New Radiopharmaceuticals for Imaging Rheumatoid Arthritis

By Chianelli, M; D’Alessandria, C; Conti, F; Priori, R; Et al

Rheumatoid arthritis (RA) is an incapacitating chronic inflammatory disease of the joints that, because of frequent relapses, requires life-long treatment. In patients affected with RA an important treatment objective is to achieve specific immune suppression in order to extinguish the immune process and arrest the disease, thus preventing or delaying complications and avoiding disease recurrence. The side effects of anti-inflammatory drugs given to improve the quality of life of these patients can be reduced with the use of specific immune therapies that block, as selectively as possible, the pathologic mechanism responsible for the disease. New therapeutic options for specific, targeted therapies for treating RA are being developed, and trials to assess the efficacy and safety of these approaches are underway. However, these therapies rely primarily on clinical assessment to evaluate treatment efficacy. It would be useful, therefore, to have an objective and reliable method that directly highlights the immune processes underlying the disease. Currently available radiopharmaceuticals for imaging RA, with a special emphasis on recently developed agents and their use in therapy decision-making and follow-up are the focus of this article.

KEY WORDS: Arthritis, rheumatoid, diagnosis – Arthritis, rheumatoid, therapy – Nuclear medicine.

Pathogenesis of rheumatoid arthritis (RA)

RA is a polyarticular chronic inflammatory disease characterized by synovial pannus formation leading to cartilage destruction and hone erosion. RA most commonly presents in the 3rd through the 5th decades of life, although it may begin at any age, including childhood. Patients with RA have inflammatory arthritis in a symmetrical distribution. Commonly involved joints include the wrists and small joints of the hands and feet, although any synovial joint may be affected.

While theories abound concerning possible causative factors for RA, no definitive explanation has yet been found. RA has the features of an autoimmune disease; the autoantibodies that are produced in RA are generally specific for ubiquitous antigens. Rheumatoid factor (RF) measures autoantibodies directed against human imnumoglobulin (HIG), typically IgG. Although a positive RF is present in about 85% of patients with RA, this test may he positive in other diseases and even in normal individuals as well. The frequency of a false-positive result increases with age. Several additional autoantibody specificities have been studied in early RA, including anti-hnRNP A2/RA-33, anti-α enolase, anti-Sa, anti- calpastatin, and anti-cyclic citrullinated peptide (anti-CCP).1 Anti- CCP displays high specificity for RA, accompanied by reasonably high (80%) sensitivity. Detection of anti-CCP antibodies is a useful diagnostic tool, particularly in the early stages of the disease, and a predictive factor for disease progression and radiological damage.However, RA-associated autoantibodies can be considered signs of immune defects but not the mediators of classical autoimmune responses to autoantigens uniquely available in the synovium. Since several genetic loci correlate with increased susceptibility to RA. it is likely that common genetic features in RA patients predispose them to develop the disease when exposed to an appropriate environmental trigger. Specific human leukocyte antigen (HLA)- defense response (DR) genes, which reside in the major histocompatibility complex, are associated with the disease. HLA antigens are cell surface proteins that play a critical role in antigen presentation. The relationship between IILA-DR and RA is the strongest genetic link in RA; this gene has been mapped to the 3rd hypervariable region of DR chains, The susceptibility epitope is glutamine-leucine-arginine-alanine-alamine (QKRAA) or QRRAA. This sequence is found in multiple RA-associated DR genes, including DR4, DR14 and DR1 (e.g., DRB*0401, DRB*0404, DRB*0101 and DRB*1402). The susceptibility epitope may also influence disease severity; the risk of extra-articular and erosive disease is greater in patients with RA-associated DR genes and is further increased by homozygosity.3 However, other pathogenetic factors are clearly involved, given that the concordance of RA in identical twins is only about 15%.

Although no single causative factor for RA has been identified, advances have Ix-en made in elucidating the subsequent steps in its pathogenesis. In RA-affected joints, the synovial lining layer becomes hyperplastic and hypertrophie, forming an aggressive, inflammatory tissue (pannus) which erodes into the cartilage and bone. Several important lessons have been learned from examining the therapeutic effects of imnumomodulatory interventions such as tumor necrosis factor-α (TNF-α) blocking agents and other biologic reagents. The clinical efficacy of these novel immunosuppressive therapies lor treating RA has emphasized the complexity of the disease process and the multitude of pathways that probably contribute to persistent inflammation.

