Article

Clinical Value of FDG-PET/CT for the Evaluation of Rheumatic Diseases: Rheumatoid Arthritis, Polymyalgia Rheumatica, and Relapsing Polychondritis

April 2017
Seminars in Nuclear Medicine 47(4)

DOI:10.1053/j.semnuclmed.2017.02.005

Authors:

Kazuo Kubota

National Center for Global Health and Medicine in Japan

Hiroyuki Yamashita

National Center for Global Health and Medicine in Japan

FDG is a tracer for visualizing glucose metabolism. PET/CT using FDG is widely used for the diagnosis of cancer, because glycolysis is elevated in cancer cells. Similarly, active inflammatory tissue also exhibits elevated glucose metabolism because of glycolysis in activated macrophages and proliferating fibroblasts. Elevated FDG uptake by active inflammatory tissues, such as those affected by arthritis, vasculitis, lymphadenitis, and chondritis, has enabled the diagnosis of inflammatory diseases using FDG-PET/CT. Rheumatoid arthritis (RA) is a systemic, chronic inflammation of the joints resulting in synovitis. Several clinical studies of RA have demonstrated that FDG uptake in affected joints reflects the disease activity of RA, with strong correlations between FDG uptake and various clinical parameters having been noted. Furthermore, the use of FDG-PET for the sensitive detection and early monitoring of the response to RA therapy has been reported. RA is sometimes associated with subclinical vasculitis, which is related to systemic inflammation. FDG-PET/CT can be used to evaluate subclinical vasculitis in the aorta or carotid artery. Polymyalgia rheumatica (PMR) is an autoimmune musculoskeletal disease of unknown etiology characterized by pain and stiffness in the shoulder, neck, and pelvic girdle, but not in the small finger joints in the hands, together with fever, fatigue, and weight loss. There is no specific test for PMR, and its diagnosis is based on clinical diagnostic criteria and the exclusion of other diseases with similar symptoms. However, FDG-PET/CT reveals a characteristic FDG uptake by the bursitis in ischial tuberosity, greater trochanter, lumbar or cervical spinous process, and scapulohumeral joint. A combination of FDG-PET/CT findings showed a high diagnostic value for PMR in a differential diagnosis from RA. FDG-PET/CT is also very useful for evaluating large vessel vasculitis, which is often associated with PMR. Relapsing polychondritis is a rare multisystem disease of unknown etiology involving cartilaginous and proteoglycan-rich structures. Its rarity and diversity of symptoms often result in a delayed diagnosis. FDG-PET/CT reveals unique FDG uptake findings for chondritis in the auricular, nasal, trachea, bronchial tree, and costal cartilage and in the cartilage of joints. Thus, the spread of knowledge regarding these very specific FDG-PET/CT findings could promote the early diagnosis and improved disease control of relapsing polychondritis.

Clinical utility of 18 fluorodeoxyglucose positron emission tomography-computed tomography in rheumatology

Article

Apr 2021

Background Several studies with ¹⁸ fluorodeoxyglucose positron emission tomography with computed tomography ( ¹⁸ FDG PET-CT) have indicated that 18fluorodeoxyglucose uptake in affected tissues reflects the disease activity. In addition, the usage of PET-CT for early detection, extent and monitoring of the treatment response has been reported. Methods In this retrospective study, all ¹⁸ FDG PET-CTs requested by rheumatologists were reviewed retrospectively. The clinical findings and scan findings were noted. Considering the final diagnosis made by the clinician as “gold standard”, he sensitivity, specificity and positive were calculated. Results Out of 48, ¹⁸ FDG PET-CT requests, two were excluded (39 females, mean age – 39.22 ± 15.349). The indications included establishing diagnosis ( n = 31 [67.4%]) and disease activity/extent ( n = 15 [32.6%]). It contributed to the diagnosis in 9 (31%), when 18F FDG PETCT is used for establishing the diagnosis. It identified abnormalities in 14/15 when used for disease activity and active disease was identified in 10. Seventeen patients had a final diagnosis of fibromyalgia. Overall, ¹⁸ FDG PET-CT had 100 sensitivity and NPV. The diagnostic accuracy was 56.52%. Conclusions The ¹⁸ FDG PET-CT has high diagnostic sensitivity and poor specificity in rheumatology practice with respect to establishing the diagnosis as well as to detect the extent and activity of disease.

Positron Emission Tomography/Computed Tomography in Polymyalgia Rheumatica: When and for What—A Critical Review

Article

Full-text available

Jul 2024

Polymyalgia rheumatica (PMR) is an inflammatory disease common in people aged 50 years and older. This condition is characterized by the presence of pain and stiffness involving mainly the shoulder and pelvic girdle. Besides the frequent association with giant cell arteritis (GCA), several conditions may mimic PMR or present with PMR features. Since the diagnosis is basically clinical, an adequate diagnosis of this condition is usually required. Positron emission tomography/computed tomography (PET-CT) has proved to be a useful tool for the diagnosis of PMR. The use of 18F-FDG-PET imaging appears promising as it provides detailed information on inflammatory activity that may not be evident with traditional methods. However, since PET-CT is not strictly necessary for the diagnosis of PMR, clinicians should consider several situations in which this imaging technique can be used in patients with suspected PMR.

PET-CT in Polymyalgia Rheumatica: When and for what—A Critical Review

Preprint

Full-text available

Jun 2024

Polymyalgia rheumatica (PMR) is an inflammatory disease common in people aged 50 years and older. This condition is characterized by the presence of pain and stiffness involving mainly the shoulder and pelvic girdle. Besides the frequent association with giant cell arteritis (GCA), several conditions may mimic PMR or present with PMR features. Since the diagnosis is basically clinical, an adequate diagnosis of this condition is usually required. Positron emission tomography-computed tomography (PET-CT) has proved to be a useful tool for the diagnosis of PMR. The use of 18F-FDG-PET imaging appears promising as it provides detailed information on inflammatory activity that may not be evident with traditional methods. However, since PET-CT is not strictly necessary for the diagnosis of PMR, clinicians should consider several situations in which this imaging technique can be used in patients with suspected PMR.

Musculoskeletal imaging

Chapter

Mar 2023

Nuclear medicine and the array of different radiotracers have an important role in the diagnosis and evaluation of a variety of musculoskeletal diseases. Conventional radiography has long been considered the first‐line diagnostic for suspected traumatic fracture. Broadly speaking, stress fractures fall into one of two categories: fractures that arise from normal loading on abnormal bone, termed “insufficiency fractures,” and fractures that arise from abnormal loading on normal bone, termed “fatigue fractures”. Rheumatoid arthritis is an inflammatory disorder with a main target for the synovial membrane of joints, bursae, and tendon sheaths. Radiography is the mainstay in the preliminary evaluation of rheumatoid arthritis. Diabetic patients are at risk for foot infections due to underlying diabetic neuropathy, which leads to a loss of protective sensation and development of anatomic deformities and altered weight‐bearing, and peripheral vascular disease, which limits access of phagocytic cells and antibiotics to infected sites due to impaired circulation.

Systematic Review: Targeted Molecular Imaging of Angiogenesis and Its Mediators in Rheumatoid Arthritis

Article

Full-text available

Jun 2022
INT J MOL SCI

Extensive angiogenesis is a characteristic feature in the synovial tissue of rheumatoid arthritis (RA) from a very early stage of the disease onward and constitutes a crucial event for the development of the proliferative synovium. This process is markedly intensified in patients with prolonged disease duration, high disease activity, disease severity, and significant inflammatory cell infiltration. Angiogenesis is therefore an interesting target for the development of new therapeutic approaches as well as disease monitoring strategies in RA. To this end, nuclear imaging modalities represent valuable non-invasive tools that can selectively target molecular markers of angiogenesis and accurately and quantitatively track molecular changes in multiple joints simultaneously. This systematic review summarizes the imaging markers used for single photon emission computed tomography (SPECT) and/or positron emission tomography (PET) approaches, targeting pathways and mediators involved in synovial neo-angiogenesis in RA.

The effects of limb laterality and age on the inflammation and bone turnover of the acromioclavicular shoulder joint: 18F-fluorodeoxyglucose and 18F-sodium-fluoride-PET/computed tomography study

Article

May 2022
NUCL MED COMMUN

Purpose: The acromioclavicular (AC) joint is a common site of injury and degenerative changes such as osteoarthritis (OA) of the shoulder. Physical manifestations of OA are preceded by molecular changes, detection of which may enhance early prophylaxis and monitoring of disease progression. In this study, we investigate the use of 18F-FDG and 18F-NaF-PET/CT to assess the effects of limb laterality and age on the inflammation and bone turnover of the AC shoulder joint. Methods: We analyzed FDG and NaF-PET/CT scans of 41 females (mean age of 43.9 ± 14.2 years) and 45 males (mean age of 44.5 ± 13.8 years) using a semiquantitative technique based on predefined ROI. Results: There was a greater NaF uptake in the right side of the AC joint compared with the left in both females (left: 2.22 ± 1.00; right: 3.08 ± 1.18; P < 0.0001) and males (left: 2.57 ± 1.49; right: 2.99 ± 1.40; P = 0.003). No consistent correlation between age and NaF or FDG uptakes were found in both females and males. There was also a positive correlation between FDG and NaF uptakes in both left (P = 0.01; r = 0.37) and right (P = 0.0006; r = 0.53) AC joints of male subjects. Conclusion: Our study is the first to reveal the varying effect of right-left limb laterality and aging on FDG and NaF uptake at the AC joint. Future studies correlating the history of shoulder trauma, pain, and degenerative change with FDG and NaF-PET/CT findings will be critical in the adoption of molecular imaging in the clinical setting.

The Combination of 18F-Fluorodeoxyglucose Positron Emission Tomography Metabolic and Clinical Parameters Can Effectively Distinguish Rheumatoid Arthritis and Polymyalgia Rheumatic

Article

Full-text available

Apr 2022
CONTRAST MEDIA MOL I

Objective: To evaluate 18F-fluorodeoxyglucose positron emission tomography (18FDG PET) and clinical parameters to differentiate rheumatoid arthritis (RA) and polymyalgia rheumatic (PMR). Patients and Methods. This retrospective study evaluated 54 patients with suspected RA (n = 23) and PMR (n = 31) who underwent 18F-FDG PET/CT before treatment. The complete diagnosis was based on each classification criterion and at least followed up for 6 months. Demographic and clinical data were also collected. Semiquantitative analysis (maximum standardized uptake value, SUVmax) of abnormal 18F-FDG uptake was undertaken at 17 musculoskeletal sites, and two scoring systems (mean reference (liver/control) scores) were evaluated. The differential diagnostic efficacy of each independent parameter was evaluated using the receiver operating characteristic (ROC) curve. Integrated discriminatory improvement (IDI) and bootstrap tests were used to evaluate the improvement in diagnostic efficacy using a combination of multiple parameters. Results: The ROC curve analysis of SUVmax indicated that the interspinous ligament showed the highest discriminative diagnostic value (sensitivity, 64.5%; specificity, 78.3%; area under the curve (AUC), 0.764; positive predictive value, 0.800; negative predictive value, 0.621). The combined model with the rheumatoid factor (RF) and metabolic parameters of 18F-FDG PET resulted in the highest AUC of 0.892 and showed significant reclassification by IDI (IDI, 9.51%; 95% confidence interval: 0.021-0.175; P = 0.013). According to the bootstrap test, compared with RF alone, the combination of RF and metabolic parameters showed an improvement in ROC and was statistically significant (P = 0.017). Conclusions: The combination of 18F-FDG PET metabolic and clinical parameters can further improve the differential diagnosis of RA and PMR.

Ocular Involvement in Relapsing Polychondritis

Article

Full-text available

Oct 2021

Relapsing polychondritis (RPC) is a rare systemic immune-mediated disease characterized by recurrent inflammation of cartilaginous and proteoglycan-rich tissues throughout the body. Auricular, nasal, tracheal, and articular chondritis and arthritis are common systemic symptoms in patients with RPC. Ocular tissues are also targets of inflammation in RPC, and a variety of ocular symptoms are observed in approximately half of the patients with RPC. Scleritis/episcleritis, uveitis, and conjunctivitis are common symptoms associated with RPC. Less frequently, keratitis, retinopathy, optic neuropathy, muscle palsy, and orbital inflammation are also observed. Ocular inflammation could also be the first manifestation of RPC. Although RPC is a potentially fatal and sight-threatening disease, the rarity of the disease and its protean clinical presentation may lead to delayed diagnosis or misdiagnosis. Given the high prevalence of ocular involvement in RPC, to avoid misdiagnosis, physicians should be suspicious of RPC when they see patients with recurrent ocular inflammatory conditions and various systemic symptoms. In this article, we provide a comprehensive review of ocular manifestations associated with RPC.

TNF induces glycolytic shift in fibroblast like synoviocytes via GLUT1 and HIF1A

Article

Full-text available

Sep 2021

TNF is a central cytokine in the pathogenesis of rheumatoid arthritis (RA). Elevated level of TNF causes local inflammation that affects immune cells and fibroblast-like synoviocytes (FLS). Nowadays, only 20–30% of patients experience remission after the standard of care therapy—antibodies against TNF. Interestingly, responders show reduced levels of GLUT1 and GAPDH, highlighting a potential link to cellular metabolism. The aim of the study was to investigate whether TNF directly affects the metabolic phenotype of FLS. Real-time respirometry displayed TNF-induced upregulation of glycolysis along with a modest increase of oxidative phosphorylation in FLS from healthy donors. In addition, TNF stimulation enhanced HIF1A and GLUT1 expression. The upregulation of HIF1A and GLUT1 reflects their enriched level in FLS from RA patients (RA-FLS). The inhibition of TAK1, HIF1a and hexokinase deciphered the importance of TNF/TAK1/HIF1A/glycolysis signaling axis. To prove that inhibition of glycolysis reduced the pathogenic phenotype, we showed that 2-deoxyglucose, a hexokinase inhibitor, partially decreased secretion of RA biomarkers. In summary, we identified a direct role of TNF on glycolytic reprogramming of FLS and confirmed the potency of immunometabolism for RA. Further studies are needed to evaluate the therapeutic impact especially regarding non-responder data.

Relapsing polychondritis with aortic involvement in fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography: A case report

Article

Full-text available

Mar 2021

Aziz Gültekin

An 83-year-old male patient presented with recurrent high fever. Vegetation was determined on transesophageal echocardiography, and antibiotic treatment was initiated for infective endocarditis. Despite medical treatment, progressive aortic insufficiency occurred and aortic valve replacement was performed. However, C-reactive protein (CRP) and fever did not decrease. During the clinical follow-up, pharyngolaryngeal pain and hoarseness, swelling, pain in the left auricle and nose increased. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan was performed which revealed an increased 18F-FDG uptake in the ascending aorta, left ear, and nose. The patient was diagnosed with relapsing polychondritis (RPC). After the steroid and cyclophosphamide treatment, fever and CRP decreased dramatically. In conclusion, 18F-FDG PET/CT is an important imaging method for demonstrating RPC.

