**3. Rheumatoid arthritis**

Rheumatoid arthritis (RA) is a chronic autoimmune systemic disease of unknown origin, with an overall prevalence of 1%. It mainly affects joints with symmetrical and polyarticular pattern and may lead up to progressive structural damage, functional disability and extra– articular complications. It can affect many organ systems and it is also associated with a higher prevalence of other diseases such as infections, neoplasms and cardiovascular disease. It has been shown that 50% of patients with RA are disabled within 10 years of onset of disease and survival is reduced (Malviya et al., 2010; as cited in Solomon et al., 2003, Wolfe et al., 1994, 2002, 2003).

Conventional radiology is the most wide-spread technique for the appraisal of RA, since it allows the evaluation of the presence or absence of erosions, joint space narrowing or articular osteopenia, but only when symptoms have been present for several months or years. The importance of early diagnosis in patients with RA, based on the possibility of modifying the prognosis with an early treatment, has led to the introduction of new techniques that identify the characteristic changes in an accurate and reliable way. MRI and High-Frequency Ultrasonography (US) have shown their reliability for detecting early bony, vascular and soft tissue changes in patients with RA and are the techniques most commonly used with this aim. Nuclear medicine techniques, such as imaging with nanocolloids, PET or three-phase bone scintigraphy may also be useful in this field. Three-phase bone scintigraphy is still used in clinical practice in patients with RA because it allows the detection of changes (hyperemia, increased permeability, altered bone metabolism) before the structural lesions appear, and may display the pattern of joint involvement and even predict the development of erosions (Colamussi et al., 2004; as cited in Mottonen et al.,

injection into central venous catheter, arterial injection

metallic prosthesis (elbow, shoulder, knee and hip)

Radiopharmaceutical: Free pertechnetate (stomach, thyroid, salivary glands) Technical: Injection site, lymph node (radiotracer extravasations),

Patient: Urine contamination, patient motion, breast prosthesis,

particularly if overlying the scapula or a rib (Gnanasegaran et al., 2009). Photon-deficient areas commonly seen on the bone scan are due to metallic objects. Patients should be asked to remove metallic objects wherever possible before performing the scan. Urinary contamination is a common problem, which may simulate focal lesions, especially if close to or overlying the bone. It is useful to remove the clothing or to wash the skin and reimage the patient around the region of interest to avoid any confusion. The patient should void before the study and rarely delayed imaging or bladder catheterization may be required. Further, radioactive urine in the bladder is a frequent cause of artifact in patients evaluated with SPECT for pelvic metastases (prostate cancer) or low-back pain. Increased radioactive urine in the bladder can cause streak artifacts on the reconstructed images and overlap bony structures. Further, intense tracer retention in the bladder is reported to cause pixel overload, resulting in a relatively cold area close to the region of interest of the femoral

Rheumatoid arthritis (RA) is a chronic autoimmune systemic disease of unknown origin, with an overall prevalence of 1%. It mainly affects joints with symmetrical and polyarticular pattern and may lead up to progressive structural damage, functional disability and extra– articular complications. It can affect many organ systems and it is also associated with a higher prevalence of other diseases such as infections, neoplasms and cardiovascular disease. It has been shown that 50% of patients with RA are disabled within 10 years of onset of disease and survival is reduced (Malviya et al., 2010; as cited in Solomon et al., 2003,

Conventional radiology is the most wide-spread technique for the appraisal of RA, since it allows the evaluation of the presence or absence of erosions, joint space narrowing or articular osteopenia, but only when symptoms have been present for several months or years. The importance of early diagnosis in patients with RA, based on the possibility of modifying the prognosis with an early treatment, has led to the introduction of new techniques that identify the characteristic changes in an accurate and reliable way. MRI and High-Frequency Ultrasonography (US) have shown their reliability for detecting early bony, vascular and soft tissue changes in patients with RA and are the techniques most commonly used with this aim. Nuclear medicine techniques, such as imaging with nanocolloids, PET or three-phase bone scintigraphy may also be useful in this field. Three-phase bone scintigraphy is still used in clinical practice in patients with RA because it allows the detection of changes (hyperemia, increased permeability, altered bone metabolism) before the structural lesions appear, and may display the pattern of joint involvement and even predict the development of erosions (Colamussi et al., 2004; as cited in Mottonen et al.,

Metallic: Belt buckle, medallion, jewellery, pace maker Instrumentation: Photomultiplier tube, cobalt peak, image contrast

Treatment: Postradiotherapy Table 2. Common Artifacts in Bone Scintigraphy.

heads, which hinders its interpretation.