Within the subsynovial inflammatory tissue, lymphocytes, macrophages, and other inflammatory cells promote ongoing joint inflammation. The most frequent type of rheumatoid synovitis is a diffuse inflammatory infiltrate in which infiltrating T cells, B cells. and macrophages are scattered among tissue-resident cells; the infiltrate by itself does not achieve a higher level of organization. In 40% to 50% of patients, B cells, T cells, and dendritic cells (DCs) organize into follicular structures or, rarely, into granulomas. ‘ Recent data suggest that inflammation in rheumatoid joints is initiated by cell-cell interactions between antigen-presenting cells and CD4+ T cells,5 leading to the activation of macrophages and induction of the inflammatory process, ultimately culminating in the degradation and resorption of cartilage and bone. The cytokines generated within the joint tissue stimulate this process, with pro inflammatory overpowering anti- inflammatory cytokines. Cytokines are believed to play multiple roles in the pathogenesis of RA, beginning with the activation of antigen-presenting cells and T cells. Cytokines also maintain and perpetuate the immune response by interacting with cells that bear appropriate cell-surface receptors. Once activated, these cells produce their own cytokines; this sequential production of cytokines constitutes the “cytokine cascade”. Although many cells can respond to cytokines, fibroblasts and macrophages are believed to be particularly important in the pathogenesis of RA. Of the many cytokines present in the rheumatoid synovium, TNF-α, a cytokine produced primarily by monocytes and macrophages, Ls thought to act as a dominant cytokine in the cytokine cascade and to regulate the production of several other proinfiammatory molecules, including IL- 1, IL-6, IL-9, and granulocytemacrophage colony-stimulating factor.6

In vitro and in vivo data suggest that TNF-α is involved in the chronic inflammation of RA. In RA patients, high levels of TNF- α are present in synovial fluid and synovial tissue, where the cytokine localizes to the cartilage-pannus junction (the major site of joint destruction in RA).7 TNF-α is believed to play a key role in joint destruction, as evidenced by its ability to stimulate the production of matrix metalloproteinases and to mediate bone resorption in vitro.8 In animal models of RA, neutralization of TNF- α decreased the incidence and severity of inflammatory arthritis, while injection of TNF-α into ankle joints accelerated the onset of arthritis.9 Taken together, these data provide strong evidence of a pivotal role for TNF-α in the pathogenesis of RA. Some cytokines, particularly IL-1, increase the number and activity of osteoclasts, those cells responsible for bone matrix resorption.10 However, other new factors have been implicated in the pathogenesjs of RA; for instance, IL-18, a member of the IL- 1 family, activates synovial macrophages, increases IL6 gene expression and the production of cyclooxygenase-2 and stromelysin by chondrocytes.11 In addition, osteoclast-mediated done resorption is now known to be regulated by the RANK (receptor activator of nuclear factor-κ B) ligand (RANKL). RANKL is expressed by a variety of cell types involved in RA, including T cells and synoviocytes. These cells, in the presence of TNF-α and other cytokines, contribute to osteoclast activation. The soluble receptor to RANKL, osteoprotegerin. and RANKL are increased in RA, but normalize after treatment with TNF inhibitors.3

The role of nuclear medicine in the study of RA

Nuclear medicine techniques are sensitive diagnostic modalities for the evaluation of the state of activity of RA. This is of paramount importance, given that many therapeutic options are now available and that prompt initiation of treatment may lead to disease regression or, at least, a delay in complications. Recent developments in molecular nuclear medicine, with the production of specific radiopharmaceuticals, have contributed to the identification of the immune process responsible for the disease. With nuclear medicine studies, the referring physician obtains i\nformation not only about the activity of the disease but also about the nature of the process and so can better decide which treatment to start, when to start it and when to stop or modify it.

