Assessing Activity of Rheumatic Arthritis with Fluorescence Optical Imaging

Transcription

1 Imaging Assessing Activity of Rheumatic Arthritis with Fluorescence Optical Imaging Christoph Bremer, 1 Stephanie Werner 2 and Hans-Eckhard Langer 3 1. Professor of Radiology, University of Münster, and Head of Radiology, St Franziskus Hospital Münster; 2. Schwerpunkt für Rheumatologie, Klinische Immunologie und Osteologie am Evangelischen Krankenhaus, Düsseldorf; 3. Professor of Rheumatology, Schwerpunkt für Rheumatologie, Klinische Immunologie und Osteologie am Evangelischen Krankenhaus, Düsseldorf Abstract Fluorescence optical imaging of microcirculation in joints of the hands and fingers is a newly available imaging method to assess individual disease activity in patients with rheumatoid arthritis (RA). In this article, the basics of fluorescence optical imaging, specific applications in respect of imaging disease activity in RA and the first experimental and clinical results are reported. Overall, this new procedure (Rheumascan ) is an easy-to-use and safe procedure offering high patient comfort. First clinical results show the potential to differentiate active from inactive inflammatory disease in all joints of both hands in one single comprehensive examination. This new imaging test for RA addresses different clinical diagnostic needs, especially the assessment of early disease manifestations and the objective assessment of treatment response. Keywords Fluorescence optical imaging, rheumatoid arthritis, microcirculation imaging, Rheumascan, Xiralite Disclosure: Christoph Bremer has consulted mivenion GmbH on safety aspects of the Xiralite technology. Stephanie Werner and Hans-Eckhard Langer have no conflicts of interest to declare. Received: 29 July 2009 Accepted: 6 September 2009 Correspondence: Christoph Bremer, Klinik für Radiologie, St Franziskus Hopsital, Hohenzollernring 72, Münster, Germany. E: Christoph.Bremer@sfh-muenster.de Rheumatoid arthritis (RA) has a prevalence of ~1% in western societies, with an incidence of per 100,000/year. Prevalence increases with advanced age, rising to 5% in those over 65 years of age. Typically, first presentation is between 30 and 50 years of age, and 80% of patients develop a chronic course with recurrent episodes of active disease and progression. The chronic disease course, in combination with an ever-increasing life expectancy, results in an increased influence of RA on the daily life of patients. Recent advances in the therapy of RA have already led to an improved prognosis and quality of life for patients, but modern treatment regimens impose significant costs. In clinical routine, patients often present with a mixture of specific and unspecific symptoms, which can complicate the choice of individual treatment. However, recent evidence suggests that early aggressive treatment, including the use of biologicals (e.g. tumour necrosis factor-α inhibitors), can possibly reverse the disease course, at least in subgroups. 1 Histopathological studies of RA show a chronic proliferative synovitis with increased mitotic activity of synoviocytes. This leads to cartilage and subchondral bone damage. Associated with the synovitis is angiogenesis, which exhibits a dense mesh of capillaries in the inflamed joint mucosa. Vasodilatation and an increased capillary permeability sustain the synovitis. Current Imaging Techniques in Rheumatoid Arthritis Assessment of active disease is usually performed using the Disease Activity Score 28 (DAS 28) scoring system. 2 This score includes erythrocyte sedimentation rate, as well as clinical and patient-based assessment of 28 joints, 22 of them located in the hand and finger region. Due to the nature of this score, a certain subjectivity is inherent. In selected patients, further imaging is performed to assess the individual disease state. X-ray imaging gives an overall assessment of joint damage and may also give some indirect hints as to the disease state. Its advantage is its ease of use and availability, but X-ray is not suited for early disease assessment or an objective assessment of current disease activity. 3 Ultrasound is used for imaging of the joint space, tendons and peri-articular soft tissue. 4 Ultrasound has advantages if only a very limited number of joints are assessed. In combination with intravenous contrast, Doppler imaging can show alterations of the microcirculation. Contrast-enhanced ultrasound is superior to power Doppler ultrasound with a substantially better discrimination rate between active and inactive synovitis. 5 Contrast-enhanced magnetic resonance imaging (MRI) shows microcirculation in active synovitis even if joint morphology is normal. Thus, activity assessment is applicable on a technical basis. Limiting is the availability, cost and patient discomfort. Nevertheless, in selected patients contrast-enhanced MRI is helpful. 3 Clinical Diagnostic Need Based on the increasing evidence for intensified treatment at the earliest possible time-point in the disease course, new needs for diagnostic imaging have evolved. First, early, objective and reliable 96 TOUCH BRIEFINGS 2009

