Top research in Takayasu’s arteritis & giant cell arteritis presented at ACR Convergence 2023
Philip Seo, MD, MHS
The large vessel vasculitides, including Takayasu’s arteritis and giant cell arteritis, experienced a surge of interest at ACR Convergence 2023. Here, we highlight important points from 10 of the studies presented at this conference.
1. The Extent & Accrual of Damage in Takayasu’s Arteritis
Abstract 1567: Kermani et al.1
Takayasu’s arteritis is a granulomatous vasculitis that affects the aorta and the large vessels that branch from the aorta. When left untreated, Takayasu’s arteritis may lead to permanent vascular damage, including aortic aneurysm and arterial stenosis.
Kermani et al. determined the importance of damage to patients with Takayasu’s arteritis by analyzing 350 patients who were enrolled in a prospective observational cohort. Patients were predominantly female (91%) and had a median disease duration of 4.5 years.
In this study, damage was present at the time of the first study visit in 83% of patients; at the time of cohort enrollment, the median Vasculitis Damage Index score for patients with Takayasu’s arteritis was 3. The most common forms of damage were peripheral vascular disease (83%) and cardiac disease (42%). At the time of last follow up, 95% of patients had evidence of damage. This increase in damage was also predominantly due to incident peripheral vascular and cardiac disease, including major vessel stenosis, loss of pulses, new hypertension, arterial thrombosis, renal artery stenosis, aortic aneurysm and vascular damage requiring surgical intervention.
In patients with ANCA-associated vasculitis, damage occurs in a bimodal pattern: Most early damage is disease related, whereas most late damage is treatment related. It is, therefore, interesting to note that most of the damage recorded in this cohort was disease related, even though patients in this cohort received care in centers with expertise in the management of Takayasu’s arteritis. This implies that standard-of-care therapies may not be adequate to prevent disease progression.
The fact that most patients already had significant amounts of damage at the time of enrollment in this cohort likely reflects the challenges inherent to establishing an early diagnosis of Takayasu’s arteritis. Delays in diagnosis lead to delays in the initiation of pharmacotherapy, which allows permanent damage to accrue. Overall, this study highlights the substantial hurdles that remain in learning how to effectively manage this disease.
Author’s note: I was a co-author on this study.
2. Immune Checkpoint Inhibitors-Induced Large Vessel Vasculitis
Abstract 2562: Cottu et al.2
Immune checkpoint inhibitors, which are now commonly used to treat many malignancies, may lead to rheumatic immune-related adverse events. These immune-related adverse events may closely mimic many rheumatic diseases, including inflammatory arthritis, inflammatory myopathy and Sjögren’s disease. However, the association between immune checkpoint inhibitors and giant cell arteritis has been less clear.
This retrospective, multi-center, European study identified 15 patients who received a new diagnosis of large vessel vasculitis a median of four months after initial treatment with an immune checkpoint inhibitor. An additional four patients were noted to have had a prior diagnosis of polymyalgia rheumatica or giant cell arteritis. The median age of these patients was 70 years.
Clinically, patients were evenly divided among those who had only cranial symptoms of giant cell arteritis, those with only large vessel vasculitis manifestations and those who presented with a combination of both. Four patients had visual loss.
All patients were treated with glucocorticoids, and remission was achieved in almost all (95%) patients. Four patients did not respond to treatment or had a relapse while prednisone was tapered; this group included three patients who continued to receive therapy with immune checkpoint inhibitors following a diagnosis of giant cell arteritis. At the end of follow-up, three patients died of the initial malignancy and one died of acute coronary syndrome.
In theory, checkpoints are intrinsically involved in the pathogenesis of giant cell arteritis. It is interesting, therefore, to note that giant cell arteritis is only rarely reported as an immune-related adverse event. It would have been interesting to see a separate analysis of patients who had a new diagnosis of giant cell arteritis in association with checkpoint inhibitors vs. patients who experienced a flare of their known diagnosis. However, the high mortality reported in this cohort reinforces that the stakes are high. Notably, only one patient in this cohort received treatment with tocilizumab, which may have made a substantial difference for the four patients with relapsing or refractory disease.
3. Pregnancy Outcomes Among Patients with Vasculitis
Abstract 2425: Rector et al.3
Research in pregnancy outcomes in patients with rheumatic diseases has largely focused on rheumatoid arthritis and systemic lupus erythematosus, which predominantly affect young women. The impact of systemic vasculitis on pregnancy outcomes has been less clear.
