Decoding polymyalgia rheumatica, the role of Nuclear Medicine Imaging.

Polymyalgia rheumatica (PMR) is an inflammatory joint disease that presents in patients older than 50 years with prolonged morning pain and stiffness in the shoulder and hip joints and neck. The lack of specific clinical findings, laboratory signs, biomarkers and established imaging methods makes it difficult to diagnose patients with this disease. 18F-FDG PET/CT is a functional imaging technique that is an established tool in oncology and has also proven useful in the field of inflammatory diseases. The aim of this paper is to present literature evidence on the use of molecular imaging methods such as PET/CT for early diagnosis, assessment of disease activity and therapeutic response in PMR. At the same time, the advantages, disadvantages and contraindications of other methods are considered.

Subclinical giant cell arteritis in new onset polymyalgia rheumatica A systematic review and meta-analysis of individual patient data.

OBJECTIVES: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). METHODS: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). RESULTS: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). CONCLUSION: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed.

Clinical and FDG-PET/CT correlates in patients with polymyalgia rheumatica.

OBJECTIVES: We aimed to evaluate joint and vessel uptake in patients with polymyalgia rheumatica (PMR) by FDG-PET and correlate it with clinical findings. METHODS: Consecutive PMR patients, without clinical signs of giant cell arteritis, underwent a standardised clinical examination and FDG-PET/CT. Controls were consecutive subjects undergoing FDG-PET for the suspicion of neoplasm not confirmed by the examination. Uptake was evaluated by a qualitative visual score, using the liver uptake as reference and by the semi-quantitative mean standardised uptake value (SUV) and target-to-background ratio (TBR) methods. RESULTS: Eighty-four patients and 84 controls (55 women, median age 73 years, range 50-92 years in both groups) were studied. Sixteen patients were taking glucocorticoids (GC). PMR patients showed a higher articular uptake than controls. GC-treated patients showed uptake lower than GC-naïve patients, but still higher than controls. PMR patients showed a higher vascular uptake than controls in all districts except in the carotid arteries, when evaluated by the visual score. Conversely, the semi-quantitative approach yielded no significant differences. Forty-two patients (50%) showed PET evidence of large-vessel vasculitis (LVV), defined as uptake ≥ than that of the liver, and 11.9% showed LVV with vascular uptake higher than that of the liver. The correlation between clinical findings and uptake was scarce. Neither clinical nor laboratory findings could predict the presence of LVV. CONCLUSIONS: Patients with PMR show a typical joint pattern at FDG-PET. There are no clinical or laboratory predictors of LVV. Imaging appears to be the only tool to assess LVV in these patients.

"The added value of 18f-FDG PET/CT in the assessment of onset and steroid resistant polimyalgia rheumatica".

PMR is a common inflammatory rheumatic disease. Although its clinical characteristics are fully recognized, no specific test for its diagnosis has been established to date. Several studies have described a wide variety of diseases that present with polymyalgic symptoms. A 18FDG-PET/CT scan could help to deal with these differential diagnoses. The goal of our study is to describe the findings of the 18FDG-PET/CT scan in a cohort of PMR patients and to detail how the 18FDG-PET/CT scan improves accuracy when diagnosing other underlying conditions. This cross-sectional study enrolled patients with a diagnosis of PMR who underwent to a 18FDG-PET/CT scan to rule out other diagnosis. The 18FDG-PET/CT scan was performed either following clinical criteria at the onset of clinical symptoms or when the patient became PMR steroid resistant. Patients' demographic, clinical and analytical data at the moment of the 18FDG-PET/CT scan were recorded. The final diagnosis was confirmed according to clinical judgement. A total of 103 patients with PMR were included. In 49.51% of patients, the 18FDG-PET/CT scan was ordered to study resistance to steroid therapy. The final diagnoses of patients were PMR in 70.9% patients, large vessel vasculitis in 15.5%, neoplasms 4.8% and another diagnosis in the rest. The 18FDG-PET/CT scan is a very useful technique for the study of Polymyalgia Rheumatica, not only to help in the diagnostic process, but also due to its role in the identification of a variety of PMR-like patrons.

Prognostic impacts of glucocorticoid treatment in patients with polymyalgia rheumatica and giant cell arteritis.

