International Journal of Rheumatic Diseases 2014; 17: 248–255
REVIEW ARTICLE
Positron emission tomography/computed tomography imaging and rheumatoid arthritis Shi-Cun WANG,1 Qiang XIE1 and Wei-Fu LV2 1
PET/CT Center, Anhui Provincial Hospital, and 2Department of Radiology, Anhui Provincial Hospital, Hefei, Anhui, China
Abstract Rheumatoid arthritis (RA) is a phenotypically heterogeneous, chronic, destructive inflammatory disease of the synovial joints. A number of imaging tools are currently available for evaluation of inflammatory conditions. By targeting the upgraded glucose uptake of infiltrating granulocytes and tissue macrophages, positron emission tomography/computed tomography with fluorine-18 fluorodeoxyglucose (18F-FDG PET/CT) is available to delineate inflammation with high sensitivity. Recently, several studies have indicated that FDG uptake in affected joints reflects the disease activity of RA. In addition, usage of FDG PET for the sensitive detection and monitoring of the response to treatment has been reported. Combined FDG PET/CT enables the detailed assessment of disease in large joints throughout the whole body. These unique capabilities of FDG PET/CT imaging are also able to detect RA-complicated diseases. Therefore, PET/CT has become an excellent ancillary tool to assess disease activity and prognosis in RA. Key words: positron emission tomography, positron emission tomography/computed tomography, rheumatoid arthritis.
INTRODUCTION Rheumatoid arthritis (RA) is an inflammatory autoimmune disease featuring chronic inflammation of the joints and bone destruction.1 Clinical manifestations include pain, tenderness and symmetrical swelling of joints, and eventually loss of function.2 Although the clear mechanisms that contribute to disease pathogenesis have not been fully elucidated, accumulating evidence has suggested that this disease is related to an accommodation disorder of the immune system due to interactions with genetic and environmental factors.3 It has been widely accepted that numerous inflammatory cells such as T cells, B cells, fibroblast-like synoviocytes (FLS), antigen-presenting cells, and their extensive production of pro-inflammatory mediators, such as tumor Correspondence: Dr Shi-Cun Wang, PET/CT Center, Anhui Provincial Hospital, 17 Lujiang Road, Hefei, Anhui 230001, China. Email: [email protected] All authors are contributed equally to this work and should be considered co-first authors.
necrosis factor alpha (TNF-a), interleukin-1 (IL-1) and IL-6, are implicated in disease onset.4 FLS have been recognized to be an important contributor to the pathologic process of RA.5,6 Available evidence indicates that FLSs, which constitute the synovial lining, are key actors in pannus formation and the subsequent destruction of cartilage and bone in the joint.7,8 Histopathologic features of RA synovial tissue found significant infiltration by macrophages and T cells, proliferative synovial membranes and neovascularization.9–14 Studies have shown several imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US) to evaluate inflammatory conditions, disease activity, progression and response to therapy in RA patients. These modalities provide information about bone structure and soft tissue abnormalities, with superior sensitivity in comparison with conventional radiography, but are limited by lack of specificity regarding activity of inflammation.15–17 Scintigraphic studies are also able to find early functional impairment due to an inflammatory process,
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
PET/CT imaging and rheumatoid arthritis
by which Gallium-67 (67Ga) scintigraphy has been widely used to evaluate suspected inflammation.18 Nevertheless, its clinical application might be limited by the relatively low spatial resolution and a lack of anatomic landmarks recognizable by scintigraphy.19 Therefore, search for new imaging approaches to assess disease activity, predict progressive joint destruction and monitor the efficacy of treatment would be highly valuable. Fluorine-18 fluorodeoxyglucose (18F-FDG) is a radiolabeled glucose analog where the 2′-OH is replaced by 18 F. 18F-FDG not only accumulates in malignant tissues but also at sites of infection and inflammation (e.g., in patients with autoimmune disease with activated macrophages and granulocytes).19 After entering the cell, 18 F-FDG is phosphorylated to 2′-FDG-6 phosphate by the hexokinase enzyme. 2′-FDG-6 phosphate is not a substrate for the enzymes of the glycolytic pathway or the pentose-phosphate shunt compared with glucose-6phosphate.20 Consequently, 18F-FDG cannot be further metabolized or diffuse back into the extracellular space, and is trapped and enriched within the cell.20 The accumulated FDG can be accurately detected by the scanner. Positron emission tomography (PET) provides a unique, noninvasive, quantitative method to study the metabolic activity of target tissue in vivo. PET with 18 F-FDG has been clinically used mainly for tumor diagnosis, therapy monitoring and experimental cancer research. However, a systematic evaluation of this method for diagnosing non-neoplastic conditions has been undertaken only during the past decade. It has been known that inflammation can lead to a hypermetabolic response and an obligatory requirement for glucose aiming to support cellular metabolism.18 In addition, glucose metabolism is influenced by proinflammatory mediators such as TNF-a and characteristically up-regulated in inflamed tissue,21,22 making PET a potential technique for the detection and quantification of inflammation. A combination of functional PET imaging and CT as anatomical reference allows a more detailed identification of 18F-FDG uptake.23 In this article, we will describe the impact of PET/CT on the evaluation of RA.
