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FDG PET imaging of extremities in rheumatoid arthritis.

INTRODUCTION

Rheumatoid arthritis (RA) is a symmetric polyarticular chronic inflammatory arthritis. Patients affected with this disease suffer from major disability. Early and aggressive treatment has been shown to prevent structural damages. In a study by Brown et al., it was shown that subclinical joint inflammation detected by imaging techniques explains the structural deterioration in RA patients who are in clinical remission and are receiving conventional therapy. (1) Magnetic resonance imaging (MRI), ultrasonography (USG), and computed tomography (CT) are methods that provide morphologic information about bone structure and soft tissue abnormalities with superior sensitivity and spatial resolution in comparison to conventional radiography but are limited by lack of specificity regarding disease activity and severity of inflammation. It is difficult to evaluate all joints by ultrasound in one clinic visit as it is time consuming and the method is not standardized. MRI is an expensive tool and is used for evaluation of specific joints only. Molecular Imaging and specifically positron emission tomography (PET) imaging are functional imaging modalities that can non-invasively assess the metabolic changes in joint inflammation before any structural damage. It can evaluate multiple joints at one visit and provides objective assessment of inflammation and response to therapy. (3)

FDG PET has been well established for the staging, diagnosis, and evaluation of therapy for different types of cancer. It not only accumulates in malignant tissues but also at sites of infection and inflammation. After entering the cell, FDG is phosphorylated to FDG-6-phosphate by the enzyme hexokinase. Consequently FDG-6-phosphate cannot be further metabolized or diffuse back in to extracellular space and remains trapped within the cell. Cells with up regulated GLUT (glucose transport) receptors for example cancer cells or inflammatory cells show increased uptake of glucose and this accumulated FDG in the form of FDG-6-phosphate gets trapped inside the cells is detected by specialized PET scanners. Palmer et al. published that FDG uptake in synovial tissue correlates with metabolic activity in the joint. (3) This helps to identify the precise location of synovitis and the therapeutic target. Matsui et al. reported that FDG accumulation reflects the characteristic changes of pathological progression, such as pannus formation and bone destruction. The primary objective of this study was to assess the degree of joint inflammation in patients with RA and objectively assess the response to therapy by evaluating the changes in the degree of FDG uptake in affected joints.

MATERIAL AND METHODS

Eight subjects were enrolled in this IRB approved prospective study. Five subjects completed imaging sessions at baseline and at follow up in six months after initiation of therapy. Age of the subjects ranged from 27-59 years. All subjects were female and were diagnosed with RA according to the 1987 American College of Rheumatology criteria. All subjects underwent clinical, laboratory and radiographic evaluation at the initial visit by a rheumatologist. Assessment of inflammatory activity was made by calculation of the disease activity score using DAS3v calculator. Our calculator used ESR as one of the parameters. All subjects tested positive for cyclic citrullinated peptide antibody. 60% of the subjects had observable erosions in their baseline hand radiographs. Subjects underwent baseline FDG PET scan of their hands and feet within 2-3 days of diagnosis, before initiation of therapy. Standard FDG PET Imaging techniques were used including overnight fast prior to the FDG PET imaging, blood glucose level below 200 mg/dL prior to injection of FDG, and 60 minute uptake period after the intravenous administration of approximately 15 mCi (555 MBq) of FDG. The PET-only images were acquired on an Advance scanner (GE Healthcare) operating in 2-dimensional mode with five min per bed position. After initiation of therapy, six months later, imaging session used the same imaging protocol along with clinical assessment of the joints and a calculation of the subject's disease activity score (DAS).

Treatment was not standardized and included methotrexate, anti-tumor necrosis factor (anti-TNF) agent Adalimumab (Humira), non-steroidal anti-inflammatory agents (NSAIDs) and prednisone. Humira was used in two patients as they had severe erosive and aggressive disease and were not responding to methotrexate adequately. The uptake of FDG in involved joints was assessed qualitatively (visual evaluation) by a board-certified nuclear medicine physician as well as semi-quantitatively by calculating the standardized uptake value (SUV) in manual regions of interest (ROIs) placed by the Nuclear Medicine Physician.