In this study, Rector et al. reviewed administrative claims data from private health insurance providers to identify 655 pregnancies among 527 patients with vasculitis and more than 4 million pregnancies among patients without vasculitis. Patients with vasculitis had a higher frequency of spontaneous abortion, elective termination, ectopic and molar pregnancies, and preterm delivery than patients without vasculitis. Approximately 12% of pregnancies among patients with vasculitis were complicated by preeclampsia. Patients with small vessel or variable vessel vasculitis had a higher frequency of preterm delivery when compared to patients with large or medium-vessel vasculitis. Patients with small vessel vasculitis had a higher rate of ectopic and molar pregnancy compared with patients with other forms of vasculitis.
As our therapeutics improve, pregnancy is becoming an option for increasing numbers of patients with systemic vasculitis. This study makes an important contribution to our understanding of pregnancy outcomes in this population. This analysis includes 160 patients with medium vessel vasculitis (e.g., polyarteritis nodosa) and 250 patients with variable vessel vasculitis (e.g., Behçet’s disease, Cogan’s syndrome), compared with 217 patients with small vessel vasculitis. Given the comparative rarity of polyarteritis nodosa and Cogan’s syndrome, and the broad clinical presentations associated with Behçet’s disease and small vessel vasculitis, it would be helpful to have additional detail regarding the specific diagnoses included in this study. Alternatively, an analysis of prescription claims could serve as a surrogate for disease severity.
4. Senescent Cells in Temporal Arteries of Patients with GCA
Abstract 2390: Veroutis et al.4
Cellular senescence is a fundamental part of aging. Senescent cells enter a state of permanent cell cycle arrest, rather than dying off. In some cases, these senescent cells help stimulate stem cell growth and tissue repair. In other cases, senescent cells become zombie cells that produce inflammatory cytokines and contribute to age-related diseases, such as Alzheimer’s dementia and cancer.
In this study, investigators explored the importance of senescent cells in giant cell arteritis by examining temporal artery biopsies from 75 patients with giant cell arteritis and 22 patients with polyarteritis nodosa, who served as control samples.
Senescent cells were more frequently present in temporal artery biopsies from patients with giant cell arteritis (9.5% vs. 2.7%, P<0.0001). Most of these senescent cells were from a fibroblast or macrophage lineage; these cells expressed interleukin-6 and were associated with the presence of vascular wall inflammation. Temporal artery biopsies from patients with giant cell arteritis were cultured. Supernatant from these cultures induced cellular senescence; this process was partially inhibited by interleukin-6 blockade.
One of the great mysteries of giant cell arteritis is the role that interleukin-6 plays in disease pathogenesis. This study provides one potential explanation. It is particularly interesting to note that interleukin-6 blockade is only partially effective in preventing cellular senescence. This may explain why interleukin-6 blockade seems to be less effective for patients with relapsing disease, who presumably already have an established population of senescent cells that may lead to more resistant disease.
5. Subclinical Giant Cell Arteritis in Polymyalgia Rheumatica: A Biomarker for High Relapse Risk
Abstract 2404: De Miguel et al.5
Approximately 20–25% of patients who have a clinical diagnosis of giant cell arteritis will have ultrasound-evidence of vascular inflammation compatible with a diagnosis of giant cell arteritis. The importance of this finding and, in particular, whether these patients require a different management strategy have been unclear.
This study included 50 patients with polymyalgia rheumatica who had ultrasound evidence of large vessel vasculitis and another 100 patients with polymyalgia rheumatica who lacked such involvement. Clinically, there were no differences between the two groups. However, patients with polymyalgia rheumatica who had ultrasound evidence of large vessel vasculitis were more likely to relapse (62% vs. 14%, P<0.001) and were treated with higher doses of glucocorticoids at disease onset (34 vs. 20 mg, P=0.001). Patients who relapsed were tapered more quickly off of prednisone during the first three months of therapy (mean dose at three months: 13 mg vs. 19 mg, P<0.01). Among patients with large vessel involvement, higher starting doses of glucocorticoids did not prevent relapse.
Clinicians don’t find it uncommon to have a patient with polymyalgia rheumatica who seems to require higher-than-usual doses of glucocorticoids to remain in remission. It seems that many of these patients may have subclinical giant cell arteritis that is clinically indistinguishable from pure polymyalgia rheumatica. In the future, vascular ultrasound may be useful for identifying this subset of patients, who may benefit from early initiation of interleukin-6 blockade as a steroid-sparing strategy.
In the meanwhile, this study highlights the importance of slow glucocorticoid tapers to keep patients with polymyalgia rheumatica in remission.
6. Risk of Large Vessel Complications in Patients with Giant Cell Arteritis
Abstract 2406: Elfishawi et al.6
Patients with giant cell arteritis have an increased risk of developing large vessel complications, including aortic aneurysms and arterial stenosis. Elfishawi et al. defined the magnitude of this risk.