PET/CT IMAGING AND RA Vijayant et al.24 found all painful and/or swollen and/or tender joints had considerable FDG avidity. Metabolically, the wrist joint was the commonest and predominantly affected followed by the ankle joints (in the high to intense category).24 In patients with nonrheumatic (NR) diseases and in healthy subjects, there
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was no significant uptake of FDG in the joint regions.25 In contrast, there was highly positive FDG uptake in the shoulder, hip, wrist and knee joints in RA patients.25–28 The positive frequencies of FDG accumulation in the shoulder, hip and knee joints using PET/ CT scan were high in RA patients. Intriguingly, the sensitivity of PET/CT was markedly higher than for MRI in the lumbar spinal processes and the ischial tuberosity. Ga scintigraphy also indicated lower sensitivity than PET/CT.25 Furthermore, the FDG uptake score and the maximal standardized uptake value (SUVmax) of the painful/swollen joints were markedly higher than those of the joints that were not painful/swollen in RA patients.29,30 C-reactive protein (CRP) level and total FDG score indicated a significant linear correlation,28–31 and the cumulative SUV was significantly correlated with swollen and tender joint counts, patient and physician global assessments, erythrocyte sedimentation rate (ESR), disease activity score and simplified disease activity index.28 Similarly, there was a significant correlation between total FDG uptake scores for the arm joints and the axillary lymph nodes, and total FDG uptake score was strongly related to FDG uptake in the atlanto-axial joint.30 However, the bone scans of the same patients indicated mild changes in the large joints, implying that this modality was not as sensitive as FDG PET.29 Nevertheless, it should be kept in mind that FDG imaging directly detects inflamed tissue while bone scanning detects the reaction of the bone to inflammation or destruction as a consequence of inflammation. These techniques are therefore complementary. In addition, bone scanning has a lower spatial resolution as well as detection sensitivity. With respect to 18F-FDG PET/CT and 18F-NaF (sodium flouride) PET/CT imaging, two patients with multiple myeloma were examined.32 In one case, intense NaF accumulation in a dorsal vertebra was noted, but the corresponding FDG uptake was unimpressive. In another patient, 18 F-FDG PET/CT indicated intense uptake in the lesions in the axial skeleton while 18F-NaF PET/CT seemed normal, and a sternal lesion displayed FDG uptake only in the center but NaF uptake only in the periphery.32 It has been recognized that numerous studies suggest 18 F-FDG PET/CT can provide more information about multiple myeloma.33–36 Although the role of 18F-NaF PET/CT in skeletal diseases is growing, it is still uncommonly used in the evaluation of multiple myeloma.37,38 In 62 patients with a variety of malignancies, 53 received simultaneous tracer injections, while nine received 18F-NaF subsequent to the initial 18F-FDG dose (average delay 2.2 h). Results indicated that 47
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patients had PET findings of malignancy.39 Of the 47 patients, a higher number of lesions were detected in 16 patients using the combined 18F-FDG/18F-NaF PET/ CT imaging in comparison with 18F-FDG-only PET/CT imaging.39 In two of the 47 patients, 18F-FDG-only PET/CT imaging found soft tissue lesions that were not prospectively identified on the combined study.39 Therefore, these data suggest that 18F-FDG and 18F-NaF can be combined in a single PET/CT scan by administering the two radiopharmaceuticals, and combining these two imaging modalities has the potential to
provide more accurate information about disease extent, but the role of these two radioactive tracers in the management of disease continues to be defined. Moreover, the number of painful/swollen joints was markedly related to the number of joints with an FDG uptake score of 2 or more, and the mean number of joints per patient with an FDG uptake score of 2 or more was markedly larger than the mean number of painful/swollen joints.29,30 Collectively, these findings suggest that FDG PET/CT accurately and sensitively reflects the extent of RA disease (Fig. 1).
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Figure 1 We report a 57-year-old woman who visited our hospital because of knee pain for more than 4 years and was unable to walk for 2 months, where there was no clinical change in hands and feet. Laboratory examinations showed high levels of C-reactive protein (26.6 mg/L) and rheumatoid factor (124 IU/mL). After partial-body positron emission tomography/computed tomography with fluorine-18 fluorodeoxyglucose (18F-FDG PET/CT) imaging, results are as followings: (a) there are some small nodular lesions with high FDG uptake in both wrists, both proximal interphalangeal joints and part of the distal interphalangeal joints, maximal standardized uptake value (SUVmax) was 3.0; CT images showed narrowing joint space in both the wrists and interphalangeal joints, and the bone density was uneven. (b) there are some small nodular and circinal lesions with high FDG uptake in both feet and ankels, SUVmax was 2.7; CT images showed no aberrant changes. (c) there are some nodular and circinal lesions with high FDG uptake in both knees, SUVmax was 4.5. CT images indicated that bone density was uneven in both knees, especially the left knee and there was bone destruction, soft tissue swelling, joint space narrowing and less clear articulation. Finally, this patient was diagnosed as having rheumatoid arthritis. The PET/CT imaging in this study suggests that FDG may better detect inflamed joints than clinical symptoms, where there was no clinical change in hands and feet but PET/CT imaging showed aberrant changes in these joints. a1, b1, c1 are the PET images. a2, b3, c2 are the CT images. a3, b3, c3 are the PET/CT fusion images. a1, a2, a3 are the images of hands/fingers and wrists (both sides). b1, b2, b3 are the images of feet/toes and ankles (both sides). c1, c2, c3 are the images of knees (both sides).
