**3. Clinical application of radionuclide studies in the setting of rheumatoid arthritis and other inflammatory diseases**

#### **3.1. Rheumatoid arthritis**

cells. It is important to note that patients with favorable treatment results also show significantly lower expression of the somatostatin receptors; thus somatostatin scintigraphy may

Somatostatin receptor expression also features a good correlation with the clinical data—its sensitivity estimates 75%. Vanhagen et al. [27] also noted that no radiotracer accumulation was observed in the joints of healthy individuals. Numerous works point that somatostatin analogs may be used in RA treatment as well. It has also been found that the administration of somatostatin analogs reduced the symptoms of the disease—presumably due to the inhibition of IL-6 and IL-8 production as well as inhibited proliferation that occurs in the affected synovium. Therefore, somatostatin scintigraphy may be used as a tool in the prediction of the somatostatin analog treatment effects, although until today there has been no randomized study to confirm it. Therefore, more research is required before its utility may be introduced

Since mature T lymphocytes play a role in the development of RA, some radionuclide studies make it possible to label monoclonal antibodies against CD3 and T lymphocyte migration into the affected synovium. Recent advances allow Muromonab to be labeled with 99mTc and use it for imaging of rheumatic disease. It is essential to note that this examination correlates well with physical examination and patient history [29]. Moreover, scintigraphy with this tracer can be used in differential diagnosis of juvenile idiopathic arthritis and RA as well as other

Anti-CD4 imaging is also used for the evaluation of T lymphocyte infiltration. CD4 is expressed on the cell surface of mature T helper cells, thymocytes, and dendritic cells [30]. 99mTc-MAX.16H5, murine IgG1 was used in patients and showed affected joints in all RA patients. Studies indicate that the sensitivity of the 99mTc-MAX.16H5 scan is better than the

Almost 95% of circulating normal and malignant B lymphocytes expresses CD20 antigen [31]. Furthermore, its expression is exclusive to B lymphocytes simultaneously featuring the lack of expression in the hematopoietic stem cells. Due to this fact, Rituximab as a mouse/human monoclonal antibody can be labeled with 99mTc and used for B cell infiltration imaging [32].

TNF plays an essential role in the development of RA [33]. The promising results have been described in studies which involved the use of 123I-anakinra, infliximab (a monoclonal anti-

body that binds to membrane-bound and soluble TNF [34]) and 99mTc-Adalimumab.

also be used in the prediction of the effectiveness of the treatment [26].

to the guidelines [28].

16 Newest Updates in Rheumatology

*2.12.1. Anti-CD-3*

rheumatic diseases.

bone scan.

*2.12.4. TNF-alpha*

*2.12.2. 99mTc-anti-CD4 mAb*

*2.12.3. 99mTc-Anti-CD20 mAb*

**2.12. Other radiopharmaceuticals**

#### *3.1.1. Diagnosis and disease progression*

In vitro studies of Matsui et al. [35] has shown that in the setting of a murine model of collagen-induced arthritis, the peak of 18F-FDG uptake occurs both at the stage of pannus creation and during the destruction of the bone caused by inflammation caused by proliferating fibroblasts. Another prominent role of macrophages includes the fact that their inactivated form accumulates 18F-FDG merely to a small extent, while glucose demands after their hypoxiainduced activation increases significantly.

The degree of 18F-FDG uptake in correlation to the disorder severity:


It has been shown that the highest grade of 18F-FDG accumulation not only is related to the proliferation of fibroblasts but also to the neutrophils as well. On the other hand, resting macrophages feature moderate accumulation of 18F-FDG. In the setting of hypoxia, the activity of various inflammatory cells changes, while the activity of proinflammatory cytokines (such as TNF-alpha) increases. It has been observed that in these conditions there is increased 18F-FDG uptake by macrophages and fibroblasts, while in the case of neutrophils, it remains at the background level. T cells accumulate 18F-FDG to a small extent regardless of the microenvironment.

Summarizing, the degree of 18F-FDG uptake correlates with the activity of proliferating fibroblasts as well as macrophages activated by hypoxia; hence allowing the 18F-FDG study to be used in the evaluation of the disease severity.

