Pathologic Markers Determining Prognosis in Patients With Treated or Healing Giant Cell Arteritis

doi:10.1016/j.ajo.2018.05.031

American Journal of Ophthalmology

Volume 193, September 2018, Pages 45-53

https://doi.org/10.1016/j.ajo.2018.05.031 Get rights and content

Purpose

To provide quantitative evidence linking the CD68 (cluster of differentiation 68)+ macrophage marker found on temporal artery biopsies (TABs) with disease prognosis.

Design

Retrospective, cross-sectional study.

Methods

We examined 42 consecutive patients who had undergone unilateral TABs at a single hospital in 2015. Clinical data, laboratory data, and histopathologic features of TABs were recorded. Inclusion criteria were clinical diagnosis of giant cell arteritis (GCA) with TAB performed at the same center. CD68 immunohistochemistry was used to label macrophages in the TABs. Primary outcome was multiple logistic regression and bivariate comparisons to measure the association between CD68+ cells per histologic section with placement on immunomodulatory therapy (IMT).

Results

Twenty seven patients were female (64%), with a mean age of 72 (standard deviation [SD.] ±7.7). Eleven patients (26%) were placed on IMT, 17 (40%) had disease recurrence during steroid taper, and 25 (60%) were referred to rheumatology. Of 42 biopsies, 35 underwent staining with CD68 to confirm active inflammation in suspicious, but not diagnostic, specimens. Patients eventually placed on IMT had increased CD68+ cells per slice compared to those not on IMT (median 5.00 [25th-75th quartile 2.00–7.15] vs 1.21 [0.38–2.57], P = .031, respectively). A receiver operating characteristic (ROC) curve demonstrates that 2.17 CD68+ cells/slice predicts placement on IMT with an odds ratio of 1.54 (95% confidence interval 1.02–2.33, P = .038).

Conclusions

Patients refractory to initial steroid tapers and those eventually placed on IMT had increased CD68 cells per section. CD68+ macrophages and their location on the internal elastic lamina may predict disease severity in patients with presumed GCA. Our results suggest that this marker may expedite patient triaging to alternate treatment to the usual steroid therapy.

Section snippets

Methods

This retrospective, consecutive case series was approved by the Houston Methodist Hospital institutional review board (Pro00013783). Clinical history of patients with suspected GCA were reviewed and correlated with a histologic sections of their TABs.

Results

Forty-two patients, 27 (64%) of whom were female, were reviewed. At diagnosis, the median age was 71 years, with a 25th-75th percentile interquartile range (IQR) of 66-79 years. Median follow-up time was 53.6 (25.0-78.9) weeks. Median time between clinical evaluation and TAB was 16.5 (3.0-35.3) days; during this time, patients were on corticosteroids. All suspected patients referred from external ophthalmologists were given oral steroids on the day of presentation at the external

Discussion

Many studies have investigated the correlation between examination findings,4, 5, 6 laboratory findings,¹¹ and histopathologic features9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 in the diagnosis of patients with GCA. Genetic polymorphisms in various regulatory elements related to cell types or processes, such as in endothelial cells or angiogenesis, respectively, have been found to increase one's risk for developing GCA and in worsening its severity.22, 23 This study specifically examined

Conclusions

This study provides data supporting the use of CD68 immunohistochemical staining in TABs and demonstrates that patients with greater numbers of CD68+ cells per histologic section were more likely to require additional immunomodulatory therapy and to have more recalcitrant disease. Our data did not show an association between prolonged steroid courses and decreased CD68+cells per slice. Continued future study of the potential use of quantitative immunologic markers (eg, CD68) in the TAB should

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Cited by (19)