F‐FAPI versus F‐FDG PET/CT in the Diagnosis of Relapsing Polychondritis

Article

Full-text available

Dec 2024

Relapsing polychondritis (RP) is a rare immune‐mediated systemic inflammatory disease with diverse clinical manifestations. Independent involvement of the respiratory system in RP is uncommon. In the event of respiratory involvement as the initial airway‐only manifestation, the diagnosis of RP is challenging and might be delayed, and patients with respiratory involvement exhibit a poor prognosis. However, no specific diagnostic method is currently available for RP with respiratory system involvement as the main clinical manifestation. We present a 49‐year‐old female with the complaint of chronic dry cough accompanied by shortness of breath after exercise that has persisted for over a year. The patient was treated using corticosteroids. The patient's symptoms improved rapidly with the administration of 5 days of methylprednisolone sodium succinate at a dose of 40 mg/day. The treatment was then switched to methylprednisolone tablets at a dose of 40 mg/day, and the dosage was reduced by 4 mg every week until the cessation of therapy. Meanwhile, oral cyclophosphamide tablets were administered once every day at a dose of 100 mg each time. After 1 month of treatment, the symptoms of cough disappeared, the modified british medical research council (mMRC) grade dropped from 4 to 2, and the COPD assessment test (CAT) score dropped from 30 to 17. Repeated CT of the chest revealed that the tracheal wall thickening had alleviated. No recurrence was revealed in the follow‐up visit 12 months after drug withdrawal. The patient underwent ¹⁸F‐FDG PET/CT examination before hormone and immunosuppressive therapy, and ¹⁸F‐FAPI PET/CT examination was performed 5 days later. The ¹⁸F‐FDG PET/CT method revealed slight thickening of the local wall of the trachea and the left and right main bronchus, with no increase in the FDG metabolism, and no abnormalities in the rest of the cartilage. ¹⁸F‐FAPI PET‐CT imaging showed increased FAPI uptake in various parts of the body, including trachea and bronchus. The present study reports that compared to ¹⁸F‐FDG PET/CT, the ¹⁸F‐FAPI PET/CT revealed more lesions and provided a better image contrast, suggesting the latter as a suitable diagnostic method for RP, which could assist in improving the clinical management of RP patients.

A Methodology to Measure Glucose Metabolism by Quantitative Analysis of PET Images

Article

Full-text available

Sep 2024

Positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) tracer is the standard clinical technique to measure myocardial and vessel metabolism and viability and to investigate the metabolic syndrome associated with cardiovascular diseases. The quantitative analysis of PET images allows one to study the cardiovascular physiological processes, by extracting quantitative parameters from the analysis of the tracer kinetic. Here, we propose a new methodology to quantify and evaluate the evolution of glucose metabolism inside the myocardium and the large vascular structures over time. We merge and analyze PET and CT cardiac images, extracting different volumes of interest (VOI) and performing quantitative measurements. To validate it, we apply the methodology to merge images of the aorta vessel for patients affected by metabolic syndrome. The application of the proposed approach to the use case reveals a correlation between administered drugs and metabolic syndrome, measuring the glucose metabolic rate (MRGlu) in both the myocardium and aorta. The proposed methodology can be used to evaluate some cardiovascular risk indexes of diabetic patients, too. The proposed methodology can also be deployed to analyze other application domains.

Diagnosis and Evaluation of Treatment Response in Relapsing Polychondritis Using 18F-FDG PET/CT

Article

Feb 2024

A 58-year-old man presenting with dyspnea, weight loss, and night sweating underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) because of a suspicion of malignancy. 18F-FDG PET/CT demonstrated mild to moderate uptake on nasal, cricoid, and tracheobronchial tree cartilages and costovertebral junctions. The diagnosis was relapsing polychondritis, which is a rare multisystem disease characterized by inflammation of cartilage. In addition, subsequent 18F-FDG PET/CT after treatment showed complete metabolic response.

Overview of Rheumatoid Arthritis and Scientific Understanding of the Disease

Article

Full-text available

Aug 2023

Rheumatoid arthritis (RA), a chronic inflammatory autoimmune disorder, is characterised by persistent synovial inflammation, erosion of bones and cartilage, leading to joint destruction. Clinical manifestations are morning stiffness, pain in shoulder, neck and pelvic girdle, loss of mobility with fever, fatigue, malaise, loss of body weight, and development of rheumatoid nodules. Environmental and genetic factors are important contributors in its susceptibility. Association between RA and diet, cigarette smoking, hormones, alcohol, microbiota, infection, and coffee have also been reported. To diagnose patients with RA, American college of rheumatology (ACR, 2010) criteria, developed by European league against rheumatism (EULAR). Inflammation produced in RA patients is due to cell-mediated immune response. The rheumatoid synovium consists of a large number of CD4⁺ T cells suggesting pathogenic nature of T cells in this disorder. B-cells may also participate in the pathogenesis by several means such as autoantibodies, by instigation of T-cells through expression of co-stimulatory molecules, by generating pro-inflammatory and anti-inflammatory cytokines and by organisation of other inflammatory cells. The conventional management of RA usually focuses over reducing pain and limiting the disability by medical therapies which include a number of classes of agents such as non-steroidal anti-inflammatory drugs (NSAIDs), non-biological and biological agents, disease-modifying anti rheumatic drugs (DMARDs), immunosuppressants, and corticosteroids. However, only proper rehabilitation can promote the objective to achieve the joint functionality and ease of motion which improves independence as well as quality of life in patient suffering from Rheumatoid Arthritis.

EXPLORing Arthritis with Total-body Positron Emission Tomography

Article

Nov 2023

Arthritis has significant adverse consequences on musculoskeletal tissues and often other organs of the body. Current methods for clinical evaluation of arthritis are suboptimal, and biomarkers that are objective and measurable indicators for monitoring of arthritis disease activity are in critical demand. Recently, total-body positron emission tomography (PET) has been developed that can collect imaging signals synchronously from the entire body at ultra-low doses and reduced scan times. These scanners have increased signal collection efficiency that overcomes several limitations of standard PET scanners in the evaluation of arthritis, and they may potentially provide biomarkers to assess local and systemic impact of the arthritis disease process. This article reviews current results from using total-body PET in the assessment of common arthritic conditions, and it outlines future opportunities and challenges.

Headache attributed to giant cell arteritis complicated with rheumatic polymyalgia diagnosed with F18-fluorodeoxyglucose positron emission tomography and computed tomography: a case report

Article

Full-text available

Sep 2023

Giant cell arteritis (GCA) is a kind of systemic vasculitis affecting individuals over 50 years old and is often the cause of new-onset headaches in older adults. Patients with GCA sometimes have rheumatic polymyalgia (PMR). The diagnosis of GCA generally depends on clinical manifestation, elevated erythrocyte sedimentation rate (ESR) or C-reactive protein, and positive imaging findings commonly obtained by ultrasound or temporal artery biopsy. In this study, we report a case of an 83-year-old woman with a new-onset headache and an elevated ESR. The result of the temporal artery ultrasound did not distinguish between vasculitis and atherosclerosis. The F18-fluorodeoxyglucose positron emission tomography and computed tomography (18F FDG PET-CT) were performed and suggested large vessel vasculitis with temporal artery involvement. In addition, polyarticular synovitis and bursitis were also revealed. Finally, the diagnosis of secondary headache attributed to CGA complicated with PMR was established. The patient experienced remission of symptoms after glucocorticoid therapy. PET can become a powerful tool for diagnosis and differential diagnosis when the ultrasound result is ambiguous and a biopsy is not obtained.

THE DIAGNOSTIC ROLE OF 18F-FDG-PET/CT IN PATIENTS WITH CONSTITUTIONAL SYMPTOMS

Article

Full-text available

Mar 2023

Imaging methods in polymyalgia rheumatica: a systematic review

Article

Full-text available

Feb 2023
RHEUMATOL INT

Polymyalgia rheumatica (PMR) is an inflammatory joint disease in patients over 50 years of age with pain and prolonged morning stiffness in the shoulder and hip girdles and neck. The lack of specific clinical findings, laboratory signs, biomarker and established imaging methods makes it difficult to diagnose patients with this disease. The aim of the systematic review is to present the literature data on the use of imaging methods for early diagnosis, assessment of disease activity and therapeutic response in PMR. At the same time, the advantages, disadvantages and contraindications of each method are considered. A literature search was carried out in PubMed and Scopus up to June 2022. Studies were selected that met the following criteria: (1) English language publications in peer-reviewed journals, (2) cohort or case–control studies and a series of more than five clinical cases, (3) studies of newly diagnosed or suspected PMR patients according to classification criteria or expert opinion, (4) imaging evaluation of articular, extraarticular and vascular impairment in PMR. Out of a total of 1431 publications, 61 articles were selected, which differed in the imaging techniques used: radiography (5), scintigraphy (4), magnetic resonance imaging (14), PET/CT (14) and ultrasound (24). Prevalence of extraarticular involvement (tendons, entheses and bursae) was identified in patients with PMR. In a significant number of cases, subclinical vasculitis of the large vessels was found, confirming the common pathogenetic pathways of the two diseases. The diagnostic, therapeutic and prognostic potential of imaging methods in PMR has been relatively poorly studied and remains to be clarified.

F18-FDG PET/CT in a patient with Antisynthetase Syndrome

Article

Full-text available

Jan 2023

More prevalent in women than men, Antisynthetase Syndrome is a rare and poorly defined autoimmune disease associated with interstitial lung disease, polymyositis, and dermatomyositis. In addition to various diagnostic tools, imaging modalities are needed in certain situations. A 42-year-old woman with Anti-Jo-1-positive Antisynthetase Syndrome presented with thoracic muscular pain. She underwent whole-body Fluorodeoxyglucose positron emission tomography/computed tomography (F18-FDG PET/CT) to evaluate the total extent of the muscles affected. Depicting symptomatic symmetric myositis of the intercostal muscles, F18-FDG PET/CT additionally revealed unusually extensive fasciitis of the lower extremities.

18F-FDG PET molecular imaging: A relevant tool to investigate chronic inflammatory rheumatisms in clinical practice?

Article

Full-text available

Nov 2022

F-Labeled Fluorodeoxyglucose-Positron Emission Tomography ( ¹⁸ F-FDG PET) is a molecular imaging tool commonly used in practice for the assessment of many cancers. Thanks to its properties, its use has been progressively extended to numerous inflammatory conditions, including chronic inflammatory rheumatism (CIR) such as rheumatoid arthritis (RA), spondylarthritis (SpAs) and polymyalgia rheumatica (PMR). ¹⁸ F-FDG PET is currently not recommended for the diagnostic of CIRs. However, this whole-body imaging tool has emerged in clinical practice, providing a general overview of systemic involvement occurring in CIRs. Numerous studies have highlighted the capacity of ¹⁸ F-FDG PET to detect articular and extra articular involvements in RA and PMR. However, the lack of specificity of ¹⁸ F-FDG limits its use for diagnosis purpose. Finally, the key question is the definition of the best way to integrate this whole-body imaging tool in the patient’s management workflow.

Multimodality Molecular Imaging in Arthropathy Associated with Multiple Myeloma

Article

Full-text available

Nov 2022

We report a patient with multiple myeloma (MM) and polyarthritis of large joints. During the staging of the disease, bone marrow diffusely involved by MM was clearly demonstrated by 99mTc-2-methoxy-isobutyl-isonitrile (MIBI) single-photon emission computed tomography/computed tomography (SPECT/CT) but not by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/CT images. On the other hand, a very intense uptake of 18F-FDG was detected in periarticular tissues of multiple joints, with nonabnormal 99mTc-MIBI accumulation. Rheumatology tests were negative. A subsequent bone scintigraphy demonstrated radiolabeled bisphosphonate accumulation in periarticular tissues, suggesting amyloid arthropathy.

Preclinical evaluation and pilot clinical study of [18F]AlF-NOTA-FAPI-04 for PET imaging of rheumatoid arthritis

Article

Full-text available

Jun 2022
EUR J NUCL MED MOL I

Purpose Fibroblast-like synoviocytes (FLSs) are key effector cells in the inflamed joints of patients with rheumatoid arthritis (RA). Previous studies have suggested that fibroblast activation protein (FAP) is highly expressed in RA-derived FLSs and is a specific marker of activated RA FLSs. In this study, we developed aluminum-[¹⁸F]-labeled 1,4,7-triazacyclononane-N,N′,N″-triacetic acid–conjugated FAP inhibitor 04 ([¹⁸F]AlF-NOTA-FAPI-04) to image RA-FLSs in vitro and arthritic joints in collagen-induced arthritis (CIA) mice and RA patients. Methods RA FLSs and NIH3T3 cells transfected with FAP were used to perform in vitro–binding studies. Biodistribution was conducted in normal DBA1 mice. Collagen-induced arthritis (CIA) models with different arthritis scores were subjected to [¹⁸F]AlF-NOTA-FAPI-04 and ¹⁸F-FDG PET imaging. Histological examinations were performed to evaluate FAP expression and Cy3 dye–labeled FAPI-04(Cy3-FAPI-04) uptake. Blocking studies with excess unlabeled FAPI-04 in CIA mice and NIH3T3 xenografts in immunocompromised mice were used to evaluate the binding specificity of [¹⁸F]AlF-NOTA-FAPI-04. Additionally, [¹⁸F]AlF-NOTA-FAPI-04 PET imaging was performed on two RA patients. Results The binding of [¹⁸F]AlF-NOTA-FAPI-04 increased significantly in RA FLSs and NIH3T3 cells overexpressing FAP compared to their parental controls (FAP-GFP-NIH3T3 vs. GFP-NIH3T3, 2.40 ± 0.078 vs. 0.297 ± 0.05% AD/10⁵ cells; RA FLSs vs. OA FLSs, 1.54 ± 0.064 vs. 0.343 ± 0.056% AD/10⁵ cells). Compared to ¹⁸F-FDG imaging, [18F]AlF-NOTA-FAPI-04 showed high uptake in inflamed joints in the early stage of arthritis, which was positively correlated with the arthritic scores (Pearson r=0.834, P<0.001). In addition, the binding of [¹⁸F]AlF-NOTA-FAPI-04 to cells with high FAP expression and the uptake of [¹⁸F]AlF-NOTA-FAPI-04 in arthritic joints both could be blocked by excessive unlabeled FAPI-04. Fluorescent staining showed that the intensity of Cy3-FAPI-04 binding to FAP increased accordingly as the expression of FAP protein increased in cells and tissue sections. Furthermore, the uptake of [¹⁸F]AlF-NOTA-FAPI-04 in FAP-GFP-NIH3T3 xenografts was significantly higher than that in GFP-NIH3T3 xenograft (35.44 ± 4.27 vs 7.92 ± 1.83% ID/mL). Finally, [¹⁸F]AlF-NOTA-FAPI-04 PET/CT imaging in RA patients revealed nonphysiologically high tracer uptake in the synovium of arthritic joints. Conclusion [¹⁸F]AlF-NOTA-FAPI-04 is a promising radiotracer for imaging RA FLSs and could potentially complement the current noninvasive diagnostic parameters.