Beckers et al. [36] assessed that the sensitivity of this technique in the setting of rheumatoid arthritis equals approx. 90%. Some works indicate that the study allows the identification of lesions in the subclinical phase of the disease as well as at the stage of its clinical remission. This fact plays a particularly important role in the treatment [37].

18F-FDG PET-CT study also allows the assessment of the disease severity in other maladies, such as spondyloarthritis, polymyalgia rheumatica, Still's disease, polychondritis, IgG4 related disease, polymyositis, and dermatomyositis [38].

Some of the studies aimed to assess the usefulness of 11C-choline as a marker for both the diagnosis and the severity assessment tool in rheumatic diseases. These indicated that it might be a good marker for the proliferation progress, which occur not only in the setting of tumors but also in the rheumatic conditions as well.

Roivainen et al. [39] made a comparison between 11C-choline PET-CT to 18F-FDG and gadolinium-enhanced MRI. The authors have shown that there is very high compliance between the pharmacokinetics of 18F-FDG and 11C-choline at the site of the affected joints. Regardless of the clinical symptoms of the inflammatory process, the accumulation of both markers occurred in the same joints that featured a clear contrast enhancement in the MR study. Moreover, authors state that 11C-choline may be a very promising tracer for quantitative imaging of proliferative arthritis changes. However, to characterize the relationship of PET-CT results with the clinical and functional measures of inflammation, a subsequent prospective study involving a larger number of patients is necessary [39]. Among other radiopharmaceuticals, 11C-(R)-PK11195 isoquinoline carboxamide is also being used for both the diagnosis of RA as well as an assessment of the disease severity. It was noted that this tracer tends to accumulate primarily in the activated macrophages and its degree of uptake highly corresponds to the severity of synovitis priorly assessed by histopathological examination. This examination turned out to be highly sensitive in both localizations of acute phase inflammation spots and the assessment of initial phase of the disease. It is considered that increased PET signal in inflamed joints occurs as a result of specific PBR-mediated uptake of 11C-(R)-PK11195 caused by activated macrophages.

stiffness, and edema). However, none of the studied parameters correlated with the outcome of the treatment. Authors concluded that both morphological pictures visible in MRI study and the functional test of PET study allow the assessment of the quantitative effectiveness of

Molecular Imaging

19

http://dx.doi.org/10.5772/intechopen.77200

Similar results were presented in 2004 by Beckers et al. who have shown a direct correlation between the clinical picture of a joint with the findings of an ultrasound examination and the degree of 18F-FDG uptake in PET-CT [36]. Additionally, as it turned out, the degree of 18F-FDG uptake in the affected joint highly correlates to the thickness of the synovial membrane priorly assessed in the ultrasound examination. Moreover, another correlation has been found between the number of joints with increased 18F-FDG uptake (with consideration of their total uptake value) and the duration of the disease together with the degree of severity. In 2004, Brenner et al. indicated in his work that despite confirmed correlation between <sup>18</sup>F-FDG uptake and the effectiveness of the treatment, PET-CT is still not recommended as a routine evaluation tool due to its high costs and limited availability [44]. This technique would be more indicated if the findings could provide parameters that are not obtainable by other tests (such as MRI, bone scan or ultrasound examination). However, authors pinpoint few of such parameters, that is, the possibility of quantitative assessment of disease severity of each affected joint and the assessment of disease progression as well as monitoring of treatment effectiveness. Authors emphasize that further studies are necessary for the better

Beckers et al. [36] presented a noteworthy work which aimed to study the response to the anti-TNF-alpha treatment [44]. Authors in their work showed a significant correlation between the degree of 18F-FDG uptake, MRI findings, synovial membrane thickness, and the concentration of matrix metalloproteinase (MMP)3 and CRP levels. Similarly, Elzinga et al. [45] showed in their work that decreased uptake of 18F-FDG after application of anti-TNF therapy is an

Elzinga et al. [45] concluded that decreased 18F-FDG uptake in the metacarpophalangeal and wrist joints 2 weeks following the infliximab (anti-TNF-alpha) therapy allowed to predict the outcome of the treatment after 14 and 22 weeks. It was all possible to achieve that because of the presence of clear correlation between the fall of the tracer uptake and the severity of the disease, which has subsequently contributed to the development of disease activity score (DAS). However, this type of correlation was not found in later observations; thus it requires further research. Perhaps another radiopharmaceutical will turn out to be more useful in

