Gout and Hyperuricemia

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1 Gout and Hyperuricemia 100 Access publication Sep Computed tomography manifestation of gouty arthritis Hu Yabin 1, Yang Qing 1, Cao Qiang 2, Ren Jianan 1, Yang Qing * Objective: Of the most commonly involved joint in gouty arthritis is the first metatarsophalangeal joint, followed by other foot joints, ankle joints, hand and wrist joints and knee joint, etc. Gouty arthritis includes soft tissue swelling, monosodium urate deposition (tophus), bone destruction, and joint effusion. We intended to explore the joint characteristics of gouty arthritis via computed tomography (CT) scanning. Methods: Image capture of 31 patients with gout by Philips brilliance 16 rows CT scanner and analysis of joint characteristics. Results: The average density of tophus was 158 ± 65 Hounsfield units. The diameter of bony destruction was correlated with the diameter of surrounding tophus (r=0.83, p<0.01). The CT value of tophus was associated with the course of gout (r=0.51, p<0.01), and the CT value of tophus was related to the mean levels of five-year serum uric acid (r=0.49, p<0.05). Conclusion: Combining clinical and laboratory tests, the characteristic CT features of gouty arthritis can help correctly diagnose gout arthritis. Key words: Gout; Arthritis; Computed tomography; X-ray 1 Department of Radiology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. 2 Department of Radiology, Binzhou People s Hospital, Binzhou, Shandong, China. * Corresponding author: Yang Qing Department of Radiology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. YQ9799@126.com Tel: Fax: Submitted on Oct. 14, 2016; accepted on Oct. 16, , Gout and Hyperuricemia. Published by Dong Fong Health Co. LTD in Taiwan. All right reserved. Introduction Gout is caused by abnormal purine metabolism and/or constantly increased serum uric acid. Its clinical features include hyperuricemia and tophus deposition in/near joint. Gouty arthritis (GA) attacks may occur repeatedly, and even lead to joint deformities. Evidence of tophi or monosodium urate (MSU) crystals within the joint fluid are the major criteria for diagnosis of GA, but analysis of joint fluid is not routine. Additionally, chronic GA sometimes present atypically like tumor or infection, so computed tomography (CT) can efficiently diagnose GA. Multi-angle imaging of spiral CT can show subtle tophus deposition, calcification, and bone destruction better than plain radiographs [1]. Here we analyze CT exams of patients with gout, which was diagnosed according to the American College of Rheumatology (ACR) classification criteria, and discuss the correlations between CT manifestations and gout clinical features. Methods Study population 28 male and three female gouty arthritis patients were included in this study, all of whom were diagnosed according to the ACR classification criteria from the affiliated hospital of Qingdao university gout laboratory, and two out of these patients were confirmed by pathological diagnosis after surgery. Patients were years old with the course of disease ranging from 0-22 years. All patients had acute disease accompanied by fever, joint swelling, pain, and impaired activities. 22 patients had high uric acid levels ( µmol/L) while the other nine had stable levels as a result of allopurinol treatment (Table 1).