Identifying comorbidities in polymyalgia rheumatica/giant cell arteritis (PMR/GCA) is crucial for patients' outcomes. The present study aimed to evaluate the impact of the inflammatory process and glucocorticoid treatment on aortic arterial stiffness and body composition in PMR/GCA. 77 patients with newly diagnosed PMR/GCA were treated with oral glucocorticoids and followed for 40 weeks. Aortic pulse wave velocity (PWV) was measured at baseline and during the follow-up period and compared to the results of temporal artery biopsy (TAB) and 18F-FDG PET/CT. Body composition was assessed by total body DXA at baseline and the end of the study. Of 77 patients (49 (63.6%) female, mean of age: (71.8 ± 8.0)), 64 (83.1%) had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. Compared to baseline values, aortic PWV was initially decreased at week 16 (p = 0.010) and remained lower than baseline at week 28 (p = 0.002) and week 40 (p < 0.001), with no association with results of TAB and 18F-FDG PET/CT. Aortic PWV was significantly associated with age, male gender, left systolic and diastolic blood pressure, right diastolic blood pressure, and CRP. Total bone mineral content (BMC) was decreased in both genders (p < 0.001), while fat mass (FM) was significantly increased (p < 0.001). However, lean body mass did not significantly change during the study. Changes in FM were correlated with cumulative prednisolone dose (rho: 0.26, p = 0.031). Glucocorticoid treatment of patients with PMR/GCA had several prognostic impacts. Arterial stiffness was decreased due either to the treatment or a reduction in the inflammatory load. Additionally, treatment led to changes in body composition, including a decrease in BMC and FM excess.

Abnormalities at three musculoskeletal sites on whole-body positron emission tomography/computed tomography can diagnose polymyalgia rheumatica with high sensitivity and specificity.

PURPOSE: To evaluate the sensitivity and specificity of PET/CT findings in PMR and generate a diagnostic algorithm utilizing a minimum number of musculoskeletal sites. METHODS: Steroid-naïve patients with newly diagnosed PMR (2012 EULAR/ACR classification criteria) were prospectively recruited to undergo whole-body 18F-FDG PET/CT. Each PMR case was age- and sex-matched to four PET/CT controls. Control scan indication, diagnosis and medical history were extracted from the clinical record. Qualitative and semi-quantitative scoring (maximum standardized uptake value [SUVmax]) of abnormal 18F-FDG uptake at 21 musculoskeletal sites was undertaken for cases and controls. Results informed the development of a novel PET/CT diagnostic algorithm using a classification and regression trees (CART) method. RESULTS: Thirty-three cases met the inclusion criteria and were matched to 132 controls. Mean age was 68.6 ± 7.4 years for cases compared with 68.2 ± 7.3 for controls, and 54.5% were male. Median CRP was 49 mg/L (32-65) and ESR 41.5 mm/h (24.6-64.4) in the PMR group. The predominant control indication for PET/CT was malignancy (63.6%). Individual musculoskeletal sites proved insufficient for diagnostic purposes. A novel algorithm comprising 18F-FDG uptake ≥ 2 adjacent to the ischial tuberosities in combination with either abnormalities at the peri-articular shoulder or interspinous bursa achieved a sensitivity of 90.9% and specificity of 92.4% for diagnosing PMR. CONCLUSIONS: The presence of abnormal 18F-FDG uptake adjacent to the ischial tuberosities together with findings at the peri-articular shoulder or interspinous bursa on whole-body PET/CT is highly sensitive and specific for a diagnosis of PMR. TRIAL REGISTRATION: Clinical Trial Registration: Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au , ACTRN1261400696695.

Muscle involvement on 18F-FDG PET-CT in polymyalgia rheumatica. A controlled retrospective study of 101 patients.

18F-fluoro deoxy glucose PET scanner (18F-FDG-PET-CT) has shown its interest in the diagnosis of polymyalgia rheumatica (PMR) and makes possible to evaluate the metabolic activity of the entire musculoskeletal system and in particular muscular structures. The purpose of this study was to evaluate muscle involvement using 18F-FDG-PET-CT in the case of PMR, compared to a non PMR population. METHODS: This is a monocentric retrospective study of patients with PMR (ACR/EULAR 2012 criteria) who had an 18F-FDG-PET-CT examination. A control group composed of subjects without rheumatological manifestations who had such an examination as part of neoplastic research or follow-up of neoplastic diseases was also evaluated. The PET assessment included 17 sites suggesting a PMR, as previously reported. Areas of muscle hypermetabolism were classified in the same way according to the same semi quantitative classification. Muscle activity sites were identified. A comparison of patients with PMR with and without muscle damage was performed using the exact Mann-Whitney or Fisher test. RESULTS: Two hundred and one cases were examined, involving 101 PMRs (mean age 68.6 years) and 100 controls (mean age 67.7 years). Overall, PET muscle damage was observed in 34 cases (34%) in PMR and 10 cases (10%) in controls (P=0.004). Lesions are bi or multi-focal in half of the cases. The affected muscle sites are: spinal muscles 19, scapular girdle 14, pelvic girdle 13, and thigh 6. Fasciitis was found in 3 cases. In patients with PMR, PET muscle involvement was not associated with age, CRP or overall PMR PET score. CONCLUSION: Muscle damage assessed by 18F-Fluorodeoxyglucose PET-CT is common in PMR (1/3 of cases), located at the usual sites of disease symptoms, without association with age, CRP levels or the overall PET PMR score. The muscle must be carefully evaluated during a PET examination in cases of PMR.