A PET-CT study is a useful tool in the diagnosis of concomitant neoplastic disorders in patients with lupus, systemic sclerosis, dermatomyositis/polymyositis or Sjögren syndrome. Epidemiological data in these groups of patients showed the occurrence is noticeably higher;

important prognostic factor that indicates the effectiveness of the treatment.

prognosis of anticipated outcomes of the given treatment.

especially lymphoma, pharyngeal, and pancreatic cancer [46–48].

**3.2. Diagnosis of concomitant diseases**

the applied therapy.

*3.1.3. Prognosis*

determination of PET-CT study indications.

Van der Laken et al. [40] performed one of the first studies in the setting of the rheumatic disease. The authors concluded in their work that 11C-(R)-PK11195 uptake on the PET scans was significantly higher in severely inflamed joints in comparison to those with moderate or mild signs of inflammation. Additionally, tracer uptake in contralateral, unaffected by inflammation knee joints of RA patients was significantly higher than in joints of healthy individuals from the control group (with no history of inflammatory joint disease or the presence of any subclinical disease activity). PET tracer uptake in the affected joints is highly correlated with PBR staining of sub-lining of synovial tissue, which also proves its correlation to CD68 staining of macrophages.

It is believed that this tracer may allow imaging of the ongoing pathology prior to its clinical manifestation due to the fact that macrophages infiltration into synovial joints is a common feature of asymptomatic synovitis in early RA [41, 42]. Furthermore, the application of 11C-(R)-PK11195 imaging to RA may prove to be relevant to patient management since the presence and the number of macrophages in rheumatoid synovium strictly correlates with the progression of joint erosions that can be seen in the X-ray. Another use of this trace encompasses diagnosis of subclinical synovitis in patients with arthralgia. Last but not least, increased uptake of the tracer correlates with the progression of the disease.

#### *3.1.2. Treatment control*

Numbers of works indicate that 18F-FDG is an excellent marker in the assessment of treatment effectiveness. The utility of 18F-FDG as the marker in this assessment was suggested by Palmer et al. back in 1995 [43]. The authors in their work studied the influence of prednisolone and subsequent methotrexate treatment on findings in MRI and 18F-FDG PET-CT. Results showed that as the volume of the pannus seen on MRI decreased, so did the uptake of 18F-FDG not to mention the improvement of the clinical picture (such as reduction of pain sensation, stiffness, and edema). However, none of the studied parameters correlated with the outcome of the treatment. Authors concluded that both morphological pictures visible in MRI study and the functional test of PET study allow the assessment of the quantitative effectiveness of the applied therapy.

Similar results were presented in 2004 by Beckers et al. who have shown a direct correlation between the clinical picture of a joint with the findings of an ultrasound examination and the degree of 18F-FDG uptake in PET-CT [36]. Additionally, as it turned out, the degree of 18F-FDG uptake in the affected joint highly correlates to the thickness of the synovial membrane priorly assessed in the ultrasound examination. Moreover, another correlation has been found between the number of joints with increased 18F-FDG uptake (with consideration of their total uptake value) and the duration of the disease together with the degree of severity. In 2004, Brenner et al. indicated in his work that despite confirmed correlation between <sup>18</sup>F-FDG uptake and the effectiveness of the treatment, PET-CT is still not recommended as a routine evaluation tool due to its high costs and limited availability [44]. This technique would be more indicated if the findings could provide parameters that are not obtainable by other tests (such as MRI, bone scan or ultrasound examination). However, authors pinpoint few of such parameters, that is, the possibility of quantitative assessment of disease severity of each affected joint and the assessment of disease progression as well as monitoring of treatment effectiveness. Authors emphasize that further studies are necessary for the better determination of PET-CT study indications.