Extra-articular findings with FDG-PET/CT in rheumatoid arthritis patients: more harm than benefit

Article

Full-text available

Feb 2022

Objective Whole-body Positron Emission Tomography with CT-scanning using fluorine-18 fluorodeoxyglucose (18F-FDG) is occasionally used in rheumatoid arthritis (RA) patients to detect arthritis. FDG-PET/CT might also detect malignancies, but the amount of incidental findings and the number of relevant malignant disease that could be missed are currently unknown. We aimed to study the malignancy screening performance of whole-body FDG-PET/CT in longstanding RA patients with low disease activity. Methods FDG-PET/CT-scanning was done in the intervention arm of the Dose REduction Strategy of Subcutaneous TNF-inhibitors (DRESS) study, a randomized controlled trial on dose-tapering of biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs). The reference standard was clinical diagnosis of malignancy during the 3 year follow-up of the study. Prevalence of extra-articular abnormalities, follow-up, and treatments were summarized post-hoc. Results 121 scans were made in 79 patients. Extra-articular abnormalities were found in 59/121 (49%) scans, resulting in additional diagnostic procedures in 21/79 (26.6%) patients. Nine patients (7.4%) were suspected of malignancy, none turned out to be malignant. Six clinical malignancies that developed during follow-up were all negative on baseline FDG-PET/CT. Conclusion Whole-body FDG-PET/CT-scanning used in RA patients for imaging of arthritis results in frequent incidental extra-articular findings, while some who apparently had normal scans also developed malignancies. Trial registration Netherlands Trial Register, www.trialregister.nl, NL6771

Practical Implementation of Artificial Intelligence-Based Deep Learning and Cloud Computing on the Application of Traditional Medicine and Western Medicine in the Diagnosis and Treatment of Rheumatoid Arthritis

Article

Full-text available

Dec 2021

Rheumatoid arthritis (RA), an autoimmune disease of unknown etiology, is a serious threat to the health of middle-aged and elderly people. Although western medicine, traditional medicine such as traditional Chinese medicine, Tibetan medicine and other ethnic medicine have shown certain advantages in the diagnosis and treatment of RA, there are still some practical shortcomings, such as delayed diagnosis, improper treatment scheme and unclear drug mechanism. At present, the applications of artificial intelligence (AI)-based deep learning and cloud computing has aroused wide attention in the medical and health field, especially in screening potential active ingredients, targets and action pathways of single drugs or prescriptions in traditional medicine and optimizing disease diagnosis and treatment models. Integrated information and analysis of RA patients based on AI and medical big data will unquestionably benefit more RA patients worldwide. In this review, we mainly elaborated the application status and prospect of AI-assisted deep learning and cloud computation-oriented western medicine and traditional medicine on the diagnosis and treatment of RA in different stages. It can be predicted that with the help of AI, more pharmacological mechanisms of effective ethnic drugs against RA will be elucidated and more accurate solutions will be provided for the treatment and diagnosis of RA in the future.

Rheumatoid Arthritis with Generalized Lymphadenopathy Mimicking Lymphoma on Positron Emission Tomography/Computed Tomography with 18F-Fluorodeoxyglucose

Article

Full-text available

Oct 2021

A 42-year-old male presented with weight loss and progressively increasing pain and swelling in joints over the past 3 months. Contrast-enhanced computed tomography (CT) demonstrated pleuropulmonary opacities and supra/infradiaphragmatic lymph nodes enlargement. Positron emission tomography (PET/CT) with 18F-fluorodeoxyglucose showed intensely increased tracer uptake in joints, in pulmonary opacities, as well as in thoracic, iliac, and inguinal nodes. On suspicion of lymphoma with synovial involvement, he was submitted to lymph node and synovial biopsy, which revealed reactive follicular lymphadenopathy and synovium inflammatory changes, respectively. Rheumatoid factor resulted increased, and thus, diagnosis of rheumatoid arthritis with related lung and lymph node involvement was made.

Putative Association between Low Baseline Gene Expression in the Peripheral Blood and Clinical Remission in Rheumatoid Arthritis Patients Treated with Tofacitinib

Article

Full-text available

Dec 2021

We investigated the importance of the baseline expression of genes involved in energy generation, as prognostic biomarkers of the treatment response to tofacitinib in patients with rheumatoid arthritis (RA). Peripheral blood samples were obtained from 28 patients with RA who received 3 months of tofacitinib therapy from 26 healthy controls. Clinical response was evaluated based on the disease activity score, the erythrocyte sedimentation rate (DAS28-ESR), and the serum levels of ACPA, RF, CRP, and ESR. Clinical remission was assessed based on DAS28 score <2.6. Protein concentrations were measured using ELISA. Total RNA isolated from whole blood was used for gene expression analysis using quantitative RT-PCR. All patients were diagnosed with Steinbrocker’s radiographic stage II-III at baseline, and most showed erosive arthritis with ACPA and RF positivity. Tofacitinib treatment significantly decreased the disease activity. Upon study completion, seven patients showed remission. Before and after TOFA therapy, a significantly higher expression of succinate dehydrogenase and pyruvate kinase genes was observed in all the examined patients compared to healthy subjects. However, the pre-therapy expression of these genes and corresponding proteins was significantly (p ≤ 0.05) lower in patients who showed remission than in other patients with RA. Moreover, we observed that, during follow-up, patients who developed remission showed an increasing trend in the expression of the examined genes, whereas the others showed some decreases in gene expression, although this was not statistically significant. We concluded that, compared with RA patients maintaining persistent moderate or high disease activity, those with clinical remission following tofacitinib treatment showed a significantly lower baseline expression of genes involved in energy generation.

A eficácia da técnica PET/CT na determinação precoce do câncer: uma revisão integrativa da literatura/ Effectiveness of the PET/CT technique in early cancer determination: an integrative literature review

Article

Jul 2021

Raimundo Fagner Mendes da Silva

Regulation of inflammatory mediators and immune cell recruitment in different inflammatory stages of psoriasis arthritis mouse models

Thesis

Jan 2021

Madelaine Hahn

Psoriatic arthritis (PsA) is an autoimmune disorder affecting close to 1 % of the general population. Psoriasis vulgaris is defined by inflamed and scaling skin plaques that are clearly separated from the surrounding skin. Up to 30 % of psoriasis patients develop additional arthritis symptoms, resulting in a PsA phenotype. PsA is characterized by inflammation of especially distal interphalangeal joints, enthesitis, dactylitis and axial spondyloarthritis, new bone formation and psoriatic skin plaques. The symptoms occur in recurrent flares and without treatment, the disease becomes chronic and disabling. The pathogenesis of PsA is characterized by deregulated interactions between stromal and immune cells and an uncontrolled network of cytokines and chemokines, which leads to failure of resolution. Prominent mediators are immune cells such as neutrophil granulocytes, monocytes and macrophages, T cell subtypes and synovial fibroblasts, which exert their proinflammatory effector function by cytokines and chemokines like tumor necrosis factor alpha (TNFα), Interleukin (IL)-6, IL-17 and IL-36. The influencing factors of psoriasis vulgaris and rheumatoid arthritis are overlapping, but the final connection and cause of development of PsA is not yet identified. For this reason, the overall aim of this thesis was to investigate the regulation of inflammatory mediators and immune cells in the phase of inflammation and resolution in PsA. For this purpose a doxycycline-inducible human TNFα transgenic (ihTNFtg) mouse model and a mannan-induced model of PsA-like inflammation were used. In both models the mice develop PsA-like symptoms such as paw swelling and skin inflammation and are able to undergo resolution. First, the development of psoriatic and arthritic symptoms, immune cell infiltration, increased osteoclast numbers and osteophyte formation confirmed the ihTNFtg mouse as a suitable model for investigating human PsA. Flow cytometric analyses as well as in vivo imaging of myeloid peroxidase (MPO) activity revealed increased numbers of activated neutrophils and monocytes in affected tissues during inflammation. Additionally, macrophage specific cytokines and chemokines e.g. IL-6 and chemokine C-C motif ligand 2 (CCL2) were detected in tissue as well as in in vitro cultured inducible synovial fibroblasts. Depletion of neutrophils did not change the velocity of the resolution phase. By contrast, depletion of macrophages resulted in reduced paw swelling and skin inflammation along with diminished mRNA expression of proinflammatory mediators such as keratinocyte-derived cytokine (KC/ IL-8) or matrix metalloproteinases. Moreover, in vitro experiments revealed that TNFα impairs alternatively activated macrophage (aaMφ) differentiation and promotes proinflammatory classically activated macrophage (caMφ) phenotype, implying that macrophage subpopulations contribute to TNFα-driven pathogenesis of PsA. In the second part, IL-36 cytokines were analysed. IL-36 cytokine expression was increased in samples of paws and especially skin of ihTNFtg mice during inflammation. Addition of IL-36α in in vitro fibroblast experiments and injection of recombinant IL-36α cytokine in vivo resulted in an increase of the expression of other proinflammatory mediators such as IL-1β and IL-6. These results confirmed the proinflammatory capacity of IL-36. Nonetheless, IL-36 was only shown to participate in disease development and maintenance, but not to be a responsible initiator, at least in joint inflammation. Bulk-RNA sequencing analyses of a comparison of paws from ihTNFtg mice at naïve status, peak of inflammation and after resolution could approve the current received results, also in regard to the importance of monocytes/macrophages, IL-36 cytokines and MPO activity. Deeper analyses will certainly reveal some potential new targets. In a third approach, the relevance of MPO was investigated in the mannan-induced model of PsA. In the absence of MPO several neutrophil proteases are supposed to be increased and with this for example IL-36 cytokines become truncated to a higher active form. In fact, Mpo-/- mice developed a more severe inflammation compared to wild type mice. The underlying mechanism needs to be further investigated. Together, the findings of the current thesis provide the basis for a better understanding of the severe inflammatory skin and joint disease PsA and for developing new therapeutic strategies targeting chronic inflammation.

Systematic review of imaging tests to predict the development of rheumatoid arthritis in people with unclassified arthritis

Article

Oct 2021
SEMIN ARTHRITIS RHEU

Objective To estimate and compare the diagnostic accuracy of magnetic resonance imaging (MRI) and ultrasound, for the prediction of rheumatoid arthritis (RA) in unclassified arthritis (UA). Methods MEDLINE, Embase and BIOSIS were searched from 1987 to May 2019. Studies evaluating any imaging test in participants with UA were eligible. Reference standards were RA classification criteria or methotrexate initiation. Two authors independently extracted data and assessed validity using QUADAS-2. Sensitivities and specificities were calculated for each imaging characteristic and joint area. Summary estimates with 95% confidence intervals (CI) were estimated where possible. Results Nineteen studies were included; 13 evaluated MRI (n=1,143; 454 with RA) and 6 evaluated ultrasound (n=531; 205 with RA). Studies were limited by unclear recruitment procedures, inclusion of patients with RA at baseline, differential verification, lack of blinding and consensus grading. Study heterogeneity largely precluded meta-analysis, however summary sensitivity and specificity for MRI synovitis in at least one joint were 93% (95% CI 88%, 96%) and 25% (95% CI 13%, 41%) (3 studies). Specificities may be higher for other MRI characteristics but data are limited. Ultrasound results were difficult to synthesise due to different diagnostic thresholds and reference standards. Conclusion The evidence for MRI or ultrasound as single tests for predicting RA in people with UA is heterogeneous and of variable methodological quality. Larger studies using consensus grading and consistently defined RA diagnosis are needed to identify whether combinations of imaging characteristics, either alone or in combination with other clinical findings, can better predict RA in this population.

Characteristics and Clinical Value of 18F-FDG PET/CT in the Management of Adult-Onset Still’s Disease: 35 Cases

Article

Full-text available

Jun 2021

While the diagnosis of adult-onset Still’s disease (AOSD) involves the exclusion of differential diagnoses, the characteristics and value of 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography coupled with CT (PET/CT) in the management of AOSD remain poorly known. Our retrospective study included patients from four centers, fulfilling Yamaguchi or Fautrel criteria, who underwent a PET/CT during an active AOSD. Thirty-five patients were included. At the time of PET/CT, the Yamaguchi criteria were met in 23 of 29 evaluable cases. PET/CT showed bone marrow (74.3%), lymph node (74.3%), and splenic (48.6%) FDG uptake. Despite arthralgia or arthritis in most patients, joints were rarely the sites of 18F-FDG accumulation. The spatial distribution of 18F-FDG uptake was nonspecific, and its intensity could be similar to malignant disease. Lymph node or bone marrow biopsy was performed after PET/CT in 20 patients (57.1%). The intensity of bone marrow; splenic and lymph node hypermetabolism appeared to be correlated with disease activity. Abnormal PET/CT in the cervical lymph nodes and age ≥ 60 years seemed to be predictive factors for monocyclic evolution. The clinical value of PET/CT is not in direct diagnosis; but as an aid in excluding differential diagnoses by searching for their scintigraphic features and guiding biopsy.

