Takayasu arteritis (TA) is an autoimmune disease that chiefly affects large arteries. It is characterized by inflammation and infiltration of granulomatous tissue into vessel walls with subsequent remodeling, including both dilatation and stenosis. End-organ ischemia can result in intrinsic damage to the aorta and proximal branches, such as the subclavian and carotid arteries. Secondary complications to the gastrointestinal, renal, and pulmonary systems can also arise.

The onset of TA usually occurs in individuals under age 40 years; a minority of cases occur in children, and there is a strong predominance among women. Historically, TA had been considered to be a disease that mostly affects people of East Asian descent; however, it is now understood to affect all ethnicities globally.1 Reported incidence rates vary but are generally reported to be below 3 per 1 million people.

There are numerous diagnostic challenges to TA. Many early symptoms of TA, such as headache, malaise, and fever are non-specific, making early diagnosis difficult. Biomarkers such as erythrocyte sedimentation rate and C-reactive protein are often high2, but are likewise non-specific; laboratory studies do not contribute decisively to this diagnosis. Rather, diagnosis and staging of TA rely largely on results of imaging studies, such as magnetic resonance angiography (MRA), computed tomography angiography (CTA), Doppler ultrasonography, and more recently, 18fluorodeoxyglucose positron emission tomography (18FDG-PET).


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Correlating radiologic findings with symptoms, laboratory markers, and biological disease activity remains challenging, as does ascertaining effects of drug treatment via changes in vessel appearance on imaging studies. Physicians must consider tradeoffs among spatial resolution, vessel size of interest, radiation exposure, invasiveness (ie, in conventional angiography), cost, and availability of expert personnel (ie, for Doppler ultrasonography).

Challenges such as these were discussed in a recent review by Aeschlimann and colleagues3, which described the advantages and shortcomings of various imaging modalities used to diagnose TA and assess disease variables. High-priority considerations included sufficient spatial resolution of the image, non-invasiveness, and limitation of exposure to ionizing radiation. However, such considerations may conflict. For example, MRA is non-invasive and non-ionizing, and is therefore preferred for serial studies to track disease progression. However, it has limited spatial resolution, and is relatively insensitive to subtle lesions, particularly in smaller vessels. Meanwhile, CTA offers higher spatial resolution; with the addition of contrast techniques, this may allow for better assessment of subtle vessel wall changes and treatment effects over time. However, the radiation dose delivered during CTA has been shown to increase cancer risk, particularly in children.4 Therefore, CTA is generally not recommended when MRA can be substituted.

Thus, TA presents multiple and overlapping challenges to clinicians. Advances in imaging for TA are needed not only to detect TA and assess disease activity, but also to treat the disease sufficiently as to limit disease complications while avoiding adverse effects of the steroidal and immunosuppressive drugs used to treat TA. Meeting these needs also requires a diverse clinical team across a range of specialties. To further explore these issues, we asked a rheumatologist and a radiologist with extensive experience in treating TA to share their perspectives on meeting these challenges.

Peter Grayson, MD, MSc, is an Earl Stadtman Investigator at the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases, Chief of its Vasculitis Translational Research Program, and Acting Director of the NIAMS Rheumatology Fellowship Program. Mark Ahlman, MD, is a staff clinician at the NIH Clinical Center in the nuclear medicine section of the Department of Radiology and Imaging Sciences.

What has changed over the past 5 to 10 years in the adoption and incorporation of imaging studies for TA?

Peter Grayson, MD, MSc: I definitely think things have changed. We’ve been performing vascular imaging studies and large vessel vasculitis [at the NIH Vasculitis Translational Research Program] for about 10 years. When we first started doing them, we would show these findings in the [positron emission tomography (PET)] scan and everybody would question what they’re actually teaching us. What we noticed was that if you did a PET scan on a patient with vasculitis when they were in early-stage disease and the physician thought the disease was active, [there was] a lot of activity. But, if you looked later in the disease when the physician thought things were going well, [there was still] a lot of activity. This caused a lot of confusion, and people were very skeptical about these modalities.

I think over time, people are becoming much more comfortable with the idea that these modalities are giving us a real signal. You can see that reflected in recent guidelines for management of these diseases that have come out from the European Alliance of Associations for Rheumatology (EULAR)5 and from the American College of Rheumatology6 in the last five years. Both of these sets of guidelines strongly incorporate imaging into the management of these patients. Furthermore, in January 2021, the Centers for Medicare and Medicaid Services removed a provision that prevented reimbursement of PET scan use for inflammation and infectious diseases. That has paved the way for patients to actually get access to these modalities, and potentially have insurance companies reimburse for them. In just the past year we’ve seen a spike in increased access to these technologies among patients outside of the NIH.

Would you describe how you are using these imaging modalities nowadays?

