**2.1. 18F-FDG**

specific chemical compounds that take place in the course of the disease. It is important to note that the functional character of disorders should be the basis for the choice of treatment. Over the last several decades, the introduction of new biological agents has greatly improved the effectiveness of treatment. Those agents influence the activity of specific receptor and metabolic pathways [1]. Along with the application of new agents, it has become necessary to introduce new diagnostic methods, which allow evaluation of the activity of those biological processes. Unfortunately, neither clinical examination nor laboratory tests nor conventional X-ray does not provide such findings. A clinical evaluation can be highly subjective; laboratory tests are frequently non-specific and inconsistent, while conventional X-ray shows struc-

It seems that the introduction of molecular imaging techniques may lift those limitations. The fundamental methods of molecular imaging are radionuclide studies. Recent advances in nuclear medicine allowed to develop target-specific agents making it possible to reveal molecular level disturbances that take place on the course of the ongoing disease [2]. The fundamental radionuclide studies include a PET, SPECT, and classic scintigraphy. Moreover, hybrid devices are used more frequently in diagnostics these days—these consist of gamma camera and CR/MRI. Thanks to hybrid techniques, it is possible to perform CT/MRI combined with scintigraphy (for example PET-CT, PET-MRI, and SPECT-CT). It is also important to mention that the combination of those techniques allows applying attenuation correction of the absorbed radiation that is being emitted by radioisotope, as well as making it possible to determine the exact location of the abnormal

uptake of the radiopharmaceutical. Finally, the images obtained are of very high quality.

were affected by synovitis and tenovaginitis as identified on contrast-enhanced MRI.

allows imaging of vast amounts of pathologies.

MRI is second modern imaging modality that is very useful in the diagnosis of rheumatic diseases. This method features a very high resolution and similarly good contrast between the soft tissues. Thanks to the new sequences and specific contrast agents, and modern MRI

Both of these methods provide the information about molecular pathological mechanisms that accompany the disease; thus allowing a better understanding of the pathophysiology of rheumatic diseases. Moreover, they allow a search of the new forms of molecular treatment

Technological advances allow obtaining images of much better resolution and allow combining both structural and functional data. Vogel et al. noted in his study that hybrid imaging technique 18F-FDG PET-CT, apart from providing the capability of assessing the degree of inflammation localized in the tarsus of a rheumatoid arthritis (RA) patient, also allows precise localization of the disease activity in particular joints [3]. Neither physical examination nor X-ray can provide such relevant data. Furthermore, 18F-FDG PET/CT allows to visualize and diagnose metabolically active subcutaneous nodules, activated lymph nodes or other affected joints in the course of the disease (such as those of the knee or atlantoaxial joints). This method allows better discrimination between juxtaarticular disease and articular processes as well as delineation of tendon sheath and bursal inflammation. Furthermore, this method makes it possible to delineate inflammation of the tendon sheaths and bursae. Miese et al. [4] also assessed the high suitability of PET/MRI apparatus in his work about the diagnosis of RA, in which he showed increased uptake of 18F-FDG in the corresponding metacarpophalangeal joints that

tural changes only at the advanced stage of the disease.

10 Newest Updates in Rheumatology

The most commonly used radiopharmaceutical used in PET-CT studies is fluorodeoxyglucose (18F-FDG), which is a structural glucose analog. Areas of increased tracer uptake indicate the intensification of metabolic processes associated with increased glucose demand. This feature can be found both in a tumor and inflammatory setting. Increased uptake of 18F-FDG is associated with increased activity of the GLUT1 and GLUT3 transport mechanisms as well as the activity of hexokinase—these phenomena are typical for cells that undergo fast proliferation as well as other types of cells such as macrophages, neutrophils and young granulation tissue [6–8].

