Giant Cell Arteritis

DIAGNOSTIC PARAMETERS:

Our study, in GCA patients with positive temporal artery biopsy, showed the following validity, reliability, sensitivity, and specificity of the signs and symptoms of and diagnostic tests for GCA:¹

1. Systemic symptoms: In our patients with positive temporal artery biopsy, systemic symptoms and signs included headache in 56%, anorexia/weight loss in 52%, jaw claudication (that is, the jaw hurts whenever they eat) in 48%, malaise in 38%, myalgia in 29%, fever in 26%, abnormal temporal artery in 20%, scalp tenderness in 18%, neck pain in 16% and anemia in 13%.¹
   
   On the other hand, 21.2% of the patients with visual loss and positive temporal artery biopsy for GCA had no systemic symptoms of any kind whatsoever at any time and visual loss was the sole complaint, i.e. they had occult GCA.³ Therefore, absence of systemic symptoms and signs does not rule out GCA - an extremely important point to be borne in mind, because in many patients the diagnosis of GCA is dismissed straight away if they have no systemic symptoms and signs of GCA.
2. Hematologic tests: Our studies^1,6 have shown that the following three hematologic tests are key for the diagnosis of GCA.
   1. Erythrocyte sedimentation rate (ESR): A high ESR is traditionally emphasized as a sine qua non for the diagnosis of GCA. It is also well-established that estimation of ESR is an important test in diagnosis of GCA. In our study, in patients with positive temporal artery biopsy for GCA, it varied between 4 and 140 mm/hr (Westergren) (median 87.5 mm). We also evaluated ESR in 749 normal persons in whom the ESR ranged from 1-59 mm/hr (median 11 mm). We found that ESR levels increase with age and are also higher in women than in men. In the literature highly variable numbers are given for the normal values: most laboratories described it in men <10 mm/hr and in women <20 mm/hr; Miller et al.⁹ put forward a formula to calculate the normal ESR: in men age divided by 2 and in women age+10 divided by two. Our study suggested that a useful cutoff criterion for normal ESR is <30 mm/hr in men and <35 mm/hr in women, with a sensitivity and specificity of 92%.
      With the ESR values in our study varying between 4 and 140 mm/hr in GCA patients and 1 and 59 mm/hr in normal persons, there is an overlap in lower levels of ESR between the two groups. Thus, the most important fact to remember is that normal ESR does not rule out GCA. GCA is missed in a number of patients simply because of the universal misconception that every patient with GCA must have a high ESR.
   2. C-Reactive protein (CRP): Our studies indicate that estimation of CRP (an acute phase plasma protein of hepatic origin) is a highly reliable, reproducible and rapid test. CRP reaches abnormal levels within 4-6 hours and can increase up to 1,000 times, and also shows a much more rapid response to treatment than the ESR. Unlike ESR, it is not influenced by age, sex or hematologic factors. It generally runs parallel with the ESR; however, in some cases, CRP is not elevated when ESR is. This dichotomy between the two tests is very helpful when ESR is elevated due to conditions unrelated to GCA. Normal value is <0.5 mg/dl in our laboratory. In our study, in GCA patients it varied between 0.5 and 34.7 (median 4.35) mg/dl, and in the normal controls it was <0.5 to 3.3 (median <0.5) mg/dl.¹ The sensitivity and specificity of CRP in detecting GCA was 100% and 79-83% respectively. CRP is a very useful test.
   3. Thrombocytosis: In our study⁶ of biopsy proven GCA patients, 60% had thrombocytosis (defined as a serum platelet count >400 X103/µl) and that was significantly more prevalent in GCA patients than in normal control population. Sensitivity and specificity of thrombocytosis for diagnosis of GCA was 60.4% and 97.5% respectively. There was no difference in the prevalence of thrombocytosis in GCA patients with and without visual loss, as well as among those with and without systemic symptoms of GCA. There was a significantly (p<0.0001) higher prevalence of thrombocytosis in patients with GCA and arteritic AION than in those with non-arteritic AION.
   4. Other hematologic tests: In addition to these, other hematologic tests can also be helpful. Anemia is a well-known finding in GCA patients. Our recent study⁶ suggests that evaluation of white blood cell count and hemoglobin and hematocrit levels provides additional useful information, because GCA patients have significantly higher white blood cell counts and lower hemoglobin and hematocrit levels than those without GCA.

In conclusion, the combined information provided by ESR, CRP, platelet and white blood cell count and hemoglobin and hematocrit levels is highly useful in diagnosis of GCA, although none of them individually is 100% sensitive and specific.