Consensus statement on the processing, interpretation and reporting of temporal artery biopsy for arteritis
2023, Cardiovascular Pathology
Giant cell arteritis (GCA) is the most common systemic vasculitis in adults in Europe and North America, typically involving the extra-cranial branches of the carotid arteries and the thoracic aorta. Despite advances in noninvasive imaging, temporal artery biopsy (TAB) remains the gold standard for establishing a GCA diagnosis. The processing of TAB depends largely on individual institutional protocol, and the interpretation and reporting practices vary among pathologists. To address this lack of uniformity, the Society for Cardiovascular Pathology formed a committee tasked with establishing consensus guidelines for the processing, interpretation, and reporting of TAB specimens, based on the existing literature. This consensus statement includes a discussion of the differential diagnoses including other forms of arteritis and noninflammatory changes of the temporal artery.
Epidemiology and predictors of relapse in giant cell arteritis: A systematic review and meta-analysis
2023, Revue du Rhumatisme (Edition Francaise)
Cette étude avait pour objectif d’estimer le moment des rechutes, la prévalence des rechutes multiples et les facteurs prédictifs de rechute dans l’artérite à cellules géantes (ACG).
Une recherche a été effectuée dans les bases de données PubMed, Embase et Cochrane, depuis leur création jusqu’au 30 novembre 2021. Les critères d’évaluation comprennent le taux cumulé de rechute (TCR) pour la première rechute après 1, 2 et 5 ans de traitement, le TCR de deuxième et troisième rechute et les facteurs prédictifs de rechute.
Trente études (2 595 patients) ont été incluses pour l’évaluation du moment de la rechute, 16 études (1 947 patients) pour la prévalence des rechutes multiples et 40 études (4213 patients) pour les facteurs prédictifs de rechute. Les TCR à 1, 2 et 5 ans étaient respectivement de 32 % (intervalle de confiance [IC] à 95 % 22–43 %), 44 % (IC 95 % 31–59 %) et 47 % (IC 95 % 27–67 %). Une association négative a été observée entre la durée prévue de la corticothérapie et le TCR à 1 an (p = 0,03). Le TCR de deuxième et troisième rechute était de 30 % (IC 95 % 21–40 %) et 17 % (IC 95 % 8–33 %), respectivement. Le sexe féminin (odds ratio [OR] 1,43) et l’atteinte des gros vaisseaux (OR 2,04) étaient des facteurs prédictifs de rechute.
Près de la moitié des patients atteints d’ACG ont rechuté, la plupart dans les deux années suivant le diagnostic. Un patient sur trois a fait des rechutes multiples. De nouvelles études doivent être menées pour déterminer le calendrier optimal de réduction des glucocorticoïdes afin de parvenir à l’équilibre entre le plus faible risque de rechute et la plus courte durée de corticothérapie. Une corticothérapie prolongée ou l’introduction précoce d’agents d’épargne cortisonique peuvent être justifiées chez les femmes et en cas d’atteinte des gros vaisseaux.
The aim of this study was to estimate the timing of relapse, the prevalence of multiple relapses and the predictors of relapse in patients with giant cell arteritis (GCA).
PubMed, Embase and Cochrane databases were searched from inception till November, 30 2021. Outcome measures include cumulative relapse rate (CRR) of first relapse at year 1, 2, and 5 after treatment initiation, CRR of second and third relapse and predictors of relapse.
Thirty studies (2595 patients) were included for timing of relapse, 16 studies (1947 patients) for prevalence of multiple relapses and 40 studies (4213 patients) for predictors of relapse. One-year, 2-year and 5-year CRRs were 32% [95% confidence interval (CI) 22–43%], 44% [95% CI 31–59%], and 47% [95% CI 27–67%], respectively. The duration of scheduled glucocorticoid therapy was negatively associated with the 1-year CRR (p = 0.03). CRR of second and third relapse were 30% [95% CI 21–40] and 17% [95% CI 8–33%], respectively. Female sex (OR 1.43) and large vessel involvement (OR 2.04) were predictors of relapse.
Relapse occurred in almost half of GCA patients mainly during the first two years after diagnosis. One in three patients had multiple relapses. The optimal glucocorticoid tapering schedule, which seeks a balance between the lowest relapse risk and the shortest glucocorticoid duration, needs to be determined in future studies. Longer scheduled glucocorticoid therapy or early introduction of glucocorticoid-sparing agents may be warranted in female patients and patients with large vessel involvement.
Epidemiology and predictors of relapse in giant cell arteritis: A systematic review and meta-analysis
2023, Joint Bone Spine
Citation Excerpt :
Title and abstract screening yielded 121 articles eligible for full text analysis. In the final analysis, 30 studies were included for the 1-year, 2-year and 5-year CRR of first relapse (2595 patients) [13–40,42,74], 16 studies (1947 patients) [13–15,17,18,22,23,36,37,41–47] for the CRR of second and third relapse, 40 studies (4213 patients) [13,18–20,22,23,25,34,36–38,42,43,45,48–73] for the qualitative synthesis of predictors of relapse, and 16 studies (1961 patients) [13,18,23,36,37,42,45,52,55,56,58,64,66,68,69,71] for the meta-analysis of predictors of relapse. The characteristics of the included studies are presented in Table S3.
