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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 97-102

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


1 Department of Rheumatology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
2 Department of Community Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
3 Department of Nuclear Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India

Date of Submission24-Jun-2020
Date of Acceptance02-Feb-2021
Date of Web Publication17-Jul-2021

Correspondence Address:
Ranadheer Mantri
Associate Professor, Department of Nuclear Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati - 517 507, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCSR.JCSR_56_20

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  Abstract 


Background: Several studies with 18fluorodeoxyglucose positron emission tomography with computed tomography (18FDG 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 18FDG 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, 18FDG 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, 18FDG PET-CT had 100 sensitivity and NPV. The diagnostic accuracy was 56.52%.
Conclusions: The 18FDG 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.

Keywords: Diagnostic utility, fibromyalgia, 18fluorodeoxyglucose positron emission tomography with computed tomography, rheumatoid arthritis, Takayasu arteritis


How to cite this article:
Kommireddy S, Mantri R, Reddy SA, Ravisankar D, Kalawat T. Clinical utility of 18fluorodeoxyglucose positron emission tomography-computed tomography in rheumatology. J Clin Sci Res 2021;10:97-102

How to cite this URL:
Kommireddy S, Mantri R, Reddy SA, Ravisankar D, Kalawat T. Clinical utility of 18fluorodeoxyglucose positron emission tomography-computed tomography in rheumatology. J Clin Sci Res [serial online] 2021 [cited 2021 Aug 3];10:97-102. Available from: https://www.jcsr.co.in/text.asp?2021/10/2/97/321700




  Introduction Top


18Fluorodeoxyglucose positron emission tomography with computerised tomography (18FDG PET-CT) is an imaging modality that targets the glucose uptake of infiltrating granulocytes and tissue macrophages inflammatory conditions. Currently, 18FDG PET-CT is used widely in diagnosis, staging, and monitoring of therapy in oncology. When 18FDG PET-CT is done under hypoinsulinemic euglycaemic status, the tracer localises in cells expressing insulin-independent glucose transporters such as tumours, fibroblasts and macrophages apart from the brain and brown fat.

Recently, several studies have indicated that 18FDG uptake in affected tissues reflects the disease activity.[1] In the collagen-induced arthritis model, 18F FDG uptake correlated well with pannus formation.[2] Among the inflammatory cells in pannus, fibroblasts and macrophages activated by inflammatory cytokines and hypoxia contributed to 18FDG uptake. Thus, 18FDG PET-CT helps in assessing disease activity.[2] Furthermore, the utility of 18FDG PET-CT for the early detection, extent and monitoring of the response to treatment has been reported.[3]

Imaging modalities such as ultrasonography and magnetic resonance imaging have good sensitivity in early diagnosis and monitoring of disease activity when compared to conventional radiography. Molecular imaging techniques such as Technetium 99m-methyl diphosphonate (99mTc MDP) single-photon emission computed tomography (SPECT) and 18FDG PET-CT are also useful in the evaluation of inflammation in rheumatic diseases. They carry the advantage of high sensitivity and imaging the whole body at a time. The 18FDG PET-CT, when compared to 99mTc MDP SPECT, has higher spatial resolution and standardised uptake value helps in the serial monitoring of the disease activity.[4],[5]

In the present study, we aimed to evaluate the potential role of 18FDG PET-CT in general rheumatology practice as an ancillary tool to establish the diagnosis and to assess the disease activity.


  Material and Methods Top


This is a retrospective analytical study carried out from March 2016 to December 2018 at our tertiary care teaching hospital in Tirupati, India. All 18FDG PET/CTs requested by rheumatologists were reviewed retrospectively for demographic details, indication, inflammatory markers, immunological investigations such as rheumatoid factor, anti-cyclic citrullinated peptide, anti-nuclear antibodies and other relevant findings. Based on clinical details, scan findings, and follow-up, definitions for analysis such as true positive, false positive, true negative and false negative were made as follows. True positive-18FDG PET-CT abnormality directly contributing to the diagnosis, false positive-18FDG PET-CT abnormality not contributing to the diagnosis, true negative-normal 18FDG PET-CT and no inflammatory disease detected on follow up, false negative-normal 18FDG PET-CT but disease identified at 6 months. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. A final diagnosis was made by physician assessment, other investigations, and tissue biopsy when indicated. All patients were followed up for 6 months.

Statistical analysis

Descriptive statistics for the categorical variables were performed by computing the frequencies (percentages) in each category. For the quantitative variables, the approximate normality of distribution was assessed. The variables following normal distribution were summarised by mean ± standard deviation; the remaining variables were summarised as median (interquartile range [IQR]). The sensitivity, specificity, PPV and NPV were calculated.


