The expanding role of nuclear medicine in rheumatology
Year: 2023
Type: article
Abstract: The use of radioactive tracers was introduced in the 1930s as a novel method to explore the thyroid gland. The clinical value of this approach was soon picked up and expanded by endocrinologists and oncologists as well as other medical specialists in the investigation and treatment of a wide range of diseases. The remarkable development of gamma cameras and positron emission tomography (PET) scanners has enhanced the clarity of nuclear medicine procedures to probe the metabolic effects of disease. More recently, the introduction of fused PET and computed tomography scanners (PET/CT) has allowed for metabolic imaging superimposed on anatomical mapping for an accurate localization and knowledge of various disease processes. The radioactive tracers used in diagnostic procedures are usually gamma or positron emitters with low doses, short half-lives, and no significant radiation exposure to the patients or their environment. Before radioactive tracers are administered into human body, they need to be incorporated (labeled) with a specific chemical or biological ligands that are known to be attracted to specific organs or disease process. This combination is usually referred to as radiopharmaceuticals. Examples include labeling a tracer such as technetium-99 m with a phosphonate (Tc-99 m-HDP) to visualize hydroxyapatite in bone scanning or labeling the tracer with the patient’s own leucocytes (Tc-99 m-HMPAO white blood cell [WBC] scan) to detect sites of infection or inflammation. The gold standard of this technique is the labeling of a positron emitter such as fluorine-18 with a glucose precursor (F-18 fluorodeoxyglucose [FDG]) to detect increased glucose metabolism in malignant [Figure 1] or infected/inflamed lesions.Figure 1: Fluorine-18-fluorodeoxyglucose positron emission tomography scan showing multiple bony metastases in a patient with bowel cancerThe most investigated rheumatological conditions with nuclear medicine procedures include rheumatoid arthritis (RA), vasculitis, and myopathy. Intra-articular injection of yttrium-90 colloid is the main therapeutic application in rheumatology. These are discussed further as follows. Bone scanning with Tc-99 m HDP has been used in the diagnosis of RA, to identify the joints involved and assess response to therapy. A three-phase acquisition is employed to assess blood flow (Phase 1) and blood pooling (Phase 2) and demonstrate the osteoblastic activity (bone Phase 3). In acute inflammatory RA, there is increased blood flow and pooling in the affected joints and adjacent soft tissue, followed by increased uptake in the periarticular bones demonstrated on the bone phase. The overall display reflects the synovitis and inflammation of the chondro-osseous zone culminating in edema, vascular proliferation, and synovial hypertrophy [Figure 2].Figure 2: Technetium-99 m HDP bone scan showing significantly increased uptake in the wrists and finger joints in a case of severe rheumatoid arthritisIn a study by Möttönen et al. of 13 patients with confirmed RA who underwent serial bone scans over a period of 1 year, the authors concluded that persistent activity on bone scan predates the onset of erosions while a negative bone scan excludes synovitis.[1] Another group has shown the value of negative bone scan follow-up over 3.6 years in ruling out inflammatory joint disease in all 22 patients with RA.[2] Tc-99 m-labeled WBC (Tc-99 m-HMPAO WBC), used to detect infection or inflammation, has been used to demonstrate uptake in active knee inflammation with reduction of uptake following steroid injection.[3] Further development of new procedures involving labeling specific polyclonal IgG antibodies (Tc-99 m HIG) was followed. They proved to be sensitive in predicting the development of RA in patients with arthralgia.[4] More recently, several monoclonal antibodies such as anti-TNFa, anti-CD20, and anti-E-selectin antibodies have been labeled and used in imaging to detect affected joints and identify the ones that may respond to therapy with the same antibodies.[5] Molecular imaging with F-18-FDG PET detects increased glucose metabolism and provides diagnostic and staging data in RA and can assess response to therapy with disease-modifying and anti-inflammatory therapy [Figure 3]. However, FDG is nonspecific and shows similar uptake in malignant lesions or active osteoarthritis. Therefore, new and more specific PET tracers were introduced. One example is macrophage imaging with PET using carbon-11 tracer (C-11-(R)-PK11195) which binds to the peripheral benzodiazepine receptors on macrophages. In a study of 11 patients with RA of the knees, C-11-(R)-PK11195 PET imaging was correlated with arthroscopy and immunohistochemistry staining of obtained samples. The results showed higher uptake in inflamed joints and significantly high uptake in contralateral noninflamed joints, suggesting a prognostic role in picking up disease prior to clinically evident synovitis.[6] Other PET tracers such as gallium 68 labelled with angiogenesis marker PRGD2 (Ga-68 PRGD2) was used by Zhu et al. to image angiogenesis in synovial membranes of joints affected by RA.[7] They investigated 20 patients with untreated RA and compared imaging with Ga-68 PRGD2 and F-18 FDG PET/CT scans and correlated these with core variables of disease activity including clinical disease activity index. They found that posttherapy changes noted on Ga-68 PRGD2 correlated significantly better with clinical disease activity index [Figure 4].Figure 3: Fluorodeoxyglucose positron emission tomography scan showing significantly increased uptake in major joints in rheumatoid arthritisFigure 4: Gallium 68 labeled with angiogenesis marker PRGD2 positron emission tomography scan showing increased angiogenesis activity in major joints in rheumatoid arthritisVasculitis is an inflammatory condition of blood vessels characterized by vascular infiltration and, if not treated at early stages, resulting in the destruction of the vessel wall and adjacent structures with significant consequences such as infarction. Conventional cross-sectional imaging such as CT and magnetic resonance imaging (MRI) can demonstrate the anatomical changes once they are established, but lack the capacity of detecting early inflammatory changes which are potentially treatable with resultant impact on outcome and survival.