The aim of this study was to estimate the timing of relapse, the prevalence of multiple relapses and the predictors of relapse in patients with giant cell arteritis (GCA).
PubMed, Embase and Cochrane databases were searched from inception till November, 30 2021. Outcome measures include cumulative relapse rate (CRR) of first relapse at year 1, 2, and 5 after treatment initiation, CRR of second and third relapse and predictors of relapse.
Thirty studies (2595 patients) were included for timing of relapse, 16 studies (1947 patients) for prevalence of multiple relapses and 40 studies (4213 patients) for predictors of relapse. One-year, 2-year and 5-year CRRs were 32% [95% confidence interval (CI) 22–43%], 44% [95% CI 31–59%], and 47% [95% CI 27–67%], respectively. The duration of scheduled glucocorticoid therapy was negatively associated with the 1-year CRR (P = 0.03). CRR of second and third relapse were 30% [95% CI 21–40] and 17% [95% CI 8–33%], respectively. Female sex (OR 1.43) and large vessel involvement (OR 2.04) were predictors of relapse.
Relapse occurred in almost half of GCA patients mainly during the first two years after diagnosis. One in three patients had multiple relapses. The optimal glucocorticoid tapering schedule, which seeks a balance between the lowest relapse risk and the shortest glucocorticoid duration, needs to be determined in future studies. Longer scheduled glucocorticoid therapy or early introduction of glucocorticoid-sparing agents may be warranted in female patients and patients with large vessel involvement.
Diagnosis of giant cell arteritis using clinical, laboratory, and histopathological findings in patients undergoing temporal artery biopsy
2022, Clinical Neurology and Neurosurgery
Citation Excerpt :
Of particular interest is the significance of cluster of differentiation 68 (CD68) staining in GCA specimens. The CD68 marker stains macrophages that invade and destroy the IEL of affected arteries in GCA, which are precursors of epithelioid giant cells that are pathognomonic for active arteritis diagnosis [14]. There is no consensus regarding the significance of CD68-positive staining in the arterial walls of specimens that do not otherwise demonstrate active or classic healed arteritis, such as disruption or destruction of the IEL or transmural inflammatory changes.
To identify the clinical, laboratory, and histopathological features that may predict the diagnosis of giant cell arteritis (GCA).
A retrospective chart review was performed on patients who underwent temporal artery biopsy (TAB) between January 1, 2011 and March 31, 2019. Patient demographics, clinical characteristics, laboratory features, histopathological features, and biopsy results were collected. GCA status was determined by a neuro-ophthalmologist (OOA). Stepwise logistic regression analysis was performed to identify features that predict GCA status.
Of 101 patients who underwent TAB, 31 (31%) were diagnosed with GCA. Age was found to be statistically significant for the diagnosis of GCA (P = 0.009), with an average age of 74.4 years ( ± 8.1) in those with GCA vs. 68.9 years ( ± 10.0) in those without. The incidence of transient vision loss was higher in GCA than non-GCA patients (P = 0.005). Anterior arteritic ischemic optic neuropathy (n = 3), ophthalmic artery occlusion (n = 2), and posterior ischemic optic neuropathy (n = 1) were seen only in the GCA group. Of the 31 GCA patients, 15 had active GCA (48%), 3 (10%) had healed temporal arteritis (HTA), 8 (26%) had suggested HTA, and 5 (16%) had false negative biopsies. Of the 70 non-GCA patients, 63 (90%) had negative biopsies, 2 (3%) had HTA, and 5 (7%) had suggested HTA. Histopathological analysis revealed that CD68 staining had a sensitivity of 69% and specificity of 86%. Both presence of multinucleated giant cells (MNGC) and transmural inflammation had 100% specificity; however, sensitivity was ≤ 50%. In patients with negative TABs and complete risk factor data available (n = 66), the odds of GCA increased 2.16-fold every 5 years of age, and 1.08-fold every mg/day of oral steroid use. A biopsy result of HTA had an odds ratio of 84.7 and suggested HTA of 49.2 against a negative TAB for diagnosis of GCA.
Age at time of biopsy, HTA, and suggested HTA are predictive for the diagnosis of GCA. Transient vision loss is more commonly seen in GCA, and anterior arteritic ischemic optic neuropathy, ophthalmic artery occlusion, and posterior ischemic optic neuropathy are important ophthalmic manifestations of GCA. CD68 staining is more sensitive but less specific for diagnosing GCA in comparison to other histopathologic findings such as presence of MNGC and transmural inflammation. Further work is recommended to investigate the importance of the specific histopathologic finding of CD68 staining in the diagnosis of GCA.
High risk and low prevalence diseases: Giant cell arteritis
2022, American Journal of Emergency Medicine
Citation Excerpt :