Polymyalgia rheumatica in the 2018–2020 guidelines. Part II: diagnosis of vasculitis

Article

Full-text available

Apr 2021

The issue of improved diagnosis of both rheumatic diseases of the elderly and aortic diseases does not lose its relevance. In terms of aortic aneurysms, dissection and ruptures and their attended pathogenesis, both inflammation and structural wall damages may be detected with imaging methods whose role is vital. A number of international guidelines deal with the management of polymyalgia rheumatica, giant cell arteritis, or aortic aneurysms. Aortitis is associated with up to 40 % of polymyalgia rheumatica’s cases. The clinical suspicion of aortitis is based on the detection of blood pressure and pulse asymmetry, aortic regurgitation murmur, vascular bruits, as well as persistent polymyalgia rheumatica or inflammatory dorsalgia, pelvis or leg pain. In 2020, the positron emission tomography/computed tomography’s use is approved by the Italian Society for Rheumatology for the diagnosis of vasculitis attended by polymyalgia rheumatica at the secondary healthcare level and by the European Headache Federation for the diagnosis of large vessel giant cell arteritis in the neurological practice. A review of the guideline by the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the American Society of Nuclear Cardiology (2018) was performed in terms of positron emission tomography with fluorodesoxyglucose combined with computed tomography (angiography) imaging in large vessel vasculitis and polymyalgia rheumatica. It is further compared with the clinical guidelines, other guidelines by the societies of nuclear medicine and new scientific data. Both procedure and patient’s preparation for examination are decribed. The criteria for assessing vasculitis proposed for either clinical practice or clinical studies are considered, as well as the factors influencing the test results and their interpretation (such as atherosclerosis, diabetes, age, body mass index, glucemia’s and acute phase markers’ levels). The guideline substantiates the benefit of both positron emission tomography’s use and its combination with computed tomography to detect extracranial vasculitis, as well as the value of performing computed tomography-angiography at different stages of the disease. There is a need to strengthen evidence on both standard time of fluorodesoxyglucose exposure and the benefit of combining positron emission tomography with computed tomography-angiography, in particular for detection of vasculitis relapses. Finding a consensus for early test’s performing is needed, as well as its score standardization, ensuring reimbursement and implementation of new imaging techniques for the cranial vessels. In the future, the evidence-based approach to managing vasculitis will be supplemented by teranostics.

Decision Tree With Only Two Musculoskeletal Sites to Diagnose Polymyalgia Rheumatica Using [18F]FDG PET-CT

Article

Full-text available

Feb 2021

Introduction: The aim of this study was to find the best ordered combination of two FDG positive musculoskeletal sites with a machine learning algorithm to diagnose polymyalgia rheumatica (PMR) vs. other rheumatisms in a cohort of patients with inflammatory rheumatisms. Methods: This retrospective study included 140 patients who underwent [ ¹⁸ F]FDG PET-CT and whose final diagnosis was inflammatory rheumatism. The cohort was randomized, stratified on the final diagnosis into a training and a validation cohort. FDG uptake of 17 musculoskeletal sites was evaluated visually and set positive if uptake was at least equal to that of the liver. A decision tree classifier was trained and validated to find the best combination of two positives sites to diagnose PMR. Diagnosis performances were measured first, for each musculoskeletal site, secondly for combination of two positive sites and thirdly using the decision tree created with machine learning. Results: 55 patients with PMR and 85 patients with other inflammatory rheumatisms were included. Musculoskeletal sites, used either individually or in combination of two, were highly imbalanced to diagnose PMR with a high specificity and a low sensitivity. The machine learning algorithm identified an optimal ordered combination of two sites to diagnose PMR. This required a positive interspinous bursa or, if negative, a positive trochanteric bursa. Following the decision tree, sensitivity and specificity to diagnose PMR were respectively 73.2 and 87.5% in the training cohort and 78.6 and 80.1% in the validation cohort. Conclusion: Ordered combination of two visually positive sites leads to PMR diagnosis with an accurate sensitivity and specificity vs. other rheumatisms in a large cohort of patients with inflammatory rheumatisms.

Molecular Imaging of Inflammatory Disease

Article

Full-text available

Feb 2021

Inflammatory diseases include a wide variety of highly prevalent conditions with high mortality rates in severe cases ranging from cardiovascular disease, to rheumatoid arthritis, to chronic obstructive pulmonary disease, to graft vs. host disease, to a number of gastrointestinal disorders. Many diseases that are not considered inflammatory per se are associated with varying levels of inflammation. Imaging of the immune system and inflammatory response is of interest as it can give insight into disease progression and severity. Clinical imaging technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) are traditionally limited to the visualization of anatomical information; then, the presence or absence of an inflammatory state must be inferred from the structural abnormalities. Improvement in available contrast agents has made it possible to obtain functional information as well as anatomical. In vivo imaging of inflammation ultimately facilitates an improved accuracy of diagnostics and monitoring of patients to allow for better patient care. Highly specific molecular imaging of inflammatory biomarkers allows for earlier diagnosis to prevent irreversible damage. Advancements in imaging instruments, targeted tracers, and contrast agents represent a rapidly growing area of preclinical research with the hopes of quick translation to the clinic.

The frequency of occult solid malignancy in patients with polymyalgia rheumatica-like symptoms

Article

Full-text available

Jan 2021
Ther Adv Musculoskelet Dis

Aims We aim to evaluate the clinical usefulness of systematic screening for occult cancer in patients with polymyalgia rheumatic (PMR)-like symptoms in real-life practice. Methods All patients seen by rheumatologists in Burgundy, France, between March 2016 and December 2018 for new-onset PMR that met the 2012 ACR/EULAR classification criteria were prospectively included. Patients underwent systematic screening including determination of the erythrocyte sedimentation rate, serum C-reactive protein levels, thoracic, abdominal and pelvic computed tomography (CT-TAP) and, in men, serum prostate-specific antigen. The standardized incidence ratio (SIR) for cancers was calculated using 2012 national estimates of cancer incidence. Potential predictive factors for the diagnosis of cancer were then evaluated using univariate and multivariate analyses. Results Among the 118 patients included, nine cases of cancer were confirmed and diagnosed with CT-TAP: kidney carcinoma ( n = 4), lung cancer ( n = 2), pancreatic, colon, and ampullary carcinoma ( n = 1 each). Among these cancers, five were localized (four kidney, and one ampullary carcinoma) and were treated with complete surgical resection. The expected incidence of cancer in the general population was 1.95, leading to an overall SIR of 4.6 (95% CI 2.4–8.9, p < 0.0001). An additional analysis was performed for the kidney carcinoma, and it showed a highly significant increase in SIR: 80.8 (95% CI 30.3–215.4). In 80% of patients, the PMR-like syndrome regressed during cancer treatment. No other predictive factors for cancer were found. Conclusion Systematic screening for cancer including CT-TAP in real-life practice revealed occult solid malignancy, mostly early-stage cancer, in a relevant proportion of patients presenting PMR-like symptoms. The high proportion of kidney cancer (40%) is worth highlighting, especially considering that it is not one of the most frequent cancers after 50 years of age.

Diagnostic value of [18F]FDG-PET/CT in polymyalgia rheumatica: a systematic review and meta-analysis

Article

Full-text available

Jun 2021
EUR J NUCL MED MOL I

Purpose Polymyalgia rheumatica (PMR) can be difficult to diagnose. Whole-body [18F]FDG-PET/CT allows for a comprehensive evaluation of all relevant articular and extra-articular structures affected by PMR. We aimed to summarize current evidence on the diagnostic value of [18F]FDG-PET/CT for a diagnosis of PMR. Methods PubMed/MEDLINE and the Cochrane Library database were searched from inception through May 31, 2020. Studies containing patients with PMR who underwent [18F]FDG-PET/CT were included. Screening and full-text review were performed by 3 investigators and data extraction by 2 investigators. Risk of bias was examined with the QUADAS-2 tool. Diagnostic test meta-analysis was performed with a bivariate model. Results Twenty studies were included in the systematic review, of which 9 studies (n = 636 patients) were eligible for meta-analysis. [18F]FDG positivity at the following sites was associated with a diagnosis of PMR: interspinous bursae (positive likelihood ratio (LR+) 4.00; 95% CI 1.84–8.71), hips (LR+ 2.91; 95% CI 2.09–4.05), ischial tuberosities (LR+ 2.86; 95% CI 1.91–4.28), shoulders (LR+ 2.57; 95% CI 1.24–5.32) and sternoclavicular joints (LR+ 2.31; 95% CI 1.33–4.02). Negative likelihood ratios (LR−) for these sites, as well as the greater trochanters, were all less than 0.50. Composite [18F]FDG-PET/CT scores, as reported in 3 studies, provided a pooled LR+ of 3.91 (95% CI 2.42–6.32) and LR− of 0.19 (95% CI 0.10–0.36). Moderate to high heterogeneity was observed across the studies, mainly due to differences in patient selection, scanning procedures and/or interpretation criteria. Conclusion Significant [18F]FDG uptake at a combination of anatomic sites is informative for a diagnosis of PMR. [18F]FDG-PET/CT might be an important diagnostic tool in patients with suspected PMR. This study also highlights the need for adherence to published procedural recommendations and standardized interpretation criteria for the use of [18F]FDG-PET/CT in PMR.

Imaging in polymyalgia rheumatica: which technique to use?

Article

Full-text available

Nov 2020

Polymyalgia rheumatica (PM) is an inflammatory rheumatic disorder characterised by pain and stiffness, mainly in the neck, shoulders, and pelvic girdle and possible association with giant cell arteritis. Currently, there is no diagnostic gold standard for PM, however, an extensive assessment of patients' inflammatory status aided by imaging evaluation is crucial for disease stratification. Many imaging techniques study PM features and their possible complications or associations with giant cell arteritis: radiography, ultrasound, scintigraphy, magnetic resonance imaging, and positron emission tomography/computed tomography. Each one has different advantages and disadvantages. The aim of this review is to clarify the current uses of imaging in PM for diagnosis and follow-up through a literature review of the last 10 years.

LAT1 transporter as a target for breast cancer diagnosis and therapy

Article

Nov 2024
EUR J MED CHEM

Application of 18F-FDG PET/CT in rheumatic diseases

Article

Oct 2024

Objective: To explore the application of 18F-flurodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in rheumatic diseases, to compare these different imaging features, and to describe the current PET/CT imaging status in clinical practice. Methods: A total of 486 cases in our department from January 2012 to December 2018 were enrolled in this study, and 18F-FDG PET/CT examination was performed in all the patients. The clinical use of 18F-FDG PET/CT was retrospectively analyzed to discuss the clinical application and its imaging characteristics of rheumatic diseases. Categorical data were used to ascertain prevalence statistics, whereas continuous data were used to delineate means and standard deviations. Independent sample t test, Chi square test and Mann-Whitney U test were used for statistical analysis. A P-value of < 0.05 was considered significant. Results: (1) From 2012 to 2018, totally 486 patients in the Department of Rheumatology and Immunology underwent 18F-FDG PET/CT examination, accounting for 5.30% of the total number of PET/CT examinations in the whole hospital. In this study, 304 of the 486 patient were female (62.55%), 182 of them were male (37.45%), the average age of the patients was (53.21±18.81) years, and the proportion of the patients aged 45-65 (227/486, 46.71%) was the highest group. (2) Three leading purposes of the PET/CT examination in our department were to exclude cancers (55.56%), assist in diagnosis (24.60%) and evaluate the disease activity (19.84%). (3) Of the 486 patients who underwent 18F-FDG PET/CT, 327 cases might indicate a differential diagnosis of rheumatic disease, of which, 292 cases were highly suggestive of diagnosis, including 61 cases of myositis, 60 cases of vasculitis, 37 cases of adult still's disease, 32 cases of IgG4 related diseases, 30 cases of rheumatoid arthritis, 22 cases of Sjögren's syndrome, 22 cases of systemic lupus erythematosus, and 9 cases of rheumatic polymyalgia; the remaining 35 cases only prompted the possibility of autoimmune disease. Of the 486 patients, 74 cases suggested the diagnosis of cancers, 25 cases indicated the diagnosis of infectious diseases, while 60 cases could not show any diagnostic values. Ten patients with rheumatic disease were followed up with a post-treatment repeat PET/CT, and the findings in remission showed reduced 18F-FDG metabolic activity as well as a reduction in the extent of metabolic hypertrophic lesions. Conclusion: There are some typical sign of 18F-FDG PET/CT for diffuse connective tissue diseases, therefore 18F-FDG PET/CT has auxi-liary effect on the classification diagnosis of rheumatic diseases, especially for the exclusion of cancers.

Relapsing Polycondritis

Chapter

Sep 2024

Relapsing polycondritis (RP) is a rare disease described for the first time a century ago under the term “polycondropathy” by Wartenhorst [1] and which owes its current name to Pearson et al. [2]. It is a systemic inflammatory immune-mediated disease that affects the cartilage tissues of ears, nose, and tracheobronchial tree but also the joints, eyes, inner ear, and cardiovascular system among several other systemic manifestations [3, 4]. It can present with different phenotypes. Some are life threatening such as the hematological phenotype associated with myelodysplasia and the respiratory one with predominant tracheobronchial involvement; other phenotypes are more benign, such as those characterized by isolated intermittent involvement of the cartilage of the nose and ears [5]. It is a very rare disease, with an estimated incidence of 0.7–3.7 per million person years [6–8]. A recent estimated prevalence of RP was in the United States 4.5 per million [9], while in the Hungarian population a prevalence of 20 per million has been calculated [8]. It appears to be ubiquitous across all ethnic groups although the majority of patients reported are of Caucasian origin and the disease is rare among sub-Saharan Africans [10]. It can appear at any age even although appears more frequently between the age of 40 and 50 years. For some authors there is a slight female predominance [11], while for others the disease affects both sexes similarly [10]. Predisposing genetic factors have been hypothesized and the occurrence of the disease in the same family has been reported [12].

Multimodal positron emission tomography (PET) imaging in non-oncologic musculoskeletal radiology

Article

Mar 2024
SKELETAL RADIOL

Musculoskeletal (MSK) disorders are associated with large impacts on patient’s pain and quality of life. Conventional morphological imaging of tissue structure is limited in its ability to detect pain generators, early MSK disease, and rapidly assess treatment efficacy. Positron emission tomography (PET), which offers unique capabilities to evaluate molecular and metabolic processes, can provide novel information about early pathophysiologic changes that occur before structural or even microstructural changes can be detected. This sensitivity not only makes it a powerful tool for detection and characterization of disease, but also a tool able to rapidly assess the efficacy of therapies. These benefits have garnered more attention to PET imaging of MSK disorders in recent years. In this narrative review, we discuss several applications of multimodal PET imaging in non-oncologic MSK diseases including arthritis, osteoporosis, and sources of pain and inflammation. We also describe technical considerations and recent advancements in technology and radiotracers as well as areas of emerging interest for future applications of multimodal PET imaging of MSK conditions. Overall, we present evidence that the incorporation of PET through multimodal imaging offers an exciting addition to the field of MSK radiology and will likely prove valuable in the transition to an era of precision medicine.