PET PARAMETERS

Various parameters related to the uptake of FDG in affected joints were independently assessed for each patient. A dedicated PET workstation ADW, version 4.3; GE Healthcare was utilized for this purpose. This was performed for three zones in each extremity (proximal, mid, and distal) and the highest [SUV.sub.max] value amongst all lesions in a patient was selected for analysis. In addition, a metabolic disease burden (MDB) for each extremity was calculated. MDBmax was defined as the highest MDB value in any single extremity for a patient and was used for analysis. Subsequently, for each patient, a total metabolic disease burden (Total MBD) for all four extremities was also calculated by adding all the MDBs of all four extremities. The SUV , MDB , Total MDB, were separately correlated with DAS and ESR values at baseline and after six months of standard therapy. ESR was used as the inflammatory marker for correlation instead of CRP as ESR was already done for calculation of the DAS3v score.

RESULTS

In the five subjects who completed both imaging sessions, increased FDG uptake was noted in various joints affected by RA. Treatment induced reduction of FDG uptake was also found in certain joints. The intensity of uptake varied from mild to intense ([SUV.sub.max] ranging from 3.10-6.0). The following Figure Legend describes the visual evaluation of some of the PET images and its correlation with DAS and ESR.

STATISTICAL ANALYSIS

Spearman rank correlation coefficient (a non-parametric method) was used to assess the degree of correlation between DAS, ESR, and the different PET parameters. At baseline (pretreatment), no significant correlations were observed (p>0.05) between DAS, ESR, and the different PET parameters despite large calculated positive correlation coefficients. This was due to the small sample size (n = 5).

At post-treatment, the significant correlations are those between DAS and MDB max (RS = 0.9, p = 0.04) and between ESR and MDB max (RS = 0.9, p = 0.04). The higher the values of DAS and ESR, the larger the MDB max. The positive correlations between Total MDB and DAS (RS = 0.7) and between Total MDB and ESR are also large (RS = 0.7) but not significant. The non-significance is due to the small sample size (n = 5).

DISCUSSION

In our small pilot study, we showed that it is feasible to use FDG PET in the management of RA. The purpose of the study was evaluation of joint synovitis to facilitate assessment of response to therapy. On visual evaluation, FDG PET imaging showed varying degrees of response in different joints in the same subject. Subject 1 (Figure 1) showed correlation between [SUV.sub.max] scores of hands and feet on PET imaging and clinically as judged by DAS. Subject 2 (Figure 2) showed worsening in the [SUV.sub.max] scores of hands and feet after six months of therapy while DAS score was stable. Subject 3 showed decrease in the SUV scores of the hands but did not show any decrease in the SUV scores of the feet (Table 1 & 2) while DAS score improved. Overall the images did not correlate well with DAS and ESR in subjects 2 &3. This could be because of subclinical synovitis in joints that were difficult to evaluate clinically (for eg: mid foot joints) but were visualized by PET imaging. Subject 6 showed no change in the SUV score of the hands and worsening in the feet while DAS score was stable and subject 7 showed worsening in the [SUV.sub.max] scores of both hands and feet after six months of therapy while DAS score improved. Subject 6 had been out of methotrexate for two months and subject 7 had been on suboptimal therapy with methotrexate 10 mg po weekly and NSAIDs. PET imaging was able to pick up ongoing inflammation in these clinically difficult to evaluate joints. Thus, the current assessment of RA disease activity through physical examinations remains an essential tool, but is clearly subjective. Ultrasound is an effective and accessible tool to evaluate multiple joints but is user dependent. The method is not standardized secondary to intraobserver and interobserver variability. MRI is expensive and is used for evaluation of specific joints only. Meanwhile PET imaging can assess multiple joints in one visit and provides objective measures of synovial inflammation like standard uptake value, and metabolic disease burden for assessment of RA.

Our study showed that the degree of inflammation can be objectively assessed using the PET parameters that has been well established in FDG-PET imaging. Objective evaluation of FDG uptake in oncology has been well validated. Generally, parameters like SUV or SUL (SUV calculated on the basis of lean body mass instead of body weight) have been utilized for such purposes. Metabolic disease burden using volume of interest and SUVavg have also been utilized, but are less frequently used in oncology. In the routine clinical setting, [SUV.sub.max] is the most frequently used parameter. In our study, there was stronger correlation with [MDB.sub.max] rather than [SUV.sub.max] on the post-treatment scans. This indicates that in PET imaging inflammatory disease process may behave differently than neoplastic processes and the volume of the disease along with the intensity of FDG uptake both may be important. In our study, none of the patients with active RA had any "cold" or photopenic areas within the diseased area to suggest necrosis. Hence, the [MDB.sub.max] seemed to be a better marker to assess disease response than [SUV.sub.max]. The total MDB that included the MDB of all four extremities also showed good correlation, but it was not statistically significant due to the relatively small number of patients in our study. Further studies with more number of patients should be pursued to confirm these results and elicit the best parameters to use.