Additionally, there is limited literature that suggests GCA may increase the risk of TIA or stroke, though it is unclear what the incidence of these conditions may be in the setting of GCA specifically [75]. Current data suggest stroke may occur in 1.5–7.5% of patients within the first 4 weeks of diagnosis [76-78], and ischemic stroke more commonly displays vertebrobasilar involvement and rarely intracranial involvement [79]. Beyond aortitis, branches of the external carotid artery are typically affected in GCA.
Giant cell arteritis (GCA) is a serious condition that carries with it a high rate of morbidity.
This review highlights the pearls and pitfalls of GCA in adult patients, including presentation, diagnosis, and management in the emergency department (ED) based on current evidence.
GCA is an immune-mediated vasculitis of medium-sized vessels that primarily affects those over the age of 50 years. Patients can present with a variety of signs and symptoms, including headache, vision changes, and systemic findings such as fever. Findings including jaw and limb claudication, vision changes, and temporal artery abnormalities are specific for diagnosis. While there are no highly sensitive features of the history and examination, the disease should be suspected in patients over the age of 50 years with vision changes, new headache, temporal artery abnormalities, or jaw claudication, especially in the setting of systemic symptoms. Inflammatory markers including erythrocyte sedimentation rate and c-reactive protein in combination are sensitive but not specific for GCA. Delay in diagnosis is associated with vision loss and other complications including aortitis. If suspected, the emergency physician should administer steroids and consult the ophthalmology and rheumatology specialists.
An understanding of GCA can assist emergency clinicians in diagnosing and managing this potentially dangerous disease.
New insights into the pathogenesis of giant cell arteritis: are they relevant for precision medicine?
2021, The Lancet Rheumatology
Citation Excerpt :
Notably, GM-CSF and M-CSF are early inducers of monocyte differentiation and might promote and sustain these macrophages in the context of giant cell arteritis.62 Using a stratified medicine approach, it is worth noting that macrophage infiltration seems higher in temporal artery biopsies of patients who do not respond to initial steroid tapering compared with patients who do respond, and might predict disease severity in patients with giant cell arteritis.65 In giant cell arteritis, activated dendritic cells througout the arterial wall that express class II MHC and the co-stimulatory molecules CD83, CD80, and CD86 strongly contribute to the activation of CD4+ T lymphocytes.
Giant cell arteritis is a primary granulomatous vasculitis characterised by a strict tissue tropism for large and medium-size vessels, occurring in people older than 50 years. Although considerable progress in understanding some of the pathophysiological mechanisms involved in the pathogenesis of giant cell arteritis has been made in the past 10 years, specific triggers of disease and mechanisms of chronic damage have not yet been identified. The definition of a specific pro-inflammatory hierarchy between the multiple cell types and the different cytokines or chemokines involved in the inflammatory process are still unexplored areas of study. The overall goal of precision medicine is to identify the best possible therapeutic approach for an individual or group of individuals with a given disease. The fundamental prerequisite of this approach is the identification, at baseline, of clinical and imaging findings and of molecular biomarkers that allow a precise stratification of patients and an adequate prediction of the therapeutic response. In this regard, the possibility of obtaining temporal artery biopsies for diagnostic purposes offers incredible exploratory possibilities to define different disease pathotypes potentially susceptible to different therapeutic interventions. In this Series paper, we will describe the most recent evidence relating to the pathogenesis of giant cell arteritis, trying to define, if possible, a new pathogenetic-centred approach to patients with giant cell arteritis.

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: Stacy Smith is currently at Houston Methodist Neurological Institute, The Woodlands, Texas, USA.

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Original articlePathologic Markers Determining Prognosis in Patients With Treated or Healing Giant Cell Arteritis

Purpose

Design

Methods

Results

Conclusions

Section snippets

Methods

Results

Discussion

Conclusions

Ophthalmology

Ophthalmology

Blood

Ophthalmology

Ophthalmology

Ophthalmology

J Autoimmun

Am J Hum Genet

Semin Arthritis Rheum

Lancet

Epidemiology of giant cell arteritis and polymyalgia rheumatica

Arthritis Rheum

Does this patient have temporal arteritis?

JAMA

Predictors of relapse and treatment outcomes in biopsy-proven giant cell arteritis: a retrospective cohort study

Rheumatology (Oxford)

Risk factors for early visual deterioration in temporal arteritis

J Neurol Neurosurg Psychiatry

Original article
Pathologic Markers Determining Prognosis in Patients With Treated or Healing Giant Cell Arteritis