Rheumatology meets radiology in the hot soup of Gutta

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.

Gout is the most common infl ammatory arthritis in men and an increasingly frequent cause of arthritis in women, and is often not treated adequately [1]; the prevalence of gout is about 2 to 4% in Europeans and North-Americans. It is a chronic disease based on metabolic urate accumulation and immunologic (hyper)response ( Figure 1). Gout is characterized by a spectrum consisting of at least four stages: 1) asymptomatic hyperuricemia, 2) acute arthritic attack, 3) an intercritical period (attack free episodes), and 4) advanced destructive gout (due to urate accumulation and/or acute attacks). During the intercritical period, subjective complaints are lacking but a chronic smoldering infl ammation is often present. Chronic infl ammatory responses in gout and its sequelae in the locomotor and/ or cardiovascular system are not fully understood, but with modern targeted therapies and translational in vitro research we are starting to unravel these processes. With this information, and if pharmacotherapeutic options are administered appropriately, we, as clinicians, should be able to solve the devilish problems of ancient 'gutta' . Gutta is the origin of the word gout, the Latin word for a droplet of devilish fl uid, which later turned out to consist of monosodium urate (MSU).
MSU crystal deposition is due to focal hypersaturation and may be associated with reduced blood fl ow on the one hand, and more acidic and colder microenvironments providing conditions for focal deposition on the other. Changes in the relative proportion of glycosamino-and proteoglycans and lipid concentration add to this process. Both chondroitin sulphate and phosphatidylcholine are constituents of the matrix of joint tissue/ hyaline cartilage and are continuously released into the synovial fl uid, where they refl ect joint tissue metabolism. MSU crystals can be found in cartilage, tendon sheaths, synovial fl uid and subcutaneous tissue. Th e earliest articular changes result from a coating type of deposition where MSU crystals spread on to and over the cartilage surface as if coated with 'icing sugar' (Figure 2).
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. Th e corona is surrounded by a fi brovascular 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 impli cated to play a pivotal role in bone destruction. Blocking the IL-1 pathway may result in uncoupling of erosiveness in tophaceous disease.
Th e 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 osteo clastogenesis will prevent the formation of erosions, despite the presence of synovial infl ammation. 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

Abstract
If left untreated, gout may result in radiographic abnormalities, that is, cartilage loss and periarticular osteopenia plus more-or-less gout-specifi c radiographic abnormalities: spurs, sclerosis, and periostal new bone formation. In the current issue, Dalbeth and colleagues describe fi ndings 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. of the proinfl ammatory cytokine TNF and the TNFinducible lytic enzymes MMP-2 and MMP-9. MSU crystals reduce the eff ects 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 osteo clastogenesis. Th e eff ects of the IL-1 receptor antagonist on markers of bone erosion and cartilage damage appear to be superior to its eff ects on infl ammation, 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 signifi cantly 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 specifi c radiographic lesions. Dalbeth and colleagues [4] 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.
Charac teristic but not diagnostic for gout are radiographic features such as punched-out lytic lesions of articular bone [4], 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 [5]. In the presented series about 30% of small hand joints were 'erosive' at radio graphy, and a similar percentage at tomography. Th ese 'erosive' lesions diff er from rheumatoid arthritis with respect to appearance and the high frequency of occur rence in gout cases. Displacement of the margin probably refl ects 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 [6].
If left untreated, new bone formation occurs in joints aff ected by gout [4]. 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 [4]. Intraosseous MSU accumulation is correlated with spurs and sclerosis and only weakly corre lated with ankylosis and periostal new bone formation. Th e study by Dalbeth and colleagues [4] does not show data on the (ir)reversibility or patho physiology of bone erosion in gout, still important unanswered clinical questions. Where exactly do IL-1, TNF, MMP and RANKL fi t in, and can therapeutic modulation with anti-IL-1,  anti-TNF, anti-RANKL and anti-MMP inhibit progression in gout. Clearly, imaging techniques have exciting new applications [7] (Table 1): dual energy CT reveals later features of gout (that is, tophaceous load), high resolution CT the interrelation between bone erosions and tophi, MRI bone marrow edema/osteitis/tophi/synovitis, and ultrasound early abnormalities, such as snow storm (leukocytes/ urate needles in solution) and double contour sign (a fi ne layer like icing sugar over the cartilage; Figure 2), and power Doppler can semiquantitatively measure active infl ammation.
As bone is a living tissue one would hypothesize that many, if not all, bone changes can be repaired, contrary to cartilage loss. Th en, 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 [8], or T-cell-modulating therapy to reduce stromal infi ltrates of T cells producing RANKL [9]. Th e 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.