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Rheumatoid arthritis patients treated with triple combination oral disease-modifying anti-rheumatic drugs (DMARDs) (methotrexate, sulfasalazine, hydroxychloroquine and low-dose glucocorticoids) reduced mean Disease Activity Score-28 (DAS-28) (ESR) from 5.6 1.3 (baseline) to 2.2 0.8 (week 12).23 All the patients achieved a European League against Rheumatism (EULAR) response, with 59% achieving disease remission.23 After treatment, 18F-FDG uptake was down-regulated in some joints (e.g., hands, wrist, shoulder, elbow, knees and ankle), where there were 76% and 81% of patients showing reduced SUVmax from baseline to week 2 and week 4, respectively. In addition, reductions in 18F-FDG uptake measures on PET imaging were related to DAS-28 scores, ESR and CRP.23 Furthermore, Szalay et al.40 enrolled 19 treatment-naive (early) RA patients and initiated glucocorticoids (in a dose of 16 mg/day for 4 weeks; then 8 mg/day). Methotrexate, 10 mg/week, was started at week 4. Results showed that T helper 1 (Th1), Th2 and Th17 prevalence was higher, while regulatory T cell (Treg) prevalence was lower in early RA than healthy controls. After treatment, glucocorticoids alone decreased Th2 prevalence, while glucocorticoids + methotrexate decreased Th17 prevalence.40 In addition, early RA patients exhibited increased levels of CRP and ESR, and had a high disease activity score as measured by the DAS-28. The patients also had higher serum levels of total cholesterol, plasma levels of small dense lowdensity lipoprotein cholesterol (sdLDL-C) whereas their serum high-density lipoprotein cholesterol (HDL-C) levels were significantly lower compared with controls. After administration of methotrexate and prednisone, patients showed a significant increase in HDL-C levels.41 Treatment led to a significant decrease in the inflammatory markers CRP and ESR, as well as in the reduction of DAS-28.41 Similarly, PET/CT images showed intense articular uptake in hands and wrists before anti-TNF therapy (infliximab). After 2 months treatment, reduced FDG articular uptake in hands and wrists were found in RA patients.42 Furthermore, active RA patients underwent whole-body FDG PET and clinical assessment before and after treatment with infliximab for 3 months.43 Results indicated that the PETbased total joint score was similarly high before onset as was the clinical total joint score. The decrease of FDG joint uptake in the follow-up PET scans was significantly related to the clinical assessment.43 In addition, 6 months after the anti-TNF therapies (infliximab, etanercept), the average values of DAS-28, DAS-28 (CRP), ESR and matrix metalloproteinase-3 (MMP-3) were
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markedly decreased compared with baseline.14,44 The SUV of the right ankle, right hip, right elbow, left shoulder, bilateral wrists and bilateral knees were decreased in comparison with the SUV at baseline in each patient.45 These data imply that usage of FDG PET/CT is available and effective in monitoring treatment response (DMARDs and anti-TNFs).31 Collagen-induced arthritis (CIA) is an animal model of RA that has been used to discuss the pathogenesis of the disease and to validate therapeutic targets. The dominant pathological features of CIA involved proliferative synovitis, erosion of bone, cartilage degradation, pannus formation, with infiltration of polymorphonuclear and mononuclear cells. In CIA mice, 18F-FDG PET depicted swollen joints, and 18F-FDG accumulation increased with the progression of arthritis.46,47 Histologically, a higher level of 18F-FDG accumulation was related to the pannus rather than the infiltration of inflammatory cells around the joints.46 Similarly, the mean SUVmax of 18F-FDG for knees and ankles was significantly higher for CIA mice than for control mice, respectively.47,48 The arthritis score of knee joints in CIA mice increased with the progression of arthritis gradually, and the arthritis score was positively correlated with the SUVmax,47 while in glucose-6-phosphate isomerase (G6PI)-induced arthritis, tracer enrichment was restricted to tissue with high basal metabolic activity (e.g., heart muscle and eyes) or organs of the excretory system (e.g., kidneys and bladder) before arthritis onset (day 2).20 However, additional 18F-FDG signaling can be detected in the joints of fore and hind paws in acute experimental arthritis at day 13, suggesting a specific 18F-FDG uptake in inflamed joints. PET/CT imaging showed hot spots of inflammatory metabolic activity in wrist and ankle joints. After treatment of human sTNFR (etanercept) or saline with G6PI-induced mice, PET/CT found a marked 4.9-fold decrease of total 18 F-FDG uptake in sTNFR (etanercept)-treated arthritic mice. Comparable results were obtained using histopathological assessment of therapeutic intervention.20 Thus, PET/CT is a convenient technique for monitoring disease activity or efficacy of treatment in experimental arthritis. It is noteworthy that FDG PET/CT may help predict therapeutic response to novel treatments. In a group of active RA patients, before infliximab treatment, all patients indicated enhanced 18F-FDG uptake in at least one metacarpophalangeal region or wrist.49 After 14 and 22 weeks, DAS decreased to 4.3 1.5 and 3.9 1.3, respectively. The change in mean SUV after 2 weeks of infliximab treatment correlated markedly
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with DAS at 14 and 22 weeks, respectively.49 The study found a strong correlation between early changes in 18 F-FDG uptake in hand joints and clinical disease activity after 14 and 22 weeks of treatment. At a group level, the findings suggest that 18F-FDG PET may therefore be a valuable technique for predicting the efficacy of infliximab therapy as early as 2 weeks after initiation of treatment. Rituximab, a chimeric monoclonal antibody against the CD20 antigen, has been approved for the treatment of RA patients.50 Tran et al.51 radiolabeled rituximab with 124Iodine (124I) for PET imaging. Results showed that patients who did not receive pre-treatment with unlabeled rituximab indicated localization of nearly all radioconjugate in the spleen and to a lesser extent bone marrow, examined by PET/CT imaging 10 min after administration of 124I-rituximab.51 Findings after 24 h indicated that the uptake in the spleen was largely diminished while the radioactivity accumulated in the thyroid.51 In contrast, 124I-rituximab has favorable pharmacokinetics for targeting pathological B cells after pre-treatment with unlabeled rituximab, where patients predosed with unlabeled rituximab indicated persistent tracer availability in the central circulation for multiple days, with almost no splenic uptake.51 Furthermore, PET imaging of patients received 124I-rituximab at 24 h and later exhibited accumulation of the tracer in joints (e.g., shoulder, elbow, wrist, ankle, hands and knees), suggesting that the visualized signal represents active targeting of the antibody to the CD20 epitope.15 Combined PET/CT images confirmed the localization of the tracer in thickened synovia in knee joints.15 Therefore, pre-treatment with rituximab is necessary for saturating the peripheral binding sites, and visualization of the CD20-antigen expression could provide a tool to localize sites of inflammation and could be of additive value in the treatment follow-up of RA patients.