**3. Rheumatoid arthritis** 

Wolfe et al., 1994, 2002, 2003).

1988). The intensity of uptake on scintigraphy is correlated to some clinical and laboratory indexes of disease activity (De Leonardis et al., 2008; as cited in Park et al., 1977) and the monitoring during treatment can evaluate the effectiveness of it (De Leonardis et al., 2008; as cited in Palmer et al., 1993; Elzinga et al., 2010). It is also a useful technique when an additional pathology (eg, osteonecrosis, stress fractures or metastatis) is suspected. Furthermore, in patients with nonspecific polyarthralgia, normal bone scan excludes the presence of active arthritis (Colamussi et al., 2004; as cited in Shearman et al., 1982). It is a sensitive tool but not highly specific, and may be altered in other diseases such as osteoarthritis. Nevertheless, planar bone scintigraphy is clearly less sensitive than SPECT in the evaluation of early stages of this disease or mild abnormalities. Multipinhole SPECT of the hands has been used to identify patients with minimal changes in bone metabolism (Gotthardt et al., 2010). This technique proven to equal MRI in sensitivity and also detected increased bone metabolism in two patients in whom MRI had negative results, demonstrating that multipinhole SPECT may be even more sensitive than MRI in some cases (Gotthardt et al., 2010; as cited in Ostendorf et al., 2010). PET may also be used for imaging of synovial inflammation. The most commonly used radiotracer in clinical PET scanning is fluorodeoxyglucose (18F-FDG), and since inflammation is a glucose-avid oxidative process, 18F-FDG-PET allows a quantitative measurement of the uptake of tracer concentration with a positive correlation with the degree of joint inflammation in patients with RA. Recently, it has been demonstrated its correlation with parameters of disease activity (swelling, tenderness, serum markers) and findings from gold standard techniques such as US and MRI. This quantitative assessment could be useful for evaluating the therapeutic effectiveness. Besides 18F-FDG, tracers such as 11C-choline may be used for measurement of cell proliferation and evaluation of synovitis with high accuracy (Gotthardt et al., 2010; as cited in Roivainen, 2003). Other techniques, including the imaging of sinovitis with 99mTc-nanocolloids, have shown high sensitivity and specificity in this field. Thus, nuclear medicine techniques, especially PET and multipinhole SPECT of small joints, may play a role in identifying RA at an early stage, but the usefulness of these techniques compared with MRI and US needs to be proven in RA imaging. Currently, US and MRI are the techniques of choice for serial assessments of patients with RA due to practical reasons and the required exposure of the patient to radiation in the nuclear medicine studies. Large systematic prospective studies on the efficient use of imaging modalities to assess the efficacy of treatment in early RA are lacking. Nevertheless, new imaging modalities are assuming an important role in the investigation and management of RA. Tagging important cellular and protein mediator may allow us improving the knowledge of RA pathophysiology. In recent years, the use of labelled immunoglobulins (Igs) that head for areas of inflammation and where they stay accumulated (aspecific polyclonal IgG-type antibodies labelled in most cases with Tc-99m), has been developed (**Table 3**).


Table 3. Molecular imaging of RA by radiolabelled monoclonal antibody (mAbs).

