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Introduction

  1. Top of page
  2. Introduction
  3. Case Report
  4. Discussion
  5. Acknowledgements
  6. REFERENCES

Corticosteroid treatment usually induces rapid and dramatic relief of giant cell arteritis (GCA)–related clinical manifestations. In addition, corticosteroids reduce the risk of ischemic complications attributed to GCA. This observation is supported by the marked reduction in frequency of ischemic events since corticosteroid therapy was first used to treat GCA in the 1950s (1) by the fact that patients rarely experience ischemic complications after starting treatment, and by the observation that corticosteroids may abrogate recurrent episodes of amaurosis fugax and may sometimes reverse visual loss if administered promptly (2). Therefore, high-dose corticosteroids remain the initial treatment of choice for patients with GCA.

Corticosteroids rapidly induce functional changes in temporal artery lesions. Expression of interleukin-2 (IL-2), IL-2 receptor, endothelial cell adhesion molecules (e.g., E-selectin and vascular cell adhesion molecule 1), and proinflammatory cytokines (e.g., IL-1β and IL-6) has been shown to be significantly lower in temporal artery lesions from patients with GCA or in GCA-affected human temporal arteries engrafted into severe combined immunodeficient mice upon corticosteroid treatment (3–5). It is likely that these and other functional changes contribute to remission of clinical symptoms.

Although functional changes occur rapidly after corticosteroid administration, persistence of inflammatory infiltrates can be found in totally asymptomatic individuals receiving corticosteroid treatment, and in fact recurrences are frequent when corticosteroids are tapered or withdrawn (6). Over months or years, lesions usually evolve to a healing or obsolescent stage defined histologically by the presence of fibrotic changes in the media, irregular intimal thickening, and persistence of scattered foci of inflammatory cells (7).

Corticosteroid requirements are highly variable among patients (6, 8). Some patients easily enter sustained remission with relatively short duration of treatment, whereas others experience relapsing chronic disease that requires remarkable cumulative corticosteroid therapy to maintain remission (6, 8).

Early reports prior to the corticosteroid era depicted instances of spontaneous remission, although no long-term systematic followup of these patients was described (9, 10). In addition, a survey of 100 unselected necropsies revealed “healing” GCA lesions in the temporal arteries of 2 elderly patients who died from unrelated conditions and had never been recognized to have symptoms of GCA, suggesting that in these patients, GCA had been asymptomatic, or not symptomatic enough to require medical attention (11). These observations suggest that, in some cases, the GCA inflammatory process may spontaneously evolve into an obsolescent, clinically silent stage. We illustrate this point by describing 2 patients with biopsy-proven GCA who underwent spontaneous, long-lasting clinical remission with no treatment.

Case Report

  1. Top of page
  2. Introduction
  3. Case Report
  4. Discussion
  5. Acknowledgements
  6. REFERENCES

Patient 1.

A 90-year-old man was referred by his primary care physician after observing an enlarged, hard, pulseless right temporal artery. He was totally asymptomatic except for stable leg claudication, which started 4 years before. He was a past smoker and had experienced several pulmonary infections in the past few years due to bronchiectasia. He had mild hyperglycemia that was controlled with diet. He had also had an episode of left ocular pain 2 years before with subsequent decrease in visual acuity, which remained stable. Physical examination revealed a pulseless right temporal artery; the left temporal artery was also abnormal, but to a lesser degree. He had bruits in his femoral arteries, and his erythrocyte sedimentation rate (ESR) was moderately elevated (60 mm/hour). Funduscopy revealed sequelae from chronic glaucoma. Temporal artery biopsy sample disclosed GCA (obsolescent pattern) (Figure 1).

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Figure 1. Temporal artery biopsy specimen from patient 1. Irregular intimal hyperplasia, fibrosis of the medial layer, and scattered remaining small inflammatory infiltrates (arrows) can be observed, defining a giant cell arteritis healing (obsolescent) pattern (7, 11).

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We did not know exactly when the disease began or what to treat. The patient and his family were informed about the risk/benefit of corticosteroid treatment. Because he was totally asymptomatic and his main medical problem was recurrent pulmonary infection, their choice was no treatment. His followup was uneventful, and he died from pneumonia at age 94.

Patient 2.

A 62-year-old man was referred for diagnosis after a prolonged episode of malaise, weight loss, and elevated ESR (110 mm/hour) that started 4 months earlier. He had undergone an extensive examination to rule out malignancy, including abdominal ultrasonography, gastroscopy, and a chest computed tomography scan, before referral. His symptoms progressively improved. He was HLA–B27 positive and had been diagnosed with ankylosing spondylitis 15 years before evaluation, which was easily controlled with nonsteroidal antiinflammatory drugs and had remained inactive since diagnosis.