### **2.2. 11C-choline**

Choline is another tracer that features high sensitivity for proliferative processes that occur in the course of the disease. This tracer is uptaken by quickly dividing cells where it undergoes phosphorylation by choline kinase into phosphorylcholine. Choline is essential for phospholipids synthesis, especially phosphatidylcholine (also known as lecithin) which serves as the building block of the cell membranes. Increased uptake of choline depends on the mechanisms responsible for active transport via the cell membrane as well as on congestiondependent passive diffusion. It has been found that increased uptake can be seen even in the early phase of the inflammation. Once present, its grade of accumulation corresponds with both the extent of the contrast-enhanced signal in an MRI study (with Gadovist as a tracer) and the accumulation of 18FDG [9].

• Phase I—hyperemia,

**2.6. Labeled leukocytes**

in the affected left knee.

• Phase II—increased volume of the vascular bed,

SPECT-CT technique if one is available.

ing pathology (inflammation and destruction of the cartilage).

specific for inflammation occurring in the course of the rheumatic diseases.

• Phase III—metabolic turnover and remodeling of the osseous tissue as a result of the ongo-

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This method is highly sensitive but features low specificity, which can be improved by hybrid

It is important to note that the accumulation of described radiopharmaceuticals in tissues affected by inflammation is non-specific because these tracers accumulate similarly in neoplastic foci. Due to that fact, there is recently ongoing research that aims to develop markers

Since the inflammation features the migration of leukocytes, there was an idea to use that mechanism in the diagnosis and localization of the inflammatory foci. Nuclear medicine has

**Figure 1.** Triphasic bone scan after 99mTc-MDP administration in patient with RA shows increased blood flow (A), blood pool (B), and increased accumulation of the radiotracer in the bony phase (C) which indicates increased bony turnover

### **2.3. 67Ga-citrate**

This radiopharmaceutical has been used in both the diagnosis of cancer as well as acute and chronic foci of inflammation for several years. Gallium (administered via i.v. infusion) acts as an iron analog that binds to transferrin, ferritin, and leukocytes (primarily neutrophils) [10]. These molecules accumulate within the foci of inflammation secondary to increased capillary permeability. At the time when 67Ga-bound macromolecules reach the inflammatory interstitial space, the isotope undergoes the process of transchelation into lactoferrin, ferritin and bacterial siderophores (if present). Moreover, lactoferrin is then being secreted by neutrophils that are present in the inflammatory foci caused by the disorders of the connective tissue [11]. Recently, 67Ga-citrate is rarely used because of the vast availability of other—frequently much better—markers as well as other factors such as the unfavorable energetic profile of the emitted radiation, the long-lasting radioactivity of the blood (due to high affinity to the white blood cells) and relatively long half-life time. This results in significantly increased absorbed radiation dose in comparison to other radioisotopes, not to mention low quality of the obtained images. Another disadvantage of 67Ga-citrate is the lack of specificity for inflammation because it accumulates similarly in neoplasms.

#### **2.4. 99mTc and 111In HIG**

Both 99m-technetium and 111-indium can be used for labeling of human (polyclonal) immunoglobulins (HIG). HIG accumulate in the inflamed tissues because its mechanism of accumulation is related to the increased permeability of the vascular capillaries as well as increased blood flow to the inflamed area. This technique features very high sensitivity, not to mention that the grade of its accumulation highly corresponds to the severity of the inflammation, hence making it a useful prognostic tool. On the other hand, one of the disadvantages of this radiopharmaceutical includes lack of specificity [12].

#### **2.5. 99mTc-diphosphonates**

Similarly to gallium-67, 99mTc-diphosphonates are non-specific tracers used in the diagnosis of the inflammation—its mechanism of uptake relies on the metabolism of the osseous cells its degree of uptake depends on the activity of osteoblasts (hence its perfect for imaging of the bone turnover). Bone scintigraphy is readily available and cheap method of evaluation of bones [13, 14]. As the severity of the inflammation progress, the uptake increases. In the setting of inflammation evaluation, the bone scan comes in the form of a triphasic examination, which consists of vascular, parenchymal, and late (bony) phase (**Figure 1**). Each phase presents a specific aspect of the pathology:

• Phase I—hyperemia,

mechanisms responsible for active transport via the cell membrane as well as on congestiondependent passive diffusion. It has been found that increased uptake can be seen even in the early phase of the inflammation. Once present, its grade of accumulation corresponds with both the extent of the contrast-enhanced signal in an MRI study (with Gadovist as a tracer)

This radiopharmaceutical has been used in both the diagnosis of cancer as well as acute and chronic foci of inflammation for several years. Gallium (administered via i.v. infusion) acts as an iron analog that binds to transferrin, ferritin, and leukocytes (primarily neutrophils) [10]. These molecules accumulate within the foci of inflammation secondary to increased capillary permeability. At the time when 67Ga-bound macromolecules reach the inflammatory interstitial space, the isotope undergoes the process of transchelation into lactoferrin, ferritin and bacterial siderophores (if present). Moreover, lactoferrin is then being secreted by neutrophils that are present in the inflammatory foci caused by the disorders of the connective tissue [11]. Recently, 67Ga-citrate is rarely used because of the vast availability of other—frequently much better—markers as well as other factors such as the unfavorable energetic profile of the emitted radiation, the long-lasting radioactivity of the blood (due to high affinity to the white blood cells) and relatively long half-life time. This results in significantly increased absorbed radiation dose in comparison to other radioisotopes, not to mention low quality of the obtained images. Another disadvantage of 67Ga-citrate is the lack of specificity for inflam-

Both 99m-technetium and 111-indium can be used for labeling of human (polyclonal) immunoglobulins (HIG). HIG accumulate in the inflamed tissues because its mechanism of accumulation is related to the increased permeability of the vascular capillaries as well as increased blood flow to the inflamed area. This technique features very high sensitivity, not to mention that the grade of its accumulation highly corresponds to the severity of the inflammation, hence making it a useful prognostic tool. On the other hand, one of the disadvantages of this

Similarly to gallium-67, 99mTc-diphosphonates are non-specific tracers used in the diagnosis of the inflammation—its mechanism of uptake relies on the metabolism of the osseous cells its degree of uptake depends on the activity of osteoblasts (hence its perfect for imaging of the bone turnover). Bone scintigraphy is readily available and cheap method of evaluation of bones [13, 14]. As the severity of the inflammation progress, the uptake increases. In the setting of inflammation evaluation, the bone scan comes in the form of a triphasic examination, which consists of vascular, parenchymal, and late (bony) phase (**Figure 1**). Each phase

and the accumulation of 18FDG [9].

mation because it accumulates similarly in neoplasms.

radiopharmaceutical includes lack of specificity [12].

presents a specific aspect of the pathology:

**2.3. 67Ga-citrate**

12 Newest Updates in Rheumatology

**2.4. 99mTc and 111In HIG**

**2.5. 99mTc-diphosphonates**


This method is highly sensitive but features low specificity, which can be improved by hybrid SPECT-CT technique if one is available.

It is important to note that the accumulation of described radiopharmaceuticals in tissues affected by inflammation is non-specific because these tracers accumulate similarly in neoplastic foci. Due to that fact, there is recently ongoing research that aims to develop markers specific for inflammation occurring in the course of the rheumatic diseases.

#### **2.6. Labeled leukocytes**

Since the inflammation features the migration of leukocytes, there was an idea to use that mechanism in the diagnosis and localization of the inflammatory foci. Nuclear medicine has

**Figure 1.** Triphasic bone scan after 99mTc-MDP administration in patient with RA shows increased blood flow (A), blood pool (B), and increased accumulation of the radiotracer in the bony phase (C) which indicates increased bony turnover in the affected left knee.

come to meet this need and has developed a radionuclide examination that makes it possible to label leukocytes of the patient (both in vitro and in vivo depending on the technique). In the setting of inflammation, neutrophils and monocytes are being recruited, and due to the phenomena of chemotaxis, they accumulate in the foci of inflammation. Thanks to this mechanism of accumulation, labeled leukocytes can be used in the diagnosis of RA as well as other inflammatory diseases. Labeled leukocytes emphasize two main techniques—in vivo and in vitro assay.