2 101 CT manifestation of gouty arthritis Table 1. Characteristics of clinical and laboratory parameters in gouty arthritis patients. Parameters Age (mean ± SD; years) 43 ± 5.2 Gender (male/female; n) 28/3 Course (mean ± SD; years) 7.3 ± 1.3 Uric acid (mean ± SD; µmol/l) 471 ± 67.7 Five years average of uric acid (mean ± SD; µmol/l) 475 ± 46.3 Involved joints (n; %) 190 (100%) First metatarsophalangeal joints 55 (28.9%) Foot joints (except first metatarsophalangeal joints) 47 (24.7%) Ankle joints 36 (18.9%) Hand and wrist joints 29 (15.3%) Knee joints 17 (8.9%) Elbow joints 6 (3.2%) Table 2. The parameters of computed tomography examination in gouty arthritis patients. Parameters Tophus Number 199 Density (mean ± SD; Hounsfield units) 158 ± 35.7 Diameter (mean ± SD; mm) 8.3 ± 1.5 Bone erosion number 138 Diameter (mean ± SD; mm) 4.6 ± 0.3 Tissue swelling 181 Joint effusion 25 narrowed joint space 2 Study design All joints of gout patients were scanned by the Philips brilliance 16 rows CT scanner. All scans performed the same imaging standards: 1 mm thick layer of scanning, 0.5 mm width between layers, 0.7 mm thread pitch, 327 mm 2 field of view (FOV), and 140kV and 200mAs scanning condition. All images were multiple planar reformation (MPR) reconstruction, but some cases were 3 dimensions reconstruction. All CT images were analyzed by two musculoskeletal system diagnostic radiologists with 10 years of experience in the field; conclusions for inconsistent diagnoses were made after discussions in person. The diagnosis records contained the location of the tophus, morphological characteristics and CT value, the position and morphology of the destroyed bones, and presence of soft tissue swelling, joint effusion and joint space narrowing. Using the picture archiving and communication (PACS) system, we measured bone erosion, tophi whose diameter 1mm, and tophi adjacent to bone erosion. Measuring surface, whose shortest diameter is defined as the diameter, were described as maximum cross-sectional area of bone erosion and tophi. We recorded the average of three measuring diameters on axial, coronal and sagittal planes. The CT values were gathered from measuring 5 mm diameter circle of tophi for the maximum cross-sectional area on transverse, coronal and sagittal planes. We avoided measuring calcified area since the CT value of calcification is >250 Hounsfield units (HU) (Table 2). Statistical analysis Descriptive analysis was performed for CT manifestations of tophi and bone destruction. Spearman s correlation coefficients between diameter of bone destruction and diameter of adjacent tophi, and between CT value and course and five years mean levels of uric acid were calculated. Results Tophi distribution and morphology Formed tophi were found in soft tissue around joint or joint spaces such as tendons, ligaments, bones, joint capsule, synovial cavity, and subcutaneous tissue around joint in 174 joints out of 23 cases. MSU were most often found deposited in attachments of ligaments and tendons around joints. Tophi were circular, oval, or irregular shaped ground-glass opacities with diameter between 1-35mm. The tophus density was 158HU, always uneven and with unclear edges. MSU spots, plaques, lines, or nodular deposits were found in tophi (Figure 1AB). Bone destruction 138 joints had bone destruction in 21 cases, resulting in different sizes of chisel-like, cystic, or arc-shaped shapes, and sharp and hard edges. Multiple bone destructions are more common than singular involvement. In addition, bony destruction was often located eccentrically, and edges were warped like a fish mouth shape and protruded forward to tophus nodules. Serious damage to the bone often resulted in wavy, arc and honeycomb shapes (Figure 1A).

3 CT manifestation of gouty arthritis 102 Figure 1. A man aged 82 year old who suffered gout disease for 20 years. A) two-foot computed tomography (CT) images showed multiple tophi deposits and eccentric bone defect in coronary position; B) Two- foot three dimensions reconstruction image showed widely tophi deposits; C) and D) showed tophi deposits and joint effusion in double knee joint. Figure 2. A man aged 55 years old showed tissue swelling and increased density on the back of inside first metatarsophalangeal joints (arrow pointed); A) Horizontal axis position B) Coronary position. Joint effusion 165 joint effusions, mostly in ankle or knee joint, are illustrated in Figure 1CD. Soft tissue swelling Figure 3. A man aged 56 years old who suffered gout disease for 20 years. Behind the pubic chick, the elbow computed tomography (CT) image in coronary position showed soft tissue swelling, urate deposits, and merged with chick slippery bursa phlogistic (arrow). 