2 Assessing Activity of Rheumatic Arthritis with Fluorescence Optical Imaging diagnosis is key to the improved treatment algorithms currently available. A future imaging tool requires the capability to diagnose the extent of inflammation, as well as to determine the exact location and number of affected joints. Second, there is a need for a diagnostic tool that is able to reliably discriminate between true inflammation and mere swelling or pain, as the latter might well be residual aspects of a prior, yet currently inactive, inflammatory process. In fact, a significant number of patients are very pain-sensitive and report pain intensity that does not correlate with the true disease state. Thus, these patients are vulnerable to unnecessary treatment intensification. Third, using modern, effective, but also expensive, treatments with their profile of adverse events, an objective and timely assessment of therapy response is necessary, but not available. 6 A diagnostic test should display the inflammatory activity in a quantitative or semiquantitative way and allow comparison of disease activity over time. Such a diagnostic procedure is necessary with the increasing number of biologicals available on the market so that physicians can choose reliably the right treatment for each individual patient. Optical Technologies in Medicine Light has an established role in diagnosing and treating disease. The properties of light can be adapted to the different tasks in medicine by modulation of the wavelength and energy of photons. Lasers and light-emitting diodes in combination with adequate filters are used as light sources. The non-reflected part of light is absorbed within the first few millimetres of skin. Haemoglobin-containing molecules and water are the most important substances in this process. Nevertheless, in the near-infrared (NIR) spectral range (700 1,000nm) there is a so-called optical window where light is absorbed the least by the body and penetration depth may reach centimetres. This spectral range is best suited for diagnostic imaging, because in the NIR range light can traverse the body a couple of centimetres and activate fluorophores, which can be detected by appropriate sensitive camera technologies. Optical methods for diagnosing RA have been established on an experimental level for more than 10 years. Two fundamentally different methods can be distinguished. The first, a diffuse light-scattering method without the use of contrast agents, utilises the finding that diseased tissue scatters light differently from healthy tissue. Transmission of light through tissue thus leads to different signal intensities. The main limitation of this method is the need for exact quantification that correlates to the individual disease state. Clinical studies using light-scattering technologies for imaging of RA in finger joints failed to show appropriate diagnostic certainty of this approach. A further method for optical imaging is measuring fluorescence signal intensities of applied contrast agents. In this approach, a contrast agent is used that enhances in inflamed tissue. Experimental studies in different arthritis animal models have shown that molecular markers and fluorescence angiographic dyes are suitable to detect inflammation. For molecular imaging, different markers have been validated, such as ED-B fibronectin, metalloproteinase 9, ανβ 3 integrin and interleukin-1. Nevertheless, these markers are available only for pre-clinical use. 7 9 Indocyanine green (ICG), an angiographic fluorescence dye, has demonstrated its ability for imaging of arthritis in different animal models. 10 In contrast to target-specific molecular markers, which need up to a couple of hours for target-specific contrast enhancement (after clearing for non-bound circulating probes), ICG leads to a profound signal in inflammation early after injection, representing mainly a non-specific, angiogenesis-related perfusion pattern. The feasibility of this approach in humans was first published in Fluorescence Optical Diagnostics Fluorescence optical imaging employing ICG is an established procedure in a variety of indications worldwide. Overall, about six million examinations are performed every year, mostly fluorescence angiographies of the eye. Other indications are Recent advances in the therapy of rheumatoid arthritis have already led to an improved prognosis and quality of life for patients, but modern treatment regimens impose significant costs. perfusion measurements, liver function tests and diagnosing microcirculation. Diagnosing age-related macular degeneration in the eye is based on the ability of fluorophores such as ICG to depict alteration of the microcirculation. 