Rheumatology meets radiology in the hot soup of Gutta
© BioMed Central Ltd 2012
Published: 19 December 2012
If left untreated, gout may result in radiographic abnormalities, that is, cartilage loss and periarticular osteopenia plus more-or-less gout-specific radiographic abnormalities: spurs, sclerosis, and periostal new bone formation. In the current issue, Dalbeth and colleagues describe findings from about 800 joints in 20 mostly tophaceous patients, which can help clinicians to identify osteopathologic gout: spurs, osteosclerosis, ankylosis and periostal new bone formation, all symptoms of advanced, untreated gout. These are hallmarks of chronic untreated gout and are to be prevented.
Gouty tophi consist of foreign body granulomas composed of mono- and multinucleated macrophages surrounding deposited MSU crystals: the central zone bears MSU crystals, and is surrounded by the corona, a cellular zone of macrophages, mast cells, and plasma cells. The corona is surrounded by a fibrovascular zone. In bone these deposits will result in erosive and destructive disease due to the granulomatous response, which as a process is similar in gout, sarcoidosis and tuberculosis. Tophaceous bone erosions are mediated via the receptor for activation of nuclear factor kappa B (RANK) and RANK ligand (RANKL) pathway [2, 3]. Gout arthritis results in IL-1 beta production, which has been implicated to play a pivotal role in bone destruction. Blocking the IL-1 pathway may result in uncoupling of erosiveness in tophaceous disease.
The overhanging appearance of erosions in gout is due to the internal growth process of tophi - that is, they grow inside the erosion. Blocking essential molecules of osteoclastogenesis will prevent the formation of erosions, despite the presence of synovial inflammation. Where osteoclasts are involved in bone erosions via RANKL and IL-1, macrophages are implicated in erosion of unmineralised cartilage via matrix metalloproteinases (MMPs). Recruitment of macrophages into the tophus occurs continuously, and this is the motor for production of the proinflammatory cytokine TNF and the TNF-inducible lytic enzymes MMP-2 and MMP-9. MSU crystals reduce the effects of anabolic osteoblasts, and seem to alter the normal balance between RANKL and osteoprotogerin, thereby indirectly promoting osteoclastogenesis in MSU-induced arthritis. IL-1 is a key molecule in TNF- and RANKL-induced osteoclastogenesis. The effects of the IL-1 receptor antagonist on markers of bone erosion and cartilage damage appear to be superior to its effects on inflammation, at least in rheumatoid arthritis.
Early detection and treatment of arthritic gout attacks have been prioritized over the past decades. Polarisation microscopy of the punctate (gold standard) and ultrasonography significantly contribute to early diagnosis in gout. Common radiology contributes to late gout diagnoses as it often takes years to develop radiographic abnormalities. In longstanding, often non-arthritic gout, tophaceous bulky disease may even coincide with common as well as more specific radiographic lesions. Dalbeth and colleagues  performed a quantitative analysis of radiography and tomography (798 joints photographed) in longstanding, often (80%) tophaceous gout (20 patients with about 20 years of exposure to a serum urate of about 0.49 mmol/l), an interesting experimental setting indeed.
Gout attacks are considered to result in soft tissue swelling, cartilage loss and periarticular osteopenia. Characteristic but not diagnostic for gout are radiographic features such as punched-out lytic lesions of articular bone , not to be confused with rheumatoid erosions. In gout these lytic lesions appear as sharp, often marginated lucent pockets, or discrete subchondral 'pseudocysts' seemingly not connected to the joint. Sclerotic margins signal bone repair in temporarily nonusurating foci. At the periphery of this 'erosive' lesion the bone margin appears to even hang over the tophaceous debris, particularly in hand/foot radiographs . In the presented series about 30% of small hand joints were 'erosive' at radiography, and a similar percentage at tomography. These 'erosive' lesions differ from rheumatoid arthritis with respect to appearance and the high frequency of occurrence in gout cases. Displacement of the margin probably reflects a gradual increase in size of the urate nidus, growing by multicentric deposition of urate crystals. In the vicinity of tophi, osteoblast activity is reduced and osteoclast activity enhanced. MSU crystals result in cell activation, cytokine production and proteases, all of which enhance focal erosiveness, resulting in bone fragility .