  Results Top


From March 2016 to December 2018, 18FDG PET-CT was done in 48 cases. Two cases were excluded as they lost to follow-up. Their mean age was 39.2 ± 15.3 years. There were 39 females (84.8%). The median erythrocyte sedimentation rate (ESR in mm 1st h) was 38 (IQR 130 − 3 = 127) (available for 45 cases). Main indications for 18FDG PET-CT include unexplained polyarthralgia/myalgias (n = 19), pyrexia of unknown origin (PUO) (n = 6), suspected large vessel vasculitis (n = 2), panniculitis (n = 2), suspected spondyloarthropathy (n = 1), myositis (n = 1) and for assessment of disease activity or extent (n = 15). We used 18FDG PET-CT in polyarthralgia/myalgia, PUO, suspected large vessel vasculitis, panniculitis, suspected spondyloarthropathy (SPA) and myositis for the diagnosis of disease.

Among 19 indications for polyarthralgia/myalgias, 13 had a final diagnosis of fibromyalgia. Others had rheumatoid arthritis (RA) (n = 2), osteoarthritis (OA) (n = 2, in one it was associated with fibromyalgia), degenerative tendoachilis enthesitis (n = 1) and granulomatous chelitis (n = 1).

Among six indications of PUO, 5 had PUO in a known case of rheumatological disorders (systemic lupus erythematosus [SLE] =3, RA = 1 and juvenile idiopathic arthritis [JIA] = 1). The final diagnosis turned out to be fever due to active SLE = 2, SLE with probable tuberculosis, fever due to active RA and JIA (one case each). The characteristics of all PUO cases are enlisted in [Table 1]. One was a fresh patient with PUO in whom the diagnosis of Takayasu arteritis was established.
Table 1: Characteristics of patients with PUO

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When 18FDG PET-CT was utilised for the diagnosis of the disease (n = 31), it contributed to diagnosis in 9/31 (29%) cases (RA = 3, active SLE = 2, Koch's = 2, SPA = 1 and Takayasu arteritis = 1). There were six true negatives and all of them had a pre-test diagnosis of fibromyalgia, and it remained the same after 18F FDG PET/CT. The sensitivity in this setting was 100% and specificity 27.3%.

The 18FDG PET-CT was carried out to assess disease activity in 15 cases. The underlying rheumatic diseases in these cases were Takayasu arteritis (n = 5), RA (n = 5), SPA (n = 2), JIA (n = 1), dermatomyositis (n = 1) and sarcoidosis (n = 1). The 18FDG PET-CT identified abnormalities in 14 (93.3%) cases. An increase in disease activity/extent was noted in 10 cases. A new diagnosis of fibromyalgia was established in 1 case of seronegative RA. One case of Takayasu arteritis with non-specific symptoms had a normal scan (true negative). One case of JIA on diclofenac, disease-modifying anti-rheumatic drugs (DMARDs) methotrexate 20 mg and sulphasalazine 3g, with a clinical suspicion of fibromyalgia, 18FDG PET-CT was requested before starting biological DMARDs to look for disease activity, showed mild arthritis involvement at the right shoulder, bilateral sacroiliac joints, bilateral knee, right ankle and right tendoachilis enthesitis. His final diagnosis was fibromyalgia without active JIA at 6 months and was considered false positive.

Seventeen cases of fibromyalgia were diagnosed finally. Out of 17 cases, 15 had had exclusively fibromyalgia (one had associated active RA and one had OA). Among 17, 12 had a pre-test diagnosis of fibromyalgia (others JIA-1, RA-3 and RA/SPA-1).

The 18FDG PET-CT identified abnormalities in 39/46 (84.7%) cases. It contributed to diagnosis in 19 cases, i.e., true positives (RA = 6; Takayasu arteritis = 5; SPA, erythema nodosum-TB 2 patients each, SPA with TB of ankle, SLE with myositis 1, SLE with probable TB, Sarcoidosis 1 patient each). Non-specific abnormalities were identified in 20 cases (false positives = 20). Normal scans were identified in seven cases (true negatives). There were no false negatives in this study. It has 100% sensitivity and NPV. The diagnostic accuracy of 18FDG PET-CT was 56.5%. Diagnostic utility of 18FDG PET-CT is summarized in [Table 2].
Table 2: Diagnostic test evaluation

