Use of Pet/CT in different scenarios on rare and orphan diseases of autoimmune origin

Liset Sánchez Ordúz¹, Marylin Acuña Hernandez^2, Gerardo H. Cortés Germán^3,

1. Nuclear Medicine Specialist, Centro Médico Carlos Ardila Lulle and Professor specializing in nuclear medicine, Autonomous University of Bucaramanga (UNAB), Bucaramanga, Colombia. http://orcid.org/0000-0001-9794-9017
2. Nuclear Medicine Specialist, Instituto Nacional de Cancerologia (INC) and Rimab S.A.S, Bogota, Colombia. http://orcid.org/0000-0001-7381-1910
3. Nuclear Medicine Specialist, Tadashi SAS and Clinica del Country, Bogota, Colombia.

 

OPEN ACCESS

PUBLISHED: 31 December 2024

CITATION: SÁNCHEZ ORDÚZ, Liset; ACUÑA HERNANDEZ, Marylin; CORTÉS GERMÁN, Gerardo H.. Use of Pet/CT in different scenarios on rare and orphan diseases of autoimmune origin. Medical Research Archives, [S.l.], v. 12, n. 12, dec. 2024. Available at: <https://esmed.org/MRA/mra/article/view/5994>. 

COPYRIGHT: © 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI: https://doi.org/10.18103/mra.v12i12.5994

ISSN 2375-1924

 

Abstract

Autoimmune diseases are on the rise, likely due to a combination of genetic predisposition, dietary changes, climate modifications, and exposure to xenobiotics. These diseases can affect five, people, such as systemic lupus erythematosus, which has a low prevalence of 5 per 10,000 people, are potentially fatal, chronically debilitating, and have a genetic origin.

In the United States, the National Conference of State Legislatures’ defined them as diseases affecting fewer than 200,000 Americans, considering them neglected diseases. Their treatments are not profitable due to their rarity.

This type of pathology presents a challenge in diagnosis, treatment, and follow-up challenges. The biological heterogeneity of autoimmune diseases leads to difficulties in clinical diagnosis, and the lack of specific diagnostic tests complicates the identification of these diseases.

In this review, we will discuss the role of Positron Emission Tomography/Computed Tomography (PET/CT), as it is a non-invasive imaging technique that allows for the execution of staging, prognosis, treatment planning, evaluation of therapeutic response, and follow-up of patients.

Keywords

Autoimmune diseases, PET/CT, rare diseases, orphan diseases, imaging techniques

 

Introduction

According to the World Health Organization (WHO)¹, orphan or rare diseases include around 5,500 diseases that can affect approximately 30 million people in the United States, according to the U.S. Food and Drug Administration (FDA)².

European Commission³, considering rare diseases have a low prevalence of 5 per 10,000 people, are potentially fatal, chronically debilitating, and have a genetic origin.

In the United States, the National Conference of State Legislatures⁴ defines them as diseases affecting fewer than 200,000 Americans, considering them neglected diseases. Their treatments are not profitable due to their cost.

This type of pathology presents a diagnosis, treatment, and follow-up challenge. The natural history of these diseases needs to be better known and studied. Their biology is complex, leading to difficulties in developing drugs, biological products, and devices to treat these conditions.

For this reason, in 1997, INSERM (French National Institute of Health and Medical Research), with subsequent support from the European Commission starting in 2002, created the Orphanet strategy⁵. This strategy includes multiple medical aspects of this type of pathology, including a comprehensive classification for the methodology explained later.

As for autoimmune diseases, the National Institute of Allergy and Infectious Diseases (NIAID)⁶ and the National Cancer Institute (NCI)⁷ define these pathologies as those in which antibodies are formed that attack the immune system.

The National Health and Nutrition Examination Survey (NHANES), a study program by the Centers for Disease Control and Prevention (CDC), found that approximately 32% of adults aged 60 or older may have at least four autoantibodies. Globally, an increase in the frequency of autoimmune diseases has been observed, with an estimated annual increase in incidence and prevalence of 19.1% and 12.5%, respectively⁸.

In recent years, there has been a rise in the use of Positron Emission Tomography/Computed Tomography (PET/CT), as it is a non-invasive imaging study used as a diagnostic method in various clinical scenarios: detection, classification, staging, prognosis, treatment planning, evaluation of response to therapy, and surveillance in oncological, cardiovascular, neurological, inflammatory, and infectious disorders, among others⁹.

We did not find a specific list of autoimmune and orphan diseases; therefore, we combined the lists to identify orphan autoimmune diseases.

For this reason, this scoping review aims to describe the different PET/CT tracers used in rare or orphan diseases of autoimmune origin, as defined in the ICD-11 classification.

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Methodology

REVIEW QUESTION
What utility and characteristics are reported in the literature regarding using PET/CT with its different tracers in autoimmune orphan diseases?

The databases of available orphan diseases from Orphanet and autoimmune diseases from the Global Autoimmune Institute were cross-referenced, resulting in a list of orphan autoimmune diseases.