11 The use of signal enhancers in the form of contrast dyes leads to improved tissue differentiation and specificity of the diagnostic test. Precondition is the ability of the applied contrast agent to achieve increased drug levels in the diseased tissue compared with healthy controls due to higher microvascular density, vascular leakage or increased capillary blood flow of the inflamed tissue. ICG has been shown to enhance inflamed tissue similar to contrast agents for MRI. 28 ICG is approved in Europe for diagnosing cardiac, vascular, microcirculation and liver function. Imaging of inflammation in RA is based on microcirculation diagnostics. Clinical Use of Fluorescence Imaging for Diagnostics of Microcirculation Contrast-enhanced optical procedures are established worldwide for imaging of small vessels. Most common is fundus angiography in the eye, whereby either fluorescein or ICG is used as a fluorophor. Besides imaging of small vessels as directly visible structures, the more 2D aspect of contrast enhancement caused by the microcirculation is an integral part of the examination. Regionally less perfused areas are visible as focal inhomogeneities of contrast enhancement. 12 Imaging of microcirculation with ICG is well established in plastic and reconstructive surgery. The post-operative microvascular perfusion of transplanted vascularised flaps has been examined. In a study of 15 patients, Lamby et al. 13 analysed the use of ICG and other imaging modalities for imaging of microvascular perfusion of vascular parascapular flaps transplanted to the forefoot. ICG allowed verification of microvascular perfusion of the transplanted flaps. Most EUROPEAN MUSCULOSKELETAL REVIEW 97

3 Imaging interestingly, increased enhancement was seen at the rim of the transplant, yet no reason for this was given in the study. Diseases leading to disturbance of microcirculation can be diagnosed with fluorescence-based optical imaging, e.g. for patients with tumours of the eye. Schaller et al. 14 studied 13 patients with choroidal melanomas before and for one year after brachytherapy using ICGbased fluorescence imaging. Microcirculation of the tumours was are well established for the assessment of disease activity during the clinical work-up of patients with RA in the hands. 22,23 Due to the direct visualisation of increased blood supply to the tissue during disease activity, both methods are, in principle, superior to other clinical and imaging tests, which do not show this early pathophysiological process of inflammation. 24 In a review of the evaluation of treatment response to modern treatment, Brown 6 has clearly stated the need for imaging on the basis of early pathophysiological processes for RA. On this basis it is clear that an appropriate imaging test is superior to currently established clinical procedures. Overall, ICG-based fluorescence optical imaging is well suited to delineating changes of the microcirculation throughout a variety of clinical entities. visualised. In 10 of the 13 patients the microvascular effects of brachytherapy were seen, causing a reduction of visible microvascular vessels. The authors concluded that this information was helpful for clinical assessment of the therapy. Experimental Evidence As outlined above, optical imaging with a fluorophor such as ICG is capable of delineating microvascular changes in humans, and microvascular alterations are an integral part of active inflammatory processes, e.g. in RA. Hansch et al. 25 used Cy5.5 as a fluorophor in an experimental study with mice suffering from arthritis. In joints with acute arthritis, a significant increase of the fluorescence signal was noted compared with the contralateral, healthy joints. The authors believe that the enhancement was caused by the increased and alterated perfusion of the inflamed tissue. This process was further enhanced by the protein binding of Cy5.5 with its unspecific targeting. They concluded that fluorescence imaging in the NIR spectral range, using Cy5.5 as a fluorophor, is suited for delineation of arthritic joints in vivo. In two further studies of the same group, the diagnostic potential of ICG-based microcirculation imaging was further substantiated. In one study, non-treated choroidal melanomas were imaged with fluorescein- and ICG-based angiography. Fluorescein angiography was capable of showing microvessels in 12 patients (24%). Using ICG-based optical imaging, microvessels in 47 of the 50 tumours (94%) were identified in vivo. ICG is thus better suited for imaging of microvessels and is able to show microcirculation in vivo, which otherwise only histology can. The authors concluded that these findings open up the possibility of assessing the potential biological course of individual tumours to a treatment without invasive histology. In a slightly different experimental