Past racliopharmaceuticals

^sup 99m^Tc-labeled nanocolloids

^sup 99m^Tc-labelled nanocolloids are small particles, 30 nM in diameter, produced from albumin, that are taken up by the cells of the reticuloendothelial system and are rapidly cleared from the circulation following uptake by the liver, spleen and bone marrow. Owing to increased vascular permeability, they leak into inflamed tissues nonspecifically and accumulate following phagocytosis by macrophages.12 The technique is inexpensive and easy to perform. The uptake of ^sup 99m^Tc-nanocolloids in inflamed lesions is relatively small compared with that of other radiopharmaceuticals 13 but because they are rapidly cleared from the blood, a satisfactory target-to-background ratio is quickly achieved, permitting completion of the study usually within about 1 h. In a comparative study on RA, radiolabeled nanocolloids showed a diagnostic accuracy similar to that of ^sup 99m^Tc-HIG and ^sup 99m^Tc-HMPAO labeled leukocytes.14

Nonspecific immunoglobulins

Radiolabeled nonspecific HIGs have also been used for the diagnosis and localization of sites of inflammation and infection. Their use is safe and simple. They are of human origin, produce no allergic reactions or side effects, and are easily prepared. Their mechanism of action has not been completely elucidated; it is assumed to be, at least in part, nonspecific, following increased vascular permeability.15 Specific uplake by binding to the Fc receptor expressed by infiltrating cells may also play a role.16 In RA, however, the mechanism of uptake is mainly nonspecific.17

Several studies with radiolabelled HIG have been performed in RA. In general, this scintigraphic method shows a good correlation with disease activity and can accurately detect the severity and extent of disease. HIG accumulation has also been shown to correlate with the degree of histologically detected synovitis and has proved more accurate than physical examination and bone scan.18-20

De Bois et al. showed that HIG scintigraphy can also be used to predict RA in patients with arthralgia, and it accurately detects the effects of treatment in such patients.21,22 At present, radiolabeled HIG is the commercially available radiopharmaceutical most frequently used for the study of RA.

Monoclonal antibodies and antibody fragments against adhesion molecules

Following exposure to proinflammatory cytokines, adhesion molecules such as ICAM-1, VCAM, and K-selectn are specifically expressed on activated endothelium and bind to circulating granulocytes and lymphocytes, promoting their active migration into inflammatory foci.23 In particular, E selectin is an adhesion molecule specifically expressed on activated endothelium but is not expressed on noninflamed tissues.24 A novel approach to the detection of inflammation is based on the use of radiolabeled monoclonal antibodies directed against adhesion molecules.

One advantage of this approach is the antibody’s easy access to the target antigen expressed on the external side of the vessel; therefore, the MoAb does not need to migrate into the inflamed tissue. In a recent suidy, ^sup 111^In-labelled anti-E-selectin MoAb demonstrated higher diagnostic accuracy than ^sup 99m^TC-HIG in the evaluation of RA patients.25 In another study, the use of anti E- selectin F(ab’)^sub 2^ fragments versus ^sup 111^In-HIG was compared in 12 RA patients.26 The accumulation of anti E-selectin F(ab’)^sub 2^ fragments in active joints correlated with the patients’ clinical scores, and the agent’s sensitivity was higher than that of ^sup 111^In-HIG.

Radiolabeled leukocytes

Radiolabeled leukocytes have also been employed to study RA patients. These agents are characterized by high specificity, as they only accumulate as a consequence ol active migration into inflamed joints. Their use provides good evidence for leukocyte migration into the inflamed joint. A comparative study by Liberatore et al.,14 however, showed that they were no more accurate than radiolabeled HlG. Consequently, because of the disadvantages of the in vitro labeling procedure, labeled leukocyte imaging is no longer used in the study of RA.27, 28

Monoclonal antibodies and antibody fragments against lymphocytes

Few antibodies have been successfully applied to detect tissue- infiltrating lymphocytes. A ^sup 99m^Tc-labeled anti-CD4 antibody (Max.16H5, IgG1) 29 to localize diseased joints in patients affected by RA has been studied. In this study, 5 patients were investigated using the anti-CD4 antibody and a three-phase bone scan. All patients showed labeled antibody accumulation in diseased joints as early as 90 min Lifter injection. The antibody uptake correlated with the clinical signs and the early phase of the MDP scan, while a weak correlation was observed with the late bone scan, confirming the specificity of anti-CD4 uptake in inflamed joints. In another study by the same group,30 the specificity of the same anti-CD4 antibody was compared with ^sup 99m^Tc-labelled polyclonal HIG. The anti-human CD-4 MoAb showed a higher target-to-background ratio in arthritic knee and elbow joints than polyclonal HIG, indicating that the former accumulates at sites rich in CD4-positive lymphocytes. Studies with technetium-labeled anti-CD3 MoAb to evaluate RA patients produced encouraging results, but side effects developed because of the high biological activity of this agent.31