The study employed the broad population, concept, and context (PCC) framework indicated by the Joanna Briggs Institute for scoping reviews, as illustrated in Figure 1.

ELIGIBILITY CRITERIA

Articles were deemed eligible for inclusion if they reported case reports, case series, descriptive, or analytical observational studies published without date limitation that included the orphan autoimmune diseases from the cross-referenced list created for this study in which a PET/CT study had been conducted.

During the literature review, the following diseases were excluded due to the quantity and quality of available information, which allows for the execution of systematic reviews: polymyositis, immune-mediated necrotizing myopathy, psoriatic arthritis, psoriasis, sarcoidosis, reactive arthritis, rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus, acute disseminated encephalomyelitis, multiple sclerosis, myopathies, myositis, myasthenia gravis, connective tissue diseases, Guillain-Barré syndrome, IgG4-related disease, giant cell arteritis, antiphospholipid syndrome, granulomatosis with polyangiitis, autoimmune hepatitis, autoimmune pancreatitis, dermatomyositis, acute disseminated encephalomyelitis, and autoimmune diseases of the nervous system.

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SEARCH STRATEGY

Initially, considering the methodology described by the Joanna Briggs Institute for scoping reviews, two researchers conducted a systematic search independently in indexed databases such as MEDLINE, OVID (including Embase), Cochrane Library, Epistemonikos, Scielo, LILACS, and JBI Evidence Synthesis, and gray literature such as OpenGrey and GreyNet using all the keywords included in the DECS, MESH, and Entry Terms. Annex 1 contains the search methodology.

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SOURCE OF EVIDENCE SELECTION

All search result articles were uploaded to Mendeley Software, and duplicates were removed. Subsequently, two independent reviewers assessed the titles and abstracts, selecting the compositions according to the inclusion and exclusion criteria for the review. When there were disagreements between the reviewers, an additional reviewer was consulted, and an agreement was reached. This section’s results are presented as a flow diagram (Figure 2) following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping review (PRISMA-ScR) guidelines.

 

 

DATA EXTRACTION

For data extraction, two reviewers considered specific details of the articles, such as authors, year of publication, type of study, disease, PET/CT tracer, and main findings.

The items to be assessed by the two reviewers were not disagreeable, and complete information was found in the included articles to evaluate the results.

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Results

The results obtained from the literature review are summarized by disease in the tables described below.

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Table 1 – Acromegaly

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Table 2. Aplastic Anemia, Aplastic Anemia and Systemic Lupus Erythematosus, and Bullous Pemphigoid

Table 3. Chagas Disease

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Table 4. Castleman’s Disease

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Table 5. Castleman’s Disease AND POEMS Syndrome and Cogan’s Syndrome

Table 6. Cold Agglutinin Disease and Churg-Strauss Syndrome

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Table 7. Eosinophilic Fasciitis

Table 8. Henoch-Schönlein Purpura and Immune Thrombocytopenic Purpura

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Table 9. Neuromyelitis Optica Spectrum Disorder

Table 10. Paraneoplastic Pemphigus

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Table 11. Paraneoplastic Pemphigus AND Castleman’s Disease and Paraneoplastic Cerebellar Degeneration

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Table 12. POEMS Syndrome

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Table 13. Polyarteritis Nodosa and Postural Orthostatic Tachycardia Syndrome

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Discussion

Autoimmune diseases are characterized by spontaneous hyperactivity of the immune system, leading to the production of additional antibodies, which often results in inflammation that can affect all organs and tissues of the body, especially lymphoid tissues, joints, skin, muscles, salivary glands, blood vessels, and bone marrow.⁸⁸

As established in the results section, multiple autoimmune diseases are considered within the spectrum of orphan diseases. Therefore, from the perspective of molecular diagnostic studies, this review aimed to compile the available findings in the literature so that readers can become familiar with these types of pathologies and find a diagnostic aid for these conditions in these studies.

As for the pathophysiology, inflammation is the host’s initial defense against pathogens and other triggering stimuli. It plays an essential role in tissue repair and eliminating harmful pathogens. However, an inadequate response can damage normal cells adjacent to the affected tissue. In many autoimmune diseases, sterile inflammation occurs.

Molecular imaging allows for the visualization, characterization, and measurement of biological processes at the molecular and cellular levels, with PET/CT being the most widely used molecular imaging study in clinical practice.⁸⁹

The European Association of Nuclear Medicine (EANM), in conjunction with the Society of Nuclear Medicine and Molecular Imaging (SNMMI), published a guideline in 2013 on the use of [¹⁸F]FDG in inflammation and infection based on the evidence available at that time. In 2018, along with the PET Interest Group (PIG) and endorsed by the American Society of Nuclear Cardiology, they published a guideline on the use of PET/CT in the diagnosis and follow-up of patients with suspected or diagnosed large vessel vasculitis and Polymyalgia Rheumatica.