Beckers et al. [36] presented a noteworthy work which aimed to study the response to the anti-TNF-alpha treatment [44]. Authors in their work showed a significant correlation between the degree of 18F-FDG uptake, MRI findings, synovial membrane thickness, and the concentration of matrix metalloproteinase (MMP)3 and CRP levels. Similarly, Elzinga et al. [45] showed in their work that decreased uptake of 18F-FDG after application of anti-TNF therapy is an important prognostic factor that indicates the effectiveness of the treatment.

#### *3.1.3. Prognosis*

Roivainen et al. [39] made a comparison between 11C-choline PET-CT to 18F-FDG and gadolinium-enhanced MRI. The authors have shown that there is very high compliance between the pharmacokinetics of 18F-FDG and 11C-choline at the site of the affected joints. Regardless of the clinical symptoms of the inflammatory process, the accumulation of both markers occurred in the same joints that featured a clear contrast enhancement in the MR study. Moreover, authors state that 11C-choline may be a very promising tracer for quantitative imaging of proliferative arthritis changes. However, to characterize the relationship of PET-CT results with the clinical and functional measures of inflammation, a subsequent prospective study involving a larger number of patients is necessary [39]. Among other radiopharmaceuticals, 11C-(R)-PK11195 isoquinoline carboxamide is also being used for both the diagnosis of RA as well as an assessment of the disease severity. It was noted that this tracer tends to accumulate primarily in the activated macrophages and its degree of uptake highly corresponds to the severity of synovitis priorly assessed by histopathological examination. This examination turned out to be highly sensitive in both localizations of acute phase inflammation spots and the assessment of initial phase of the disease. It is considered that increased PET signal in inflamed joints occurs as a result of specific PBR-mediated uptake of 11C-(R)-PK11195 caused

Van der Laken et al. [40] performed one of the first studies in the setting of the rheumatic disease. The authors concluded in their work that 11C-(R)-PK11195 uptake on the PET scans was significantly higher in severely inflamed joints in comparison to those with moderate or mild signs of inflammation. Additionally, tracer uptake in contralateral, unaffected by inflammation knee joints of RA patients was significantly higher than in joints of healthy individuals from the control group (with no history of inflammatory joint disease or the presence of any subclinical disease activity). PET tracer uptake in the affected joints is highly correlated with PBR staining of sub-lining of synovial tissue, which also proves its correlation to CD68 stain-

It is believed that this tracer may allow imaging of the ongoing pathology prior to its clinical manifestation due to the fact that macrophages infiltration into synovial joints is a common feature of asymptomatic synovitis in early RA [41, 42]. Furthermore, the application of 11C-(R)-PK11195 imaging to RA may prove to be relevant to patient management since the presence and the number of macrophages in rheumatoid synovium strictly correlates with the progression of joint erosions that can be seen in the X-ray. Another use of this trace encompasses diagnosis of subclinical synovitis in patients with arthralgia. Last but not least, increased uptake of the tracer correlates with the progres-

Numbers of works indicate that 18F-FDG is an excellent marker in the assessment of treatment effectiveness. The utility of 18F-FDG as the marker in this assessment was suggested by Palmer et al. back in 1995 [43]. The authors in their work studied the influence of prednisolone and subsequent methotrexate treatment on findings in MRI and 18F-FDG PET-CT. Results showed that as the volume of the pannus seen on MRI decreased, so did the uptake of 18F-FDG not to mention the improvement of the clinical picture (such as reduction of pain sensation,

by activated macrophages.

18 Newest Updates in Rheumatology

ing of macrophages.

sion of the disease.

*3.1.2. Treatment control*

Elzinga et al. [45] concluded that decreased 18F-FDG uptake in the metacarpophalangeal and wrist joints 2 weeks following the infliximab (anti-TNF-alpha) therapy allowed to predict the outcome of the treatment after 14 and 22 weeks. It was all possible to achieve that because of the presence of clear correlation between the fall of the tracer uptake and the severity of the disease, which has subsequently contributed to the development of disease activity score (DAS). However, this type of correlation was not found in later observations; thus it requires further research. Perhaps another radiopharmaceutical will turn out to be more useful in prognosis of anticipated outcomes of the given treatment.