181 joints had surrounding soft tissue swelling, characterized by limitations, side swelling around joints, and increased swelling of the soft tissue density (Figure 2 and Figure 3). There were spots, line and nodular MSU deposits in 162 joints with soft tissue swelling when tophi formed. There were surrounding soft tissue swelling and increased density uniformity in 19 joints (10.5%). Joint space narrowing Two patients had joint space narrowing, and their course of gout arthritis were 16 and 22 years, respectively. They had a history of multiple gouty attack recurrences. They had irregular bony joint surface with corrosive damage to bones. There was a strong correlation between diameter of bone destruction and its adjacent tophus diameter (r=0.83, p<0.01) and a relationship between CT value of tophi and the course of disease (r=0.51, p<0.01). CT value of tophi and the 5 year mean serum uric acid value were significantly correlated (r=0.49, p<0.05). Discussion Gout is a metabolic disease characterized by elevated serum uric acid, acute arthritis attacks, MSU deposition in or around joints, bone destruction, uric acid renal

4 103 CT manifestation of gouty arthritis stones, etc. Gout often occurs in years old men, and the risk is higher in men compared to women. 90% of primary gout patients have gouty arthritis, yet only 5% of those patients are postmenopausal women. Clinical gout is divided into asymptomatic hyperuricemia, acute attack, intermittent attack, and chronic phase. About 50% of patients experience the first gout attack in the first metatarsophalangeal joint [2]. Pain often occurs suddenly at night, and is difficult to endure. The joints quickly become red, warm and tender, which are features of inflammation. Gout attack usually occurs in a single joint of the lower limb in young men at first. Those joints includes foot joints, ankles and knees. In the early stage, arthritis often occurs in a single joint, and then develops into multi-articular involvement. The imaging features of gout in the early stage may only include soft tissue swelling around joints, but bone joints are generally normal. In acute attack phase, soft tissue often swells markedly. In CT images, the soft tissue around the joint has deposits of MSU, which is usually a spot or high density flocculence. Due to repeated gout attacks, molecules such as MSU, uric acid, protein matrix, inflammatory cells and foreign body giant cells deposit in tissues, and then tophi form gradually. These tissues may be tendon, ligament, cartilage, bones, or other soft tissues, such as joint capsule, synovial cavity, and subcutaneous tissue around joint. Due to the uneven distribution of MSU and uneven density of tophi, our average CT value of tophi was 158HU, consistent with another study [3]. CT can clearly show MSU crystals in tophi; its CT value is about 160HU, while calcium salt is obviously higher than tophi (>250HU). Studies have revealed that gout often occurs in ligaments and tendons, consistent with our findings, and tophus might wear down the strength of ligaments and tendons, leading to easy tears. Deposition of tophi may be similar to space-occupying lesions, and can cause carpal tunnel syndrome in wrist joints, intervertebral disc inflammation and spine paraplegia. Erosions around the joint with dangling and sharp edges are characteristic findings of chronic gouty arthritis [4]. In our findings, the shape of destroyed bone was varied. So far, the pathological mechanism of gouty arthritis destruction is unclear. A chronic foreign body reaction occurs when MSU deposits around joints or in subcutaneous tissue, and then epithelial cells and megakaryocyte surround the sediment. Tophi harden with fibrous tissue hyperplasia, resulting in erosion and damage to adjacent bone, which stimulates periosteum hyperplasia and ossification around the joint. In consequence, soft tissues around the joint are eccentric and have an elevated density. The bone may have an irregularly deep or shallow arc defect adjacent to tophi, including sclerotic margins with periosteum hyperplasia and ossification that tend to envelope the tophi, which consequently form into overhanging edges. Another characteristic of gout is that the density of bone is normal until later stage. Disuse osteoporosis appears after repeated attacks in later stages when pain limits joint flexibility. The joint spaces are normal until later stages as well. There were only two patients with late stage gout whose joint spaces were narrow and abnormal, consistent with a previous study [5]. We revealed that there is an obvious correlation between bone erosion and its adjacent tophi in gouty arthritis patients. Although tophus cannot be found in all small defected areas of bone, which may be due to the limitation of CT resolution, tophi can be found in almost all large defected areas. Thus, infiltration of tophus into bone is a main mechanism by which gouty arthritis develops bone erosion and joint damage. The CT study compared the differences between tophi in bone and locations other than bone in chronic gout, which showed similar density and calcification. Additionally, the diameter of tophus in bone was larger than non-bone locations. This indicates that the load of MSU crystal in joint is an important factor in the development of gout-related bone erosion. There is a high correlation between CT value of tophi and course