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  Discussion Top


The role of 18FDG PET-CT in rheumatology has been increased recently due to the complexity and diversity of rheumatic diseases. Apart from its role in the evaluation of PUO and ruling out malignancy, 18FDG PET-CT helps in assessing disease activity.[6]

Nuclear imaging techniques such as triple-phase bone scintigraphy, 18FDG PET-CT offer the advantage of evaluating multiple joints at a time. So far, there are no studies that have compared triple-phase bone scintigraphy with 18FDG PET-CT in the evaluation of arthritis.[1]

In RA, 18FDG PET-CT helps assess disease activity, monitor response to DMARDs or biological drugs, and in predicting disease progression. It can also be useful in identifying extra-articular manifestations such as atlantoaxial subluxation/dislocation, lymphadenopathy, subcutaneous nodules and subclinical vasculitis.[1] We had seven cases with RA, of which 18FDG PET-CT was used to assess disease activity in 4. One case with established RA, presented with active inflammatory polyarthritis along with fever. Before prescribing biologic drugs, 18FDG PET-CT was requested to rule out infection. The 18FDG PET-CT [Figure 1] ruled out any coexisting infection and confirmed fever due to active arthritis. He is doing well with biologic drugs. The other two cases presented with polyarthralgia/myalgia and diagnosed to have RA.
Figure 1: 18FDG PET-CT in a 60-year-old male with rheumatoid arthritis presented with pyrexia of unknown origin and inflammatory polyarthritis. MIP of hand (a) and lower limbs (b) showed intensely increased fluorodeoxyglucose concentration in multiple small joints of both hands, wrists, knee, ankle and multiple small joints of the foot. Images (c) and (d) are sagittally fused 18FDG PET-CT images of the left knee and left ankle showing intensely increased fluorodeoxyglucose concentration in the knee and ankle (arrows) 18FDG PET-CT = 18Fluorodeoxyglucose positron emission tomography computed tomography; MIP = Maximum intensity projection

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In SPA, 18FDG PET-CT can serve as an alternating modality in the early diagnosis by detecting enthesitis, sacroiliitis and arthritis.[7],[8] We had two cases with SPA in which it was used for assessing disease activity. There were two cases of JIA (subtype enthesitis-related arthritis). In one case, we used to assess disease activity versus associated fibromyalgia, and in another case, we used to rule out infection.

The 18FDG PET-CT can be a single-step investigation for the diagnosis, evaluation of extent or severity in polymyalgia rheumatica (PMR) or large vessel vasculitis.[9] PMR is often diagnosed by pelvic and shoulder girdle pain, constitutional symptoms, elevated ESR, C-reactive protein (CRP), and exclusion of other diseases such as elderly onset RA, fibromyalgia and paraneoplastic syndrome.[10] The 18FDG PET-CT helps in identifying articular involvement, extra-articular synovial involvement and associated large vessel vasculitis and in assessing response to treatment. It also helps in excluding occult malignancy.[9]

We had six cases with Takayasu's arteritis. Five of them were true positives and one true negative. One young female aged 16 years presented with PUO with non-specific myalgias and pain abdomen. The 18FDG PET-CT [Figure 2] confirmed the diagnosis of Takayasu's arteritis. Thus, in large vessel vasculitis, 18FDG PET-CT can be helpful in early diagnosis, assessing disease activity and the extent and it correlated well with inflammatory markers.[11] The role of 18FDG PET-CT in medium and small-vessel vasculitis is limited due to the limited spatial resolution of 18FDG PET-CT .
Figure 2: 18FDG PET-CT in a 16-year-old female, presented with pyrexia of unknown origin without any localising symptoms or signs. MIP image (a), axial section (b) and sagittal section image (c) fused 18FDG PET-CT showing diffusely increased fluorodeoxyglucose concentration in the ascending and descending aorta, associated with wall thickening (arrows), sugggestive of Takayasu arteritis 18FDG PET-CT = 18Fluorodeoxyglucose positron emission tomography computed tomography; MIP = Maximum intensity projection

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The role of 18FDG PET-CT in inflammatory myositis is limited due to lower sensitivity in detecting myositis. It can be used as a screening tool for malignancy-associated myositis. A study[12] evaluated the role of 18FDG PET-CT in identifying myositis or extramuscular manifestations in 24 patients of active inflammatory myositis (11 polymyositis and 13 dermatomyositis) and compared with 69 patients with a lung mass and without muscle disease. FDG uptake in muscles was noted in eight patients (33%). Lung uptake was identified in 7 out of 18 patients with interstitial lung disease. Lung uptake was noted in one patient of dermatomyositis with malignancy. This study[12] has concluded that 18FDG PET-CT has low sensitivity (33%) for myositis. However, it has high specificity (97%).[12] We had two cases of myositis. One was diagnosed as mitochondrial myopathy (based on muscle biopsy), and the other case was inactive dermatomyositis. Both of them had non-specific abnormalities.