J001X

J001X is a non-pyrogenic acyhited polygalactoside isolated from the membrane proteoglycans of a nonpathogenic strain of Klebsiella pneumoniae. It binds to CD11b, the complement receptor 3 expressed on monocytes, NK cells and macrophages, and to CD14, a lipopolysaccharide receptor expressed on monocytes macrophages. J001X labeled with ^sup 99m^Tc has been successfully used in an arthritis model in rabbits.32

New therapeutic approaches to RA

Progress in understanding the biological mechanisms of RA has led to better targeted therapies that have joined, and in many cases replaced, more traditional treatments. The approach to the RA patient has changed from the traditional therapeutic pyramid, where disease-modifying antirheumatic drugs (DMARDs) were added only after a long period of active disease, to an earlier more aggressive treatment, where disease-modifying agents are prescribed soon after the disease is diagnosed. In recent decades, so-called biological drugs, i.e. drugs capable of modifying biological response (biological response modifiers [BRMs]), have evolved from theoretical concept to clinical trials to world market. It is estimated that by 2005 they had been prescribed to almost 1 million patients, the majority with RA. The spectrum of indications for this rapidly expanding new class of drugs includes ankylosing spondylitis, psoriasis, and psoriatic arthritis. Few of these drugs are currently approved for use in RA: 3 are TNF-α antagonists (Infliximab, Hlanercept and Adalimumab) and 1 inhibits IL-1 (Anakinra). These BRMs suppress the clinical manifestations of RA, improve patient mobility, and retard the radiographic progression of joint erosion. They are more effective when treatment is begun shortly after disease onset.33, 34

Infliximab, a chimeric IgG1 anti-TNF-α antibody formed by the antigen-binding region of mouse antibody linked to the constant region of the human antibody, binds soluble and membrane-bound TNF- α, impairing its binding to the specific receptor. In addition, Infliximab also mediates the apoptosis of cells expressing TNF- α. The drug is administered intravenously (3-5 mg/kg) as a 4-8 weekly infusion generally in combination with methotrexate (MTX) to minimize the formation of anti-Infliximab antibodies; its half-life is 9 days. A multicenter study has demonstrated that the combination of Infliximab and MTX is superior to MTX alone in improving clinical response and radiographic progression.35 Etanercept is a soluble TNF- receplor fusion protein composed ol 2 dimers, each having the ligand binding portion of the type 2 receptor (p75) linked to the Fc portion of human IgG1; it has a hall-life of-4 days. It binds to both TNF-α and lymphotoxin-α, preventing interaction with their respective receptors. Also for Etanercept (25 mg administered subcutaneously twice a week), combination therapy with MTX was shown to be significantly better in reducing disease activity and promoting the delay of radiographic progression than either therapy alone. Based on the observation that the combination therapy resulted in a negative progression of the modified Sharp radiological score compared to baseline, a repair of previous joint damage its been hypothesized.36 The binding of TNT-α to its receptor can be precluded by Adalimumab, too, the latest TNF-α antagonist marketed for RA (40 mg given subcutaneously every other week). This recombinant completely human IgG1 monoclonal antibody also lyses cells expressing cytokine on their surface: its half- life is 2 weeks. Adalimumab (40 mg given subcutaneously every other week) plus MTX sustained clinical response and remission in KA patients during a 4-year observation period.37 More recently, the PREMIER study has shown that Adalimumab combined with MTX is superior to both MTX and Adalimumab monotherapy in improving signs and symptoms of disease, inhibiting radiographie progression, and producing clinical remission38

According to Maini. “for the treatment of established RA that is unresponsive to DMARDs (the usual clinical scenario), failure of treatment with MTX is most successfully treated by adjunctse therapy with an anti-TNF-α agent.”39

No randomized head-to-head comparisons of these therapies have been published, so it is difficult to compare results from randomiz\ed trials because they involve different patient populations and employ different study designs and treatment strategies. Moreover, there seem to be differences not only in the route of administration chosen and in the agents’ pharmacokinetic and pharmacodynamic properties, but also in the exact mechanisms of action, clinical efficacy and safely profile of these agents, all of which could explain the positive results obtained using an alternative anti-TNF- agent when the original one has failed. Long- term data on the overall safety of anti-TNF- agents are awaited: patients treated with anti-TNF- antagonists are more susceptible to infection (even though such a risk is higher per se in RA patients), especially those caused by intracellular organisms in areas with a high endemic load. The repoited unexpected development and reactivation of demyelinating diseases during treatment with anti- TNF-α and the new appearance of autoanlibodies in the absence of a clearly increased risk of developing additional autoimmune disorders have raised concern about the risk of lymphoproliferative malignancies and cytopenia after the use of anti-TMF-α therapies.34