Assessing the feasibility of SUVindex (a metric derived from FDG PET/CT) for the diagnosis of polymyalgia rheumatica

Article

Jun 2023
CLIN RADIOL

Aim: To evaluate the feasibility of standard uptake value (SUV) index (ratio lesional maximum SUV [SUVmax] to liver mean SUV [SUVmean]) as a metabolic parameter for diagnosing polymyalgia rheumatica (PMR). Materials and methods: A retrospective group of patients with PMR and controls with symptoms similar to PMR but diagnosed with other diseases. Semiquantitative and qualitative analysis of 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) uptake at 18 sites was undertaken for all patients. The diagnostic value of positron-emission tomography/computed tomography (PET/CT) for PMR was assessed by R software using logistic regression and a generalised additive model (GAM). All images were examined independently by two nuclear medicine physicians with extensive work experience. Results: The characteristic sites of PMR were the ischial tuberosity, interspinous bursa, periarticular hip, and symphysis pubis enthesis. The area under the curve (AUC) of the characteristic site SUV index was 0.930, and the best cut-off value was 1.685 with a sensitivity of 84.6% and a specificity of 92.6%. After adjusting for potential confounders, the probability of PMR diagnosis increased as the characteristic site SUV index increased and there was a nonlinear correlation between the two. When the characteristic site SUV index was ≥2.56, the probability of PMR gradually reached the threshold effect, which was as high as 90% or more. Conclusion: The characteristic site SUV index is an independent factor for diagnosing PMR, and PMR should be highly suspected when it is ≥ 1.685. Nonetheless, it is important to note that these findings are based on an initial retrospective single-centre study and require external validation and further prospective evaluation before being translated into clinical practice.

Rheumatology experience with FDG PET / CT in inflammation of unknown origin: a single - centre report for determining factors associated with diagnostic precision

Article

Jun 2023
CLIN RHEUMATOL

Unlabelled: BACKGROUND / AIM: The use of PET / CT is becoming more common in the elucidation of inflammatory processes in which the underlying cause cannot be determined by conventional examinations. Although PET / CT is an effective method for detecting inflammatory foci, the precise diagnosis may not be obtained in all cases. In addition, considering factors such as radiation exposure and cost, it becomes important to identify patients who can get results with PET / CT. In this study, it was aimed to examine the factors that can predict the differential diagnostic value of PET / CT by retrospectively scanning patients who underwent PET / CT for inflammation of unknown origin (IUO) in rheumatology practice. Methods: Demographic, clinical and laboratory information of the patients followed up in our clinic and who underwent PET / CT for differential diagnosis were enrolled. Whether they were diagnosed after PET / CT and during the follow - up period, and their diagnoses were examined. Results: A total of 132 patients were included in the study. A previous diagnosis of rheumatic disease was present in 28.8 % of the patients, and a history of malignancy was present in 2.3 % . The patients were divided into three groups: group 1 patients with increased FDG uptake in PET / CT and diagnosis confirmed by PET / CT, group 2 patients with increased FDG uptake in PET / CT but diagnosis was not confirmed, and group 3 patients without increased FDG uptake in PET / CT. Increased FDG uptake in PET / CT was detected in 73 % of the patients. While PET / CT helped the diagnosis in 47 (35.6 %) patients (group 1), it did not help the diagnosis in 85 (64.4 %) (groups 2 and 3). Thirty - one (65.9 %) of the diagnosed patients were diagnosed with a rheumatologic disease. When the 3 groups were compared, male gender, advanced age, CRP levels, presence of constitutional symptoms, SUVmax values and number of different organs with increased FDG uptake were higher in Group 1. Sixty - six percent and 74 % of the patients in groups 2 and 3 were not diagnosed during the follow - up period. No patient in group 3 was diagnosed with malignancy during follow - up. Conclusion: PET / CT has high diagnostic value when combined with clinical and laboratory data in the diagnosis of IUO. Our study revealed that various factors can affect the diagnostic value of PET / CT. Similar to the literature, the statistically significant difference in CRP levels shows that patients with high CRP levels are more likely to be diagnosed with an aetiology in PET / CT. Although detection of involvement in PET / CT is not always diagnostic, there was an important finding that no malignancy was detected in the follow - up in any patient without PET / CT involvement. Key points • PET / CT is an effective method for detecting inflammatory foci. • PET / CT has proven to be effective in the diagnosis of rheumatological diseases, the extent of disease and the evaluation of response to treatment. • Indications for the use of PET / CT in the field of rheumatology and the associated factors and clinical features supporting the diagnosis with PET / CT are still to be fully clarified. • In routine practice, with PET / CT, both delays in diagnosis and examinations performed during diagnosis and the cost can be reduced.

Nuclear Medicine Application of Pentixafor/Pentixather Targeting CXCR4 for Imaging and Therapy in Related Disease

Article

Dec 2022
MINI-REV MED CHEM

C-X-C-motif chemokine receptor 4 (CXCR4) is a novel predictive biomarker for metastasis and poor prognosis in individuals with malignancies. CXCL12 is the only cognate ligand of CXCR4. CXCL12/CXCR4 signaling pathways are involved in the cross-talk among cancer cells, T cells, stromal cells, and their microenvironments, including the regulation and direction of T cell migration (chemotaxis), proliferation, and differentiation of immature progenitor stem cells. As CXCR4 overexpression is related to tumor prognosis, it is essential to quantitatively evaluate CXCR4 expression levels in vivo. 68Ga-Pentixafor, as a radiolabeled tracer, shows high specificity and affinity for CXCR4 in tumors. Thus, CXCR4-directed imaging with 68Ga-Pentixafor has been investigated to evaluate CXCR4 expression in patients non-invasively. In recent years, many small cohorts, including those of individuals with hematologic malignancies, solid tumors, and cardiovascular and infectious diseases, have been reported. So far, 68Ga-Pentixafor has been used successfully in individuals with hematologic malignancies. In addition, Lutetium-177 (177Lu) or Yttrium-90 (90Y)-labeled Pentixather (an analog of Pentixafor) suggested high potential applicability in tumor endoradiotherapy (ERT) with CXCR4 overexpression. Patients with advanced-stage multiple myeloma, refractory acute leukemia, and diffuse large B-cell lymphoma received a certain amount of 177Lu-Pentixather or 90Y-Pentixather. This review aimed to overview the current CXCR4-directed positron emission computed tomography (PET) molecular imaging based on Pentixafor in several diseases and ERT.

Glycolysis in Innate Immune Cells Contributes to Autoimmunity

Article

Full-text available

Jul 2022

Autoimmune diseases (AIDs) refer to connective tissue inflammation caused by aberrant autoantibodies resulting from dysfunctional immune surveillance. Most of the current treatments for AIDs use non-selective immunosuppressive agents. Although these therapies successfully control the disease process, patients experience significant side effects, particularly an increased risk of infection. There is a great need to study the pathogenesis of AIDs to facilitate the development of selective inhibitors for inflammatory signaling to overcome the limitations of traditional therapies. Immune cells alter their predominant metabolic profile from mitochondrial respiration to glycolysis in AIDs. This metabolic reprogramming, known to occur in adaptive immune cells, i.e., B and T lymphocytes, is critical to the pathogenesis of connective tissue inflammation. At the cellular level, this metabolic switch involves multiple signaling molecules, including serine–threonine protein kinase, mammalian target of rapamycin, and phosphoinositide 3-kinase. Although glycolysis is less efficient than mitochondrial respiration in terms of ATP production, immune cells can promote disease progression by enhancing glycolysis to satisfy cellular functions. Recent studies have shown that active glycolytic metabolism may also account for the cellular physiology of innate immune cells in AIDs. However, the mechanism by which glycolysis affects innate immunity and participates in the pathogenesis of AIDs remains to be elucidated. Therefore, we reviewed the molecular mechanisms, including key enzymes, signaling pathways, and inflammatory factors, that could explain the relationship between glycolysis and the pro-inflammatory phenotype of innate immune cells such as neutrophils, macrophages, and dendritic cells. Additionally, we summarize the impact of glycolysis on the pathophysiological processes of AIDs, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and ankylosing spondylitis, and discuss potential therapeutic targets. The discovery that immune cell metabolism characterized by glycolysis may regulate inflammation broadens the avenues for treating AIDs by modulating immune cell metabolism.

Positron Emission Tomography/ Magnetic Resonance Imaging (PET/MRI) in musculoskeletal benign conditions

Article

Feb 2022
Q J Nucl Med Mol Imag

Simon Wan

A wide spectrum of benign musculoskeletal (orthopaedic and rheumatological) conditions affect the general population. Collectively, these are common and they can inflict significant morbidity with resultant negative impact on the quality of life of patients. For many of these conditions, there is established evidence for research and clinical use of PETCT and MRI for assessment of disease. Introduction of integrated PET/MRI around a decade ago brought optimism that combining the strength of PET and MRI techniques on a single platform could have synergistic effect to benefit imaging assessment of patients, including in the context of benign musculoskeletal conditions. This review specifically focuses on the progress that has been made. This aims to showcase clinical studies derived primarily from the integrated PET/MRI platforms for the evaluation of common orthopaedic and rheumatological conditions. Despite enthusiasm and progress by early adopters of the PET/MRI technology, significant barriers are present for its wider adoption, validation, and translation to routine clinical practice. Attenuation correction is a particular challenge which affects regions close to the skeleton and impacts PET/MRI assessment of musculoskeletal disorders. Continued effort on research and validation, as well as promotion of its multimodal multiparametric capability to clinical and pharmaceutical stakeholders, and increased availability through increased adoption of PET/MRI scanners internationally, may accelerate its translation into routine clinical practice in this domain.

Clinical analysis of relapsing polychondritis with airway involvement

Article

Feb 2022
J Laryngol Otol

Objective To identify the clinical characteristics, treatment, and prognosis of relapsing polychondritis patients with airway involvement. Methods Twenty-eight patients with relapsing polychondritis, hospitalised in the First Hospital of Shanxi Medical University between April 2011 and April 2021, were retrospectively analysed. Results Fifty per cent of relapsing polychondritis patients with airway involvement had a lower risk of ear and ocular involvement. Relapsing polychondritis patients with airway involvement had a longer time-to-diagnosis ( p < 0.001), a poorer outcome following glucocorticoid combined with immunosuppressant treatment ( p = 0.004), and a higher recurrence rate than those without airway involvement ( p = 0.004). The rates of positive findings on chest computed tomography and bronchoscopy in relapsing polychondritis patients with airway involvement were 88.9 per cent and 85.7 per cent, respectively. Laryngoscopy analysis showed that 66.7 per cent of relapsing polychondritis patients had varying degrees of mucosal lesions. Conclusion For relapsing polychondritis patients with airway involvement, drug treatment should be combined with local airway management.

PET Imaging of Autoimmune Diseases and Inflammatory Bowel Diseases

Chapter

Jan 2021

In the field of inflammation, molecular imaging methods can be considered as a non-invasive tool that allow the early detection and localization of antigens, receptors or cells within the affected tissues. Many inflammatory diseases have specific molecular signatures featured by a number of detectable biomarkers. The most common way to detect these signatures, followed by anatomical changes of target organs, is still tissue biopsy. However, it reveals sometimes to be expensive, invasive, hard to make and not easy to be interpreted. Moreover, pathophysiological changes generally occur before clinical onset of symptoms and before the development of anatomical changes, that are commonly detected by radiological procedures. At this purpose, molecular imaging represents a good compromise among the current diagnostic tools. There is continuous research for more specific and targeted radiopharmaceuticals able to directly identify the offending mechanism of these diseases. In this chapter nuclear medicine techniques for diagnostic purposes in chronic inflammatory conditions and autoimmune diseases (Sjogren syndrome, Vasculitis, rheumatoid arthritis, Type 1 diabetes mellitus, inflammatory bowel diseases, Coeliac disease, autoimmune thyroid diseases and so on) will be described. In particular, the role of PET imaging will be highlighted in order to get more insights of the improvements for diagnosis, therapy decision making and follow up of these kinds of disorders.

Imágenes isotópicas del aparato locomotor

Article

Dec 2021

Resumen La prueba de imagen isotópica es una técnica de imagen funcional y metabólica que permite visualizar diferentes procesos fisiopatológicos en función del radiofármaco utilizado. Para el estudio de las patologías benignas del aparato locomotor, existen principalmente tres familias de radiofármacos. La primera familia de radiofármacos sirve para visualizar la actividad osteoblástica de las lesiones óseas. En la gammagrafía ósea, el radiofármaco utilizado es un bifosfonato marcado con tecnecio 99m (99mTc). La gammagrafía ósea está indicada en la búsqueda de patologías osteoarticulares infecciosas o inflamatorias (osteomielitis, síndrome de dolor regional complejo, etc.), en complicaciones ortopédicas con presencia de material de osteosíntesis (búsqueda de aflojamiento de implantes, seudoartrosis) o en la búsqueda de fracturas de esfuerzo. Además, la gammagrafía permite obtener imágenes de todo el esqueleto, lo que resulta útil para evaluar enfermedades óseas benignas como la displasia fibrosa. En la tomografía por emisión de positrones (PET), el radiofármaco utilizado para visualizar la actividad osteoblástica es el fluoruro de sodio marcado con ¹⁸F (¹⁸F-NaF). La PET acoplada a tomografía computarizada (PET-TC) con ¹⁸F-NaF tiene mejor resolución que las gammagrafías óseas y podría sustituirlas en muchas indicaciones. Sin embargo, su uso no está muy extendido en la práctica debido a su coste y a su limitada disponibilidad. La segunda familia de radiofármacos permite marcar los leucocitos. Así, una gammagrafía con leucocitos marcados hace posible la detección de leucocitos que se acumulan en los focos de infección. La sensibilidad de este método varía según el lugar de la infección, con una mejor sensibilidad para las infecciones del esqueleto apendicular distal o periprotésico que para las del esqueleto axial. El último radiofármaco utilizado es la fluorodesoxiglucosa marcada con ¹⁸F (¹⁸F-FDG). Se trata de un análogo de la glucosa que permite localizar focos musculoesqueléticos con un elevado metabolismo de los glúcidos, como los focos infecciosos, inflamatorios o neoplásicos.

Fluorine-18 labeled fluorodeoxyglucose positron emission tomography/computed tomography used in diagnosing connective tissue diseases in fever of unknown origin/inflammatory of unknown origin patients

Article

Oct 2021

To explore the significance of Fluorine-18 labeled fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in diagnosing connective tissue diseases (CTDs) in fever of unknown origin (FUO) or inflammation of unknown origin (IUO) patients. Clinical and image data of 242 consecutive FUO/IUO patients who underwent PET/CT examination and eventually diagnosed CTDs were retrospectively analyzed, including distribution of diseases, clinical characteristics, and PET/CT imaging findings. The role of FDG PET/CT in differential diagnosis of CTDs was evaluated through clinical questionnaire survey. Patients diagnosed as CTDs accounted for 48.1% of FUO/IUO patients. Among them, adult-onset Still’s disease was most frequently diagnosed. Other common diseases included systemic vasculitis, undifferentiated connective tissue disease, rheumatoid arthritis, idiopathic inflammatory myopathy, systemic lupus erythematosus, and polymyalgia rheumatica. On FDG PET/CT examination, 97.9% of the patients had positive findings. Inflammatory lesions were detected in 66.5% and non-specific abnormal uptakes were found in 31.4%. Detected lesions distributed consistently with corresponding susceptible organs and tissues in various diseases. Clinical questionnaire results shown that FDG PET/CT excluded malignant tumors, focal infections, or other typical CTDs in 45.5% of the patients; indicated important diagnostic clues or appropriate biopsy sites in 20.6% of patients; and directly suggested the diagnosis of a CTD in 33.1% of patients. FDG PET/CT could reveal inflammatory lesions in organs and tissues that reflect the clinical characteristics in different CTDs, thus providing an objective evidence for differential diagnosis, classification, and treatment decision of these diseases. Key Points • FDG PET/CT is a useful tool for differential diagnosing connective tissue diseases among patients with fever of unknown origin/inflammatory of unknown origin.

