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Rheumatology Advance Access originally published online on February 19, 2008
Rheumatology 2008 47(4):488-490; doi:10.1093/rheumatology/ken012
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Is intimal hyperplasia a marker of neuro-ophthalmic complications of giant cell arteritis?

D. Makkuni1, A. Bharadwaj1, K. Wolfe2, S. Payne2, A. Hutchings3 and B. Dasgupta1

1Department of Rheumatology, 2Department of Pathology, Southend University Hospital, Westcliff on Sea, Essex and 3Health Services Research Unit, London School of Hygiene & Tropical Medicine, London, UK.

Correspondence to: B. Dasgupta, Department of Rheumatology, Southend University Hospital, Prittlewell Chase, Westcliff on Sea, Essex SS0 0RY, UK. E-mail: bhaskar.dasgupta{at}southend.nhs.uk


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. The ischaemic complications of giant cell arteritis (GCA) such as blindness and stroke may result from luminal narrowing of the affected arteries. This study focuses on the association between the severity of intimal proliferation on temporal artery biopsy (TAB) histology and neuro-ophthalmic complications (NOCs) of GCA.

Method. We identified 30 cases of biopsy-proven temporal arteritis. One histopathologist (blinded to the clinical details) evaluated the TAB specimens and categorized the degree of maximum stenosis due to intimal hyperplasia into four grades: grade 1 is <50% luminal occlusion due to intimal hyperplasia, grade 2 is 50–75%, grade 3 is >75% and grade 4 is complete luminal occlusion. A second histopathologist (also blinded to the clinical details) independently evaluated the TAB specimens using the same grading system. The NOCs in these patients were noted after a case record review.

Results. Of the 30 patients, 12 had NOC-10 with eye complications (complete visual loss, anterior ischaemic neuropathy, visual field defects), one patient had cerebral infarcts and one had both cerebral infarcts and vision loss. There was evidence for a statistically significant trend of NOC associated with higher intimal hyperplasia scores (P = 0.001). The scores of the histopathologists agreed for 23 (77%) patients and differed by 1 category for the remaining 7 ({kappa}-statistic 0.88).

Conclusions. Our study suggests that the degree of intimal hyperplasia on TAB histology (routinely available to all hospital units) seems to be closely associated with NOCs of GCA. The study highlights the possible prognostic as well as diagnostic role of the biopsy. We feel that intimal hyperplasia noted in biopsy specimens may help us in the risk stratification of GCA patients and targeting of appropriate and novel therapies.

KEY WORDS: Intimal hyperplasia, Giant cell arteritis, Neuro-ophthalmic complications


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Giant cell arteritis (GCA) is a common vasculitis of the elderly typically affecting the superficial temporal artery. However, other vessels such as the external carotid, the internal carotid, aorta and its branches may also be involved [1]. Vision loss occurs early in GCA due to involvement of posterior ciliary arteries and central retinal artery (branches of ophthalmic artery) and it can be a presenting feature in 21.2% of the patients. Early diagnosis and treatment of this condition can prevent vision loss. Hence GCA can be considered an ophthalmic emergency where it is important to identify early, any risk factors in presentation that may predict ischaemic complications.

The pathology of GCA is characterized by transmural inflammatory cell infiltration with giant cell formation, intimal hyperplasia and luminal occlusion. Blindness and stroke result from tissue ischaemia as a direct consequence of intimal hyperplasia and luminal narrowing of the affected blood vessels. In normal arteries, the intima and media are avascular and only the adventitia has a capillary network of vasa vasorum. In inflamed temporal arteries, intimal proliferation seems to be dependent on neovascularization [2]. This angiogenesis is promoted by the expression of vascular endothelial growth factor (VEGF) [3]. The hyperplastic reaction is also triggered by platelet-derived growth factor (PDGF) that acts as a growth factor for myofibroblasts [3]. Kaiser et al. [4] have shown that concentric intimal hyperplasia was associated with the accumulation of PDGF producing multinucleated giant cells and macrophages at the intima–media junction. Excessive production of MMPs by macrophages causes oxidative injury in the artery resulting in destruction of internal elastic lamina and aids in the migration of smooth muscle cells from media to intima [5]. Higher levels of IFN-{gamma}, a critical cyotokine helping the function and differentiation of macrophages, and IL-1β expression are also seen in the affected arteries contributing to the intimal hyperplasia and correlate with ischaemic outcomes [6]. Macrophages in the adventitia secrete the inflammatory cytokines like IL-1 and IL-6. These cytokine patterns on temporal artery biopsy (TAB) may correlate with clinical outcomes and it is postulated that the inflammatory reaction in the inflamed artery is a consequence of specific cytokine activation.

