Crystal-induced arthropathies are a group of disorders that involve deposition of crystals in joints and soft tissues, resulting in articular and periarticular inflammation and injury. Two types of crystals — monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) — are commonly involved in gout and CPPD disease, which are described in this chapter.
Gout
Definition
Gout is a crystal-deposition disease caused by the super saturation and precipitation of MSU crystals in tissues resulting in inflammation and tissue damage. Gout is characterized by acute and subacute attacks. The clinical course of gout can be summarized into three stages:
Acute gout,
Intercritical gout and recurrent gout,
Chronic tophaceous gout.
Hyperuricemia is the underlying metabolic aberrancy in gout and is defined as a serum urate level >6.8 mg/dL, a level at which urate precipitates into MSU crystals.
Prevalence
Gout is a relatively common disease, with a higher prevalence in men than in women. Between 3 and 8 million American adults (about 3% of the population) are estimated to have gout.1-3 The estimated prevalence is nearly 7% among men older than 65 years.4
Overall, the prevalence of gout has been increasing.5 Factors contributing to this rise include increases in alcohol use, purine-rich diets, rates of obesity and the metabolic syndrome, and use of diuretic agents.6
There is a link between elevated levels of serum urate and the incidence of gout. Patients with serum urate levels ≤7 mg/dL have an annual incidence below 1%; for patients with serum urate levels ≥9 mg/dL, the incidence is more than 5%.7
Pathophysiology
Gout is an inflammatory crystal arthropathy resulting from the pathogenic effect of MSU crystals in the joints and soft tissue. Uric acid in body fluid at pH 7.4 exists in the urate form. Thus, when referring to uric acid in physiologic fluid, it is preferable to use the term urate.
Uric acid comes from the metabolism of purine nucleotides. Purine metabolism leads to inosine then hypoxanthine. Hypoxanthine is metabolized to xanthine, which is metabolized to uric acid. These two last steps are catalyzed by the enzyme xanthine oxidase, which is the major site for pharmacologic intervention by allopurinol. In humans, uric acid is the final product; humans lack the ability to degrade urate further.
Minimal amounts of urate are eliminated through the urinary and intestinal tracts. If the body is unable to eliminate large burdens of urate, hyperuricemia develops. As urate levels increase and saturate the synovial fluid or soft tissues, crystals precipitate, leading to tissue damage and the development of tophi. The accumulation of urate crystals in soft tissues and joints activates monocytes and macrophages to clear the crystals by phagocytosis. This leads to the release of proinflammatory cytokines and chemokines into the surrounding area, triggering a cascade of acute inflammatory reaction and influx of neutrophils into the joints, resulting in swelling of the joint or soft tissue.
The mechanisms leading to the self-limited inflammatory process are not fully known. The innate anti-inflammatory processes, possibly mediated by anti-inflammatory cytokines, may interrupt the inflammatory process. The natural course of gout resolves spontaneously, on average, in 1 to 2 weeks.8,9
An additional proposed mechanism involves the role of an inflammasome and interleukin 1 (IL-1) in the pathogenesis of inflammation induced by MSU (the crystal in gout) and CPPD (the crystal in CPPD disease). Cryopyrin inflammasome detects MSU and CPPD crystals and activates IL-1, resulting in an inflammatory cascade. These IL-1–mediated inflammatory effects of MSU crystals could be blocked by IL-1 inhibitors. This pathway presents an opportunity to treat patients with gouty arthritis who are otherwise intolerant of or inadequate responders to standard anti-inflammatory therapies. Large randomized, controlled trials are needed to assess the efficacy and side effects of blocking IL-1 in this patient population.
Clinical Manifestations
large tophi
Figure 1A: Click to Enlarge
monosodium urate salts
Figure 1B: Click to Enlarge
monosodium urate salts
Figure 1C: Click to Enlarge
first metatarsophalangeal joint
Figure 2: Click to Enlarge
Tophi along the second proximal interphalangeal
Figure 3: Click to Enlarge
tophi along forearm
Figure 4: Click to Enlarge
The acute inflammation of the joint or soft tissue associated with gout is clinically manifest as arthritis, direct soft tissue damage, and accumulation of MSU crystals (tophi) in soft tissue and bones (Figures 1-4). Hyperuricemia can cause uric acid nephrolithiasis and, possibly, nephropathy, if uric acid accumulates in the renal interstitium and tubules.
The arthritis in acute gout usually manifests as asymmetric monoarticular or oligoarticular inflammation, lasts 3 to 10 days, and resolves spontaneously. Eventually the attacks occur more frequently, last longer, and do not resolve completely, leading to chronic gouty arthropathy. Gouty arthropathy can lead to erosions and joint destruction. Gouty arthropathy is distinguished from rheumatoid arthritis by the absence of joint space narrowing and periarticular osteopenia.
In general, gout includes joint swelling in both the lower and upper extremities. Inflammation in the first metatarsophalangeal (MTP) joints is termed podagra, and it is highly suggestive of gout; however, any joint in the feet, ankles, knees, hands, wrists, or elbows may be involved. Acute gout can occur in the bursae, such as the olecranon or prepatellar bursae, where it causes bursitis, and can also occur in tendons such as the Achilles tendon and other soft tissue. Occasionally, a gout attack triggers a systemic inflammatory response manifesting with fevers, leukocytosis, elevated sedimentation rates, and elevated C-reactive protein (CRP).
Acute attacks can be precipitated by several factors. These include increased alcohol consumption (especially beer), diet (organ meat, shellfish), dehydration, trauma, and use of diuretics, cyclosporine, or urate-lowering drugs that can lead to sudden fluctuations in urate levels. Table 1 lists the common risk factors associated with gout.
Table 1: Common Risk Factors Associated with Gout
Hyperuricemia Risk factors
Increased uric acid production
Diet high in purines (eg, meats, especially organ meats, some seafood), fructose-sweetened beverages
Excessive alcohol consumption, especially beer and liquor
Obesity
Myeloproliferative disorders
Lymphoproliferative disorders
Reduced uric acid excretion
Metabolic syndrome (abdominal obesity, elevated triglycerides, hypertension, hyperlipidemia, hyperglycemia)
Diabetes
Chronic renal failure
Medications increasing urate levels: Diuretics, cyclosporine, low-dose aspirin
When urate accumulates in a supersaturated medium, it can deposit in soft tissue or bones and form a tophus. Tophi can be present over the helices of the ears, extensor areas of the limbs, pressure areas such as the finger pads, and over the Achilles tendons. Most can be detected on a physical examination. On x-rays, they look like cystic or mass-like lesions. In general, tophi are radiolucent on x-rays, but when one occurs over a calcified nodule, it may be radiopaque.
Diagnostic Testing
If clinical suspicion of gout is raised, investigational studies are needed to confirm the diagnosis; elevated serum urate levels alone are not sufficient to make the diagnosis. The clinical presentation, medical history, and physical examination coupled with supportive evidence from additional testing, preferably synovial fluid analysis, can usually confirm the diagnosis. If inconclusive, additional studies may be needed, such as an x-ray, other imaging studies, or histopathology from surgical resections.