Anakinra. an IL-1 receptor antagonist, competes with IL-1 for binding to its receptor, subsequently down regulating IL-1 activity. It is administered by daily subcutaneous injection and. in combination with MTX. has been reported to be an effective and safe treatment for RA patients not responsive to MTX alone. However, indirect evidence exists that the efficacy of Anakinra is somewhat lower than that of TNF-α antagonists.40

Of the other therapeutic proinflammalory cytokines, IL-6 is considered an attractive therapeutic candidate for RA. MRA is a humanized ami-human IL-6R monoclonal antibody that is able to inhibit the binding of IL-6 to soluble IL-6R or cell surface IL-6R. The drug reduces disease activity, but its effect on radiographie progression still needs to be evaluated.33 Other blocking agents directed against cytokines involved in the inflammation process, such as 1L-15, 1L-17 and 11-18, have been developed. Further research on these agents is needed.

A promising approach to the treatment of KA is the use ol co- stimulation blockers. Cytotoxic T-lymphocyle-associated antigen 4 Ig (CTLA4 Ig) (Abatacept) is a fusion protein consisting of the extracellular domain of human CTLA4 and a fragment of the Fc-domain IgG 1, which blocks the high-avidily receptor for CD80 and CD86. It is administered intravenously and inhibits T-cell function without T- cell depletion.41 In recent years. Rituximab, a genetically engineered chimcric anti-CD20 monoclonal antibody, has been gaining a wider role in the treatment of RA; its efficacy has been demonstrated in blind randomized controlled trials.42

New radiopharmaceuticals

New needs for therapy decision-welking and follow-up

Although most patients show good response to anti-TNF therapy, a subset of those with RA do not respond to TNF neutralization, probably because of large inter- and intraindividual variability in the level of TNF-α expression or because of a major involvement of other pro inflammatory cytokines in the disease. Some patients may form antibodies against TNF-α inhibitors. Knowing whether TM-α is expressed in the affected joints of a patient with RA would be useful for selecting those patients likely to respond to anti-TNF-α biological treatment. This information might be a helpful aid to optimize, and monitor the effect of TNF-α antagonism. Because RA is a polyarticular disease, imtmmohistological assessment cannot be routinely used to evaluate the degree of TNF-α expression in diseased joints. Imaging studies tor targeting and visualizing TNF-α in vivo are an important alternative to other, more invasive techniques. The use of radiolabeled mAbs for specific targeting of membrane-bound or a soluble form of TNF can provide accurate information about disease activity, severity, extension, and localixation. Infliximab (a chimeric mouse human anti-TNF-α mAb) and Adalimumab (a fully human mAb) are 2 biological agents approved for treating RA. In several preliminary studies they have been labeled with ^sup 99m^Tc and used for imaging.

Radiolabeled anti-TNF-α antibodies

PUBLISHED DATA ON RADIOLABELED INFLIXIMAB

Infliximab (Remicade), a chimeric mouse/human anti-TNF-α antibody, has been shown to be highly effective in reducing chronic symptoms of RA by binding TNF-α with high affinity and specificity (Kd 110^sup -10^ M) both in soluble and membrane-bound form. The use of Infliximab radiolabeled with technetium for in vivo detection of articular TNF-α-mediated inflammation in RA patients has been successfully assessed in a pilot study by our group. Seven RA patients eligible for intra-articular therapy with Infliximab (9 joints studied) were enrolled in the study. Patients received an intra-articular administration of 100 mg of Remicade and were evaluated by scintigraphic imaging with radiolabeled infliximab before and 3 months after treatment. Infliximab was directly radiolabeled using methylen-diposphonate (MDP) as a weak competitor ligand, after reduction of disulfide bridges by 2-ME, according to the method described by Mather et al.43 Planar images of the inflamed joints were acquired at 3 h, 6 h and 24 h after injection of 15 mCi of ^sup 99m^Tc-Infliximab (0.2 mg). In these preliminary studies in humans, ^sup 99m^Tc-Infliximab showed specific targeting of inflammation with high joint-to-blood ratio, no uptake in normal tissues and a human anti-mouse antibody response after treatment. Post-treatment scintigraphy showed different amounts of accumulation of the radiopharmaceutical in the joints: ^sup 99m^TcInfliximab uptake disappeared in 1 joint (≥95% reduction), was significantly reduced in 2 joints (50-75%), slightly reduced in 4 (17-38%) and was unchanged in 2 (<5%). These preliminary results in humans suggest that radiolabeled Infliximab may provide relevant information for the clinical management of RA patients. Radiolabeled anti-TNF-α scimigraphy can be used for improving the selection of those patients who could benefit most from local or systemic treatment with unlabeled Infliximab. This procedure could be useful for obtaining a more objective evaluation of immunoiherapy efficacy and treatment of asymptomatic joint inflammation with a view to avert future clinical relapses.