PET/CT AND COMPLICATIONS OF RA AND TREATMENT In one study, Minamimoto et al.52 examined an RA patient who complained of cervical lymphadenopathy at 66 months after initiation of methotrexate (MTX) treatment for RA. PET/CT imaging showed an FDG-avid lesion at bilateral tonsils, bilateral supraclavicular fossa, bilateral axillary nodes and left inguinal region. Diffuse large B cell lymphoma (DLBCL) was proven from the biopsy tissue of the FDG-avid lesion at the right supraclavicular fossa. In another patient with a 10-year history of RA, splenomegaly, liver tumor and left renal
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tumor were identified on CT examination. After a week’s withdrawal of MTX, these lesions shrank, but rapid regrowth occurred when MTX therapy was restarted. PET/CT imaging showed FDG-avid foci at the right inguinal region, para-aortic region, bilateral adrenal glands and liver.52 These findings showed the usage of FDG PET/CT for diagnosis and follow-up of patients with MTX-related malignancies. The mean of aortic maximum 18F-FDG target-tobackground ratios (TBRmax) in the whole aorta was significantly higher in RA patients in comparison with cardiovascular disease (CVD) patients.44 Similarly, there was a marked rightward shift in the distribution of TBRmax at baseline in RA patients compared with CVD patients, and RA patients had a higher proportion of hot slices within the aorta than were found in CVD patients.44 However, after anti-TNF therapy (adalimumab, etanercept), PET/CT images showed a strong reduction in mean aortic TBRmax and reduced proportion of hot slices.44 Similarly, 18F-FDG PET/CT imaging on RA patients showed distinct areas of extra-articular soft tissue FDG uptake, such as axillary lymph nodes, epitrochlear lymph node, cervical lymph nodes, inguinal nodes, thyroid gland and subcutaneous (possibly rheumatoid) nodules.24,42,43,53–57 In addition, PET/CT imaging can find RA-complicated diseases such as interstitial pneumonia,58 multiple extra-articular synovial cysts,59 rheumatoid lung disease60,61 and atlantoaxial osteoarthritis.62 Collectively, these data suggest that FDG PET/CT is not only able to find RA-complicated tumors, but also has the potential to detect RAcomplicated inflammatory diseases.
CONCLUSION Positron emission tomography/computed tomography has become a valuable ancillary tool for evaluating RA. This technique can visualize the degree of disease activity or ‘burden of inflammation’. It may be helpful for the assessment of the extent of RA throughout the whole body, including high-risk lesions such as those in the atlanto-axial joint. It is also able to assess the response to treatment with drugs that modify cellular activity. These unique capabilities of PET/CT imaging may indeed be helpful in the management of RA. However, several points should be considered: first, the final goal of PET/CT imaging used in RA is to find the optimal timing of therapy (DMARDs or biologics therapy, such as anti-TNF therapy), aiming for complete remission of RA. Therefore, a multicenter prospective study involving therapeutic intervention should be conducted
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in the future.29,30 Second, PET/CT imaging used in RA can do whole-body scans to see all involved areas, but has poor specificity and is expensive. Third, limited evidence has suggested that 124I-rituximab PET/CT can detect inflamed joints in RA, with a seemingly reasonable sensitivity, but further research is required to determine the diagnostic accuracy of this procedure, and to establish the clinical value of the findings.15,51
ACKNOWLEDGEMENTS None.
CONFLICT OF INTEREST None to declare.
