Purpose
To assess the clinical utility of the American College of Rheumatology criteria for the diagnosis of giant cell arteritis (GCA) in patients with positive and negative temporal artery biopsies.
Design
Retrospective case series of all patients undergoing temporal artery biopsy.
Methods
Retrospective chart review of all patients seen in the Neuro-ophthalmology Service of the Wills Eye Institute undergoing biopsy. One hundred twelve patients were identified between October 2001 and May 2006. Charts were reviewed for American College of Rheumatology criteria, biopsy results, and progression of visual loss after diagnosis.
Results
Nine of 35 patients (25.7%) with positive biopsies would not have been diagnosed with GCA using American College of Rheumatology criteria alone. An additional 16 patients (45.7%) met only 2 criteria and required the positive biopsy to establish the American College of Rheumatology diagnosis of GCA. Eleven of 39 patients (28.2%) with negative biopsies met the criteria and would have been diagnosed with GCA. Diagnostic agreement between the American College of Rheumatology criteria without biopsy results and biopsy results alone was 51.4%; with the addition of biopsy results to the criteria, this increased to 73.0%.
Conclusions
The current American College of Rheumatology criteria should not be used to diagnose GCA and all patients suspected of having GCA should undergo a temporal artery biopsy.
Giant cell arteritis (GCA), a systemic vasculitis, is associated with a wide range of symptoms including fatigue, fever, headaches, jaw claudication, loss of vision, scalp tenderness, polymyalgia rheumatica, and aortic arch syndrome. The potential for severe, nonreversible loss of vision makes the early diagnosis of GCA critical to prevent blindness. In addition, the treatment for GCA—systemic corticosteroids—is not without risk. Therefore, the accuracy of the criteria used to establish or exclude the diagnosis of GCA is crucial to preserve vision and minimize medication morbidities.
Several studies have attempted to define clinical diagnostic criteria for GCA. The American College of Rheumatology classification criteria are used frequently to identify patients with GCA. These criteria specify that the diagnosis may be made when patients meet 3 of the following 5 criteria: age over 50 years, new onset of localized headache, temporal artery tenderness or decreased temporal artery pulse, erythrocyte sedimentation rate (ESR) greater than or equal to 50 mm/hr, or a positive temporal artery biopsy. Two recently published studies conclude that temporal artery biopsy results often do not affect the management of patients with suspected GCA; they conclude that the diagnosis is generally made on clinical criteria alone and that the “low pick-up rate” of GCA by biopsy renders it unnecessary in the majority of cases. The purpose of our study was to determine if the American College of Rheumatology classification criteria are sufficient to accurately establish the diagnosis of GCA without performing a temporal artery biopsy, and to determine the concordance between the American College of Rheumatology criteria vs temporal artery biopsy alone as diagnostic criteria for GCA.
Materials and Methods
The records of every patient (n = 112), evaluated by 1 neuro-ophthalmologist (P.J.S.), undergoing a temporal artery biopsy for possible GCA at Wills Eye Institute from October 1, 2001 to May 31, 2006 were reviewed for age, sex, biopsy results, corticosteroid treatment, presence of headache, temporal artery tenderness or decreased pulse, ESR, initial vision and visual fields, and the length of follow-up.
Inclusion criteria for the study were as follows: patients undergoing temporal artery biopsy for investigation of GCA; evidence of visual loss from either ischemic optic neuropathy, central retinal artery occlusion, or choroidal ischemia; and minimum follow-up of 1 month. Patients were excluded from the study if corticosteroids were administered prior to presentation, if the biopsy was performed more than 5 days after starting corticosteroids, if the biopsy specimen was less than 2 cm in length, and if corticosteroids were not discontinued immediately after a negative temporal artery biopsy result. These exclusion criteria were created to avoid masking, by continued corticosteroid use, possible GCA with false-negative temporal artery biopsies and to clinically diagnose progression or recurrence of GCA with follow-up examinations.