PRELIMINARY DATA ON RADIOLABELED HUMIRA

Because the amino acid sequence of mouse proteins is usually different from their human counterparts, mouse proteins tend to be immunogenic. Patients treated with mouse human chimeric antibodies can develop human anti-mouse antibodies, which may reduce the clinical effectiveness of the drug. In an attempt to minimize this problem, antibodies have been molecularly engineered to reduce the percentage of murine sequences. Adalimumab (Humira), a fully human IgG1 anti-TNF mAb, has been developed using phage display technologies. This compound has high specificity and affinity for TNF-α (Kd 610^sup -10^ M). Phase I and III studies have shown that repeated administration of the agent results in rapid and sustained clinical improvement as well as radiological regression in patients with RA.44 Adalimumab has been radiolabeled with technetium using a bifunctional chelating agent (S-HYNIC) conjugated to the antibody and a co-ligand (Tricine) in the presence of stannous chloride as a reducing agent, The ability of radiolabeled Humira to specifically detect TNF-α in inflamed joints was evaluated in 10 RA patients. ^sup 99m^Tc-anti-TNF mAb was systemically administered 10 study its distribution and whether imaging with this agent is sensitive to changes in disease activity. Prior to imaging, patients received a single intravenous subtherapeutic close of 0.1 mg (20 mCi) of ^sup 99m^Tc labeled human anti-TNF mAb to assess its biodistribution in vivo. An excess anti-TNF mAb competition study was followed by a second scintigraphy to assess the agent’s specificity for TNF targeting and its sensitivity to reflect decreased inflammation after the administration of systemic corticosteroid.45 Adalimumab has also been radiolabelled with technetium by the direct method used for labeling Infliximab in order to compare radiolabeled Infliximab versus Humira in terms of biodistribution. specific targeting, and sensitivity of imaging in 10 patients, The results obtained using ^sup 99m^Tc-anti-TNF mAb raeliolabeled with the 2 strategies were comparable. On the scans, the inflamed joints imaged using ^sup 99m^Tc-Humira were clearly visualized at 4 h and 24 h after injection, and the increase in uptake at 20 h was 20% to 30%. No uptake of ^sup 99m^Tc-anti-TNF mAb was seen in the unaffected joints. Radioimmunoscintigraphy with a ^sup 99m^Tc-labeled human anti-TNF mAb is feasible and can be used to image diseased joints in patients with active RA. The localization and retention of ^sup 99m^Tc-labelled human anti-TNF mAb in inflammatory foci is to a large extent caused by specific targeting TNF in the arthritic joints, These results are supported by the reduced uptake of this radiolabeled agent in inflamed joints, when an excess of unlabelled antiTNF mAb is administered.

Future prospect

The use of radiolabeled anti-TNF-α MoAb has pioneered a new strategy to assess additional therapeutic options in RA based on the identification of a ,specific molecule target of the biotherapy. This may be a useful aid to validating new drugs and to better understanding the feasibility of treatment, in that it can demonstrate in the individual patient the presence of a target molecule and how it will be modulated after treatment. Many BRMs are currently being developed for treating RA: Etanercept (Embrel ) is a dimeric fusion protein that joins the human p7S TNF-α receptor to the Fc domain of human IgG1,4\6 CDP3870 is a genetically engineered human anti-TNFα antibody fragment attached to polyethylene glycol,47 Abatacept (CTLA4-Ig) is the first in a new class of agents for treating RA that selectively modulate the CD80 or the CD86-CD28 co-stimulatory signal required for full T-cell activation,48 Lenercept is a soluble p55 TNF receptor construct.49 These new pharmaceuticals are large proteins that can be easily racliolabeled with 99m-technetium. It is envisaged that their radiolabeled analogues will provide an important aid for validating novel therapeutic options.