We therefore hypothesized that the histology of TAB on light microscopy may correlate with clinical outcomes. Our earlier Anglo–Swedish collaborative study tried to establish a reliable histological scoring system by reviewing TAB specimens using a standardized score for general inflammation, presence of giant cells, intimal proliferation, fibrinous exudates and neovascularization. Among these parameters intimal proliferation produced maximum intra-observer reliability [7]. There was also a suggestion that intimal proliferation was more pronounced in patients with visual symptoms. [8].

This current study focuses on the association between the severity of intimal proliferation in the TAB specimens and neuro-ophthalmic complications (NOCs) of GCA.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Thirty consecutive patients with positive TAB were identified from the histopathology database for TAB from a period of 2000–06. The NOCs were recorded [decrease in visual acuity, complete/sectoral visual loss, anterior ischaemic neuropathy (AION), constriction of visual fields and cerebral infarcts] from a case record review. Southend Hospital Eye Unit is the regional referral centre for Essex and receives a large number of referrals of GCA with NOC.

The length of temporal artery specimens varied from 5 to 20 mm and the specimens were divided in to 2–3 mm segments. Each segment was then embedded end-on to visualize the complete transection of the artery. Routine haematoxylin and eosin staining method was used before examining the specimen. One histopathologist (blinded to the clinical details) evaluated the TAB specimens and categorized the degree of maximum stenosis due to intimal hyperplasia into four grades: grade 1 is described as <50% luminal occlusion due to intimal hyperplasia, grade 2 is 50–75%, grade 3 is >75% and grade 4 is complete luminal occlusion (Figs 1–4GoGoGo). A second histopathologist (also blinded to the clinical details) independently evaluated the TAB specimens using the same grading system. Ethics approval for the study was obtained from the South Essex Research Ethics Committee.


Figure 1
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  		FIG. 1. Grade 1 intimal hyperplasia (<50% luminal occlusion).

 

Figure 2
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  		FIG. 2. Grade 2 intimal hyperplasia (50–75% luminal occlusion).

 

Figure 3
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  		FIG. 3. Grade 3 intimal hyperplasia (>75% luminal occlusion).

 

Figure 4
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  		FIG. 4. Grade 4 intimal hyperplasia with complete luminal occlusion.

 
Data analysis
Agreement between the scores of two histopathologists was evaluated using the quadratic-weighted {kappa}-statistic [9, 10]. Using scores from the first histopathologist we tested for a trend in the proportion of patients with NOC by severity of the intimal hyperplasia using a Mantel–Haenszel test stratified for sex.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
The intimal hyperplasia scores of the histopathologists agreed for 23 (77%) patients and differed by 1 category for the remaining 7 patients. The {kappa}-statistic was 0.88, representing ‘almost perfect’ agreement.

Of the 30 patients, 12 had NOC-10 with eye complications (complete visual loss, AION, visual field defects), 1 patient had cerebral infarcts and 1 had both cerebral infarcts and vision loss (Table 1). There was evidence for a statistically significant trend of NOC associated with higher intimal hyperplasia scores (P = 0.001).


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  		TABLE 1. Rates of NOC by grade of intimal hyperplasia score

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
Our study suggests that the degree of intimal hyperplasia on TAB seems to be closely associated with NOC. The severity of intimal hyperplasia can be routinely graded by an experienced histopathologist with good inter-observer variability and may be a marker for ischaemic complications. Prospective studies are now needed to see whether TAB histology may serve a prognostic as well as a diagnostic role in suspected cases of GCA.

Up to 20% of patients with GCA will suffer permanent vision loss. The higher occurrence of NOC in our series may reflect a referral bias since our hospital is the regional eye unit for Essex. Permanent ischaemic complications occur early in GCA and rarely after steroid therapy [11, 12]. There is evidence that vision loss, ‘early’ as it may be, is on careful clinical evaluation often discovered to have been preceded by weeks or months of unrecognized symptoms such as headaches, jaw claudication, constitutional features and even visual symptoms [13]. In eyes with impending visual loss there is better chance of visual improvement with early diagnosis and immediate start of steroid therapy [14].

There is a need for markers that may help in risk and treatment stratification in GCA. Amaurosis fugax and jaw claudication are two clinical features that are associated with higher incidence of vision loss. Higher levels of IFN-{gamma} in TAB have also shown association with ischaemic GCA complications. Our study finding, that the grades of intimal hyperplasia on TAB are directly associated with NOC, adds an important marker that is easily accessible to most hospital units.