This study included 119 patients with giant cell arteritis who were followed for a mean of 8.9 years. When compared with an age- and sex-matched control population, patients with giant cell arteritis had a greater risk of developing large vessel complications (hazard ratio 2.67, 95% confidence interval [CI] 1.6–4.5), particularly large artery stenosis (hazard ratio 2.98, 95% CI 1.6–5.5). Patients with giant cell arteritis also had a higher risk of thoracic aortic aneurysm (hazard ratio 13.46, 95% CI 1.78–101.98), even following adjustment for age, sex and comorbid conditions. The incidence rate of any large vessel complication at five years was higher among patients with giant cell arteritis compared with control patients (27.8% vs. 11.2%); this risk increased at 15 years (49.2% vs. 19.2%). However, giant cell arteritis was not associated with an increased risk of abdominal aortic aneurysm or death.
This study confirms prior work from the Mayo Clinic demonstrating that patients with giant cell arteritis have an increased long-term risk of large vessel complications. This study further demonstrates that these complications become increasingly common with time; almost half of patients with giant cell arteritis will develop some large vessel issue after 15 years of follow-up. It is reassuring to note that the increased risk of developing thoracic aortic aneurysms is not associated with an increased risk of death. How patients with giant cell arteritis should be screened for the development of thoracic aortic aneurysms remains an open question.
7. Clinicopathologic Features of Patients with Giant Cell Arteritis and Thoracic Aorta Repair: A Single Center Experience over Two Decades
Abstract 2557: Kaymakci et al.7
After diagnosis, patients with giant cell arteritis are largely assessed using surrogate markers of disease activity, such as acute phase reactants and imaging studies.
This interesting study examined pathologic specimens from 49 patients with giant cell arteritis who underwent thoracic aortic surgery between 2000 and 2001 at the Mayo Clinic, Rochester, Minn. Almost all of the patients (84%) had the cranial symptoms associated with giant cell arteritis, and 88% either met 1990 ACR Classification Criteria for giant cell arteritis or had a temporal artery biopsy that confirmed the diagnosis.
All patients were deemed to be in clinical remission at the time of surgery. However, 82% had biopsy evidence of active aortitis a median of six years following the initial diagnosis of giant cell arteritis; 39% were receiving immunosuppressive therapies at the time of the aortic surgery. In 44% of aorta samples, granulomatous inflammation was noted; lymphoplasmacytic infiltrates were noted in an additional 35% of biopsies.
Parallel work conducted at the Mayo Clinic, Rochester indicates that patients with giant cell arteritis may develop loss of self-tolerance and a decline in regulatory T cells. This immunologic shift permits the rise of self-renewing T-cells; these cells induce chronic inflammation of the aorta. This model is supported by the histopathologic studies presented in this abstract, and may explain the higher long term risk of vascular complications noted in Abstract 2406, discussed above. It is less clear whether this abstract means that we should double-down on immunosuppressive therapies even in patients who seem to be in clinical remission, or if we need to simply accept that this particular form of vascular inflammation is completely resistant to current therapeutics.
8. Aortic Aneurysms in Patients with Aortitis Related to Giant Cell Arteritis Treated with Tocilizumab
Abstract 2558: López et al.8
Tocilizumab is widely used for both patients with the classic cranial symptoms of giant cell arteritis (e.g., headache, visual changes) and the large vessel manifestations of giant cell arteritis, which are associated with aortitis and arterial stenosis. However, how effective tocilizumab is for the management of aneurysms associated with giant cell arteritis is less clear.
This is an observational study of 196 patients with positron emission tomography-confirmed aortitis due to giant cell arteritis, 10 of whom had aortic aneurysms. Patients were diagnosed with giant cell arteritis either by the ACR Classification Criteria, temporal artery biopsy or characteristic imaging features. All patients were treated with tocilizumab.
After a mean follow-up of 25 months, none of the 95 patients who did not have an aneurysm initially developed an aneurysm while receiving treatment with tocilizumab. Of the 10 patients who already had an aortic aneurysm at the time tocilizumab therapy was initiated, five required surgery and three demonstrated aneurysmal growth. The other two patients remained stable.
This study indicates that tocilizumab may be effective for the prevention of aneurysms in patients with giant cell arteritis, which is of particularly importance when considered in light of abstract 2406, discussed above. How to interpret the outcomes of the 10 patients who had aortic aneurysms before tocilizumab therapy was initiated is less clear. It seems possible aortic aneurysms are associated with greater tissue inflammation, which may be resistant to tocilizumab. On the other hand, aneurysmal dilation also implies that structural damage to the aortic wall has already taken place; in this case, both aneurysmal growth and the need for surgical intervention might simply reflect that damage, which would not be expected to respond to tocilizumab.