Figure 1.-Palmr view of both hands 3 h after the injection of ^sup 99m^Tc-HYNIC-TOC (370 MBq) in a patient with rheumatoid arthritis (RA) and secondary Sjgren’s syndrome. Patient were receiving conventional drugs at time of the study, which was performed to assess disease activity before Infliximab therapy for refractory disease. The high uptake in both hands demonstrates active synovitis despite treatment.

Radiolabeled octreotide

Octreotide is a small peptide which, compared with larger molecules like proteins and MoAbs, exhibits rapid uptake and retention in target tissues, good penetration, along with rapid plasma clearance via renal excretion.

Somatostatin receptors are expressed on both activated lymphocytes and inflamed vascular endothelium. Hyperexpression of the somatostatin receptor has been found in vitro in patients with active RA.50 In a study of 14 consecutive RA patients, SSTR scintigraphy demonstrated ^sup 111^In-pentetreotide uptake in inflamed joints, with a lesion-related sensitivity of 74%.51 Somatostatin receptors have also been detected on synovial cells. In vitro studies have shown that synovial cell proliferation in RA patients could be inhibited by somatostatin. This may provide a rationale for the therapeutic use of a long-acting somatostatin analogue for treating the disease.52 Somatostatin receptor scintigraphy offers important information because it demonstrates the presence of inflammation and in positive patients provides a rationale for the use of unlabeled somatostatin for treating RA in selected cases. In a clinical trial by Paran et al., significant clinical improvement was found in patients with refractory RA.53 A recent study has described the use of a new somatostatin analogue, ^sup 99m^Tc-HYNIC-tyr(3)-octrcotide, ibr tlie diagnosis of the state of disease activity in patients with RA and secondary Sjgren’s syndrome. Patients refractory to conventional treatments were studied before and after therapy with Infliximab. ^sup 99m^Tc-HYNIC- tyr(3)-octreoticle scintigraphy detected active joints in symptomatic patients before treatment (Figure 1 ); the accumulation of ^sup 99m^TcHYNIC-tyr(3)-octreotide was significantly reduced in most patients after treatment.54

^sup 18^F-FDG

The use of ^sup 18^F-FDG has been proposed for the study of RA. A recent study by Beckers et al. on 21 patients with active RA showed uptake of the agent in 63% of joints. The degree of uptake and the number of affected joints correlated with clinical and laboratory parameters of disease activity.55 To elate, no data support the use of ^sup 18^F-FDG for the routine study of KA, so further studies are needed to understand the clinical usefulness of this technique.

Conclusions

RA is a common and debilitating disease that requires major attention tor successful management. New potent and effective drugs are now available that can modify the natural history of the disease. Nuclear medicine techniques may contribute to understanding the best set-up for specific new therapeutic approaches. The challenge for the future is to choose from among therapy options tor individual patients in a timely manner according to an optimal strategy. The combination of novel imaging technologies, genetic evaluation and clinical phenolyping will be crucial in reaching, if possible, the objective of longterm remission of RA and healing of the damage the disease causes.

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M. CHIANELLI 1,2, C. D’ALESSANDRIA 1, F. CONTI 3, R. PRIORI 3, G. VALESINI 3, A. ANNOVAZZI 2, 4, A. SIGNORE 2,4

1 Department of Nuclear Medicine

Regina Apostolorum Hospital, Albano, Rome, Italy

2 Department of Nuclear Medicine and Molecular Imaging

University Medical Center Groningen, The Netherlands

3 Rheumatology Unit, Department of Medical Therapy

La Sapienza University of Rome, Rome, Italy

4 Department of Nuclear Medicince, 2nd Faculty of Medicine

La Sapienza University of Rome, Rome, Italy

Conflict of interest: none declared.

Address reprint requests to: Prof. A. Signore, MD, Medicina Nucleare, University “La Sapienza”, Ospedale S. Andrea, Via di Grottarossa 1035, 00189, Roma, Italy. E-mail: alberto.signore@uniromal.it

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