Temporal artery biopsy specimens were at least 20 mm in length. Each specimen was sectioned transversely in a “breadloaf” fashion into 8 or more segments that were processed routinely for light microscopy, embedded in single paraffin block, and stained with hematoxylin-eosin and periodic acid–Schiff. Three slides containing several levels cut from each block were prepared. In selected cases, additional levels were prepared. The histopathology was evaluated by 1 ophthalmic pathologist (R.C.E.) with extensive experience in the assessment and diagnosis of temporal artery biopsy specimens. The pathologist was masked to the clinical data. Histopathologic criteria for the diagnosis of GCA included the presence of chronic granulomatous inflammation in the vessel wall that included epithelioid histiocytes, segmental loss or disruption of internal elastic lamina, compromise and/or obliteration of the arterial lumen, atrophy and scarring of the muscularis, and adventitia fibrosis. Giant cells were not required for the diagnosis.
Patients were divided into 2 groups based on histopathologic findings: those with GCA and those without. The “GCA group” was defined as those patients with histologic findings on temporal artery biopsy consistent with GCA as described above. If the temporal artery biopsy was negative, patients were included in the “no GCA group.”
All patient clinical, laboratory, and pathology data were reviewed and information was extracted to determine which of the American College of Rheumatology criteria were present. The history and clinical examinations were all completed in the same fashion by a single investigator. Patients were classified as “GCA according to American College of Rheumatology classification” if 3 of 5 criteria were met. Analysis was undertaken to determine the number of patients who satisfied 3 criteria independent of temporal artery biopsy results; how many patients met 2 criteria prior to a positive temporal artery biopsy, providing the third necessary criterion for American College of Rheumatology diagnosis; and how many patients did not satisfy the criteria even with a positive biopsy. These results were then compared to the diagnosis of GCA if based purely on the results of the temporal artery biopsy. Additionally, a diagnostic agreement study was performed to evaluate the concordance between American College of Rheumatology classification and temporal artery biopsy results as diagnostic modalities.
Statistical Methods
χ 2 analysis was used to determine any difference in the distribution of the other 4 clinical American College of Rheumatology criteria between the temporal artery biopsy–positive and temporal artery biopsy–negative patients. We also used χ 2 testing to determine any difference in how many patients met criteria for the diagnosis of GCA independent of temporal artery biopsy results in the biopsy-positive and biopsy-negative groups.
A diagnostic agreement study was performed comparing the patients with positive (≥3/5 of the American College of Rheumatology criteria; positive temporal artery biopsy results) to negative (≤2/5 of the American College of Rheumatology criteria; negative temporal artery biopsy results) diagnosis. A receiver operating characteristic (ROC) curve was plotted to compare the accuracy of American College of Rheumatology criteria and temporal artery biopsy results.
Additional Analyses
We evaluated the likelihood that some of our biopsy-negative patients actually had GCA. For this purpose, we used the results of 2 recent prospective studies, which determined the rates of progressive or new visual loss in treated patients with biopsy-positive GCA. Because some patients with GCA who have visual loss will develop further visual loss even when treated aggressively, at least an equal number of patients, and possibly more, would have developed visual loss if they had GCA and were not treated. In fact, it is estimated that between 55.6% and 88.7% of patients with GCA and resultant visual loss who are untreated will go on to develop further visual loss within the first 2 weeks of presentation.
Best-corrected visual acuity was used as the primary measure of progression of visual loss. Visual acuity was measured using a standard Snellen chart. Visual loss was considered to have progressed if patients lost 2 or more additional lines of Snellen acuity in either eye. Perimetry was used as a secondary measure of progressive visual loss. Visual field loss was considered to have progressed in patients with a 2-decibel or more worsening in mean deviation on SITA (Swedish Interactive Threshold Algorithm) standard Humphrey perimetry. Larger stimulus sizes were used, or kinetic perimetry (Goldmann) or confrontation fields were recorded, in patients in whom vision was too poor to perform a SITA standard test.
Fisher exact test was used to compare the temporal artery biopsy–positive and temporal artery biopsy–negative groups with regard to progression of visual loss. We further compared the progression of visual loss in the subset of patients in each group who met American College of Rheumatology criteria for GCA to see if meeting more criteria increased the likelihood of “biopsy-negative GCA.”