This study does have several limitations. The study population was very small. Larger populations must be studied to assess the overall value of FDG-PET in RA. FDG-PET does add risk to subjects and patients due to the radiation dose. To decrease this risk, a strategic decision was made to utilize PET imaging with isotope transmission attenuation correction as opposed to PET/ CT imaging. However, the accompanying CT images can provide additional information including better anatomic localization and morphological assessment of the involved joints. The PET acquisition could easily be expanded to include whole body images since no additional radiopharmaceutical dose is required and this can provide additional information about extra-synovial sites of inflammation and can potentially add another parameter in assessing response to treatment. Lastly, since only one physician performed the visual assessments and ROI placement of FDG uptake, further studies are required to assess for intra- and inter-observer variability as well.

In conclusion, this study shows that FDG PET can potentially play an important role in the management of RA patients. FDG PET imaging involves assessment of disease activity metabolically and response to therapy before any structural damage occurs thus allowing aggressive disease control from the initial stages. In combination with clinical evaluation parameters FDG PET evaluation of synovitis can serve as an adjunct in clinical decision making for each individual patient to tailor therapy.

Acknowledgements: This study received financial support from the Cruvant Fund (an intramural PET Imaging Research award at LSUHSC-S). The authors have no relevant conflicts of interest to declare.

REFERENCES

(1.) Catherine Beckers, MD; Clio Ribbens, MD, Ph.D et al. Assessment of Disease Activity in Rheumatoid arthritis with 18F-FDG PET. J Nucl Med. Vol 45,No 6, June 2004.

(2.) Palmer WE, Rosenthal DI, Schoenberg OI et al. Quantification of inflammation in the wrist with gadolinium-enhanced MR imaging and PET with 2-F-18flouro-2-deoxy-D-glucose.Radiology.1995; 196:647- 655.

(3.) Lin, P.W, R.S. Liu, T.H. Liou et al Correlation between joint F-18 FDG-PET uptake and synovial TNF- alpha concentration; a study with two rabbit models of acute inflammatory arthritis. Appl. Radit. Isot. 2007. 65:1221-1226

(4.) Matsui, T.N. Nakata, S. Nagai et al. Inflammatory cytokines and hypoxia contribute to 18F-FDG uptake by cells involved in pannus formation in rheumatoid arthritis Nuc. Med 2009.50:920-926.

(5.) A. Wunder, R.H. Straub, s. Gay et al. Molecular imaging; novel tools in visualizing rheumatoid arthritis. Rheumatology 2005; 44:1341-1349.

(6.) Gerhard W. Goerres, Adrian Forster, et al.F-18 FDG Whole-Body PET for the assessment of Disease Activity in Patients with Rheumatoid arthritis. Clin Nucl Med. Vol 31, No 7, July 2006.

(7.) Shi-Cun WANG, Qiang XIE, Wei-Fu LV et al.Positron emission tomography/ computed tomography imaging and rheumatoid arthritis. Int J Rheum Dis 2014; 17:248-255.

(8.) Kazuo Kubota, Kimiteru Ito, et al. FDG PET for rheumatoid arthritis; basic considerations and whole- body PET/CT.Ann.N.Y.Acad.Sci.1228 (2011)2938.

(9.) Buscombe J, Signore A. FDG-PET in infectious and inflammatory disease. Eur J Nucl Med Mol Imaging. 2003; 30:1571-1573.

(10.) El-Haddad G, Zhuang H, Gupta N, Alavi A. Evolving role of positron emission tomography in the management of patients with inflammatory and other benign disorders. Semin Nucl Med. 2004 Oct; 34(4):313-29.

(11.) Takalkar AM, Bruno GL, Makanjoula AJ, El-Haddad G, Lilien DL, Payne DK. A Potential Role for F-18 FDG PET/CT in Evaluation and Management of Fibrosing Mediastinitis. Clin Nucl Med. 2007 Sep; 32(9):703-6.

Drs. Dhawan & Kyla Lokitz are associated with the Center of Excellence for Arthritis and Rheumatology at the Louisiana State University Health Services Center; Drs. Takalkar & Stephen Lokitz are associated with the PET Imaging Center, Biomedical Research Foundation of Northwest Louisiana & the Department of Radiology at the Louisiana State University Health Services Center; Dr. Caldito is associated with the Section of Neurology at the Louisiana State University Health Sciences Center, all in Shreveport, LA.