Dr Grayson: An increasing number of imaging modalities are available, and now physicians are using multimodal imaging to help with diagnosis. We can use vascular ultrasonography at the bedside; this is inexpensive and doesn’t expose the patient to radiation. In the past we used catheter-based angiography; now we have noninvasive imaging modalities that are even better than catheter-based ones. You can get a [magnetic resonance imaging (MRI)-based] or CT-based angiography with a lot of specific sequences to look for damage in both the lumen of the arteries and in the vascular wall, specifically. More recently we have 18FDG-PET scans. By combining all those sources of information, [we can] make better diagnoses.

The newest imaging technology we’re working with now at the NIH is called a PET-MRI. This allows you to combine or synthesize data by performing an MRI angiogram, examining the structure of the arteries, and in the same imaging session, converting that machine to a PET scanner to examine for possible inflammation in the walls of those arteries.

Mark Ahlman, MD: The reference standard for confirming a diagnosis of large vessel vasculitis is temporal artery biopsy, but that’s an invasive procedure. Meanwhile, with CTA and MRA, we can visualize vessel wall thickening, aneurysms, and stenosis; however, these are the consequences, or endpoints, of the disease process at one or more sites. We may miss an early inflammatory process or stenotic process at a different site. We want to be able to detect that before it results in an irreversible change.

It’s true we’re starting to describe the MRA part of things a little better. We can use various techniques of contrast enhancement to enhance the vessel wall image and signal suppression, nullify the signal from the blood, and highlight the water signal from the vessel wall. So that now we can see edema or fluid in the vessel wall, or abnormal thickness of the vessel wall, [we can] infer that we’re visualizing active inflammation at that site. That’s pretty exclusive to MRA and it still requires further research. For now, physicians can use 18FDG-PET to evaluate active inflammation a little more directly.

In 2012 in the Department of Radiology, we wanted to use MRA associated with a PET scan. This was right about the time that Dr Grayson was developing his vasculitis protocol. Our aim was to use this PET-MRI, in part, to avoid having to do that invasive biopsy. When we started doing that, we could see inflammation not just at the arteries that were causing symptoms in a patient, but also in numerous arteries whose involvement we weren’t aware of. It’s taken a while to refine the protocol, but now, given the CT, the MRI, the 18FDG-PET and the PET-MRI, we can put all these pictures together to assess the disease state and the long-term consequences for a patient with TA. It’s not enough to use one modality. By putting these data sources together, we’re seeing patterns that are so characteristic that we can limit the need for a biopsy to confirm a diagnosis of large vessel vasculitis.

How do you approach the challenge of staging in TA — of differentiating active from inactive disease?

Dr Grayson: Part of the reason that this is so challenging is that patients can have arterial disease and catastrophic events that are not preceded by any symptoms. As physicians, we’re very comfortable making treatment decisions based off of our assessment at the bedside. We’re much less comfortable when our assessment doesn’t align with another source of information. Therefore, we have to figure out how to integrate all of those inputs. We consider the patients’ clinical symptoms and look very carefully at their vascular examination over time and how they may or may not be changing. We look at their laboratory markers, and we look at various combinations of imaging assessments. When we put all of those pieces together to see how they integrate, we try to make the best possible decision for the patient. Even then, we’re constantly humbled by the complexity of these diseases. Many times, there are surprises around the corner.

Added to this is the challenge of monitoring the results of a patient’s ongoing drug treatment.

Dr Grayson: Yes, and we have to do that in a patient who may not have any symptoms! That’s why we think vascular imaging is really critical, both from a clinical perspective and from a research perspective. How is it going to help a doctor take better care of patients? How is it going to give us different insight into these disease processes? Can we use these imaging metrics as outcome measures to demonstrate effectiveness of the treatments that we’re trying? Does the treatment hit the target directly? Does it directly improve vascular inflammation? Can we measure that? We’ve known for decades from autopsy studies that these diseases don’t necessarily go away. But if we have variables that we can measure and follow, then we can leverage that to discover more effective therapies that put a patient in a more durable remission.

Dr Ahlman: I would say we typically do see an improvement on imaging if there’s been an effective change in medical treatment. When we image at baseline, we’re more reliant on the rheumatologist’s clinical interpretation. The rheumatologist may suspect large vessel vasculitis, and often multiple imaging modalities will support the diagnosis: the CT, the MRI, and the PET. In some cases that aren’t advanced, only the 18FDG-PET will show us the inflammation, edema, or stenosis, although in some cases I’ll only see those findings on the CT and MRI. Sometimes it’s a different, unexpected mix of modalities that confirms the diagnosis.

Usually, however, the 18FDG-PET is what changes most markedly during effective treatment, and may even normalize substantially. This has started to come into clinical use in just the past couple of years since the FDA approved 18FDG-PET for this indication.

What other lessons do you see emerging as a result of these advances in imaging for TA?

Dr Ahlman: I suspect we’re going to find that large vessel vasculitis is underdiagnosed. Epidemiological data indicate it’s very rare, but on numerous occasions I’ve come across it incidentally in clinical practice, especially with patients with cancer, and that’s traditionally what the 18FDG-PET is for. If I read 10 of those scans per day, every few months I may find one with classic signs of large vessel vasculitis. This could reflect a predisposition in some patients who are receiving certain cancer medications, and we’re able to alert the treating physician to this. Certainly, the literature on both systemic lupus erythematosus and psoriasis indicates that vascular inflammation is increased in those patients7, so that may be similarly detectable on this type of imaging study.