Limitations and Pitfalls of FDG-PET/CT in Infection and Inflammation

Article

Jul 2021
SEMIN NUCL MED

White blood cells activated by either a pathogen or as part of a systemic inflammatory disease are characterized by high energy consumption and are therefore taking up the glucose analogue PET tracer FDG avidly. It is therefore not surprising that a steadily growing body of research and clinical reports now supports the use of FDG PET/CT to diagnose a wide range of patients with non-oncological diseases. However, using FDG PET/CT in patients with infectious or inflammatory diseases has some limitations and potential pitfalls that are not necessarily as pronounced in oncology FDG PET/CT. Some of these limitations are of a general nature and related to the laborious acquisition of PET images in patients that are often acutely ill, whereas others are more disease-specific and related to the particular metabolism in some of the organs most commonly affected by infections or inflammatory disease. Both inflammatory and infectious diseases are characterized by a more diffuse and less pathognomonic pattern of FDG uptake than oncology FDG PET/CT and the affected organs also typically have some physiological FDG uptake. In addition, patients referred to PET/CT with suspected infection or inflammation are rarely treatment naïve and may have received varying doses of antibiotics, corticosteroids or other immune-modulating drugs at the time of their examination. Combined, this results in a higher rate of false positive FDG findings and also in some cases a lower sensitivity to detect active disease. In this review, we therefore discuss the limitations and pitfalls of FDG PET/CT to diagnose infections and inflammation taking these issues into consideration. Our review encompasses the most commonly encountered inflammatory and infectious diseases in head and neck, in the cardiovascular system, in the abdominal organs and in the musculoskeletal system. Finally, new developments in the field of PET/CT that may help overcome some of these limitations are briefly highlighted.

Giant Cell Arteritis and Polymyalgia Rheumatica: 2016 Update

Article

Full-text available

Oct 2016

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are both more common among people of North European decent than among Mediterranean people. Women are 2–3 times more commonly affected. Giant cell arteritis and PMR are extremely rare before age 50 years. Polymyalgia rheumatica may be “isolated” or associated with GCA. There is increased expression of inflammatory cytokines in temporal arteries of PMR patients, without overt histological evidence of arteritis. One-third of “isolated” PMR patients have vascular uptake in positron emission tomography (PET) scans, suggesting clinically unrecognized, “hidden” GCA. Typical manifestations of GCA are headache, tenderness over temporal arteries, jaw claudication, PMR, acute vision loss, and low-grade fever. Bilateral aching of the shoulders with morning stiffness is typical for PMR. In both conditions sedimentation rate and C-reactive protein are elevated, and anemia and thrombocytosis may occur. Color duplex ultrasonography of the temporal arteries may aid in GCA diagnosis. Temporal artery biopsy showing vasculitis, often with giant cells, confirms GCA diagnosis. In cases with negative biopsy one must rely on the clinical presentation and laboratory abnormalities. The diagnosis of PMR is made primarily on clinical grounds. Other conditions that may mimic GCA or PMR must be excluded. Glucocorticoids are the treatment of choice for both conditions. Prompt treatment is crucial in GCA, to prevent irreversible complications of acute vision loss and stroke. Addition of low-dose aspirin may further prevent these complications. The average duration of treatment is 2–3 years, but some patients require a prolonged course of treatment, and some may develop disease-related or treatment-related complications. No steroid-sparing agent has been proven to be widely effective thus far, but some promising therapeutic agents are currently being studied.

The usefulness of 18F-FDG PET/CT for assessing methotrexate-associated lymphoproliferative disorder (MTX-LPD)

Article

Full-text available

Aug 2016
BMC CANCER

Background Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a benign lymphoid proliferation or malignant lymphoma in patients who have been treated with MTX. MTX withdrawal and observation for a short period should be considered in the initial management of patients who develop LPD while on MTX therapy. Here we evaluated the diagnostic accuracy and predictive value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for MTX-LPD. Methods We retrospectively investigated the cases of 15 patients clinically suspected of having MTX-LPD. A total of 324 anatomic regions (207 nodal and 117 extranodal regions) were assessed by 18F-FDG PET/CT and by multi-detector row CT (MDCT). Each anatomic region was classified as either malignant or benign. The uptake of 18F-FDG was assessed semi-quantitatively with the standardized uptake value maximum (SUVmax), the whole-body metabolic tumor volume (WBMTV), and the whole-body total lesion glycolysis (WBTLG) in order to investigate predictive factors of spontaneous regression after the withdrawal of MTX. ResultsMTX-LPD lesions were observed in 92/324 (28.4 %) regions. 18F-FDG PET/CT showed 90.2 % sensitivity, 97.4 % specificity, and 95.4 % accuracy, values which were significantly higher than those of MDCT (59.8, 94.8, and 84.9 %, respectively. p < 0.002). After the withdrawal of MTX, 9/15 patients (60.0 %) achieved complete response (CR). The SUVmax, WBMTV and WBTLG values of the CR patients were 9.2 (range 2.8–47.1), 44.3 (range 0–362.6) ml, 181.8 (range 0–2180.9) ml, respectively, which were not significantly different from those of the non-CR patients: 10.6 (range 0–24.9), 15.7 (range 0–250.1) ml, and 97.4 (range 0–1052.1) ml. Conclusions Although 18F-FDG PET/CT was a useful tool to detect MTX-LPD lesions, none of the 18F-FDG PET parameters before the withdrawal of MTX could be used to predict CR after the withdrawal of MTX.

Differentiation between Polymyalgia Rheumatica (PMR) and Elderly-Onset Rheumatoid Arthritis Using 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography: Is Enthesitis a New Pathological Lesion in PMR?

Article

Full-text available

Jul 2016
PLOS ONE

Background: It is difficult to differentiate polymyalgia rheumatica (PMR) from elderly-onset rheumatoid arthritis (EORA) in clinical practice. We compared FDG-PET/CT findings between patients with PMR and those with EORA and extracted factors useful for differentiating the two disorders. Methods: We compared abnormal FDG accumulation sites and maximum standardized uptake value (SUVmax) between 15 patients with PMR and 7 with EORA in whom FDG-PET/CT was performed. Results: The proportion of patients in the PMR group with abnormal FDG accumulation at the following 9 sites on FDG-PET/CT was significantly higher than that in the EORA group: periarticular region of the scapulohumeral joint, enthesis of the pectineus muscle, vicinity of the enthesis of the rectus femoris muscle, lateral side of the greater trochanter, ischial tuberosity, hip joint, spinous process of the lower cervical vertebra, intervertebral joint of the lumbar vertebra, and spinous process of the lumbar vertebra. The PET/CT score was evaluated at 9 sites consisting of the abovementioned sites. The median score in the PMR group was 8, which was significantly higher than that of 0 in the EORA group (P = 0.0003). ROC curve analysis was performed with the PET/CT scores, and a score of 5 was shown to maximize the area under the ROC curve (sensitivity: 86.7%, specificity: 86.7%). Conclusions: FDG-PET/CT is useful for differentiating PMR from EORA. In patients with PMR, abnormal FDG accumulation was observed at the entheses, suggesting the presence of enthesitis in addition to bursitis and synovitis.

18F-fluorodeoxyglucose positron emission tomography and the risk of subsequent aortic complications in giant-cell arteritis: A multicenter cohort of 130 patients

Article

Full-text available

Jun 2016
MEDICINE

Previous studies reported a 2- to 17-fold higher risk of aortic complications (dilation or dissection) in patients with giant-cell arteritis (GCA). We aimed to determine whether or not GCA patients with large-vessel involvement demonstrated by positron emission tomography with ¹⁸F-fluorodeoxyglucose combined with computed tomography (FDG-PET/CT) have a higher risk of aortic complications. We conducted a retrospective multicenter study between 1995 and 2014. Patients were included if they fulfilled at least 3 American College of Rheumatology criteria for GCA, or 2 criteria associated with extratemporal biopsy-proven giant-cell vasculitis; they underwent at least 1 FDG-PET/CT scan at diagnosis or during follow-up; and the morphology of the aorta was assessed by medical imaging at diagnosis. Patients with an aortic complication at the time of diagnosis were excluded. Of the 130 patients included [85 women (65%), median age 70 (50–86)], GCA was biopsy proven in 77 (59%). FDG-PET/CT was performed at diagnosis in 63 (48%) patients and during the follow-up period in the 67 (52%) remaining patients. FDG-PET/CT was positive in 38/63 (60%) patients at diagnosis and in 31/67 (46%) patients when performed during follow-up (P = NS). One hundred four patients (80%) underwent at least 1 morphological assessment of the aorta during follow-up. Nine (9%) patients developed aortic complications (dilation in all and dissection in 1) at a median time of 33 (6–129) months after diagnosis. All of them displayed large-vessel inflammation on previous FDG-PET/CT. A positive FDG-PET/CT was significantly associated with a higher risk of aortic complications (P = 0.004). In our study, a positive FDG-PET/CT was associated with an increased risk of aortic complications at 5 years.

Influence of triple disease modifying anti-rheumatic drug therapy on carotid artery inflammation in drug-naive patients with recent onset of rheumatoid arthritis

Article

Full-text available

Jun 2016

Objective. Increased atherosclerosis in RA is not fully explained by the ordinary risk factors, but it may be related to vascular inflammation. The aim of this study was to investigate the degree of carotid artery inflammation in drug-naive patients with early RA before and after DMARD triple therapy. Methods. Fifteen non-diabetic patients with recently diagnosed RA [age 51 (16) years, 6 males] were examined before and at 2 and 4 weeks after the initiation of combination therapy with MTX, SSZ, HCQ and ⩽10 mg/day oral prednisolone. Eight healthy males aged 49 (6) years were examined once as controls. Inflammation in the carotid artery was quantified, using [18F]fluorodeoxyglucose (18F-FDG)-PET/CT, as the maximum standardized uptake value (SUVmax) and the maximum target-to-background ratio (TBRmax). Results. Before the treatment, patients with RA had significantly higher carotid artery 18F-FDG uptake, as compared with healthy controls [TBRmax 1.78 (0.07) vs 1.51 (0.08), P = 0.03]. The 4-week DMARD therapy reduced the TBRmax to the level of healthy controls [1.53 (0.05), P = 0.84]. Compared with the baseline, the TBRmax decreased by 12.4 (16.8)% (P = 0.01) during 4-week DMARD therapy. At baseline, the SUVmax correlated with ESR (r = 0.52, P = 0.02) and CRP (r = 0.65, P = 0.01). Change in SUVmax correlated with changes in ESR and CRP after 4 weeks of treatment, as did the changes in TBRmax and SUVmax with DAS at 12 weeks of treatment. Conclusion. 18F-FDG-PET/CT revealed that drug-naive patients with early RA show carotid artery inflammation that can be efficiently reduced by 1-month DMARD triple therapy.

Unexpected arterial wall and cellular inflammation in patients with rheumatoid arthritis in remission using biological therapy: A cross-sectional study

Article

Full-text available

May 2016
ARTHRITIS RES THER

Background: Increasing numbers of patients (up to 40 %) with rheumatoid arthritis (RA) achieve remission, yet it remains to be elucidated whether this also normalizes their cardiovascular risk. Short-term treatment with TNF inhibitors lowers arterial wall inflammation, but not to levels of healthy controls. We investigated whether RA patients in long-term remission are characterized by normalized inflammatory activity of the arterial wall and if this is dependent on type of medication used (TNF-inhibitor versus nonbiological disease-modifying antirheumatic drugs (DMARDs)). Methods: Arterial wall inflammation, bone marrow and splenic activity (index of progenitor cell activity) was assessed with (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) in RA patients in remission (disease activity score (DAS28) <2.6 for >6 months) and healthy controls. We performed ex vivo characterization of monocytes using flow cytometry and a transendothelial migration assay. Results: Overall, arterial wall inflammation was comparable in RA patients (n = 23) in long-term remission and controls (n = 17). However, RA subjects using current anti-TNF therapy (n = 13, disease activity score 1.98[1.8-2.2]) have an almost 1.2-fold higher (18)F-FDG uptake in the arterial wall compared to those using DMARDs (but with previous anti-TNF therapy) (n = 10, disease activity score 2.24[1.3-2.5]), which seemed to be predominantly explained by longer duration of their rheumatic disease in a multivariate linear regression analysis. This coincided with increased expression of pro-adhesive (CCR2) and migratory (CD11c, CD18) surface markers on monocytes and a concomitant increased migratory capacity. Finally, we found increased activity in bone marrow and spleen in RA patients using anti-TNF therapy compared to those with DMARDs and controls. Conclusions: A subset of patients with RA in clinical remission have activated monocytes and increased inflammation in the arterial wall, despite the use of potent TNF blocking therapies. In these subjects, RA disease duration was the most important contributor to the level of arterial wall inflammation. This increased inflammatory state implies higher cardiovascular risk in these patients, who thus may require more stringent CV risk management.

High-resolution (18)F-FDG PET/CT for assessing disease activity in Rheumatoid and Psoriatic Arthritis: findings of a prospective pilot study

Article

Full-text available

Apr 2016
BRIT J RADIOL

Objectives: Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) commonly affect the small joints of the wrist and hand. We evaluated the performance of a new, high-resolution extremity PET/CT scanner for characterizing and quantifying pathologies associated with the two arthritides in the wrist and hand joints. Methods: RA or PsA patients underwent (18)F-FDG PET/CT wrist and hand imaging respectively on the high-resolution scanner. Calibrated CT images and co-registered PET images were reconstructed. PET/CT were derived for the radiocarpal and pisiform-triquetral compartments, joints with erosive changes, sites of synovitis or tenosynovitis and the nail bed, and were correlated with clinical and MRI findings. Results: Significantly elevated (18)F-FDG uptake was measured for the radiocarpal and pisiform-triquetral compartments and at sites of bone erosion, synovitis, pannus and edema, compared to unaffected joints (p<0.05) in RA patients, consistent with their clinical findings. In PsA patients significantly elevated (18)F-FDG uptake was measured for joints with synovitis compared to unaffected joints (p<0.05), with patterns of (18)F-FDG uptake along the tendons, at the enthesis and in the nail bed, consistent with tenosynovitis, enthesitis and nail dystrophy, respectively. Conclusions: High-resolution (18)F-FDG PET/CT imaging of the wrist and hand is feasible in an RA or PsA patient cohort and is capable of providing quantifiable measures of disease activity (synovitis, enthesitis, edema and bone destruction). Advances in Knowledge: High-resolution PET/CT imaging shows promise as a tool for understanding the pathogenesis of the arthritic process and for non-invasive, objective assessment of RA or PsA severity and therapy selection.

