Pathways Case Report: A Case of Extracranial Giant Cell Arteritis

A 90-year-old woman presented to the hospital with 3-4 weeks of back pain radiating to her chest and abdomen without additional constitutional symptoms. Her medical history was notable for atrial fibrillation (a type of cardiac arrhythmia) treated with ablation and warfarin, sick sinus syndrome (a disorder that impacts heart rhythm), which was previously treated with a permanent pacemaker, heart failure with mid-range ejection fraction, chronic kidney disease, and amiodarone-induced lung toxicity.

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The laboratory workup was most notable for elevated C-reactive protein (CRP) levels, a protein that becomes elevated in response to inflammation. Infectious and other inflammatory workup was negative with normal complement components C3 and C4, low to normal IgG subclasses, and negative for rheumatoid factor, cyclic citrullinated peptide, and antineutrophilic cytoplasmic antibody (ANCA). A CT-angiography scan of the chest, abdomen, and pelvis visualized inflammation surrounding the distal thoracic aorta at the level of the diaphragm without contrast extravasation. These findings were suggestive of thoracic aortitis. The main causes of aortitis can be divided into inflammatory (e.g., giant cell arteritis [GCA], Takayasu arteritis, IgG4-related disease, ANCA-associated vasculitis) and infectious conditions (luetic or mycobacterial aortitis for infectious conditions). Given the patient's clinical presentation, increased inflammatory markers, and imaging findings of vessel inflammation, she was diagnosed with extracranial GCA.

The Pathways Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on understanding how autoimmunity develops in GCA, driven by three questions:

1. Why are women more prone to develop GCA?
2. Why does GCA affect older populations?
3. What biochemical pathways determine specific intracranial and extracranial manifestations of GCA?

Background and Diagnosis

GCA occurs due to genetic and environmental risk factors that create a setting where auto-reactivity and loss of self-tolerance develop. Epidemiologic studies indicate that GCA mainly affects older populations (>50 years old), women, and individuals primarily of northern European origin who tend to have lower BMI. Smoking has been identified as a factor that confers additional risk. Two main types of risk alleles were identified using genome-wide association studies: those involved in HLA class II and in vascular remodeling including PLG (encodes for plasminogen) and P4HA2 (encodes for prolyl 4-hydroxylase subunit alpha 2)¹. The genetic predisposition indicates important roles for antigen presentation, T cell differentiation, and endothelial damage as key mechanisms driving loss of self-tolerance in GCA².

No autoantibodies or antigens have been identified in GCA, which highlights the need for ongoing research. However, the role of CD4 helper cells, and in particular Th1, Th17, and Tregs CD4 cell subsets has been described. Polarization of Th1 and Th17 cells is linked to inflammation, leading to tropism and symptom manifestations in GCA, with Th17 cells primarily contributing to constitutional symptom onset, and Th1 cells associated with vascular damage³. The concentration of Tregs, which are known for dampening the inflammatory response and protecting against autoimmunity, is also lower in GCA-affected individuals². CD4 T cell differentiation and response is regulated by signaling pathways in antigen presentation, including immune checkpoint expression and cytokine release. These pathways are also affected in GCA, with known immune checkpoint dysfunction leading to T cell activation². Although a general framework exists for what drives autoimmunity in GCA, the questions posed regarding why women, why older age, and why different vessels are involved remain relatively unanswered.

Sex differences in autoimmune disease are a well-established phenomenon, with GCA being three times more prevalent in women than in men⁴. Explanations for this difference include the effect of hormone signaling, the X-linked nature of certain genes involved in autoimmunity (e.g., transcription factor FOXP3 involved in Treg signaling), and the 'micro-genderome' (the impact of hormone signaling on sex differences in the microbiome of the GI tract⁵). Though no studies are available in GCA, prior studies suggest that a more proinflammatory microbiome in otherwise healthy females following puberty leads to increased expression of Th17 pathway genes and peripheral T cell activation with the opposite effect in males. Different microbiota are associated with increased levels of short-chain fatty acid bacterial metabolites in males, which in turn is associated with Treg induction and IL-6 suppression⁶. More research is needed to continue understanding this relationship.

The second risk factor in our patient for GCA was her age. Indeed, age affects the immune system in important ways which can be summarized as immuno-senescence⁷. The hallmarks of immuno-senescence are demonstrated by persistent low-grade inflammation ("inflammaging"), decreased ability to fight cancer or infection, an impaired response to new antigens, increased incidence of autoimmunity, and weakened wound repair. There is no consensus on specific biomarkers of inflammaging, but elevated levels of CRP and proinflammatory cytokines are common indicators. Potential driving forces are seen in chronic stimulation of the immune system by viruses and an increase in the translocation of microbial products from the gut to the circulation, which is facilitated by decreased intestinal epithelial barrier integrity with age⁸. With respect to GCA, the decreasing number/function of Treg cells results in less effective suppression of proinflammatory T cell populations², which may contribute to the increased risk in aged populations.

There is currently no accepted explanation for why different vessels are affected in different patients with GCA, such as why certain patients have temporal versus aortic involvement. Histopathology remains similar in temporal artery GCA and aortic GCA⁴, which implies that the underlying pathophysiology for temporal artery GCA and aortic GCA may be shared. Perhaps the fact that autoimmunity involves an immune response to a self-antigen⁹ may explain differences in affected territories in different patients with GCA. For example, different vessels have different embryologic origins¹⁰, which could result in differences in the basic cellular and molecular makeup of the vessels. Thus, the different embryological etiology of the temporal artery and aorta have the potential to develop unique self-antigens that the immune system targets in patients with different presentations of GCA.

In addition to differences in vascular tropism, temporal arteries respond differently compared to the aorta in GCA². Temporal involvement is typically characterized by intimal hyperplasia, while aortic disease involves elastin degradation and vessel dilatation. Furthermore, endothelial permeability is an important aspect of the pathophysiology of GCA. Indeed, gene mutations in vessel wall remodeling have been associated with GCA, which is hypothesized to lead to increased exposure of vessel self-antigens to the immune system¹. It is possible that local differences in different vessel walls in individuals could result in differing levels of self-antigen exposure, which may influence the specific vessels that are predisposed to be affected by disease.

Summary and Future Steps

As of now, the mainstay therapy in GCA is a protracted course of glucocorticoids, with the transition to tocilizumab, an IL-6R binding biologic that blocks IL-6 signaling. Understanding key mechanisms in CD4 differentiation, inflammatory response, and vascular remodeling could present breakthroughs for additional steroid-sparing therapeutics. For example, IL-17 blockade, IL-12 blockade, abatacept (inhibits CD28-mediated T cell activation), and endothelin receptor antagonism are under investigation as potential therapies for GCA². Finally, while there are no formal studies specifically for GCA yet, CAR-Tregs have been a proposed therapy to treat autoimmune diseases in general as a way to support T-reg function in promoting self-tolerance and combating autoimmunity¹¹. Since impaired Treg function is thought to play a large role in the pathogenesis of GCA², these therapies targeting Treg function could be promising for GCA patients.

References

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8. Sadighi Akha AA. Aging and the immune system: An overview. J Immunol Methods. 2018;463:21-6. Epub 20180814. doi: 10.1016/j.jim.2018.08.005. PubMed PMID: 30114401.
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