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55 Chhakchhuak CL, Khosravi M, Lohr KM (2013) Role of (18)F-FDG PET scan in rheumatoid lung nodule: case report and review of the literature. Case Rep Rheumatol 2013, 621340. 56 Ozcan Kara P, Kaya B, Kara Gedik G, Sari O (2011) Epitrochlear and axillary lymph node visualization on FDGPET/CT imaging in a patient with rheumatoid arthritis. Rev Esp Med Nucl 30, 168–70. 57 dos Anjos DA, do Vale GF, Campos Cde M et al. (2010) Extra-articular inflammatory sites detected by F-18 FDG PET/CT in a patient with rheumatoid arthritis. Clin Nucl Med 35, 540–1. 58 Nishiyama Y, Yamamoto Y, Dobashi H, Kameda T (2010) Clinical value of 18F-fluorodeoxyglucose positron emission
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tomography in patients with connective tissue disease. Jpn J Radiol 28, 405–13. Kirino Y, Ihata A, Shizukuishi K et al. (2009) Multiple extra-articular synovial cysts complicated with rheumatoid arthritis. Mod Rheumatol 19, 563–6. Bagga S (2007) Rheumatoid lung disease as seen on PET/ CT scan. Clin Nucl Med 32, 753–4. Gupta P, Ponzo F, Kramer EL (2005) Fluorodeoxyglucose (FDG) uptake in pulmonary rheumatoid nodules. Clin Rheumatol 24, 402–5. Kaneta T, Hakamatsuka T, Yamada T et al. (2006) Atlantoaxial osteoarthritis in rheumatoid arthritis: FDG PET/CT findings. Clin Nucl Med 31 (4), 209.
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Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
REVIEW ARTICLE
Positron emission tomography/computed tomography imaging and rheumatoid arthritis Shi-Cun WANG,1 Qiang XIE1 and Wei-Fu LV2 1
PET/CT Center, Anhui Provincial Hospital, and 2Department of Radiology, Anhui Provincial Hospital, Hefei, Anhui, China
Abstract Rheumatoid arthritis (RA) is a phenotypically heterogeneous, chronic, destructive inflammatory disease of the synovial joints. A number of imaging tools are currently available for evaluation of inflammatory conditions. By targeting the upgraded glucose uptake of infiltrating granulocytes and tissue macrophages, positron emission tomography/computed tomography with fluorine-18 fluorodeoxyglucose (18F-FDG PET/CT) is available to delineate inflammation with high sensitivity. Recently, several studies have indicated that FDG uptake in affected joints reflects the disease activity of RA. In addition, usage of FDG PET for the sensitive detection and monitoring of the response to treatment has been reported. Combined FDG PET/CT enables the detailed assessment of disease in large joints throughout the whole body. These unique capabilities of FDG PET/CT imaging are also able to detect RA-complicated diseases. Therefore, PET/CT has become an excellent ancillary tool to assess disease activity and prognosis in RA. Key words: positron emission tomography, positron emission tomography/computed tomography, rheumatoid arthritis.
INTRODUCTION Rheumatoid arthritis (RA) is an inflammatory autoimmune disease featuring chronic inflammation of the joints and bone destruction.1 Clinical manifestations include pain, tenderness and symmetrical swelling of joints, and eventually loss of function.2 Although the clear mechanisms that contribute to disease pathogenesis have not been fully elucidated, accumulating evidence has suggested that this disease is related to an accommodation disorder of the immune system due to interactions with genetic and environmental factors.3 It has been widely accepted that numerous inflammatory cells such as T cells, B cells, fibroblast-like synoviocytes (FLS), antigen-presenting cells, and their extensive production of pro-inflammatory mediators, such as tumor Correspondence: Dr Shi-Cun Wang, PET/CT Center, Anhui Provincial Hospital, 17 Lujiang Road, Hefei, Anhui 230001, China. Email: [email protected] All authors are contributed equally to this work and should be considered co-first authors.
necrosis factor alpha (TNF-a), interleukin-1 (IL-1) and IL-6, are implicated in disease onset.4 FLS have been recognized to be an important contributor to the pathologic process of RA.5,6 Available evidence indicates that FLSs, which constitute the synovial lining, are key actors in pannus formation and the subsequent destruction of cartilage and bone in the joint.7,8 Histopathologic features of RA synovial tissue found significant infiltration by macrophages and T cells, proliferative synovial membranes and neovascularization.9–14 Studies have shown several imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US) to evaluate inflammatory conditions, disease activity, progression and response to therapy in RA patients. These modalities provide information about bone structure and soft tissue abnormalities, with superior sensitivity in comparison with conventional radiography, but are limited by lack of specificity regarding activity of inflammation.15–17 Scintigraphic studies are also able to find early functional impairment due to an inflammatory process,
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
PET/CT imaging and rheumatoid arthritis
by which Gallium-67 (67Ga) scintigraphy has been widely used to evaluate suspected inflammation.18 Nevertheless, its clinical application might be limited by the relatively low spatial resolution and a lack of anatomic landmarks recognizable by scintigraphy.19 Therefore, search for new imaging approaches to assess disease activity, predict progressive joint destruction and monitor the efficacy of treatment would be highly valuable. Fluorine-18 fluorodeoxyglucose (18F-FDG) is a radiolabeled glucose analog where the 2′-OH is replaced by 18 F. 18F-FDG not only accumulates in malignant tissues but also at sites of infection and inflammation (e.g., in patients with autoimmune disease with activated macrophages and granulocytes).19 After entering the cell, 18 F-FDG is phosphorylated to 2′-FDG-6 phosphate by the hexokinase enzyme. 2′-FDG-6 phosphate is not a substrate for the enzymes of the glycolytic pathway or the pentose-phosphate shunt compared with glucose-6phosphate.20 Consequently, 18F-FDG cannot be further metabolized or diffuse back into the extracellular space, and is trapped and enriched within the cell.20 The accumulated FDG can be accurately detected by the scanner. Positron emission tomography (PET) provides a unique, noninvasive, quantitative method to study the metabolic activity of target tissue in vivo. PET with 18 F-FDG has been clinically used mainly for tumor diagnosis, therapy monitoring and experimental cancer research. However, a systematic evaluation of this method for diagnosing non-neoplastic conditions has been undertaken only during the past decade. It has been known that inflammation can lead to a hypermetabolic response and an obligatory requirement for glucose aiming to support cellular metabolism.18 In addition, glucose metabolism is influenced by proinflammatory mediators such as TNF-a and characteristically up-regulated in inflamed tissue,21,22 making PET a potential technique for the detection and quantification of inflammation. A combination of functional PET imaging and CT as anatomical reference allows a more detailed identification of 18F-FDG uptake.23 In this article, we will describe the impact of PET/CT on the evaluation of RA.