Our findings lend greater strength to recommendations that the management of suspected GCA incorporate the need for an urgent TAB (EULAR recommendations for the management of large vessel vasculitis; manuscript in preparation). Steroids need to be started as soon as the diagnosis is suspected but we feel that escalation of treatment may well be needed in the presence of predictive markers of ischaemia such as jaw claudication, amaurosis fugax, other visual symptoms and intimal hyperplasia on TAB. We speculate that TAB histology might help us to stratify therapy, the more intensive immuno-suppression reserved for patients with higher grades of intimal hyperplasia. These patients may also benefit from closer supervision and addition of anti-platelet drugs [15].

The emerging new therapies to block angiogenesis (e.g. VEGF and PDGF blockade) might be useful to reduce intimal hyperplasia thereby preventing NOCs of GCA. Such clinical trials in GCA are now urgently indicated.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
We are very grateful to P. J. Weller and W. L. Alexander for arranging the temporal artery biopsies.

Funding: Funding to pay the Open Access publication charges for this article was provided by the Rheumatology Department, Southend University Hospital.

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum (1990) 33:1122–8.[Web of Science][Medline]
  2. Weyand CM, Goronzy JJ. Arterial wall injury in giant cell arteritis. Arthritis Rheum (1999) 42:844–53.[CrossRef][Web of Science][Medline]
  3. Kaiser M, Younge B, Bjornsson J, Goronzy JJ, Weyand CM. Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by mulitinucleated giant cells. Am J Pathol (1999) 155:765–74.[Abstract/Free Full Text]
  4. Kaiser M, Weyand CM, Bjornsson J, Goronzy JJ. Platelet derived growth factor, intimal hyperplasia and ischaemic complications in giant cell arteritis. Arthritis Rheum (1998) 41:623–33.[CrossRef][Web of Science][Medline]
  5. Rodriguez-Pla A, Bosch-Gil JA, Rossello-Urgell J, Huguet-Redecilla P, Stone JH, Vilardell-Tarres M. Metalloproteinase-2 and -9 in giant cell arteritis: involvement in vascular remodeling. Circulation (2005) 112:264–9.[Abstract/Free Full Text]
  6. Weyand CM, Tetzlaff N, Bjornsson J, Brack A, Younge B, Goronzy JJ. Disease patterns and tissue cytokine profiles in giant cell arteritis. Arthritis Rheum (1997) 40:19–26.[Web of Science][Medline]
  7. Bharadwaj A, Dasgupta B, Wolfe K, Nordborg C, Nordborg E. Difficulties in the development of histological scoring of the inflamed temporal arteries in giant cell arteritis. Rheumatology (2005) 44:1579–80.[Free Full Text]
  8. Bharadwaj A, Wolfe K, Dasgupta B. GCA patients with visual involvement shows significantly more intimal hyperplasia-results of a histological score study. Arthritis and Rheum (2005) 52(Suppl):S220.
  9. Fleiss JL, Levin B, Cho PM. Statistical methods for rates and proportions. (2003) 3rd. Hoboken, NJ: Wiley.
  10. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics (1977) 33:159–74.[CrossRef][Web of Science][Medline]
  11. Salvarani C, Cimino L, Macchioni P, et al. Risk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis. Arthritis Rheum (2005) 53:293–7.[CrossRef][Medline]
  12. Font C, Cid MC, Coll-Vinent B, Lopez-Soto A, Grau JM. Clinical features in patients with permanent visual loss due to biopsy proven giant cell arteritis. Br J Rheumatol (1997) 36:251–4.[Abstract/Free Full Text]
  13. Gonzalez-Gay MA, Blanco R, Rodriguez-Valverde V, et al. Permanent visual loss and cerebrovascular accidents in giant cell arteritis: predictors and response to treatment. Arthritis Rheum (1998) 41:1497–504.[CrossRef][Web of Science][Medline]
  14. Hayreh SS, Zimmerman B, Kardon RH. Visual improvement with corticosteroid therapy in giant cell arteritis. Report of a large study and review of literature. Acta Ophthalmol Scand (2002) 80:355–67.[CrossRef][Medline]
  15. Nesher G, Berkun Y, Mates M, Baras M, Rubinow A, Sonnenblick M. Low dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum (2004) 50:1332–7.[CrossRef][Web of Science][Medline]
Submitted 1 June 2007; revised version accepted 7 January 2008.
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