**2.9. 99mTc-RP128**

99mTc-RP128 is a peptide tracer used for imaging of leukocytes recruitment used for labeling of neutrophils and mononuclear phagocytes. 99mTc-RP128 is a pentapeptide tuftsin analog antagonist (TKPPR) that mediates the receptor-specific interaction and subsequently binds to tuftsin receptors. Tuftsin is an organic chemical compound consisting of amino acid residues such as threonine, lysine, proline, and arginine. It is produced by the spleen and its function is to stimulate macrophages and granulocytes to phagocytosis and chemotaxis. Tuftsin is derived from proteolytic cleavage of the Fc domain of the heavy chain of IgG. Tuftsin receptor's function is to mediate the immune functions; hence they represent important molecular targets. The mechanism of RP128 imaging is based on the upregulation of tuftsin receptors located in activated macrophages. Chaudhuri et al. [22] noted that the affinity of radiotracer is fourfold greater than their endogenous ligand. Despite that fact, this radiotracer was described only in a few works; thus there is a need for further research that would confirm its utility. Studies show that it accumulates in other organs to an only small extent (except kidneys). The grade of accumulation in healthy joints was moderate—in contrast to the affected joints, which featured a very high uptake. The sensitivity of the scan was 69% for swollen joints, 76% for

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Adhesion is another mechanism used in the diagnosis of the inflammation. Molecules responsible for this phenomena cause leukocytes to bind to the activated endothelial vessels resulting in their transendothelial migration. One of such molecules that are used in the diagnosis of the inflammation is E-selectin labeled with 99mTc or 111In. E-selectin (CD62E, ELAM1) is a transmembrane glycoprotein that is transiently expressed on the luminal surface of activated vascular endothelium during a normal inflammatory response. E-selectin mediates the initial tethering and rolling of granulocytes, monocytes, and some lymphocytes via specific interactions with its carbohydrate-based ligands. It is then activated by interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and bacterial LPS—it has to be noted that this may occur only in the setting of inflammation [24]. 111In-1.2B6 monoclonal antibody (mAb) is another antibody that was used for imaging of selectin activity. Since this is a murine antibody, the administration of this radiopharmaceutical comes with a risk of developing human anti-mouse antibody (HAMA) response, a possibly life-threatening state that requires immediate medical attention. This fact limits the repetition of the study in patients in whom treatment control is necessary. Therefore, F(ab')2 fragments of 1.2B6 mAb—devoid of its Fc portions—were introduced [25].

Octreotide is a long-acting somatostatin analog that targets the activation of endothelium and macrophage recruitment at any of five identified G-protein-coupled somatostatin receptor subtypes (SST1–5). Hyper-expression of these receptors has been thoroughly documented in numerous pathological conditions hence it can be considered as a basis for octreotide imaging. The synovia of affected joints in RA patients features overexpression of somatostatin receptors—those that are targeted by octreotide. The SST2 expression on activated venule of endothelial cells and infiltrating mononuclear phagocytes have been identified in histological and immunochemistry examinations both in the affected synovia and fibroblast-like synovial

painful joints, and 73% for joints with bone erosions [23].

**2.10. 99mTc- and 111In anti-E-selectin**

**2.11. Octreotide**


#### **2.7. 11C-PK11195**

One of the proposals involved the introduction of 11C-PK11195 isoquinoline carboxamide this radiopharmaceutical binds to both monocytes and macrophages and serves as peripheral benzodiazepine receptor (PBR) antagonist also known as translocator protein (TSPO). This peptide is particularly active on the outer surface of the mitochondrial membrane of the activated macrophages, polymorphonuclear cells as well as nervous and lymphatic tissue [16–18]. It is responsible for the process of steroidogenesis, apoptosis, cell proliferation, and immune response. It has also been proved that this radiopharmaceutical is an effective marker in neuroinfection, due to the fact that peripheral benzodiazepine receptors can be typically found on activated glial cells.