At evaluation, the patient was asymptomatic and had recovered previously lost weight. He reported prior mild, self-limiting jaw pain, and on examination his left temporal artery had a reduced pulse. His ESR was 69 mm/hour at that time. A temporal artery biopsy specimen showed inflammation in small vessels surrounding the temporal artery. There were no findings to suggest the presence of other forms of vasculitis, such as fibrinoid necrosis (12). The patient was screened for systemic vasculitis, which we have proposed for patients with vasculitis in small vessels surrounding a temporal artery (12). Chest radiograph, electrophysiologic examination of peripheral nerves, and a blind muscle biopsy were all normal. Antineutrophil cytoplasmic antibody and cryoglobulin detection were negative. Subsequent sections of the temporal artery biopsy sample revealed extension of the inflammatory infiltrates towards the adventitia that began to penetrate the media and a remarkable intimal hyperplasia (Figure 2). His ESR gradually normalized and remained normal (9 mm/hour) without treatment.

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Figure 2. First temporal artery biopsy specimen from patient 2. Inflammatory infiltrates involving small vessels surrounding the temporal artery can be appreciated (arrows), with a strong inflammatory infiltration of small vessels in some sections (inset). In some areas, inflammation involves the adventitial layer (dashed arrows). A remarkable intimal hyperplasia is present. The second temporal artery biopsy specimen disclosed features similar to Figure 1.

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The patient refused to be treated because he felt well, and was closely followed over ensuing months. Two years later, although asymptomatic, he agreed to a second temporal artery biopsy, which showed fibrotic changes in the media, intimal hyperplasia, and scattered foci of inflammatory cells. His subsequent followup was uneventful. Ten years later, he is alive and totally asymptomatic.

Discussion

  1. Top of page
  2. Introduction
  3. Case Report
  4. Discussion
  5. Acknowledgements
  6. REFERENCES

The patients described herein had spontaneous, long-lasting clinical remissions of GCA-related symptoms. During periods of extended followup, no disease-related complications occurred. To our knowledge, sustained spontaneous clinical remissions have not been reported in the postcorticosteroid era.

The majority of patients with GCA experience corticosteroid-related adverse events (6). Although there is no doubt about the clinical benefit of corticosteroids, our observations suggest that some patients may not require long-term corticosteroid treatment or corticosteroids at all. Supporting this concept, recent double-blind, placebo-controlled, randomized trials assessing the efficacy of putative corticosteroid-sparing agents have shown that a low but nonnegligible proportion of patients in the placebo arm do not relapse after an aggressive corticosteroid-tapering schedule (13, 14).

Unfortunately, at present, it is not possible to predict a patient's outcome at the time of diagnosis. Patients with GCA are universally treated with corticosteroids in variable regimes, most of them including high initial doses and long periods of treatment. Recent observations suggest that certain traits may assist in customizing therapeutic options to different patient subsets in the future. Vigorous production of proinflammatory cytokines appears to be associated with disease persistence. Patients with strong systemic inflammatory responses who have higher circulating levels of the proinflammatory cytokines tumor necrosis factor α (TNFα) and IL-6 tend to be more refractory to therapy (8). In fact, TNFα and, to a lesser extent, IL-1β messenger RNA concentrations in lesions correlate with corticosteroid requirements (15). Increased production of CCL2, a potent chemokine for macrophages and Th1 lymphocytes, is also related to disease persistence (Cid MC, et al: unpublished observation). Although these patterns may prove clinically useful in determining individual risks for poor outcomes in the future, at present their performance characteristics as prognostic markers are not adequately defined to recommend their use in routine care of patients with GCA.

Our findings demonstrate that clinical features of GCA may undergo spontaneous, long-lasting clinical remission while retaining histologic features of low-grade inflammation as seen in patients treated with steroids. Whether this minimal remaining inflammation would be clinically expressed as late vascular complications over extended periods is a matter of conjecture. Whether such patients should be treated with corticosteroids is uncertain, given the toxic effect of such treatments and the uncertain risks implied by the remaining histologic findings.

Acknowledgements

  1. Top of page
  2. Introduction
  3. Case Report
  4. Discussion
  5. Acknowledgements
  6. REFERENCES

We are grateful to Dr. Gary S. Hoffman (Cleveland Clinic, Cleveland, OH) for his critical review of this manuscript.

REFERENCES

  1. Top of page
  2. Introduction
  3. Case Report
  4. Discussion
  5. Acknowledgements
  6. REFERENCES
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