9. Risk of Gastrointestinal Perforation
Abstract 2560: Nepal et al.9
Tocilizumab is clearly effective for the treatment of giant cell arteritis. However, many clinicians continue to avoid using this agent due to a concern for colonic perforation, which has been reported among patients with rheumatoid arthritis treated with this drug.
This study used a claims database to determine the risk of colonic perforation among patients with giant cell arteritis.
Nepal et al. identified 5,142 patients with giant cell arteritis, 845 of whom received therapy with tocilizumab. In this study, tocilizumab exposure was not associated with an increased risk of gastrointestinal perforation (hazard ratio 1.05, 95% CI 0.30–1.65). Incident gastrointestinal perforations were actually less common among patients who had received tocilizumab (2.0 vs. 3.4 events/1,000 person-years); however, this difference was not statistically significant. The adjusted rate ratio for gastrointestinal perforation among patients with giant cell arteritis treated with tocilizumab was 0.56 (95% CI 0.13–2.38). Risk factors for gastrointestinal perforation included diverticulitis (rate ratio 3.51) and intravenous methylprednisolone (rate ratio 5.41).
This study confirms that pre-existing diverticulitis and exposure to high dose glucocorticoid therapy are associated with an increased risk of colonic perforation. However, it seems that the addition of tocilizumab does not substantially increase the risk of colonic perforation for patients with giant cell arteritis. This study is reassuring, and may encourage more widespread use of tocilizumab for the treatment of giant cell arteritis.
10. T Cell Activity & Clinical Outcomes in Patients with GCA
Abstract 2603: Redmond et al10
Despite the overall effectiveness of tocilizumab for the treatment of giant cell arteritis, there continue to be some patients who are treatment resistant or experience early relapse.
Asp358AIa is a single nucleotide polymorphism (SNP) found in the interleukin-6 receptor. This SNP is associated with increased activation of the interleukin-6 pathway. In this study, Redmond et al. explored the importance of this SNP for patients with giant cell arteritis.
This study demonstrated that patients with giant cell arteritis who had the Asp358AIa SNP are less likely to respond clinically to treatment with tocilizumab than patients without this variant (70% vs. 100%) and had a higher risk of relapse (50% vs. 22%). Patients with the Asp348AIa SNP were also more likely to have a positive temporal artery biopsy and ocular manifestations, although this association was not statistically significant.
CD4+ T-cells isolated from patients with the Asp358AIa variant also had higher levels of interleukin-17A expression than CD4+ T-cells from healthy control patients.
This abstract is especially intriguing when considered in light of the recently published TitAIN study, a phase 2 study that demonstrates interleukin-17A blockade with secukinumab is an effective treatment for giant cell arteritis. While phase 3 studies examining the efficacy of secukinumab for giant cell arteritis are ongoing, this abstract implies that secukinumab should be particularly effective for patients who have failed treatment with tocilizumab, a population that, unfortunately, will likely be excluded from the ongoing studies.
Philip Seo, MD, MHS, is an associate professor of medicine at Johns Hopkins University School of Medicine. He served as the third physician editor of The Rheumatologist.
References
- Kermani T, Kaymaz-Tahra S, Cuthbertson D, et al. Assessment of the extent and accrual of damage in Takayasu’s arteritis [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Cottu A, Tomelleri A, Campochiaro C, et al. Immune checkpoint inhibitors-induced large vessel vasculitis: Data from a multicenter study [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Rector A, Simard J, Shaw G, Horomanski A. Pregnancy outcomes among patients with vasculitis using administrative claims data [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Veroutis D, Argryropouou O, Goules A, et al. Characterization of senescent cells in temporal arteries of patients with giant cell arteritis reveal an inflammatory phenotype and strong dependence from IL-6 [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- De Miguel E, Karalilova R, Macchioni P, Ponte C, et al. Subclinical giant cell arteritis in polimialgia rheumatica: A biomarker of high relapse risk [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Elfishawi M, Kaymakci M, Achenbach S, et al. Risk of large vessel complications in patients with giant cell arteritis, a population-based study [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Kaymakci M, Boire N, Bois M, et al. Clinicopathologic features of patients with giant cell arteritis and thoracic aorta repair: A single center experience over two decades [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- López F, Loricera J, Martín-Gutiérrez A, et al. Aortic aneurysms in a multicenter cohort of 196 patients with aortitis related to giant cell arteritis treated with tocilizumab [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Nepal D, Sattui S, Wallace Z, Putman M. Risk of gastrointestinal perforation among patients with giant cell arteritis who received tocilizumab [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
- Redmond C, Zorc R, Sylvester M, et al. Impact of IL-6 receptor small nucleotide polymorphism Asp358Ala on T cell activity and clinical outcomes in patients with giant cell arteritis [abstract]. Arthritis Rheumatol. 2023;75(suppl 9).