Fibromyalgia is a syndrome characterised by chronic widespread pain and is often classified under central sensitivity syndromes. Most of the studies have been concentrated on neuroinflammation.[13],[14] Fibromyalgia can be primary with a prevalence of 2%–7% or secondary. Its prevalence in several rheumatic diseases varies from 11% to 30%. Recognition of primary or secondary fibromyalgia is important as it interferes with various symptoms, disease activity, and management of rheumatic diseases. Rheumatic diseases when associated with fibromyalgia, are associated with increased disease activity.[15],[16] In such a diagnostic dilemma, 18FDG PET-CT may be helpful by avoiding unnecessary medications such as steroids, DMARDs and biologics.

In our study, 17 cases had a final diagnosis of fibromyalgia. In 2 RA cases who received biologics, 18F FDG PET/CT when done due to persistence of symptoms, did not reveal active arthritis. In 2 of the cases who were being treated as RA with DMARDs, 18FDG PET-CT helped in changing the management as there was no arthritis. In one of the JIA, 18FDG PET-CT prevented us in the unnecessary prescription of biologicals.

To our knowledge, whole body 18FDG PET-CT, for the diagnosis of fibromyalgia has not been studied. In our study, 14 cases had a pre-test diagnosis of fibromyalgia. Ten cases remained as fibromyalgia. Two cases were RA. The remaining two cases had associated fibromyalgia with OA and RA. Hence, we would like to emphasise that fibromyalgia is a clinical diagnosis.

The diagnostic utility of whole body 18FDG PET-CT in inflammatory diseases that includes connective tissue diseases is evaluated in the following studies. In a retrospective study from the Netherlands, the diagnostic accuracy of PET-CT in 498 patients with PUO and inflammation of unknown origin (IUO) was 89%. The diagnosis was obtained in 331 patients. It had 89% sensitivity, 89% specificity, 94% PPV and 80% NPV. In this study when compared to elevated ESR, elevated CRP predicted true positive outcomes for PET-CT. PUO was defined as prolonged fever higher than 38.3 °C diagnosis with no diagnosis after appropriate inpatient or outpatient evaluation. IUO was defined as prolonged and perplexing inflammation– that is, either a CRP higher than 20 mg/L or an ESR more than 20 mm at the end of 1st hour, body temperatures <38.3 °C (100.9° F) on multiple occasions and without a diagnosis after a variety of conventional diagnostic procedures.[17]

In a prospective study (n = 240) to test the diagnostic utility of whole body 18FDG PET-CT in patients with PUO or IUO, final diagnosis was obtained in 192 (79.2%). The most prevalent cause of PUO was adult-onset Still's disease (15.3%). The common cause of IUO was a large vessel vasculitis (21.1%) followed by PMR (18.3%). In PUO group, immunoglobulin G4 (IgG4)-related disease (15.4%) was the most prevalent diagnosis. This study had 65% diagnostic accuracy, 91.1% sensitivity, 21.7% specificity, 65.4% PPV and 62.5% NPV. The clinical predictors helpful for 18FDG PET-CT are higher age (age >50 years), elevated CRP >30 mg/dL and absence of fever.[18]

The current study has included only connective tissue diseases. In our study, 18FDG PET-CT specificity and PPV were low as there were high numbers of false positives (43%). According to our definition of false positives, though there is tracer uptake on 18FDG PET-CT apart from physiological uptake, if it did not contribute to the final diagnosis, they were considered as false positives. The majority of the false positives (n = 10) had a final diagnosis of fibromyalgia.

This is a retrospective study, and the main limitation of the study is the small sample size. The 18FDG PET-CT has high sensitivity but low specificity in rheumatology practice in establishing the diagnosis as well as to detect the extent and activity of the disease. Currently, 18FDG PET-CT in rheumatology is utilised for assessment of disease activity, ruling out malignancy and PUO evaluation in already established connective tissue diseases. This study re-emphasises that the diagnosis of fibromyalgia is largely based on patient-reported indices and there is no laboratory biomarker or imaging technology for the diagnosis. The 18FDG PET-CT gives objective analysis and seems useful in rheumatologic diseases with concomitant fibromyalgia in assessing disease activity as most of the disease activity measures depend on patient reports.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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