Results
One hundred twelve patients underwent temporal artery biopsy during the 56 months of our review. Seventy-four patients (66.1%), 35 biopsy-positive and 39 biopsy-negative, met our inclusion criteria. Three GCA-negative patients were excluded for lack of follow-up, 6 for delayed biopsies, 7 because of corticosteroid use at referral, and 9 because corticosteroids were not discontinued after a negative biopsy. In addition, 8 GCA-positive patients were excluded who did not present with visual loss and 5 patients with delayed biopsies were excluded. Follow-up mean was 6 months and median was 2 months for the negative biopsy patients and 7.1 and 4 months respectively for those with positive biopsies.
Table 1 lists the patients excluded based on longer steroid tapers, including whether they had unilateral or bilateral biopsies, whether they had progressive loss of vision, and number of American College of Rheumatology criteria met. No patients had progressive visual loss and there was no significant difference between the number of American College of Rheumatology criteria fulfilled by this group and the temporal artery biopsy–negative patients ( P = .006). The number of patients that met the criteria in this group was significantly less than in the biopsy-positive group ( P = .313).
| Initial Visual Acuity (Right, Left) | Follow-up Visual Acuity | Number of American College of Rheumatology Criteria Met (1–5) | Temporal Artery Biopsy |
|---|---|---|---|
| 20/40, CF | 20/25, CF | 2 | Unilateral |
| CF, CF | 20/70, 20/200 | 2 | Unilateral |
| 20/200, 20/30 | 20/70, 20/40 | 2 | Bilateral |
| 20/25, 20/50 | 20/20, 20/20 | 4 | Bilateral |
| 20/50, 20/25 | 20/50, 20/25 | 2 | Bilateral |
| CF, 20/20 | CF, 20/20 | 1 | Unilateral |
| 20/30, 20/50 | 20/30, 20/25 | 3 | Bilateral |
| 20/50, 20/50 | 20/50, 20/50 | 1 | Unilateral |
| 20/40, 20/30 | 20/40, 20/30 | 1 | Unilateral |
Table 2 compares the number of patients meeting each of the American College of Rheumatology criteria, excluding temporal artery biopsy results. Using the χ 2 test, there was no significant difference in the number of patients with headache, elevated ESR, age over 50 years, or temporal artery changes between the biopsy-positive and biopsy-negative groups. The 2 groups were also equivalent by χ 2 in the total number of American College of Rheumatology criteria met prior to temporal artery biopsy. In addition, there was no difference between the 2 groups in the number of patients who met 2 criteria, and therefore would benefit from temporal artery biopsy to guide diagnosis and therapy.
| Number of American College of Rheumatology Criteria Met Before Biopsy | Positive Temporal Artery Biopsy (n = 35) | Negative Temporal Artery Biopsy (n = 39) |
|---|---|---|
| 1 | 9 (25.7%) | 11 (28.2%) |
| 2 | 16 (45.7%) | 17 (43.9%) |
| 3 | 8 (22.9%) | 10 (25.6%) |
| 4 | 2 (5.7%) | 1 (2.6%) |
Biopsy-Positive Group
Nine of 35 patients (25.7%) met only 2 American College of Rheumatology criteria, age over 50 years and a positive temporal artery biopsy, and therefore would have been diagnosed as not having GCA according to American College of Rheumatology criteria even with a positive biopsy. Sixteen patients (45.7%) met only 2 criteria prior to their biopsy and therefore required the positive biopsy to establish the diagnosis of GCA according to criteria. Only 10 patients (28.5%) met 3 or 4 criteria for the diagnosis of GCA prior to their temporal artery biopsy.
Five of the 35 patients (14.3%) had simultaneous bilateral biopsies performed. Two of these 5 patients had only age >50 years as an American College of Rheumatology criterion. The other 3 had age >50 years and 1 other criterion prior to biopsy. Therefore all of these patients required temporal artery biopsy to establish the diagnosis. All 5 patients had positive biopsies bilaterally.