PET/CT IMAGING AND RA Vijayant et al.24 found all painful and/or swollen and/or tender joints had considerable FDG avidity. Metabolically, the wrist joint was the commonest and predominantly affected followed by the ankle joints (in the high to intense category).24 In patients with nonrheumatic (NR) diseases and in healthy subjects, there
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was no significant uptake of FDG in the joint regions.25 In contrast, there was highly positive FDG uptake in the shoulder, hip, wrist and knee joints in RA patients.25–28 The positive frequencies of FDG accumulation in the shoulder, hip and knee joints using PET/ CT scan were high in RA patients. Intriguingly, the sensitivity of PET/CT was markedly higher than for MRI in the lumbar spinal processes and the ischial tuberosity. Ga scintigraphy also indicated lower sensitivity than PET/CT.25 Furthermore, the FDG uptake score and the maximal standardized uptake value (SUVmax) of the painful/swollen joints were markedly higher than those of the joints that were not painful/swollen in RA patients.29,30 C-reactive protein (CRP) level and total FDG score indicated a significant linear correlation,28–31 and the cumulative SUV was significantly correlated with swollen and tender joint counts, patient and physician global assessments, erythrocyte sedimentation rate (ESR), disease activity score and simplified disease activity index.28 Similarly, there was a significant correlation between total FDG uptake scores for the arm joints and the axillary lymph nodes, and total FDG uptake score was strongly related to FDG uptake in the atlanto-axial joint.30 However, the bone scans of the same patients indicated mild changes in the large joints, implying that this modality was not as sensitive as FDG PET.29 Nevertheless, it should be kept in mind that FDG imaging directly detects inflamed tissue while bone scanning detects the reaction of the bone to inflammation or destruction as a consequence of inflammation. These techniques are therefore complementary. In addition, bone scanning has a lower spatial resolution as well as detection sensitivity. With respect to 18F-FDG PET/CT and 18F-NaF (sodium flouride) PET/CT imaging, two patients with multiple myeloma were examined.32 In one case, intense NaF accumulation in a dorsal vertebra was noted, but the corresponding FDG uptake was unimpressive. In another patient, 18 F-FDG PET/CT indicated intense uptake in the lesions in the axial skeleton while 18F-NaF PET/CT seemed normal, and a sternal lesion displayed FDG uptake only in the center but NaF uptake only in the periphery.32 It has been recognized that numerous studies suggest 18 F-FDG PET/CT can provide more information about multiple myeloma.33–36 Although the role of 18F-NaF PET/CT in skeletal diseases is growing, it is still uncommonly used in the evaluation of multiple myeloma.37,38 In 62 patients with a variety of malignancies, 53 received simultaneous tracer injections, while nine received 18F-NaF subsequent to the initial 18F-FDG dose (average delay 2.2 h). Results indicated that 47
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patients had PET findings of malignancy.39 Of the 47 patients, a higher number of lesions were detected in 16 patients using the combined 18F-FDG/18F-NaF PET/ CT imaging in comparison with 18F-FDG-only PET/CT imaging.39 In two of the 47 patients, 18F-FDG-only PET/CT imaging found soft tissue lesions that were not prospectively identified on the combined study.39 Therefore, these data suggest that 18F-FDG and 18F-NaF can be combined in a single PET/CT scan by administering the two radiopharmaceuticals, and combining these two imaging modalities has the potential to
provide more accurate information about disease extent, but the role of these two radioactive tracers in the management of disease continues to be defined. Moreover, the number of painful/swollen joints was markedly related to the number of joints with an FDG uptake score of 2 or more, and the mean number of joints per patient with an FDG uptake score of 2 or more was markedly larger than the mean number of painful/swollen joints.29,30 Collectively, these findings suggest that FDG PET/CT accurately and sensitively reflects the extent of RA disease (Fig. 1).
(a1)
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Figure 1 We report a 57-year-old woman who visited our hospital because of knee pain for more than 4 years and was unable to walk for 2 months, where there was no clinical change in hands and feet. Laboratory examinations showed high levels of C-reactive protein (26.6 mg/L) and rheumatoid factor (124 IU/mL). After partial-body positron emission tomography/computed tomography with fluorine-18 fluorodeoxyglucose (18F-FDG PET/CT) imaging, results are as followings: (a) there are some small nodular lesions with high FDG uptake in both wrists, both proximal interphalangeal joints and part of the distal interphalangeal joints, maximal standardized uptake value (SUVmax) was 3.0; CT images showed narrowing joint space in both the wrists and interphalangeal joints, and the bone density was uneven. (b) there are some small nodular and circinal lesions with high FDG uptake in both feet and ankels, SUVmax was 2.7; CT images showed no aberrant changes. (c) there are some nodular and circinal lesions with high FDG uptake in both knees, SUVmax was 4.5. CT images indicated that bone density was uneven in both knees, especially the left knee and there was bone destruction, soft tissue swelling, joint space narrowing and less clear articulation. Finally, this patient was diagnosed as having rheumatoid arthritis. The PET/CT imaging in this study suggests that FDG may better detect inflamed joints than clinical symptoms, where there was no clinical change in hands and feet but PET/CT imaging showed aberrant changes in these joints. a1, b1, c1 are the PET images. a2, b3, c2 are the CT images. a3, b3, c3 are the PET/CT fusion images. a1, a2, a3 are the images of hands/fingers and wrists (both sides). b1, b2, b3 are the images of feet/toes and ankles (both sides). c1, c2, c3 are the images of knees (both sides).