Prediction of Large Joint Destruction in Patients With Rheumatoid Arthritis Using 18F-FDG PET/CT and Disease Activity Score

Article

Full-text available

Feb 2016
MEDICINE

The assessments of joint damage in patients with rheumatoid arthritis (RA) are mainly restricted to small joints in the hands and feet. However, the development of arthritis in RA patients often involves the large joints, such as the shoulder, elbow, hip, knee, and ankle. Few studies have been reported regarding the degree of large joint destruction in RA patients. ¹⁸F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) visualizes the disease activity in large joints affected by RA. In this study, the associations between destruction of the large joints and the findings of FDG-PET/CT as well as laboratory parameters were investigated, and factors associated with large joint destruction after the administration of biological therapy were identified in RA patients. A total of 264 large joints in 23 RA patients (6 men and 17 women; mean age of 66.9 ± 7.9 years) were assessed in this study. FDG-PET/CT was performed at baseline and 6 months after the initiation of biological therapy. The extent of FDG uptake in large joints (shoulder, elbow, wrist, hip, knee, and ankle) was analyzed using the maximum standardized uptake value (SUVmax). Radiographs of the 12 large joints per patient obtained at baseline and after 2 years were assessed according to Larsen's method. A logistic regression analysis was performed to determine the factors most significantly contributing to the progression of joint destruction within 2 years. Radiographic progression of joint destruction was detected in 33 joints. The SUVmax at baseline and 6 months, and the disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) at 6, 12, and 24 months were significantly higher in the group with progressive joint destruction. The SUVmax at baseline and DAS28-ESR at 6 months were found to be factors associated with joint destruction at 2 years (P < 0.05). The FDG uptake in the joints with destruction was higher than that observed in the joints without destruction. The SUVmax at baseline and the DAS28-ESR at 6 months after the biological treatment were identified to be significant factors predicting destruction of the large joints at 2 years.

Critical role of fibroblast-like synoviocytes glycolytic metabolism in rheumatoid arthritis

Article

Full-text available

Jan 2016

Background: Glucose metabolism up-regulation has been implicated not only in tumor cell growth but also in immune cells on activation. However, little is known about the metabolite profile in rheumatoid arthritis (RA), particularly in fibroblast-like synoviocytes (FLS). We evaluated whether changes in glucose metabolism in RA FLS could play a role in inflammation and joint damage. Methods: Glycolytic rate after LPS and PDGF stimulation was measured by Seahorse technology. FLS function was evaluated using the glycolysis inhibitor 2-Deoxy-D-glucose (2-DG). Migration scratch assay, MTT assay and ELISA measured the effect of 2-DG on migration, viability and cytokine secretion respectively, after FLS stimulation. IRDye® 800CW 2-DG was used to assess glucose uptake in arthritic joints and stroma cells after K/BxN sera injection. 3-bromopyruvate (BrPa; 5mg/kg) was injected daily i.p. to assess the effect of glycolysis inhibition in vivo. Results: Relative to osteoarthritis, the balance between glycolysis and oxidative phosphorylation is shifted towards glycolysis in RA FLS. Glucose transporter 1 (GLUT1) expression correlated with FLS baseline functions. Glucose deprivation or glycolytic inhibitors impaired cytokine secretion, proliferation, and migration. In a mouse model of inflammatory arthritis, we observed GLUT1 expression in the synovial lining cells and an increase of glucose uptake and glycolytic gene expression in the stromal compartment in arthritic joints. Glycolytic inhibition by BrPa administered in vivo significantly decreased arthritis severity. Conclusion: Targeting metabolic pathways offer a novel approach to understanding the mechanisms of disease. Glycolytic inhibition may directly modulate synoviocyte-mediated inflammatory functions and could be an effective treatment strategy for arthritis. This article is protected by copyright. All rights reserved.

Value of 18F-FDG PET/CT for therapeutic assessment of patients with polymyalgia rheumatica receiving tocilizumab as first-line treatment

Article

Full-text available

Apr 2016
EUR J NUCL MED MOL I

Purpose: To evaluate the use of (18)F-FDG PET/CT for the assessment of tocilizumab (TCZ) as first-line treatment in patients with polymyalgia rheumatica (PMR). Methods: Patients with PMR were prospectively enrolled in a multicentre clinical trial assessing TCZ therapy (the TENOR trial). The patients underwent FDG PET/CT at baseline, after the first infusion of TCZ (TCZ 1) and after the last infusion of TCZ (TCZ 3). Responses to treatment were evaluated in terms of the PMR activity score (PMR-AS), and the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) laboratory tests. Maximal standardized uptake value (SUVmax) was used for assessment of FDG uptake in regions usually affected in PMR (spinous processes, hips, shoulders, sternoclavicular region and ischial tuberosities). The Wilcoxon test was applied to evaluate the changes in parameters after the infusions and Spearman's rank correlation test was applied to assess the correlations between SUVmax and PMR-AS, CRP and ESR. Results: Of 21 patients included in the trial, 18 were evaluated. The median bioclinical parameter values decreased after TCZ 1 (PMR-AS from 38.2 to 15.7, CRP from 65.2 to 0.4 mg/l and ESR from 49 to 6.5 mm; all p < 0.05) as did the median SUVmax (from 5.8 to 5.2; p < 0.05). All values also decreased after TCZ 3 (PMR-AS from 38.2 to 3.9, CRP from 65.2 to 0.2, ESR from 49 to 2, and SUVmax from 5.8 to 4.7; p < 0.05). In a region-based analysis, all SUVmax were significantly reduced after TCZ 3, except the values for the cervical spinous processes and shoulder regions. With regard to correlations, few significant differences were found between ∆SUVmax and the other parameters including ∆PMR-AS, ∆CRP and ∆ESR in the patient-based and region-based analysis. Conclusion: FDG uptake decreased significantly but moderately after TCZ therapy in PMR patients, and might reflect disease activity.

Article

Full-text available

Jan 2016

We report the case of a 78-year-old woman with methotrexate-related gastric lymphoproliferative disorder (LPD). The patient had a history of rheumatoid arthritis (RA) and had been treated with methotrexate (MTX). Endoscopic examination revealed round elevated lesions in the stomach, and a biopsy specimen showed atypical lymphoid cell proliferation. Immunohistological study found these atypical cells to be positive for L-26 but not for CD3 or EBER. Therefore, we made a diagnosis of MTX-related LPD showing features of diffuse large B-cell lymphoma. Combined positron emission tomography-computed tomography (PET-CT) using 18F-fluorodeoxyglucose (FDG) showed increased avidity in the stomach in addition to slightly increased FDG-avidity in the mediastinum and left chest wall. We decided not to start chemotherapy but to discontinue administration of MTX, with follow-up using endoscopy and PET-CT. The endoscopic examinations after cessation of MTX demonstrated gradual regression of the elevated lesions. PET-CT 6 months after cessation showed no increased FDG avidity in the stomach. While disease regression was observed in the stomach, the other FDG-avid spots remained unchanged on PET-CT. Therefore, we performed chemotherapy as additional therapy. On PET-CT after chemotherapy, the FDG-avid spots remained unchanged for more than 1 year, and we eventually concluded that they were RA-related inflammatory lesions. In patients with MTX-related LPD, cessation of MTX may be a therapeutic option, but careful follow-up and chemotherapy in accordance with the clinical course are essential.

The diagnostic value of [(18)F]FDG PET for the detection of chronic osteomyelitis and implant-associated infection

Article

Full-text available

Apr 2016
EUR J NUCL MED MOL I

Purpose: The diagnosis of osteomyelitis and implant-associated infections in patients with nonspecific laboratory or radiological findings is often unsatisfactory. We retrospectively evaluated the contributions of [(18)F]FDG PET and [(18)F]FDG PET/CT to the diagnosis of osteomyelitis and implant-associated infections, enabling timely and appropriate decision-making for further therapy options. Methods: [(18)F]FDG PET or PET/CT was performed in 215 patients with suspected osteomyelitis or implant-associated infections between 2000 and 2013. We assessed the diagnostic accuracy of both modalities together and separately with reference to intraoperative microbial findings, with a mean clinical follow-up of 69 ± 49 months. Results: Infections were diagnosed clinically in 101 of the 215 patients. PET and PET/CT scans revealed 87 true-positive, 76 true-negative, 38 false-positive, and 14 false-negative results, indicating a sensitivity of 86 %, a specificity of 67 %, a positive predictive value (PPV) of 70 %, a negative predictive value (NPV) of 84 % and an accuracy of 76 %. The sensitivity of PET/CT was 88 %, but specificity, PPV, NPV and accuracy (76 %, 76 %, 89 % and 82 %, respectively) were higher than those of stand-alone PET. Conclusion: [(18)F]FDG PET is able to identify with high sensitivity the presence of osteomyelitis in orthopaedic surgery patients with nonspecific clinical symptoms of infection.

Various forms of (18)F-FDG PET and PET/CT findings in patients with polymyalgia rheumatica

Article

Full-text available

May 2015

Polymyalgia rheumatica (PMR) is a disease presenting with pain and stiffness, mainly in shoulders, hip joints and neck. Laboratory markers of inflammation may bolster diagnosis. PMR afflicts patients over 50 years old, predominantly women, and may also accompany giant cell arteritis. 67 patients, who fullfiled Healey´s criteria for PMR in the period between 2004 and 2013 and had positive FDG PET (PET/CT) findings were retrospectively evaluated. FDG uptake was assessed in large arteries, proximal joints (shoulders, hips and sternoclavicular joints), in extraarticular synovial structures (interspinous, ischiogluteal and praepubic bursae). Articular/periarticular involvement (A) was detected in 59/67 (88.1%) patients and extrarticular synovial involvement (E) in 51/67 (76.1%) patients either individually or in combinations. Vascular involvement (V) was detected in 27/67 (40.3%) patients only in combination with articular (A) and/or extraarticular synovial (E) involvement. These combinations were: A+E involvement in 30/67 (44.8%) patients, A+V involvement in 8/67 (11.9%) patients, E+V involvement in 6/67 (9%) patients and A+E+V in 13/67 (19.4%) patients. PMR presents by articular/periarticular synovitis, extraarticular synovitis and can be accompanied by giant cell arteritis. All types of involvement have their distinct FDG PET (PET/CT) finding, which can be seen either individually or in any of their 4 combinations. FDG PET (PET/CT) examination seems to be an advantageous one-step examination for detecting different variants of PMR, for assessing extent and severity and also for excluding occult malignancy.

Management of Large-Vessel Vasculitis With FDG-PET: A Systematic Literature Review and Meta-Analysis

Article

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Apr 2015
MEDICINE

We aimed to clarify the role of ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the management of large-vessel vasculitis (LVV), focusing on 3 issues which are as follows: describe and determine the different FDG-PET criteria for the diagnosis of vascular inflammation, the performance of FDG-PET for the diagnosis of large-vessel inflammation in giant cell arteritis (GCA) patients, and the performance of FDG-PET to evaluate the disease inflammatory activity in Takayasu arteritis (TA) patients. MEDLINE, Cochrane Library, and EMBASE database were searched for articles that evaluated the value of FDG-PET in LVV, from January 2000 to December 2013. Inclusion criteria were American College of Rheumatology criteria for GCA or TA, definition PET positivity threshold, and >4 cases included. Sensitivity (Se) and specificity (Sp) of FDG-PET for the diagnosis of large-vessel inflammation were calculated from each included individual study, and then pooled for meta-analysis with a random-effects model. Twenty-one studies (413 patients, 299 controls) were included in the systematic review. FDG-PET showed FDG vascular uptake in 70% (288/413) of patients and 7% (22/299) of controls. Only vascular uptake equal to or higher than the liver uptake was significantly different between GCA/TA patients and controls (P < 0.001). The meta-analysis of GCA patients (4 studies, 57 patients) shows that FDG-PET has high Se and Sp for the diagnosis of large-vessel inflammation in GCA patients in comparison to controls, with a pooled Se at 90% (95% confidence interval [CI], 79%–93%) and a pooled Sp at 98% (95% CI, 94%–99%). The meta-analysis of TA patients (7 studies, 191 patients) shows that FDG-PET has a pooled Se at 87% (95% CI, 78%–93%) and Sp at 73% (95% CI, 63%–81%) for the assessment of disease activity in TA, with up to 84% Sp, with studies using National Institutes of Health criteria as the disease activity assessment scale. FDG-PET showed good performances in the diagnosis of large-vessel inflammation, with higher accuracy in GCA patients than in TA patients. Although a vascular uptake equal to or higher than the liver uptake appears to be a good criterion for the diagnosis of vascular inflammation, further studies are needed to define the threshold of significance as well as the clinical significance of the vascular uptake.

A large-scale survey of patients with relapsing polychondritis in Japan

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Jun 2014

Relapsing polychondritis (RP) is a multisystem disorder characterized by recurrent inflammation and destruction of cartilage. The aim of this study is to assess the clinical characteristics of patients with RP in Japan, which remain unclear.A survey was sent to 395 experienced clinicians who worked in Japanese major institutions. The questionnaire was designed to assess patients’ profiles, clinical features, diagnosis, treatments and present complications. The response rate was 30.6% and 239 RP patient data were collected. The average age of onset diagnosis was 52.7 years (range, 3-97) and the male-to-female ratio was 1.1:1. Clinical features of patients with RP in Japan were similar to previous studies. Airway and cardiac involvement, both of which were potentially serious complications of RP, were observed in 119 (49.8%) and 17 patients (7.1 %), respectively. Four patients (1.7%) had myelodysplasia. In addition to oral prednisolone (91.6%), patients received methotrexate (19.7%), cyclophosphamide (12.6%) and cyclosporine (8.4%) with clinical response rates of 64.0%, 66.7% and 73.7%, respectively. 42 patients (17.6%) required and underwent tracheotomy, including 12 patients (5.0%) who were treated with prednisolone only. 22 patients (9.2%) underwent stent placement and/or tracheotomy. The overall mortality rate was 9.0% (22 patients) and respiratory failure and pulmonary infection were the leading causes of death in patients with RP.Airway involvement of RP was fundamentally progressive and required frequent clinical checks and appropriate intervention with administration of both prednisolone and immunosuppressant. Cardiac involvement of RP was less common in Japan as compared with that in Western countries.