Biopsy-Negative Group
Eleven of the 39 patients (28.2%) met 3 or 4 of the 5 American College of Rheumatology criteria for GCA despite the negative biopsy. Seventeen (43.6%) met 2 criteria and required the biopsy to rule out GCA. The remaining 11 biopsy-negative patients met only 1 criterion and the biopsy would not have changed the negative diagnosis by American College of Rheumatology criteria.
Four patients (10.3%) underwent bilateral, simultaneous temporal artery biopsy. Of these 4 patients, 2 met 3 American College of Rheumatology criteria prior to temporal artery biopsy and would have been diagnosed as having GCA. The other 2 patients undergoing bilateral biopsies each met 2 criteria prior to their biopsies.
Four of the 39 patients (10.3%) had further loss of visual acuity at their final follow-up. Three of these patients had slowly progressive visual loss that occurred over a time period greater than 2 weeks, the time period during which most visual loss associated with GCA is seen. The causes of visual loss in these patients were 1 instance each of a new choroidal neovascular membrane secondary to age-related macular degeneration, end-stage glaucoma, and cataract ( Table 3 ). The fourth patient experienced further visual loss during the first two weeks after presentation and was diagnosed with progressive nonarteritic ischemic optic neuropathy (NAION). Progressive visual loss over the course of 2 weeks is known to occur in 12.4% of patients with NAION. This diagnosis was corroborated over the ensuing 2 months, during which the patient did not develop the optic disc excavation that is typical for GCA but not NAION.
| Patients With Progressive Visual Loss and Negative TAB | Initial Visual Acuity (Right, Left) | Final Visual Acuity (Right, Left) | Timeline of Progression | Final Diagnosis |
|---|---|---|---|---|
| 1 | 20/40, 20/70 | 20/50, HM | 17 months | CNVM |
| 2 | 20/70, CF | 20/200, HM | 35 months | Glaucoma |
| 3 | 20/25, 20/40 | 20/60, 20/80 | 11 months | Cataract |
| 4 | 20/60, 20/70 | CF, 20/50 | 10 days | NAION |
American College of Rheumatology Criteria
Using the presence of a positive or negative temporal artery biopsy as proof of the presence or absence of GCA, the American College of Rheumatology criteria without biopsy results are 28.6% sensitive and 71.8% specific for the diagnosis of GCA. The criteria have a positive predictive value of 47.6%; the negative predictive value is 52.8%. Adding temporal artery biopsy results to the criteria increases the sensitivity to 74.3%; the specificity remains 71.8%. The positive and negative predictive values also increase to 70.3% and 75.7%, respectively, with the inclusion of temporal artery biopsy results.
The diagnostic agreement study between American College of Rheumatology criteria and temporal artery biopsy demonstrated poor agreement between these 2 diagnostic modalities, with a 51.4% agreement (95% confidence level, kappa score 0.0037). The resultant ROC curve shows poor accuracy ( Figure ) between these 2 diagnostic modalities. The addition of temporal artery biopsy results to the criteria increases the agreement to 73.0%, which improves to only “fair” agreement.
Comparison of Rate of Visual Loss
Fisher exact test was used to determine if there was a difference in progressive or additional visual acuity loss between our 2 groups. Ten of 35 patients (28.6%) in the biopsy positive group had further loss of visual acuity. After excluding the 3 patients in the biopsy-negative group with other known causes of subsequent visual loss, the difference between the 2 groups was statistically significant ( P = .002), and when the patient who lost vision in the first 2 weeks from sequential NAION was excluded, this difference was more notable ( P < .001).
Nine of the 26 biopsy-positive patients (34.6%) who were also positive by American College of Rheumatology criteria experienced further loss of visual acuity over the first 2 weeks. None of the 11 patients in the biopsy-negative group that met criteria for GCA had further loss of vision. Fisher exact test for progression of loss of visual acuity was significantly different between the 2 groups ( P = .04).
Twenty-six of 39 patients (66.7%) with a negative temporal artery biopsy had follow-up visual fields available. None of these patients showed worsening of the visual field. In the positive biopsy group, 5 of 35 patients (14.3%) had further visual field loss. Fisher exact test was significant ( P = .05) for progression of the visual field loss in the biopsy-positive group when compared to the biopsy-negative group.
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