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Rheumatoid arthritis patients treated with triple combination oral disease-modifying anti-rheumatic drugs (DMARDs) (methotrexate, sulfasalazine, hydroxychloroquine and low-dose glucocorticoids) reduced mean Disease Activity Score-28 (DAS-28) (ESR) from 5.6 1.3 (baseline) to 2.2 0.8 (week 12).23 All the patients achieved a European League against Rheumatism (EULAR) response, with 59% achieving disease remission.23 After treatment, 18F-FDG uptake was down-regulated in some joints (e.g., hands, wrist, shoulder, elbow, knees and ankle), where there were 76% and 81% of patients showing reduced SUVmax from baseline to week 2 and week 4, respectively. In addition, reductions in 18F-FDG uptake measures on PET imaging were related to DAS-28 scores, ESR and CRP.23 Furthermore, Szalay et al.40 enrolled 19 treatment-naive (early) RA patients and initiated glucocorticoids (in a dose of 16 mg/day for 4 weeks; then 8 mg/day). Methotrexate, 10 mg/week, was started at week 4. Results showed that T helper 1 (Th1), Th2 and Th17 prevalence was higher, while regulatory T cell (Treg) prevalence was lower in early RA than healthy controls. After treatment, glucocorticoids alone decreased Th2 prevalence, while glucocorticoids + methotrexate decreased Th17 prevalence.40 In addition, early RA patients exhibited increased levels of CRP and ESR, and had a high disease activity score as measured by the DAS-28. The patients also had higher serum levels of total cholesterol, plasma levels of small dense lowdensity lipoprotein cholesterol (sdLDL-C) whereas their serum high-density lipoprotein cholesterol (HDL-C) levels were significantly lower compared with controls. After administration of methotrexate and prednisone, patients showed a significant increase in HDL-C levels.41 Treatment led to a significant decrease in the inflammatory markers CRP and ESR, as well as in the reduction of DAS-28.41 Similarly, PET/CT images showed intense articular uptake in hands and wrists before anti-TNF therapy (infliximab). After 2 months treatment, reduced FDG articular uptake in hands and wrists were found in RA patients.42 Furthermore, active RA patients underwent whole-body FDG PET and clinical assessment before and after treatment with infliximab for 3 months.43 Results indicated that the PETbased total joint score was similarly high before onset as was the clinical total joint score. The decrease of FDG joint uptake in the follow-up PET scans was significantly related to the clinical assessment.43 In addition, 6 months after the anti-TNF therapies (infliximab, etanercept), the average values of DAS-28, DAS-28 (CRP), ESR and matrix metalloproteinase-3 (MMP-3) were
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markedly decreased compared with baseline.14,44 The SUV of the right ankle, right hip, right elbow, left shoulder, bilateral wrists and bilateral knees were decreased in comparison with the SUV at baseline in each patient.45 These data imply that usage of FDG PET/CT is available and effective in monitoring treatment response (DMARDs and anti-TNFs).31 Collagen-induced arthritis (CIA) is an animal model of RA that has been used to discuss the pathogenesis of the disease and to validate therapeutic targets. The dominant pathological features of CIA involved proliferative synovitis, erosion of bone, cartilage degradation, pannus formation, with infiltration of polymorphonuclear and mononuclear cells. In CIA mice, 18F-FDG PET depicted swollen joints, and 18F-FDG accumulation increased with the progression of arthritis.46,47 Histologically, a higher level of 18F-FDG accumulation was related to the pannus rather than the infiltration of inflammatory cells around the joints.46 Similarly, the mean SUVmax of 18F-FDG for knees and ankles was significantly higher for CIA mice than for control mice, respectively.47,48 The arthritis score of knee joints in CIA mice increased with the progression of arthritis gradually, and the arthritis score was positively correlated with the SUVmax,47 while in glucose-6-phosphate isomerase (G6PI)-induced arthritis, tracer enrichment was restricted to tissue with high basal metabolic activity (e.g., heart muscle and eyes) or organs of the excretory system (e.g., kidneys and bladder) before arthritis onset (day 2).20 However, additional 18F-FDG signaling can be detected in the joints of fore and hind paws in acute experimental arthritis at day 13, suggesting a specific 18F-FDG uptake in inflamed joints. PET/CT imaging showed hot spots of inflammatory metabolic activity in wrist and ankle joints. After treatment of human sTNFR (etanercept) or saline with G6PI-induced mice, PET/CT found a marked 4.9-fold decrease of total 18 F-FDG uptake in sTNFR (etanercept)-treated arthritic mice. Comparable results were obtained using histopathological assessment of therapeutic intervention.20 Thus, PET/CT is a convenient technique for monitoring disease activity or efficacy of treatment in experimental arthritis. It is noteworthy that FDG PET/CT may help predict therapeutic response to novel treatments. In a group of active RA patients, before infliximab treatment, all patients indicated enhanced 18F-FDG uptake in at least one metacarpophalangeal region or wrist.49 After 14 and 22 weeks, DAS decreased to 4.3 1.5 and 3.9 1.3, respectively. The change in mean SUV after 2 weeks of infliximab treatment correlated markedly