set-up, Wall et al. 26 were able to prove that tumoral 1,1 -bis-(4-sulfobutyl)indotricarbocyanine-5,5 - dicarboxylic (SIDAG) enhancement, a fluorophor chemically related to ICG, closely correlates to the tumour s angiogenic activity, supporting the evidence mentioned above that perfusion-type cyanine dyes can indeed delineate tissue angiogenesis non-invasively. Fischer et al. 27 were able to demonstrate the potential of direct fluorescence optical imaging of inflamed joints. In a study with induced Lyme arthritis in mice (n=20) and 20 healthy control animals, ICG and an ICG-like contrast agent (SIDAG) were used. Optical imaging was In a prospective study, Mueller et al. 16 studied the potential of ICGbased imaging of the microcirculation in the eye. Overall, 98 patients with small choroidal melanomas were classified using a variety of different parameters. Microcirculation parameters, collected with ICG-based optical imaging, had the strongest association with the time of prospective defined tumour growth. Thus, depiction of clinically relevant changes in microcirculation patterns gives relevant clinical information. Overall, ICG-based fluorescence optical imaging is well suited to delineate changes of the microcirculation throughout a variety of clinical entities. Fluorescence Imaging of Rheumatoid Arthritis Pathophysiology The true cause of RA remains unclear, despite intensive research. Varieties of immune cells are activated during active disease and secrete proinflammatory cytokines, interleukins and other factors. These mediators promote inflammation and result in destruction of the adjacent synovial structures. In addition, neoangiogenesis is triggered in the region of the synovial membrane However, this leads to synovial contrast enhancement in contrast-enhanced ultrasound, as well as in contrast-enhanced MRI. 21 Both techniques Besides the clinical possibilities of fluorescence optical imaging, a variety of further clinical diagnostic applications for imaging of rheumatoid arthritis can be envisaged. performed with an excitation wavelength of 740nm. Fluorescence signals were detected above 800nm. Both tested fluorescence dyes were able to differentiate affected from non-affected joints. The authors stated that fluorescence optical imaging of hand and foot joints with ICG is a clinically applicable method. Berger et al. 28 designed a device for clinical use with a scanning laser. Applicability was shown with phantom experiments. The ability to differentiate healthy from affected joints with this device was shown in two Lewis rats. The signal distribution in these animals matched signal distribution in contrast-enhanced MRI, as well as inflammatory activity in histology. 98 EUROPEAN MUSCULOSKELETAL REVIEW

4 Assessing Activity of Rheumatic Arthritis with Fluorescence Optical Imaging Figure 1: Set-up of the Xiralite System Figure 3: Rheumascan of Both Hands in a 55-year-old Patient with Psoriasis and Clinical Signs of Osteoarthritis in the Finger End Joints Figure 2: Rheumascan of Both Hands in a 58-year-old Patient with Clinically Active Rheumatoid Arthritis, DAS No focal contrast enhancements in the finger joints, especially the distal interphalangeal joints. Thus, no active inflammatory disease is present, substantiating the diagnosis of osteoarthritis. Figure 4: Rheumascan of Both Hands in a Healthy Female Rheumascan with Xiralite shows active inflammation in the right wrist, proximal interphalangeal joints 2 4 in both hands, left distal interphalangeal joint 4 and right metacarpophalangeal joint 2, in full alignment with clinical examination. Due to a very recent cut to the right second finger, the signal is obscured by a small band-aid. Clinical Evidence In a first proof-of-concept study (by Ebert et al. 29 ), five healthy volunteers and five patients with clinically active RA were investigated. All subjects received contrast-enhanced MRI the day before fluorescence imaging. ICG was used intravenously with 0.1mg/kg bodyweight. Healthy and diseased joints showed marked differences in fluorescence signal in vivo. Affected joints had either very early and strong fluorescence signals or an elevated signal over the entire imaging period. Thus, the authors believe that dynamic fluorescence imaging with contrast agents showing microcirculation is feasible for diagnostics of RA. In a running study of fluorescence optical imaging in RA, as of June subjects have been recruited overall. 