Nuclear Medicine in Musculoskeletal Disorders: Clinical Approach 103

negative endoscopic or radiological test results, abdominal scintigraphy with labelled leukocytes can be used to assess the abdominal involvement (Colamussi et al., 2004; as cited

In the setting of infection four entities can be established: osteomyelitis, septic arthritis, soft

Osteomyelitis is defined by infection localized to bone. It can occur as a result of hematogenous seeding, contiguous spread of infection to bone from adjacent soft tissues and joints, or direct inoculation of infection into the bone as a result of trauma or surgery (Lalani, 2011). Three-phase bone scan with 99mTc-hydroxymethylene diphosphonate or Tc-99m-MDP has long been used as the standard method for the detection of osteomyelitis (Gotthard et al., 2010), and positive focally increased uptake on all three phases (**Fig. 2**) is

Fig. 2. Three-phase bone scan: Focally increased uptake on all three phases in a patient with

In contrast, in the setting of cellulitis there is increased activity only in the first two phases and normal or mild diffuse increased activity in the third phase (Brown et al., 1993; Horwich, 2011). Radiographic studies do not show any change for at least 1- 2 weeks after initial infection, contrary to the three-phase bone scan where imaging of the infection can be seen in the first 24 - 48 hours of the infection (Díaz & De haro, 2005). Bone scintigraphy has a high sensitivity exceeding 80% and a limited specificity reaching up to 50% (Gotthard et al., 2010, as cited in Hakim et al., 2006; Palestro et al., 2002). The limited specificity can be explained by uptake of the radiopharmaceutical at all sites of increased bone metabolism irrespective of the underlying cause. Other conditions such as tumors, fractures, joint neuropathy may mimic osteomyelitis at three-phase bone scintigraphy. To improve specificity, complementary imaging with gallium-67 (67Ga) citrate (for spinal infection) or indium-111-labelled autologous

Gallium scans utilize the affinity of gallium-67 to acute phase reactants (lactoferrin, transferrin, and others) to demonstrate areas of inflammation that may be related to infection (Horwich, 2011). Intense uptake on 67Ga bone scintigraphy in two adjacent vertebrae with loss of the disc space is highly suggestive of spinal osteomyelitis (Palestro & Torres, 1997). This method is quite sensitive and more specific than three-phase bone scan (Horwich, 2011; as cited in Palestro, 1991; Tumeh, 1986). It is typically performed 24 hours following inyection and therefore should be reserved for patients who are clinically stable and do not require prompt

leukocytes (for the appendicular skeleton) is often performed (Love et al., 2003).

in Elkayam et al., 2002).

tissues infections and joint replacement infection.

**5. Infection** 

**5.1 Osteomyelitis** 

usually seen (Love et al., 2003).

osteomyelitis of the right great toe.

The immunoscintigraphy has proven to be more sensitive than clinical examination for identifying synovitis and have a high positive predictive value for the onset of RA in patients with nonspecific arthropathy, and its usefulness for monitoring and assessing treatment response (Colamussi et al., 2004; as cited in De Bois et al., 1995a, 1995b, 1996). It can also be used to detect infection, although the preferred technique in these cases is labelled leukocyte scintigraphy, in which two tracers are often used: 99mTc-HMPAO or 111In-oxine (De Gersem & Jamar, 2010). Labelled leukocyte scintigraphy is also useful in assessing therapeutic response in RA patients and it has been correlated with other indices of activity in this disease (Collamussi et al., 2004; as cited in Al-Janabi et al., 1988). However, immunoscintigraphy seems to be more accurate than labelled leukocyte scintigraphy for the identification of synovitis in RA (Collamussi et al., 2004; as cited in Liberatore et al., 1992). Other molecules and receptors (e.g. 64Cu-labelled anti-GPI, 68Ga-labelled annexin V or 123I-antileukoproteinase) are being identified as therapeutic targets and used to develop new radiopharmaceuticals which accumulate in areas of inflammation where they can be located and quantified. Their study and description will allow improving the understanding of the complex pathophysiology of RA and detecting changes in very early stages of this disease and will give us the possibility of a pre-therapy scintigraphic approach with radiolabelled monoclonal antibodies that will let us evaluate the presence of target molecules in the inflammatory lesion, thus helping in the selection of the most efficient therapy and predicting therapy response (Glaudemans et al., 2010; Malviya et al., 2010). But currently, these techniques are not used in clinical practice and remain like a research tool

inside selected laboratories. Bioluminescence and fluorescence reflectance imaging are other approaches that allow imaging, and potentially the delivery of therapeutic agents at a molecular level (McQueen & Ostergaard, 2007).
