemble that of RA.
Articular crystal deposits are associated with a variety of joint disorders. Endogenous crystals shown to be pathogenic include monosodium urate (MSU) (gout), calcium pyrophosphate dehydrate (pseudogout), and basic calcium phosphate. Exogenous crystals, such as silicone, polyethylene, and methyl methacrylate used in prosthetic joints, and the debris that accumulates with their erosion, may result in local arthritis. Crystals produce disease by triggering an inflammatory reaction that destroys cartilage.
Gout is marked by transient attacks of acute arthritis initiated by urate crystals deposited within and around joints. Whether gout is primary or secondary to some other underlying disease, the common feature is excessive uric acid in tissues and body fluids. In the primary form (90% of cases), gout is the major manifestation of the disease and the cause is usually unknown.
Hyperuricemia (plasma urate level above 6.8 mg/dL) is necessary, but not sufficient, for the development of gout.
Uric acid metabolism can be summarized as follows:
Synthesis. Uric acid is the end product of purine catabolism. Increased synthesis typically reflects some abnormality in purine production. The synthesis of purine nucleotides, in turn, involves two interlinked pathways. In the de novo pathway, purine nucleotides are synthesized from nonpurine precursors, and in salvage pathways they are synthesized from free purine bases obtained through the diet or the catabolism of purine nucleotides.
Excretion. Uric acid is filtered from the circulation by the glomerulus and virtually completely resorbed by the proximal tubule of the kidney. A small fraction of the resorbed uric acid is secreted by the distal nephron and excreted in the urine.
http://ebooksmedicine.net 824CHAPTER 21 Bones, Joints, and Soft Tissue Tumors
In primary gout, elevated uric acid most commonly results from reduced excretion, the basis of which is unknown in most patients. A small minority of primary gout is caused by uric acid overproduction as a result of identifiable enzymatic defects. For example, partial deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT) interrupts the salvage pathway, so purine metabolites cannot be salvaged and are, instead, degraded into uric acid. Complete absence of HGPRT also results in hyperuricemia, but significant neurologic manifestations of this condition (Lesch-Nyhan syndrome) dominate the clinical picture so it is classified as secondary gout. Secondary gout can also be caused by increased production (rapid cell lysis during chemotherapy for leukemia, so-called tumor lysis syndrome) or decreased excretion (chronic renal disease).
The inflammation in gout is triggered by precipitation of urate crystals in the joints, stimulating the production of cytokines that recruit leukocytes (
Fig. 21.41 ). Macrophages and neutrophils phagocytose the crystals, which activates a cytosolic sensor, the inflammasome (Chapter 5). The inflammasome activates caspase-1, which is involved in the production of active IL-1β. IL-1 is proinflammatory, and promotes accumulation of more
Precipitation of urate crystals in joints
Activation of complement
ReleaseSynovium of crystals
Lysis of neutrophils
Release of Tissue injury and