All of this new information suggests that targeting osteoclast formation or urate deposition are potential therapeutic options for joint damage in gout, Dr. Dalbeth said. Current studies are examining anti-osteoclast therapy for prevention of bone erosion, she noted. In addition, targeting urate crystals through intensive urate-lowering therapy may prevent development of joint damage or promote healing of bone erosion.
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Explore This IssueMarch 2014
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More research is needed on the pathogenesis of gout to identify what early signs point to the development of joint damage, she said. “Can we predict what patients will develop severe joint damage other than those who develop tophi? Not yet,” she said.
Limit Gouty Inflammation
The new frontier of gout research is finding ways to limit inflammation and connective tissue destruction by tophaceous disease, said Robert Terkeltaub, MD, professor of medicine at the University of California, San Diego. Two important points to note in cases of gouty arthritis with “roaring inflammation” are that urate crystal deposits often are quiescent and that acute gout usually is self-limited, Dr. Terkeltaub said. Even in patients with asymptomatic hyperuricemia, crystals form in about 25% of cases. MSU crystals may “quietly activate chondrocytes, and gout damage may start with superficial zone chondrocytes,” he added.
To understand what can limit gouty inflammation, it’s important to explore how it may be activated in these cases, Dr. Terkeltaub said. In gout, the NLRP3 inflammasome activation of IL-1 beta secretion is at the root of inflammation. This may be one clue to why gout prevalence is very high in the elderly population. “It has become apparent that aging is a heightened state of NLRP3 activation,” he added. Adaptive immunity may limit NLRP3-mediated, acute inflammation, however.
Nutrition has always played a central role in gout management. In fact, dietary substances may either inhibit or activate the inflammatory responses in gout, Dr. Terkeltaub said. Fish oil may contribute to the inhibition of the NLRP3 inflammasome and blunts the activation of NLRP3, he noted, and this action may merit further testing of fish oil supplements in both gout and recent-onset RA. “Fish oil may dampen at least the IL-1 pathway in a number of inflammatory arthropathies,” he said. Consuming low-fat dairy products, which have a low purine content and have been shown to have urate-lowering effects, also may help lower the risk of developing gout in the first place, he said.
Metabolic super-regulation by caloric restriction and pharmacologic interventions also appears to limit gouty inflammation, he said, as is the “clearing out the garbage” by M2b and M2c macrophages by achieving efferocytosis. Understanding these processes in gout will point to the development of new therapies, including IL-1 and IL-6 antagonists, NLRP3-pathway inhibitors, drugs that interface between nutrition status and inflammation, and dietary interventions or fish oil supplements, Dr. Terkeltaub concluded.
Contributions to OA
In addition to gout, non-urate, calcium-containing crystals can induce inflammation and aggravate OA, a disease where 30% to 60% of patients have these crystals in their joint fluid, said Geraldine McCarthy, MD, clinical professor and consultant rheumatologist at University College Dublin in Ireland. “Calcium-containing crystals contribute to cartilage damage through multiple mechanisms in osteoarthritis,” she noted. Calcium pyrophosphate [CPP] crystals likely contribute to cartilage degradation and synovitis in OA, and also likely play a central role in pseudogout. “Small CPP crystals are more inflammatory than larger ones,” she said.” Basic calcium phosphate (BCP) crystals also are found in OA, but are difficult to identify because they are ultramicroscopic. When these crystals were injected into murine knee joints, they led to synovial inflammation and cartilage degradation. BCP can induce mitogenesis and stimulate COX-1 and COX-2, prostaglandin production, and cytokine production, particularly IL-1 and IL-18, Dr. McCarthy said. “BCP crystals may be every bit as potent as MSU crystals” in their ability to produce matrix degradating enzymes in joints, she said.