#### **2.8. 99mTc-J001X**

Other noteworthy markers are those with the ability to label the macrophages. These kinds of cells are particularly active in inflammation based on the rheumatic disorders and play a major role in the inflammatory process. It was found that macrophages bind specifically to the proteoglycans of the bacteria. Hence a technique of proteoglycans labeling has been developed [19, 20].

Recently used tracer is called J001X—which is a poly-(1,3)-d-galactoside isolated from the cellular membrane of *Klebsiella pneumoniae*. This 99mTc labeled-substance allows tracing of the mononuclear phagocytes.

The effectiveness of this radiopharmaceutical in the diagnosis of RA-associated lung pathology appears to be promising, but until today there is no randomized study that would confirm its effectiveness. Lastly, this tracer was also used in imaging of sarcoidosis and scleroderma [21].

#### **2.9. 99mTc-RP128**

come to meet this need and has developed a radionuclide examination that makes it possible to label leukocytes of the patient (both in vitro and in vivo depending on the technique). In the setting of inflammation, neutrophils and monocytes are being recruited, and due to the phenomena of chemotaxis, they accumulate in the foci of inflammation. Thanks to this mechanism of accumulation, labeled leukocytes can be used in the diagnosis of RA as well as other inflammatory diseases. Labeled leukocytes emphasize two main techniques—in

• *In vitro assay* is a technique that involves taking a blood sample, isolating a leukocyte suspension, labeling those leukocytes with 99mTc-HM-PAO or 111In-oxine, and intravenous administration back to the patient. It is important to note that this procedure does not affect

• *In vivo assay*, on the other hand, involves intravenous administration of 99mTc-labeled monoclonal antibodies against the specific NC-1 antigen that is present on the granulocyte cell membrane. In this procedure, the labeling process occurs directly in the blood of the patient. Moreland et al. [15] in his work have shown that there is a direct correlation between the foci of increased accumulation and the clinical picture in the course of rheumatoid arthritis. This examination may also be used as a tool to control anti-inflammatory treatment [15].

One of the proposals involved the introduction of 11C-PK11195 isoquinoline carboxamide this radiopharmaceutical binds to both monocytes and macrophages and serves as peripheral benzodiazepine receptor (PBR) antagonist also known as translocator protein (TSPO). This peptide is particularly active on the outer surface of the mitochondrial membrane of the activated macrophages, polymorphonuclear cells as well as nervous and lymphatic tissue [16–18]. It is responsible for the process of steroidogenesis, apoptosis, cell proliferation, and immune response. It has also been proved that this radiopharmaceutical is an effective marker in neuroinfection, due to the fact that peripheral benzodiazepine receptors can be typically

Other noteworthy markers are those with the ability to label the macrophages. These kinds of cells are particularly active in inflammation based on the rheumatic disorders and play a major role in the inflammatory process. It was found that macrophages bind specifically to the proteoglycans of the bacteria. Hence a technique of proteoglycans labeling has been

Recently used tracer is called J001X—which is a poly-(1,3)-d-galactoside isolated from the cellular membrane of *Klebsiella pneumoniae*. This 99mTc labeled-substance allows tracing of the

The effectiveness of this radiopharmaceutical in the diagnosis of RA-associated lung pathology appears to be promising, but until today there is no randomized study that would confirm its effectiveness. Lastly, this tracer was also used in imaging of sarcoidosis and

vivo and in vitro assay.

14 Newest Updates in Rheumatology

chemotaxis.

**2.7. 11C-PK11195**

**2.8. 99mTc-J001X**

developed [19, 20].

scleroderma [21].

mononuclear phagocytes.

found on activated glial cells.