Early large vessel systemic vasculitis in adults.

Giant cell arteritis (GCA) is the most common vasculitis in individuals older than 50 years in Western countries. In addition to the typical pattern of cranial ischemic manifestations, large vessel vasculitis (LVV) involvement has emerged as a common feature of GCA. Patients with predominant LVV manifestations differ from those with the cranial pattern. They are usually affected at a younger age and often have nonspecific manifestations such as constitutional syndrome, fever of unknown origin, or refractory/atypical polymyalgia rheumatica (PMR). In these patients, cranial manifestations are often absent. Furthermore, patients with isolated PMR should be followed up because of the potential risk of severe vascular complications in the setting of an underlying GCA. Whereas temporal artery biopsy and/or color duplex ultrasound of the temporal arteries is useful for the diagnosis of cranial GCA, Doppler sonography of the subclavian and axillary arteries, fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography, magnetic resonance, and computed tomography-angiography are very useful to identify the presence of LVV, and they may play a potential role in the follow-up of these patients.

Giant cell arteritis: is the clinical spectrum of the disease changing?

BACKGROUND: Giant cell arteritis is a vasculitis of large and middle-sized arteries that affects patients aged over 50 years. It can show a typical clinical picture consisting of cranial manifestations but sometimes nonspecific symptoms and large-vessel involvement prevail. Prompt diagnosis and treatment is essential to avoid irreversible damage. DISCUSSION: There has been an increasing knowledge on the occurrence of the disease without the typical cranial symptoms and its close relationship and overlap with polymyalgia rheumatica, and this may contribute to reduce the number of underdiagnosed patients. Although temporal artery biopsy is still the gold-standard and temporal artery ultrasonography is being widely used, newer imaging techniques (FDG-PET/TAC, MRI, CT) can be of valuable help to identify giant cell arteritis, in particular in those cases with a predominance of extracranial large-vessel manifestations. CONCLUSIONS: Giant cell arteritis is a more heterogeneous condition than previously thought. Awareness of all the potential clinical manifestations and judicious use of diagnostic tests may be an aid to avoid delayed detection and consequently ominous complications.

Paraneoplastic Syndrome Presenting with Polymyalgia Rheumatica-like Accumulations on 18F-fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography.

A 70-year-old woman presented with a fever and pain in both lower extremities and the right shoulder and right upper arm continuously for approximately 3 months. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG/PET-CT) revealed the accumulation of FDG in the right shoulder, lumbar spinous processes, both ischial tuberosities, and both hips and greater trochanters, indicating polymyalgia rheumatica (PMR). In addition, upper gastrointestinal endoscopy revealed esophageal carcinoma. After endoscopic submucosal dissection was performed, her musculoskeletal symptoms spontaneously improved, and the 18F-FDG/PET-CT findings decreased. In light of these findings, she was diagnosed with paraneoplastic syndrome. When atypical features of PMR, such as asymmetric symptoms occur, we should search for malignancies.

FDG-PET/CT(A) imaging in large vessel vasculitis and polymyalgia rheumatica: joint procedural recommendation of the EANM, SNMMI, and the PET Interest Group (PIG), and endorsed by the ASNC.

Large vessel vasculitis (LVV) is defined as a disease mainly affecting the large arteries, with two major variants, Takayasu arteritis (TA) and giant cell arteritis (GCA). GCA often coexists with polymyalgia rheumatica (PMR) in the same patient, since both belong to the same disease spectrum. FDG-PET/CT is a functional imaging technique which is an established tool in oncology, and has also demonstrated a role in the field of inflammatory diseases. Functional FDG-PET combined with anatomical CT angiography, FDG-PET/CT(A), may be of synergistic value for optimal diagnosis, monitoring of disease activity, and evaluating damage progression in LVV. There are currently no guidelines regarding PET imaging acquisition for LVV and PMR, even though standardization is of the utmost importance in order to facilitate clinical studies and for daily clinical practice. This work constitutes a joint procedural recommendation on FDG-PET/CT(A) imaging in large vessel vasculitis (LVV) and PMR from the Cardiovascular and Inflammation & Infection Committees of the European Association of Nuclear Medicine (EANM), the Cardiovascular Council of the Society of Nuclear Medicine and Molecular Imaging (SNMMI), and the PET Interest Group (PIG), and endorsed by the American Society of Nuclear Cardiology (ASNC). The aim of this joint paper is to provide recommendations and statements, based on the available evidence in the literature and consensus of experts in the field, for patient preparation, and FDG-PET/CT(A) acquisition and interpretation for the diagnosis and follow-up of patients with suspected or diagnosed LVV and/or PMR. This position paper aims to set an internationally accepted standard for FDG-PET/CT(A) imaging and reporting of LVV and PMR.