[8] Earlier nuclear medicine studies have employed imaging with gallium-67 citrate and Tc-99 m-HMPAO labeled white cells in the evaluation of vasculitis such as Wegner’s granulomatosis and Kawasaki’s disease. However, their low sensitivity resulted in their replacement with molecular imaging such as F-18 FDG PET/CT. The resolution of PET scanners (the ability to detect a small lesion) is currently around 5 mm. This means that detection of vasculitis is achievable in medium and large blood vessels rather than small vessel disease. Good examples of conditions amenable for detection include giant cell arteritis (GCA) and Takayasu’s arteritis (TA). In normal subjects, the uptake of F-18 FDG PET in blood vessels is faint and close to background activity. In cases of vasculitis, this pattern changes to intense uptake, mostly in a linear pattern along the vessel walls, due to the underlying inflammatory changes. In a study by Meller et al., 15 patients with GCA and TA underwent F-18 FDG PET and MRI and correlated the findings with clinical and laboratory findings. F-18 FDG PET was shown to be better than MRI in identifying the extent of the disease, monitoring disease activity and response to therapy. They also showed that early diagnosis was possible before late complications.[9] Similar findings in a smaller group of patients were also demonstrated by our group.[10] The hallmark of diagnosis is the presence of a linear area of increased uptake along the vessel wall, which is well demonstrated in a patient with vasculitis affecting the carotid, subclavian, and axillary arteries [Figure 5].Figure 5: Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scan in a patient with carotid, subclavian, and axillary arteritis, showing linear increased uptake in the involved arteries. CT projection (a), PET projection (b), and fused PET/CT (c)Assessment of disease progression or response to therapy is achieved using a standard uptake value (SUV) measurement as part of PET imaging. Our group studied 23 patients with TA by imaging with F-18 FDG PET and calculated SUV values before and after therapy. They found it useful in assessing response to therapy and reducing the need to perform arterial biopsies or repeat angiography.[11] When comparing the results with angiography and clinical scoring, the results showed sensitivity, specificity, negative, and positive predictive values of 92%, 100%, 85%, and 100%, respectively. An accurate diagnosis of inflammatory myopathy requires a muscle biopsy, which is difficult due to the heterogeneous nature of muscle involvement. There is, therefore, a need for an imaging modality that can depict the disease activity, identify a site for biopsy, and assess disease response to therapy. Under normal conditions, there is no uptake of FDG in muscles and this is ensured by asking patients to stay still for 1 h before imaging. Therefore, any FDG uptake in a muscle should be due to unsolicited activity or the presence of abnormal metabolic activity in a muscle such as inflammatory myopathy. An interesting case report was published by Agriantonis et al., showing intense and diffuse muscle uptake on F-18 FDG scanning in a patient as a manifestation of chronic graft versus host disease (GVHD). They highlighted the value of early detection of GVHD-induced polymyositis and its early treatment to prevent devastating consequences.[12] Our group published a series of four patients investigated with F-18 FDG PET for assessment of diffuse inflammatory myopathy.[13] One of the patients had a drug-induced myopathy, in which F-18 FDG showed a significant uptake in upper and lower girdle muscles with resolution of uptake 4 months following discontinuation of the offending medication. Despite its potential in detecting early stages of myopathy, F-18 FDG is not well covered in the literature or clinical practice, possibly due to unjustified concern regarding exposure to radiation in a benign condition, cost of the procedure, or lack of awareness. Radiation synovectomy (RS) is the process of intra-articular injection of beta-emitting radioactive tracers to deliver a radiation dose to an inflamed synovium. This can provide a therapeutic effect on persistent synovitis that is resistant to nonsteroidal anti-inflammatory drugs and intra-articular injection of steroids.[14] The radiopharmaceuticals used are commonly made of small colloid particles labeled with a beta-emitter such as yttrium-90, rhenium-186, erbium-169, and samarium-153. Once inside the joints, the particles are taken by phagocytes and deliver a cytotoxic dose to the inflamed synovium. The injected joint needs to be immobilized for 24 h during which minimal local pain may be encountered which responds to simple analgesia. Most patients will experience a therapeutic effect within 3–4 weeks. A meta-analysis of published data on the efficacy of RS has shown 51%–100% success rate.[15] In another study, Jahangier et al. performed RS for RA of the knees on patients who had two or more failed steroid injection. Evaluation after 1 year showed 78% of patients with effective treatment.[16] We presented a small series of 7 patients with RA in whom a total of 10 knees were treated with Y-90. All patients had no response to 2 or more intra-articular steroid injections. The average follow-up was 23 months (range, 15–45 months). Five patients showed pain control and no recurrence of effusion for the follow-up period. Our results prompt us to raise awareness of the potential benefit of this procedure. There is less referral from the new generation of rheumatologists, leading to less experience and interest in the nuclear medicine community.[17] Nuclear medicine procedures are extremely helpful in the management of a variety of rheumatological conditions. Traditional imaging tests such as bone scanning and labeled white cells are helpful in detecting inflammatory conditions and response to treatment. However, the introduction of PET/CT with a wide range of radiopharmaceuticals has enriched the clinical practice by probing the molecular and submolecular changes in the disease process with superb resolution and accurate localization. New PET radiopharmaceuticals targeting activated macrophages such as C-11-(R)-PK11195-folate and F-18-PEG-folate are expected to further improve the imaging of inflammation, which is the underlying process of most rheumatological conditions. In addition to imaging, nuclear medicine offers pain relief through the localized cytotoxic effect of beta-emitters injected in affected joints.
Source: Arab Journal of Rheumatology
Authors: Adil Al-Nahhas, Imene Zerizer, Ali S. M. Jawad
Institution: King's College London
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4393084348