99mTc-RP128 is a peptide tracer used for imaging of leukocytes recruitment used for labeling of neutrophils and mononuclear phagocytes. 99mTc-RP128 is a pentapeptide tuftsin analog antagonist (TKPPR) that mediates the receptor-specific interaction and subsequently binds to tuftsin receptors. Tuftsin is an organic chemical compound consisting of amino acid residues such as threonine, lysine, proline, and arginine. It is produced by the spleen and its function is to stimulate macrophages and granulocytes to phagocytosis and chemotaxis. Tuftsin is derived from proteolytic cleavage of the Fc domain of the heavy chain of IgG. Tuftsin receptor's function is to mediate the immune functions; hence they represent important molecular targets. The mechanism of RP128 imaging is based on the upregulation of tuftsin receptors located in activated macrophages. Chaudhuri et al. [22] noted that the affinity of radiotracer is fourfold greater than their endogenous ligand. Despite that fact, this radiotracer was described only in a few works; thus there is a need for further research that would confirm its utility. Studies show that it accumulates in other organs to an only small extent (except kidneys). The grade of accumulation in healthy joints was moderate—in contrast to the affected joints, which featured a very high uptake. The sensitivity of the scan was 69% for swollen joints, 76% for painful joints, and 73% for joints with bone erosions [23].

#### **2.10. 99mTc- and 111In anti-E-selectin**

Adhesion is another mechanism used in the diagnosis of the inflammation. Molecules responsible for this phenomena cause leukocytes to bind to the activated endothelial vessels resulting in their transendothelial migration. One of such molecules that are used in the diagnosis of the inflammation is E-selectin labeled with 99mTc or 111In. E-selectin (CD62E, ELAM1) is a transmembrane glycoprotein that is transiently expressed on the luminal surface of activated vascular endothelium during a normal inflammatory response. E-selectin mediates the initial tethering and rolling of granulocytes, monocytes, and some lymphocytes via specific interactions with its carbohydrate-based ligands. It is then activated by interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and bacterial LPS—it has to be noted that this may occur only in the setting of inflammation [24]. 111In-1.2B6 monoclonal antibody (mAb) is another antibody that was used for imaging of selectin activity. Since this is a murine antibody, the administration of this radiopharmaceutical comes with a risk of developing human anti-mouse antibody (HAMA) response, a possibly life-threatening state that requires immediate medical attention. This fact limits the repetition of the study in patients in whom treatment control is necessary. Therefore, F(ab')2 fragments of 1.2B6 mAb—devoid of its Fc portions—were introduced [25].

#### **2.11. Octreotide**

Octreotide is a long-acting somatostatin analog that targets the activation of endothelium and macrophage recruitment at any of five identified G-protein-coupled somatostatin receptor subtypes (SST1–5). Hyper-expression of these receptors has been thoroughly documented in numerous pathological conditions hence it can be considered as a basis for octreotide imaging. The synovia of affected joints in RA patients features overexpression of somatostatin receptors—those that are targeted by octreotide. The SST2 expression on activated venule of endothelial cells and infiltrating mononuclear phagocytes have been identified in histological and immunochemistry examinations both in the affected synovia and fibroblast-like synovial 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 also be used in the prediction of the effectiveness of the treatment [26].

**3. Clinical application of radionuclide studies in the setting of** 

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 hypoxia-

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• Moderate uptake can be seen in the initial period of the disease progression, at which interstitial inflammatory cells recruitment, synovial cells hyperplasia, and edema can be seen. • Uptake of 18F-FDG noticeably increases as the bony destruction and pannus creation

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

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

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.

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-

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

**rheumatoid arthritis and other inflammatory diseases**

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

**3.1. Rheumatoid arthritis**

progresses.

the microenvironment.

used in the evaluation of the disease severity.

also in the rheumatic conditions as well.

This fact plays a particularly important role in the treatment [37].

related disease, polymyositis, and dermatomyositis [38].

*3.1.1. Diagnosis and disease progression*

induced activation increases significantly.

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 to the guidelines [28].

### **2.12. Other radiopharmaceuticals**

#### *2.12.1. Anti-CD-3*

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 rheumatic diseases.

#### *2.12.2. 99mTc-anti-CD4 mAb*

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 bone scan.

#### *2.12.3. 99mTc-Anti-CD20 mAb*

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].

#### *2.12.4. TNF-alpha*

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