Clinical value of whole-body PET/CT in patients with active rheumatic diseases

Article

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Aug 2014

Advanced imaging techniques may enable early diagnosis and monitoring of therapy in various rheumatic diseases. To prevent irreversible tissue damage, inflammatory rheumatic disease must be diagnosed and treated in pre-clinical stages, requiring highly sensitive detection techniques. Positron emission tomography (PET) provides highly sensitive, quantitative imaging at a molecular level, revealing the important pathophysiological processes underlying inflammation. This review provides an overview of the current utility of 18 F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT) in patients with active rheumatic diseases such as rheumatoid arthritis, spondyloarthritis, polymyalgia rheumatica, adult-onset Still's disease, relapsing polychondritis, immunoglobulin G4-related disease, large-vessel vasculitis, Wegener's granulomatosis, polymyositis, and dermatomyositis. We also discuss the role of FDG-PET/CT in the diagnosis and monitoring of these diseases.

FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0

Article

Full-text available

Dec 2014

The purpose of these guidelines is to assist physicians in recommending, performing, interpreting and reporting the results of FDG PET/CT for oncological imaging of adult patients. PET is a quantitative imaging technique and therefore requires a common quality control (QC)/quality assurance (QA) procedure to maintain the accuracy and precision of quantitation. Repeatability and reproducibility are two essential requirements for any quantitative measurement and/or imaging biomarker. Repeatability relates to the uncertainty in obtaining the same result in the same patient when he or she is examined more than once on the same system. However, imaging biomarkers should also have adequate reproducibility, i.e. the ability to yield the same result in the same patient when that patient would have been examined on different systems and at different imaging sites. Adequate repeatability and reproducibility are essential for the clinical management of patients and the use of FDG PET/CT within multicentre trials. A common standardized imaging procedure will help promote the appropriate use of FDG PET/CT imaging and increase the value of publications and, therefore, their contribution to evidence-based medicine. Moreover, consistency in numerical values between platforms and institutes that acquire the data will potentially enhance the role of semiquantitative and quantitative image interpretation. Precision and accuracy are additionally important as FDG PET/CT is used to evaluate tumour response as well as for diagnosis, prognosis and staging. Therefore both the previous and these new guidelines specifically aim to achieve standardized uptake value harmonization in multicentre settings

Interspinous bursitis is common in polymyalgia rheumatica, but is not associated with spinal pain

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Dec 2014

IntroductionPolymyalgia rheumatica (PMR) is a common inflammatory disease of the elderly characterized by shoulder/pelvic girdle, and cervical and, occasionally, lumbar pain. Interspinous bursitis has been suggested as a potential cause of spinal symptoms. We evaluated, by 18 F-Fluorodeoxyglucose (FDG) positron emission tomography integrated with computed tomography (PET/CT), the vertebral structures involved in PMR in a cohort of consecutive, untreated patients.Methods Sixty-five consecutive patients with PMR were studied. After a standardized physical exam, which included evaluation of pain and tenderness in the vertebral column, they underwent FDG-PET/CT. Sites of increased uptake and their correlation with spontaneous and provoked pain were recorded. For comparison, FDG-PET/CT was performed also in 65 age- and sex-matched controls and in 10 rheumatoid arthritis (RA) patients.ResultsThe most frequent site of spontaneous and provoked pain was the cervical portion. FDG uptake was more frequent in the lumbar portion than at any other locations, and in the cervical than in the thoracic portion (P <0.0001). No correlation was found between uptake and spontaneous or provoked pain. There was an association between presence of cervical and lumbar bursitis (r =0.34, P =0.007). None of the control patients and one out of ten RA patients showed interspinous bursitis.Conclusions Interspinous bursitis is a frequent finding in the lumbar spine of patients with PMR. However, it is not associated with clinical symptoms and can hardly explain the spinal pain reported by the patients. Cervical pain is more frequent than lumbar pain in PMR patients and may be caused by shoulder girdle involvement.

Evaluation of Tocilizumab Therapy in Patients with Rheumatoid Arthritis Based on FDG-PET/CT

Article

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Nov 2014
BMC MUSCULOSKEL DIS

Positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) can detect the presence of synovitis in rheumatoid arthritis (RA) patients. The aim of this study was to investigate whether the findings of FDG-PET matched the conventional assessments of the disease activity score (DAS) 28, DAS28-CRP, simplified disease activity index (SDAI) and clinical disease activity index (CDAI) in RA patients receiving tocilizumab (TCZ) therapy. Seventeen RA patients treated with TCZ were assessed. FDG-PET was performed at baseline and three and six months after the initiation of TCZ therapy. The maximum SUV (SUVmax) of the bilateral shoulder, elbow, wrist, hip, knee and ankle joints were added together (total SUV) and were used to assess the degree of FDG uptake as a representative parameter. The correlations between the DeltaSUV and the difference in the clinical parameters at baseline and at each observation period, and the differences in each clinical parameters, were assessed. The DeltaSUV, the differences in the total SUV at baseline and at three/six months after starting treatment positively correlated with the DeltaDAS28 (r = 0.615 p = 0.009/ r = 0.775 p < 0.001), DeltaDAS28-CRP (r = 0.696, p = 0.002/ r = 0.828, p < 0.001), DeltaSDAI (r = 0.652, p = 0.005/ r = 0.686, p = 0.002) and DeltaCDAI (r = 0.662, p = 0.004/ r = 0.711, p = 0.001) for each period. The total SUV was significantly decreased at three and six months after the initiation of TCZ (p < 0.05). A reduction in the FDG uptake was observed at three and six months after the initiation of TCZ therapy. The disease activity estimated on FDG-PET/CT matched the conventional parameters following the TCZ therapy in RA patients.

Differences in FDG PET/CT between EORA and PMR.

Article

Full-text available

Nov 2014

Objectives. To compare the fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) findings in patients with elderly-onset rheumatoid arthritis (EORA) with those in patients with polymyalgia rheumatica (PMR), two conditions with similar clinical presentations. Methods. We retrospectively analyzed the FDG-PET/CT findings in 10 patients with EORA and 27 patients with PMR admitted to our department between 2006 and 2012. Results: No significant difference was observed in the median patient ages at the time of FDG-PET/CT scans in the EORA and PMR groups (73.5 vs. 78.0 years, respectively). Significant differences in both FDG uptake scores and standardized uptake values were observed between the two groups in the ischial tuberosities, spinous processes, and wrists. No significant differences were detected in the shoulders and hips. However, specific uptake patterns were observed in each group: circular and linear uptake patterns were observed around the humeral head in the EORA group, whereas focal and non-linear uptake patterns were observed in the PMR group. Moreover, focal uptake in front of the hip joint, indicating iliopectineal bursitis, tended to be limited to the PMR group. High sensitivity (92.6%) and specificity (90%) were observed for PMR diagnoses when at least three of the following five items were satisfied: characteristic findings of shoulder and iliopectineal bursitis, FDG uptake in ischial tuberosities and spinal spinous processes, and lack of FDG uptake in the wrists. Conclusion. The differences in the degree of uptake at each lesion and in uptake patterns at the shoulders and hips are potentially useful for obtaining a definitive diagnosis.

Comprehensive disease control (CDC): What does achieving CDC mean for patients with rheumatoid arthritis?

Article

Full-text available

Aug 2014

Background This study assessed the impact of simultaneous achievement of clinical, functional and structural efficacy, herein referred to as comprehensive disease control (CDC), on short-term and long-term work-related outcomes, health-related quality of life (HRQoL), pain and fatigue. Methods Data were pooled from three randomised trials of adalimumab plus methotrexate for treatment of early-stage or late-stage rheumatoid arthritis (RA). CDC was defined as 28-joint Disease Activity Score using C reactive protein <2.6, Health Assessment Questionnaire <0.5 and change from baseline in modified Total Sharp Score ≤0.5. Changes in scores at weeks 26 and 52 for work-related outcomes, Short Form 36 (SF-36) physical (PCS) and mental component scores (MCS), a Visual Analogue Scale measuring pain (VAS-Pain) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were compared between patient groups defined by achievement of CDC at week 26 using linear regression with adjustment for baseline scores. Results Patients with RA who achieved CDC at week 26 (n=200) had significantly greater improvements in VAS-Pain (46.9 vs 26.9; p<0.0001), FACIT-F (13.3 vs 7.5; p<0.0001), SF-36 PCS (19.7 vs 8.9; p<0.0001) and SF-36 MCS (8.1 vs 5.0; p=0.0004) than those who did not (n=1267). Results were consistent at week 52 and among methotrexate-naive patients with early RA, methotrexate-experienced patients with late-stage RA and patients with inadequate response to methotrexate. Conclusions Patients with RA who achieved CDC at week 26 had improved short-term and long-term HRQoL, pain, fatigue and work-related outcomes compared with patients who do not. These results demonstrate that the joint achievement of all CDC components provides meaningful benefits to patients. Trial registration numbers DE019: NCT00195702, PREMIER: NCT00195702, OPTIMA: NCT00195702.

Utility of fluorodeoxyglucose positron emission tomography/computed tomography for early diagnosis and evaluation of disease activity of relapsing polychondritis: A case series and literature review

Article

Full-text available

Mar 2014

Objective: Relapsing polychondritis (RPC) is relatively rare and early diagnosis is difficult. We investigated the utility of fluorodeoxyglucose (FDG)-PET/CT for the diagnosis of RPC and evaluation of disease activity. Methods: Five RPC patients undergoing FDG-PET/CT in our hospital between 2006 and 2012 were studied. Eight RPC cases examined by PET reported in the literature were also assessed. Data from a total of 13 patients were analysed. Results: Typical FDG accumulation was noted in the tracheobronchial trees of nine patients, the costal cartilage of five, joints of five, larynx of four, nasal cavity/paranasal sinuses of three, auricles of three, lymph nodes of three and the aorta of one. One patient showed nasal chondritis on a PET scan despite the absence of nasal changes on physical examination. Of five patients with costochondritis, four remained asymptomatic. Of nine patients with airway FDG accumulation, eight developed respiratory symptoms and all had CT abnormalities. In the other patient, airway FDG accumulation was evident despite the absence of airway symptoms and a lack of abnormalities in the respiratory function test and CT. PET also revealed bronchial chondritis in asymptomatic patients. The mean maximum standardized uptake values (SUVmax) of the upper and lower airways was 5.79 (s.d. 2.87) and 6.47 (s.d. 4.08), respectively. In five patients with a PET after treatment, FDG accumulation had diminished with symptomatic and inflammatory improvement. Conclusion: FDG-PET/CT is a potentially powerful tool for the early diagnosis of RPC, especially in patients without easily biopsied organ involvement. This modality also facilitates evaluation of disease extent and disease activity during treatment.

Large vessel vasculitis in elderly patients: early diagnosis and steroid-response evaluation with FDG-PET/CT and contrast-enhanced CT

Article

Full-text available

Mar 2014
RHEUMATOL INT

Large vessel vasculitis (LVV) is an often-reported cause of inflammation of unknown origin (IUO) in elderly people. The objective of this study was to describe the usefulness of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and contrast-enhanced CT in early diagnosis and treatment follow-up of patients with LVV presenting as elderly onset IUO. We retrospectively compared contrast-enhanced CT findings and FDG-PET/CT findings of the patients diagnosed with LVV and 11 controls; all subjects were 50 years of age or older. We evaluated maximum standardised uptake value (SUVmax) and PET score of the aortic wall for quantitative comparison of FDG-PET/CT findings. We measured the aortic wall thickness (W) and its ratio against the radius (W/R) for quantitative comparison of aortic wall thickening by contrast-enhanced CT. After steroid treatment, we compared these values with those pre-treatment. Of 124 patients who were hospitalised due to advanced age and IUO, 88 underwent FDG-PET/CT and contrast-enhanced CT. Abnormal findings were observed on images from 78 patients. The findings were indicative of LVV in 13 patients (10.5 %), of whom more than half had only non-specific symptoms. Patients with LVV had significantly higher aortic wall SUVmax (3.85 vs. 1.95), PET scores by FDG-PET/CT, and aortic wall thicknesses by contrast-enhanced CT (3.8 vs. 2.6 mm) than controls. Significant improvement in aortic wall thickening was evidenced by reduced PET scores and by contrast-enhanced CT findings in patients who were followed up after treatment. LVV is an important cause of IUO with non-specific symptoms in elderly patients. Imaging examination comprising contrast-enhanced CT and FDG-PET/CT is useful for early diagnosis and early treatment evaluation of LVV, allowing for amelioration of reversible aortic wall thickening.

Clinical value of 18 F-fluoro-dexoxyglucose positron emission tomography/computed tomography in patients with adult-onset Still's disease: A seven-case series and review of the literature

Article

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Nov 2013
Mod Rheumatol

Objectives: While there are a few reports describing 18F-fluoro-dexoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) findings in patients with adult-onset Still's disease (AOSD), no summary report has yet been published. In this study, we evaluated the usefulness of FDG-PET/CT for diagnosis and activity evaluation in patients with AOSD by summarizing the findings of our patients and those reported in the literature. Methods: Seven consecutive AOSD patients who had undergone PET/CT at our department between 2007 and 2012 were included. We evaluated FDG uptake for characteristic findings in patients with AOSD. In addition, we reviewed the literature on seven previously reported AOSD patients who had undergone PET/CT. Results: FDG accumulation was positive mainly in the bone marrow (100%), spleen (90.9%), lymph nodes (80.0%) and joints (75.0%). In addition, FDG uptake was positive in the pericardium, pleura, salivary glands, eyelids, muscle and major blood vessels. Six patients underwent follow-up FDG PET/CT for evaluation of treatment efficacy. Follow-up PET/CT showed diminished FDG accumulation in the bone marrow, spleen and lymph nodes, with maximum standardized uptake value (SUVmax) being substantially reduced from 4.03 ± 0.95 to 2.20 ± 0.75 (p = 0.04), 4.04 ± 1.10 to 2.55 ± 1.13 (p = 0.04) and 5.63 ± 4.99 to 2.10 ± 1.91 (p = 0.11), respectively. No significant correlation was found between SUVmax in each lesion and the laboratory data, except for a significant correlation between lactate dehydrogenase (LDH) and spleen SUV. Conclusions: FDG-PET/CT is useful for long-term assessments of AOSD activity in individual patients. However, PET/CT findings alone are not sufficient to make a differential diagnosis of AOSD versus malignant lymphoma.

Clinical Value of FDG-PET/CT for the Evaluation of Rheumatic Diseases: Rheumatoid Arthritis, Polymyalgia Rheumatica, and Relapsing Polychondritis

Abstract

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