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with DAS at 14 and 22 weeks, respectively.49 The study found a strong correlation between early changes in 18 F-FDG uptake in hand joints and clinical disease activity after 14 and 22 weeks of treatment. At a group level, the findings suggest that 18F-FDG PET may therefore be a valuable technique for predicting the efficacy of infliximab therapy as early as 2 weeks after initiation of treatment. Rituximab, a chimeric monoclonal antibody against the CD20 antigen, has been approved for the treatment of RA patients.50 Tran et al.51 radiolabeled rituximab with 124Iodine (124I) for PET imaging. Results showed that patients who did not receive pre-treatment with unlabeled rituximab indicated localization of nearly all radioconjugate in the spleen and to a lesser extent bone marrow, examined by PET/CT imaging 10 min after administration of 124I-rituximab.51 Findings after 24 h indicated that the uptake in the spleen was largely diminished while the radioactivity accumulated in the thyroid.51 In contrast, 124I-rituximab has favorable pharmacokinetics for targeting pathological B cells after pre-treatment with unlabeled rituximab, where patients predosed with unlabeled rituximab indicated persistent tracer availability in the central circulation for multiple days, with almost no splenic uptake.51 Furthermore, PET imaging of patients received 124I-rituximab at 24 h and later exhibited accumulation of the tracer in joints (e.g., shoulder, elbow, wrist, ankle, hands and knees), suggesting that the visualized signal represents active targeting of the antibody to the CD20 epitope.15 Combined PET/CT images confirmed the localization of the tracer in thickened synovia in knee joints.15 Therefore, pre-treatment with rituximab is necessary for saturating the peripheral binding sites, and visualization of the CD20-antigen expression could provide a tool to localize sites of inflammation and could be of additive value in the treatment follow-up of RA patients.
PET/CT AND COMPLICATIONS OF RA AND TREATMENT In one study, Minamimoto et al.52 examined an RA patient who complained of cervical lymphadenopathy at 66 months after initiation of methotrexate (MTX) treatment for RA. PET/CT imaging showed an FDG-avid lesion at bilateral tonsils, bilateral supraclavicular fossa, bilateral axillary nodes and left inguinal region. Diffuse large B cell lymphoma (DLBCL) was proven from the biopsy tissue of the FDG-avid lesion at the right supraclavicular fossa. In another patient with a 10-year history of RA, splenomegaly, liver tumor and left renal
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tumor were identified on CT examination. After a week’s withdrawal of MTX, these lesions shrank, but rapid regrowth occurred when MTX therapy was restarted. PET/CT imaging showed FDG-avid foci at the right inguinal region, para-aortic region, bilateral adrenal glands and liver.52 These findings showed the usage of FDG PET/CT for diagnosis and follow-up of patients with MTX-related malignancies. The mean of aortic maximum 18F-FDG target-tobackground ratios (TBRmax) in the whole aorta was significantly higher in RA patients in comparison with cardiovascular disease (CVD) patients.44 Similarly, there was a marked rightward shift in the distribution of TBRmax at baseline in RA patients compared with CVD patients, and RA patients had a higher proportion of hot slices within the aorta than were found in CVD patients.44 However, after anti-TNF therapy (adalimumab, etanercept), PET/CT images showed a strong reduction in mean aortic TBRmax and reduced proportion of hot slices.44 Similarly, 18F-FDG PET/CT imaging on RA patients showed distinct areas of extra-articular soft tissue FDG uptake, such as axillary lymph nodes, epitrochlear lymph node, cervical lymph nodes, inguinal nodes, thyroid gland and subcutaneous (possibly rheumatoid) nodules.24,42,43,53–57 In addition, PET/CT imaging can find RA-complicated diseases such as interstitial pneumonia,58 multiple extra-articular synovial cysts,59 rheumatoid lung disease60,61 and atlantoaxial osteoarthritis.62 Collectively, these data suggest that FDG PET/CT is not only able to find RA-complicated tumors, but also has the potential to detect RAcomplicated inflammatory diseases.
CONCLUSION Positron emission tomography/computed tomography has become a valuable ancillary tool for evaluating RA. This technique can visualize the degree of disease activity or ‘burden of inflammation’. It may be helpful for the assessment of the extent of RA throughout the whole body, including high-risk lesions such as those in the atlanto-axial joint. It is also able to assess the response to treatment with drugs that modify cellular activity. These unique capabilities of PET/CT imaging may indeed be helpful in the management of RA. However, several points should be considered: first, the final goal of PET/CT imaging used in RA is to find the optimal timing of therapy (DMARDs or biologics therapy, such as anti-TNF therapy), aiming for complete remission of RA. Therefore, a multicenter prospective study involving therapeutic intervention should be conducted
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in the future.29,30 Second, PET/CT imaging used in RA can do whole-body scans to see all involved areas, but has poor specificity and is expensive. Third, limited evidence has suggested that 124I-rituximab PET/CT can detect inflamed joints in RA, with a seemingly reasonable sensitivity, but further research is required to determine the diagnostic accuracy of this procedure, and to establish the clinical value of the findings.15,51
ACKNOWLEDGEMENTS None.
CONFLICT OF INTEREST None to declare.
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Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