Over the last 10 years, the use of this diagnostic tool has rapidly evolved, and it is now considered the most utilized imaging study in nuclear medicine for diagnosing and treating various inflammatory disorders.⁹⁰

[¹⁸F]FDG is the most commonly used PET tracer; as a glucose analog, it is taken up by cells with high metabolic activity.

[¹⁸F]FDG, once phosphorylated within the cell, is not further metabolized, resulting in its continuous accumulation inside cells. This property allows PET equipment to detect the emitted photons for imaging purposes (Molecular Imaging of Autoimmune Diseases and Inflammation).

Inflammatory processes exhibit increased FDG uptake because infiltrating inflammatory cells express high levels of glucose transporters, especially GLUT1 and GLUT3. These cells also demonstrate greater glucose consumption than non-inflammatory peripheral cells, leading to increased glucose metabolism due to oxidative bursts in inflammatory cells.⁹¹

This is evidenced in our review, where the predominant finding across all the pathologies discussed was an increased uptake of FDG in affected organs or tissues. Some reports show SUVmax values greater than 4 in Castleman’s disease (CD), generalized Wegener’s granulomatosis, POEMS syndrome, and eosinophilic fasciitis. Additionally, PET/CT helped guide the diagnosis by identifying primary tumors in some cases of metastatic lesions in patients with paraneoplastic pemphigus.

Cogan’s syndrome is a rare disease of unknown origin characterized by ocular inflammation and audiovestibular symptoms; only about 5% of patients present with systemic manifestations such as vasculitis or aortitis. In this context, PET/CT facilitated the diagnosis of systemic involvement by revealing increased metabolism in the walls of blood vessels such as the thoracic aorta and subclavian arteries, as reported by Cabezas-Rodríguez et al.³⁶ and Lu et al.⁴⁰, with vasculitis affecting the brachiocephalic trunk, common carotid artery, and left subclavian artery.

Yamauchi et al. reported a case of bilateral supraclavicular and mediastinal lymph nodes showing significant FDG uptake (SUVmax 11.5). An initial biopsy of the left supraclavicular lymph node showed no evidence of malignancy and was initially diagnosed as idiopathic multicentric Castleman disease, later confirmed as Hodgkin lymphoma. PET/CT was crucial in reassessing the appropriateness of the initial diagnosis. Yamauchi and colleagues highlighted that [¹⁸F]FDG PET/CT can differentiate between the two pathologies, showing significantly lower FDG uptake and SUVmax values in non-malignant conditions compared to Hodgkin lymphoma.²⁸

Patients with chronic autoimmune and inflammatory diseases have been reported to have a higher risk of malignancy, with 2.4- and 2-fold increased risks for esophageal and pancreatic cancers, respectively. For lymphoma, the risk is approximately two times higher in patients with rheumatoid arthritis, 3–6 times higher in systemic lupus erythematosus, and 9–18 times higher in Sjögren syndrome. In dermatomyositis and polymyositis, an incidence of seven times greater cancer risk compared to the general population has been reported.⁸⁸

Oh JR et al. suggest that PET/CT is valuable in differentiating malignancy from inflammation in systemic autoimmune diseases, especially using the spleen/liver SUVmax ratio—1.5 ± 0.6 in autoimmunity vs. 0.8 ± 0.02 in malignancy patients.⁸³

In conditions such as acromegaly, Chagas disease, and Castleman disease, case reports have shown PET/CT studies using ⁶⁸Ga-DOTATATE and ⁶⁸Ga-DOTATOC, demonstrating increased uptake of these radiopharmaceuticals. Their implementation is based on the overexpression of somatostatin receptors by inflammatory and immune cells in various tissues and blood vessels.⁹²

Potential uses also include amino acid-based tracers such as L-[methyl-¹¹C]-methionine (used by Bashari et al.¹⁰ and Haber-Bosch et al.¹⁵) or [¹⁸F]FET (used by Bakker et al.¹⁷) in acromegaly cases with suspected residual lesions in the central nervous system, guided by persistent biochemical abnormalities.

In the case of [⁶⁸Ga]Ga-Pentixafor, Zuo et al.²⁹ report that a higher CXCR4 expression may be present in a heterogeneous lymphoproliferative disease such as Castleman’s disease.

For [¹⁸F]Flutemetamol and [¹⁸F]MK6240 (TAU), neuromyelitis optica associated with Alzheimer’s disease is described as characterized by a marked accumulation of amyloid beta (Aβ) and a high degree of tau deposition, respectively.⁵⁸

With the above in mind, the use of PET/CT with different tracers in the case of orphan autoimmune diseases has expanded in recent years, as it allows for imaging of the processes influencing the microenvironment of inflamed tissues. This plays a significant role in the persistence of inflammatory processes in autoimmune diseases and provides a comprehensive view of systemic involvement, which can lead to more precise guidance for the treatment and follow-up of these diseases.

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Conflict of Interest:

The authors have no conflicts of interest to declare.

Funding Statement:

None.

Acknowledgements:

None.

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