[Positron emission tomography/computed tomography in rheumatology]. / Positronenemissionstomographie/Computertomographie in der Rheumatologie.

Combined positron emission tomography/computed tomography (PET/CT) is a whole-body imaging procedure, which enables sensitive detection of inflammatory changes. It may be used to simultaneously obtain both precise anatomical and molecular information in order to comprehensively characterize diseases. The glucose analogue 18F-fluorodeoxyglucose (FDG) represents a universally applicable radiotracer for imaging of inflammatory processes. Its accumulation in tissues can be semiquantitatively characterized by use of standardized uptake values (SUV). In principle, a broad spectrum of infectious and non-infectious inflammatory and malignant diseases can be imaged. 18F-FDG PET/CT has become a valuable modality and is increasingly being used for evaluation of large vessel vasculitis and for evaluation of elevated systemic inflammatory markers without known cause. Beside the radiotracer 18F-FDG, other radiopharmaceuticals enable a non-invasive analysis of additional parameters of inflammatory disorders, such as other metabolic pathways or the expression of surface receptors.

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

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.

Circulating microparticles bearing Fibrin associated with whole-body 18FDG-PET: diagnostic tools to detect paraneoplastic polymyalgia rheumatica.

Polymyalgia rheumatica (PMR), a chronic inflammatory rheumatism, can be the expression of a paraneoplastic syndrome. The same clinical symptoms are frequently observed at the early stage of the benign and malignant forms. Here, our aim was to develop diagnostic tools to differentiate paraneoplastic PMR from essential PMR. We combined an 18FDG-PET and detection of circulating procoagulant microparticles (MPs), such as fibrin positive (FibMPs), by flow cytometry. Two patients with PMR and a similar profile were selected. In the two patients, the 18FDG-PET revealed a hypermetabolic focus. However, the concentrations of fibrin+/annexin+ microparticles detected were (10 times higher in one of the two patients, who was later found to have breast cancer. The association of 18FDG-PET and the detection of microparticle fibrin positives by flow cytometry allows separating essential PMR (hypermetabolism by 18FDG-PET, low FibMPs) from paraneoplastic PMR.

Utility of 18F-fluoro-dexoxyglucose positron emission tomography for the diagnosis of polymyalgia rheumatica: a controlled study.

OBJECTIVES: To compare (18)F-fluoro-dexoxyglucose PET/CT (FDG-PET/CT) findings in patients with polymyalgia rheumatica (PMR) and controls without rheumatologic disease. METHODS: We retrospectively included 50 patients with a diagnosis of PMR as well as 53 patients with a neoplasm as a control group. All patients underwent FDG-PET/CT. Seventeen hotspots were analysed. We performed a semi-quantitative analysis of FDG uptake (4-point score from 0 to 3). The cut-offs for the number of sites with high activity and for FDG uptake score were assessed using receiver operating characteristics curves and odds ratios (ORs). RESULTS: The two groups were comparable for the median patient age (69.3 years for PMR vs 68.1 for controls). Significant differences between the two groups were found for FDG uptake score (1.12 vs 0.34, P < 0.00001) and for the number of sites with significant uptake (score ⩾ 2): 6.36 sites vs 1.49 sites (P < 0.00001). The presence of three or more sites with significant uptake was correlated with the diagnosis of PMR with 74% sensitivity and 79% specificity (OR = 10.8). For the FDG uptake score, the cut-off was 0.53 (sensitivity 80%, specificity 77%, OR = 13.6). We found significant differences in all sites for FDG uptake score and the number of sites with significant uptake, particularly marked for shoulders, ischial tuberosities and interspinous bursitis (P < 0.00001 for FDG uptake score). CONCLUSION: Our results suggest that the number of sites with significant FDG uptake and the uptake score could be relevant criteria for the diagnosis of PMR.

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

AIM: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.