of gouty arthritis; tophi are denser with development of gouty arthritis. This can be explained by Choi et al. who found that prolonged course cause MSU to deposit in joint and disease onset [6]. Serum uric acid level control in the sub-saturated level (<6 mg/dl) has been shown to reduce recurrent frequency of erythema and reduce tophi size. With uric acid lowering treatment, the rate of subcutaneous MSU degradation relates to the average level of serum uric acid [7]. There was a positive correlation between CT value of tophi and five-year mean serum uric acid value in our study. This demonstrates the effectiveness of uric acid lowering treatment. Clinical diagnosis of gouty arthritis may be easily confused with rheumatoid arthritis (RA), osteoarthritis (OA), and calcium pyrophosphate dihydrate deposition disease (CPPD). RA is a symmetrical disease, and its incidence in women is higher than in men. The inflammatory sites are usually in the near side interphalangeal joint and wrist joint, but the foot is rare. The soft tissue around the involved joint is swollen in the early stage, while atrophy occurs late stage. Furthermore, the area of osteoporosis is clear and wide in RA, and the joint space narrows early. In most RA patients, rheumatoid factor is positive, immunoglobulin G (IgG) usually elevates and the level

5 CT manifestation of gouty arthritis 104 of uric acid is normal. Salicylic acid drugs have a curative effect on RA. The rheumatoid factor is negative or weakly positive in gout patients, and arthritis is generally asymmetric. Gout or gouty arthritis may be misdiagnosed as RA, septic arthritis, or other rheumatic diseases when the phenotype is not typical, which therefore leads to inappropriate treatment [8]. If gout mainly occur in the bone structure, osteophyte formation and relative bone mineralization retention may be similar to OA. The soft tissue nodules seen with OA may also be confused with tophus. Generally, the articular cavity can be normal until a later stage. Bone erosion is not a characteristic of OA, but it can be helpful to diagnose gout. Crystal precipitate in joint caused by calcium pyrophosphate deposition disease (CPPD) may be similar to gout. CPPD, also named pseudogout, is a common disease of the elderly as well as a common cause of arthritis in this age group. Cartilage calcification is usually seen in a single joint in CPPD (chondrocalcinosis), and the cartilage includes hyaline cartilage and fibrocartilage. Compared with gouty arthritis, the density of calcification in CPPD is too low to show easily with chondrocalcinosis [9]. In most cases, the presence of amorphous soft tissue swelling and articular cavity with bone erosion is helpful to diagnose gout. OA is also a common disease of the elderly, with equal incidence in men and women. In addition, this disease has various symptoms, and often involves multiple joints and joint space narrow. Osteophyte formation can occur in the articular edge, which can proliferate and harden joint surfaces. There are small saccate areas with reducing density under the articular surface, without bone defect in articular surface edge and extremity, and normal serum uric acid level. In conclusion, it is worth noting that gout may present as a comorbidy with any of the above-mentioned diseases, so clinical manifestation, laboratory examination results and imaging findings should be integrated in the diagnosis process to prevent misdiagnosis or missed diagnosis. To make a correct diagnosis and to evaluate efficiently, it is important to identify MSU, tophi, tophusrelated distribution of bone destruction, and features of tophi on CT examination. in gout: a quantitative analysis using plain radiography and computed tomography. Ann Rheum Dis. 2009; 68: Dalbeth N, Milligan A, Doyle AJ, Clark B, McQueen FM. Characterization of new bone formation in gout: a quantitative site-by-site analysis using plain radiography and computed tomography. Arthritis Res Ther. 2012; 14: R Mandell BF. Clinical manifestations of hyperuricemia and gout. Cleve Clin J Med. 2008; 75 Suppl 5: S Choi HK, Al-Arfaj AM, Eftekhari A, et al. Dual energy computed tomography in tophaceous gout. Ann Rheum Dis. 2009; 68: Dalbeth N, Doyle AJ, McQueen FM, Sundy J, Baraf HS. Exploratory study of radiographic change in patients with tophaceous gout treated with intensive urate-lowering therapy. Arthritis Care Res (Hoboken). 2014; 66: Carter JD, Kedar RP, Anderson SR, et al. An analysis of MRI and ultrasound imaging in patients with gout who have normal plain radiographs. Rheumatology (Oxford). 2009; 48: Loffler C, Sattler H, Peters L, Loffler U, Uppenkamp M, Bergner R. Distinguishing gouty arthritis from calcium pyrophosphate disease and other arthritides. J Rheumatol. 2015; 42: References 1.Shi Y, Mucsi AD, Ng G. Monosodium urate crystals in inflammation and immunity. Immunol Rev. 2010; 233: Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yu TF. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977; 20: Dalbeth N, Clark B, Gregory K, et al. Mechanisms of bone erosion