#### **3.2. Diagnosis of concomitant diseases**

A PET-CT study is a useful tool in the diagnosis of concomitant neoplastic disorders in patients with lupus, systemic sclerosis, dermatomyositis/polymyositis or Sjögren syndrome. Epidemiological data in these groups of patients showed the occurrence is noticeably higher; especially lymphoma, pharyngeal, and pancreatic cancer [46–48].

specificity of <sup>18</sup>F-FDG PET-CT in this setting equal 90%. In a meta-analysis performed by Balink et al. [52], the authors point out that sensitivity of this modality is higher than in any

Molecular Imaging

21

http://dx.doi.org/10.5772/intechopen.77200

Indeed, we can say that recently used studies such as MRI, CT or US in the setting of rheumatology are the marriage of convenience while radionuclide studies may be considered as a marriage of love. Such complex disease processes that occur in rheumatic diseases require comprehensive data that can be obtained only by procedures from the field of nuclear medicine.

other imaging method (**Figure 2**).

**4. Conclusion**

**Author details**

Leszek Królicki1\*

**References**

and Adrian Michno2

\*Address all correspondence to: leszek.krolicki@wum.edu.pl

1 Nuclear Medicine Department, Medical University of Warsaw, Warsaw, Poland

[1] Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for the treat-

[2] Wunder A, Straub RH, Gay S, Funk J, Müller-Ladner U. Molecular imaging: Novel tools for visualizing rheumatoid arthritis. Rheumatology (Oxford). 2005;**44**:1341-1349

[3] Vogel WV, van Riel PL, Oyen WJ. FDG-PET/CT can visualise the extent of inflammation in rheumatoid arthritis of the tarsus. European Journal of Nuclear Medicine and

[4] Miese F, Scherer A, Ostendorf B, Heinzel A, Lanzman RS, Kropil P, Blondin D, Hautzel H, Wittsack HJ, Schneider M, Antoch G, Herzog H, Shah NJ. Hybrid 18F-FDG PET-MRI of the hand in rheumatoid arthritis: Initial results. Clinical Rheumatology.

[5] Ladner U. Molecular imaging: Novel tools in visualizing rheumatoid arthritis. Rheuma-

[6] Kubota R, Yamada S, Kubota K, Ishiwata K, Tamahashi N, Ido T. Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: High accumulation in macrophages and granulation tissues studied by microautoradiography. Journal of Nuclear Medicine.

2 Department of Diagnostic Imaging, Bródno Hospital, Warsaw, Poland

ment of rheumatoid arthritis. Lancet. 2007;**370**:1861-1874

Molecular Imaging. 2007;**34**:439

tology (Oxford). 2005;**44**:1341-1349

2011;**30**:1247-1250

1992;**33**:1972-1980

**Figure 2.** 18F-FDG PET-CT in patient with RA shows increased accumulation of the tracer in the wall of the aorta.

Autoimmune disease treatment involves the use of immunosuppressants, which aim to lower the immune response of the organism, simultaneously increasing the risk of infection (including a higher risk for relapse of tuberculosis) [49]. 18F-FDG PET-CT study turns out to the most sensitive test for the diagnosis of infection. This examination can show abnormal focal uptake of the tracer in up to 90% of the patients suffering from autoimmune diseases; sensitivity and specificity in the diagnosis of neoplastic disorder equal 100 and 67%, respectively [50].

#### **3.3. Fever of unknown origin**

18F-FDG PET-CT also showed to be promising in the diagnostic process in patients with the symptoms of FUO. In cases where other imaging studies showed to be inconclusive, 18F-FDG PET-CT allows for the localization of pathological foci (either inflammation or a tumor based) in approx. 47% of the patients. Positive predictive value of this study has been assessed for 78% while negative predictive value—for 88% [51].

#### **3.4. Vasculitis**

Suspected large vascular vessels vasculitis is another indication for 18F-FDG PET-CT. The term of vasculitis emphasizes the numbers of diseases, out of which Takayasu arteritis together with giant cell arteritis accounts for the most common types of vasculitis. Sensitivity and specificity of <sup>18</sup>F-FDG PET-CT in this setting equal 90%. In a meta-analysis performed by Balink et al. [52], the authors point out that sensitivity of this modality is higher than in any other imaging method (**Figure 2**).