If left untreated, new bone formation occurs in joints affected by gout . MSU accumulation near a joint is associated with spurs, periostal new bone formation, ankylosis, and particularly osteosclerosis and osteophytosis. Tomography might be assumed to be more sensitive in detecting radiographic lesions than common radiology, and indeed was shown to be twice as sensitive at detecting spurs and 1.5-fold more sensitive at detecting osteophytes . Intraosseous MSU accumulation is correlated with spurs and sclerosis and only weakly correlated with ankylosis and periostal new bone formation. The study by Dalbeth and colleagues  does not show data on the (ir)reversibility or pathophysiology of bone erosion in gout, still important unanswered clinical questions. Where exactly do IL-1, TNF, MMP and RANKL fit in, and can therapeutic modulation with anti-IL-1, anti-TNF, anti-RANKL and anti-MMP inhibit progression in gout.
challenges for imaging in gout
Periostal new bone
In intervention study
In urate lowering therapies demonstrating efficacy
Experimental application/sporadic in daily practice
Common use in daily practice
Power Doppler sign
In diagnostic algorithm for early diagnosis (and possibly follow-up); measuring active inflammation
Experimental application/daily practice
In follow-up intervention study; measuring active inflammation
As bone is a living tissue one would hypothesize that many, if not all, bone changes can be repaired, contrary to cartilage loss. Then, what therapy in these late gout stages is most appropriate? In both early and advanced stages of disease top priority remains urate-lowering therapy to reduce the bodily urate burden; in advanced stages one may theoretically consider osteoclast-targeted therapy (anti-IL-1 or anti-RANKL) to lower osteoclastic bone resorption , or T-cell-modulating therapy to reduce stromal infiltrates of T cells producing RANKL . The most expedient therapy up to now is early starting treat-to-target urate-lowering therapy with allopurinol (and/or uricosuric) in order to prevent all the late, radiological features Dalbeth and colleagues describe.
magnetic resonance imaging
receptor for activation of nuclear factor kappa B
tumour necrosis factor.
- Doherty M, Jansen TL, Nuki G, Pascual E, Perez-Ruiz F, Punzi L, So AK, Bardin T: Gout: why is this curable disease so seldom cured?. Ann Rheum Dis. 2012, 71: 1765-1770. 10.1136/annrheumdis-2012-201687.View ArticlePubMed
- Schlesinger N, Thiele RG: The pathogenesis of bone erosions in gouty arthritis. Ann Rheum Dis. 2010, 69: 1907-1912. 10.1136/ard.2010.128454.View ArticlePubMed
- Dalbeth N, Clark B, Gregory K, Gamble G, Sheehan T, Doyle A, McQueen FM: Mechanisms of bone erosion in gout: a quantitative analysis using plain radiography and computed tomography. Ann Rheum Dis. 2009, 68: 1290-1295. 10.1136/ard.2008.094201.View ArticlePubMed
- Dalbeth N, Milligan A, Doyle AJ, Clark B, McQueen FM: Characterisation of new bone formation in gout: a quantitative site-by-site analysis using plain radiography and computed tomography. Arthritis Res Ther. 2012, 14: R165-10.1186/ar3913.PubMed CentralView ArticlePubMed
- Martel W: The overhanging margin of bone: a röntgenologic manifestation of gout. Radiology. 1968, 91: 755-756.View ArticlePubMed
- Nguyen C, Ea HK, Palazzo E, Lioté F: Tophaceous gout: an unusual cause of multiple fractures. Scand J Rheumatol. 2010, 39: 93-96. 10.3109/03009740903061428.View ArticlePubMed
- McQueen FM, Doyle A, Dalbeth N: Imaging in gout - what can we learn from MRI, CT, DECT and US?. Arthritis Res Ther. 2011, 13: 246-10.1186/ar3489.PubMed CentralView ArticlePubMed
- Dalbeth N, Smith T, Nicolson B, Clark B, Callon K, Naot D, Haskard DO, McQueen FM, Reid IR, Cornish J: Enhanced osteoclastogenesis in patients with tophaceous gout: urate crystals promote osteoclast development through interactions with stromal cells. Arthritis Rheum. 2008, 58: 1854-1865. 10.1002/art.23488.View ArticlePubMed
- Lee SJ, Nam KI, Jin HM, Cho YN, Lee SE, Kim TJ, Lee SS, Kee SJ, Lee KB, Kim N, Park YW: Bone destruction by receptor activator of nuclear factor kappa beta ligand-expressing T cells in chronic gouty arthritis. Arthritis Res Ther. 2011, 13: R164-10.1186/ar3483.PubMed CentralView ArticlePubMed