30 The study is enrolling healthy subjects, as well as patients with clinically active RA (DAS28 >3.2) and patients with inactive osteoarthritis. ICG is injected intravenously as a bolus with 0.1mg/kg bodyweight. Image acquisition is performed for 10 minutes. The study is still recruiting, thus final results are not yet available. Nevertheless, the following initial basic features have been identified: No focal contrast enhancements are seen in the joint regions. fluorescence optical imaging is a safe diagnostic procedure and offers excellent patient and operator comfort; this diagnostic test supports the physician in discriminating between active inflammatory disease and other underlying dysfunction, such as pain syndromes; and differentiation of chronic osteoarthritis and active inflammation seems possible. To the best of our knowledge, fluorescence optical imaging of microcirculation in RA is a very safe procedure. No unexpected adverse reactions were seen in the current study. In addition, a risk assessment of the applied light source and intensities did not reveal any relevant risk to the patient or the physician, respectively. During the certification process of the now available Xiralite system, no additional risk exceeding the general level was found (see Figure 1). In the current study, patients reported the procedure as comfortable. This was based on the open design, relaxed sitting position during the EUROPEAN MUSCULOSKELETAL REVIEW 99

5 Imaging examination and overall ease of the procedure. The investigators appreciated the convenient procedure and patient handling. According to these initial results, Rheumascan appears to be capable of differentiating active synovitis from inactive disease. This is due to an increased microcirculation during inflammation, which ultimately translates into an enhanced fluorescence signal. The signal characteristics mimic contrast-enhanced MRI. Figure 2 shows focal contrast enhancements in all proximal finger joints (2 4), the right wrist and the left fourth distal finger joint. The right proximal interphalangeal joint (2) is covered by a small band-aid, which is obscuring fluorescence signals. The focal contrast enhancements are in full alignment with the clinical findings. inflammatory process with other, similar, clinical conditions seems possible in an easy and cost-effective way. Nevertheless, results from large trials are not yet available. n Christoph Bremer is a Professor of Radiology and Head of Radiology at St Franziskus Hospital in Münster, and head of the research group in molecular imaging in tumour diagnostics in the Department of Clinical Radiology at Münster University. He is a member of the German, European and North American Societies of Radiology, as well as the Society of Molecular Imaging. Professor Bremer serves as a member of the Editorial Board for Der Radiologe, European Radiology and Molecular Imaging. His main research interest is the development of parametric magnetic resonance imaging methods for tumour characterisation, as well as molecular optical imaging. Figure 3 shows the Rheumascan, acquired with a Xiralite system, of a 55-year-old female with known psoriasis, as well as clinical signs of osteoarthritis of the distal finger joints. Clinical differentiation between psoriasis arthritis and osteoarthritis was inconclusive. The lack of contrast enhancement in the Rheumascan supported the final diagnosis of osteoarthritis. Figure 4 shows an image in a healthy person without focal contrast enhancement. Perspective Besides the clinical possibilities of fluorescence optical imaging, a variety of further clinical diagnostic applications for imaging of RA can be envisaged. In particular, the selection of patients suitable for an intensified treatment with biologicals, as well as early assessment of therapy response, is possible. This is based on the available preliminary results and the mode of action, in combination with results from other contrast-based imaging methods. In addition to an early assessment of therapy response after two to four weeks of therapy, a reliable and objective differentiation of an active Stephanie Werner is a Resident in Rheumatology, Clinical Immunology and Osteology at the Evangelische Krankenhaus Düsseldorf. After finishing her studies in medicine at Heinrich-Heine University Duesseldorf, she is now completing her training in internal medicine with a focus on rheumatology. Dr Werner s scientific interest is in early arthritis, and she is responsible for Xiralite and Rheumascan in the early arthritis clinic. Hans-Eckhard Langer is a Physician in Internal Medicine, Rheumatology and Physical and Rehabilitative Medicine. Since 2000 he has been Head of the Service for Rheumatology, Clinical Immunology and Osteology, as well as the Early Arthritis Clinic at the Evangelische Krankenhaus Düsseldorf. Dr Langer s scientific focus is on health services research, the development and evaluation of integrated care models and improvements for diagnosis and therapy of early arthritis. Together with the Deutsche Rheumaforschungszentrum in Berlin, he is running a study on Xiralite diagnostics for early arthritis. Dr Langer is a member of the German Society for Rheumatology and the German Society for Physical and Rehabilitative Medicine. 1. 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