TABLE 1: SJ: swollen joints; TJ: tender
joints; ESR: erythrocyte sedimentation
rate; DAS: disease activity score; FUP ESR:
follow up erythrocyte sedimentation rate;
FUP DAS: follow up disease activity score.

Subject   Age       ESR         FUP   DAS 28   FUP
ID        (years)   (mm/hour)   ESR            DAS

1         59        57          50    5.63     4.58
2         34        26          22    2.75     2.77
3         50        117         43    4.72     3.36
4         37        15          --    3.24     --
5         27        48          --    4.82     --
6         48        15          12    1.85     1.81
7         45        26          35    2.69     3.02

TABLE 2: SUV: highest standardized
uptake value amongst all lesions in a
particular subject.

Subject ID   HANDS                  FEET
             SUVmax      SUVmax 6   SUVmax      SUVmax 6
             before Rx   months     before Rx   months
                         post Rx                post Rx

1            6.0         3.4        3.6         2.8
2            2.9         3.1        3.1         4.3
3            5.3         2.8        5.1         5.4
6            2.2         2.2        4.9         5.2
7            3.3         4.7        2.8         3.0

TABLE 3

                    Patient   Patient   Patient   Patient   Patient
                    1         2         3         6         7

Methotrexate 10                                   Did not   [check]
mg po weekly                                      take it
                                                  for 2
                                                  months
Methotrexate 20     [check]   [check]   [check]
mg po weekly
Methotrexate 17.5
mg po weekly
Prednisone 5 mg               [check]
po daily
NSAIDs              [check]             [check]             [check]
Humira                        [check]   [check]

TABLE 4: Summary Statistics for Baseline
or Pre-treatment Values (n=5)

            Meant SD                 Median   Range

DAS         3.52 [+ or -] 1.58       2.75     1.85-5.63
ESR         48.20 [+ or -] 41.53     26.0     15.0-1117.0
SUV max     4.38 [+ or -] 1.22       4.40     3.10-66.0
MDB max     135.05 [+ or -] 82.31    108.96   57.16-237.4
Total MDB   329.43 [+ or -] 237.74   219.5    95.2-606.35

DAS: disease activity score; ESR:
erythrocyte sedimentation rate; sUv max:
standardized uptake value; MDB max:
metabolic disease burden; Total MDB:
total metabolic disease burden

TABLE 5: Summary Statistics for Baseline
or Post-treatment Values (n=5)

            Meant SD                 Median   Range

DAS         3.11 [+ or -] 1.00       3.02     1.81-4.58
ESR         32.40 [+ or -] 15.44     35.0     12.0-50.0
SUV max     4.76 [+ or -] 0.61       4.8      4.0-5.4
MDB max     97.45 [+ or -] 75.93     72.6     38.74-230.52
Total MDB   264.59 [+ or -] 234.57   188.91   47.58-651.66

DAS: disease activity score; ESR:
erythrocyte sedimentation rate; sUv max:
standardized uptake value; MDB max:
metabolic disease burden; Total MDB:
total metabolic disease burden

TABLE 6: Correlations at Baseline or Pre-
treatment

Correlation of   With        [R.sub.s]   p-value (1)

DAS              SUV max     0.60        0.28
                 MDB max     0.70        0.19
                 Total MDB   0.50        0.39
ESR              SUV max     0.56        0.32
                 MDB max     0.56        0.32
                 Total MDB   0.67        0.22

[R.sub.s]-Spearman rank correlation coefficient

(1) For testing null hypothesis of zero
correlation

Note: Despite the high correlations, they
are not significant because of the small

sample size (n=5)

TABLE 7: Correlations after 6 months of
therapy or Post-treatment

Correlation of   With        [R.sub.s]   p-value (1)

DAS              SUV max     -0.30       0.62
                 MDB max     0.90        0.04*
                 Total MBD   0.70        0.19

ESR              SUV max     -0.30       0.62
                 MDB max     0.90        0.04*
                 Total MBD   0.70        0.19

[R.sub.s]-Spearman rank correlation coefficient
(1) For testing null hypothesis of zero
correlation.

* Significant at 5% level (0.01<p-value<0.05)
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Title Annotation:fluorodeoxyglucose positron emission tomography
Author:Dhawan, Richa; Lokitz, Kyla; Lokitz, Stephen; Caldito, Gloria; Takalkar, Amol M.
Publication:The Journal of the Louisiana State Medical Society
Article Type:Report
Date:Sep 1, 2016
Words:2921
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