3. Temporal artery biopsy: This is considered the definite criterion for diagnosis of GCA, and in our studies we used that as our "gold standard" for GCA diagnosis. In 76 of 363 patients we did temporal artery biopsy on the second side when biopsy on one side was negative but there was a high index of suspicion for GCA from symptoms and signs; 7 of the 76 showed a positive biopsy on the second side. Thus, a total of 106 patients had a positive temporal artery biopsy.¹ None of our patients with negative temporal artery biopsy on follow-up developed evidence of GCA. Thus, so far we have never had a patient with a false-negative biopsy. We feel this is because we remove at least a one inch piece of temporal artery and do complete serial sectioning, to make sure that examination of "skip areas" does not lead to false-negative results which have been reported in the literature. For example, in one case we cut 300 sections and only one of them showed a typical GCA lesion.
   
   I have discussed at length elsewhere the various issues regarding temporal artery biopsy.⁷ The following two questions are frequently asked:
   1. Should temporal artery biopsy be done on one or both sides, and, if on both sides, should it be done simultaneously, or on second side only if the first is found to be negative? Because of the risk of complications following temporal artery biopsy and the infrequent need to do it on the second side to establish the diagnosis, I find no justification for doing biopsy on both sides at the same time.
   2. Does steroid therapy alter the temporal artery biopsy results? Most available evidence indicates that it does not.⁷ I feel that in patients with a strong index of suspicion of GCA, it is dangerous to withhold steroid therapy till the biopsy results are available, because there is every possibility that the patients may suffer irreversible visual loss in one or both eyes before the biopsy results are available.
      
      Clinical criteria most strongly suggestive of GCA: In our study, the odds of a positive temporal biopsy were 9 times greater with jaw claudication, 3.4 times with neck pain; 2.0 times with ESR 47-107 mm/hr relative to those with ESR <47 mm/hr and 3.2 times with CRP >2.45 mg/dl compared to CRP <2.45 mg/dl, and 2.0 times when the patients were aged >75 years as compared to those <75 years.¹ Other signs and symptoms did not differ significantly from those with negative biopsy.
      
      Thus, we found the following set of criteria most helpful: Jaw claudication, CRP >2.45 mg/dl, neck pain and ESR > 47 mm/hr (Westergren). CRP is more sensitive than ESR and a combination of the two provides best specificity (97%) for diagnosis of GCA.

      American College of Rheumatologists' Criteria For Diagnosis of GCA

      For diagnosis of GCA, the following 5 criteria are advocated by the American College of Rheumatologists¹⁰ as the "gold standard": (1) age > 50 years at onset, (2) new onset of localized headache, (3) temporal artery tenderness or decreased temporal artery pulse, (4) elevated ESR of > 50 mm/hour, and (5) positive temporal artery biopsy for GCA. They state that: "A patient shall be classified as having GCA if at least 3 of these 5 criteria are met." But in the American College of Rheumatologists¹⁰ study, 18 of 214 (8.4%) patients' temporal artery biopsy was either negative for GCA (15) or not done (3), and that study advocated that in such cases new headache and scalp tenderness or nodules be "used as a surrogate".

      There are some differences in the diagnostic criteria for GCA between our study^1,3,6 and those advocated by the American College of Rheumatologists¹⁰; I have discussed them in detail elsewhere⁷. The reason for the differences between the two studies is the difference in their patient populations, and that includes the following:

      1. All of our patients had temporal-artery-biopsy-confirmed GCA which is not true in the American College of Rheumatologists'¹⁰ study.
      2. Since the American College of Rheumatologists'¹⁰ study was conducted by rheumatologists, it would seem their primary criterion of inclusion was the presence of rheumatologic systemic symptoms, while our study had an unbiased group of patients with a wide variety of symptoms, since the patients were referred to us by physicians from all the medical specialties in our large medical center.
      3. The rheumatologic study would not include patients with occult GCA, since they are unlikely to consult a rheumatologist, as they have no systemic symptoms. In our study 21.2% of the patients with visual loss had occult GCA³. That must make an important difference. Since the most serious complication of GCA is visual loss, the criteria advocated by the American College of Rheumatologists'¹⁰ study may be adequate for diagnosing GCA patients with rheumatologic symptoms, but they are not good enough to prevent all GCA patients from going blind.

   Thus, in conclusion, it is evident that the American College of Rheumatologists¹⁰ study criteria are likely to result in some false-negative or false-positive diagnoses of GCA, risking visual loss.

4. Doppler tests in diagnosis of GCA: Some have advocated the use of these tests in the diagnosis of GCA. I do not find any real role of these tests in diagnosis of GCA as well as evaluation of ocular circulation in eyes with visual loss due to GCA. I have discussed problems with these tests at length elsewhere.⁷

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