Dr Grayson: From a research perspective, we strongly believe that these diagnoses are not really one disease. TA is a form of large vessel vasculitis in a young person. However, within that disease, there are many different versions that can look very different from patient to patient. It might start in a patient’s early childhood, or in their 20s, or in their 60s. The types of arteries that are affected, and the ways in which they are affected, are very different. We see these diagnoses, from a research perspective, as just umbrella terms. We can see this in how patients respond to different medications differently. It’s really important for patients to have a sense of that, as they share their stories and communicate with each other, seeing that their experiences can vary widely. It adds another of layer of complexity to these conditions.

What other clinicians might you collaborate with on a case of TA?

Dr Grayson: We work collaboratively with a set of other care providers, and also with researchers to improve our understanding of these diseases. Key stakeholders can be neurologists, because these patients can have strokes. They can be cardiologists, because the patients can have heart attacks. They can be vascular surgeons. We don’t like to perform vascular surgeries on our patients because they can be very complex with bad outcomes; but in some cases, surgical interventions are needed. They can be primary care physicians who will be dealing with various aspects of treating a chronic disease. From my perspective, as a rheumatologist, I think rheumatologists are critical in coordinating all that management. If you’re a patient with vasculitis, you likely need a care a team of care providers, but it’s also really important to have that one person who is central and managing your disease and coordinating all these other doctors, and making sure that they’re communicating well. I think rheumatologists do that really well.

What obstacles exist to progress in diagnosis, staging, and treatment in TA? And what other innovations do you see on the horizon?

Dr Ahlman: Unfortunately, I suspect PET-MRI imaging won’t become widely used in clinical practice for imaging in large vessel vasculitides because access is too limited. I do expect advances in vascular inflammation imaging to come from more specific PET tracers. 18FDG has great sensitivity, but it just shows where cells are metabolically active, which is not specific to vasculitis. But a radiotracer called fibroblast activation protein inhibitor (FAPI) is now being applied in oncology.8 When fibroblasts are active in the vessel wall, their activity can be visualized. There have been some very early reports9 regarding application to large vessel vasculitis with this radiotracer, so FAPI might become very useful.

Dr Grayson: Certain organizational changes could really facilitate and accelerate research, such as in outlier cases like clusters of large vessel vasculitis within a family. Those are incredible research opportunities, but we don’t have a systematic way to find those cases. We need to create that infrastructure. We need clinical registries, biobank registries, and ways to work together collaboratively to conduct randomized controlled trials across different countries and continents. These are diseases for which we don’t have really many approved medical therapies. There really have been very few successful randomized controlled trials. So it’s imperative, I think, that we collaborate and work together on a global scale.

References

  1. Seyahi E. Takayasu arteritis: an update. Curr Opin Rheumatol. 2017;29(1):51-56. doi:10.1097/BOR.0000000000000343
  2. Águeda AF, Monti S, Luqmani RA, et al. Management of Takayasu arteritis: a systematic literature review informing the 2018 update of the EULAR recommendation for the management of large vessel vasculitis. RMD Open. 2019;5(2):e001020. doi:10.1136/rmdopen-2019-001020
  3. Aeschlimann FA, Raimondi F, Leiner T, Aquaro GD, Saadoun D, Grotenhuis HB. Overview of imaging in adult-and childhood-onset Takayasu arteritis. J Rheumatol. 2022;49(4):346-357. doi:10.3899/jrheum.210368
  4. Miglioretti DL, Johnson E, Williams A, et al. The Use of Computed Tomography in Pediatrics and the Associated Radiation Exposure and Estimated Cancer Risk. JAMA Pediatr. 2013;167(8):700-707. doi:10.1001/jamapediatrics.2013.311
  5. Hellmich B, Agueda A, Monti S, et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020;79(1):19-30. doi:10.1136/annrheumdis-2019-215672
  6. Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline for the management of giant cell arteritis and Takayasu arteritis. Arthritis Care Res. 2021;73(8):1071-1087. doi:10.1002/acr.24632
  7. Harrington CL, Dey AK, Yunus R, Joshi AA, Mehta NN. Psoriasis as a human model of disease to study inflammatory atherogenesis. Am J Physiol-Heart Circ Physiol. 2017;312(5):H867-H873. doi:10.1152/ajpheart.00774.2016
  8. Hicks RJ, Roselt PJ, Kallur KG, Tothill RW, Mileshkin L. FAPI PET/CT: will it end the hegemony of 18F-FDG in oncology? J Nucl Med. 2021;62(3):296-302. doi:10.2967/jnumed.120.256271
  9. Wu M, Ning J, Li J, et al. Feasibility of in vivo Imaging of Fibroblast Activation Protein in Human Arterial Walls. J Nucl Med. Published online June 2022.