The Immunopathology of Giant Cell Arteritis

Diagnostic and Therapeutic Implications

We read with great interest the article “The immunopathology of giant cell arteritis: diagnostic and therapeutic implications” by Weyand et al (¹) and commend the authors on their comprehensive review of giant cell arteritis (GCA) immunopathogenesis and excellent discussion of potential new therapeutic targets. Due to the adverse effects of steroids and lack of therapeutic response in some patients with GCA, clinicians have investigated the use of steroid-sparing agents, including anti-tumor necrosis factor (anti-TNF)-α agents, for GCA treatment. Case reports on the use of anti-TNF-α antibodies for GCA and one small placebo-controlled trial investigating the use of etanercept in GCA patients have been promising (^2–7). However, occurrences of GCA despite use of anti-TNF-α antibodies have been reported in the literature (^8,9). We add to these reports with a patient who developed arteritic anterior ischemic optic neuropathy secondary to biopsy-proven GCA despite use of etanercept, an anti-TNF agent.

A 59-year-old Caucasian woman with rheumatoid arthritis treated with etanercept and leflunomide was referred for evaluation of sudden peripheral vision loss in her right eye. She reported a 2-week history of intermittent bilateral blurred vision and transient binocular vertical diplopia. She noted transient obscurations of vision during the week before her loss of vision. She also reported a 1-month history of bilateral jaw claudication, low-grade fevers and malaise, a 3-week history of daily global headaches, and weight loss of 15 lbs over the previous 6 weeks. She had been taking leflunomide for 2.5 years and etanercept for 1.5 years. Etanercept was discontinued for 3 weeks due to her low-grade fever and malaise and was restarted 1 week before her vision loss. On examination, her best-corrected visual acuity was 20/25 in each eye. Her color vision was slightly decreased in the right eye and full in the left eye (13/14 and 14/14 Hardy-Hand-Rittler plates, respectively). A right afferent pupillary defect was present. Automated visual field 24-2 SITA Standard testing demonstrated dense superior altitudinal and inferior arcuate defects in her right eye. Her left visual field was normal. Fundus examination revealed pallid optic disc edema with associated peripapillary hemorrhage in the right eye and a normal appearing disc in the left eye (Fig. 1). The right superficial temporal artery pulse was not palpable. Laboratory workup was notable for an erythrocyte sedimentation rate of 106 mm/hr and a C-reactive protein of 55.1 mg/L (normal: 0–10 mg/L). The patient was immediately treated with 100 mg of prednisone and a right temporal artery biopsy performed the same day demonstrated active GCA. She was subsequently admitted and treated with methylprednisolone (250 mg intravenously 4 times a day) for 3 days and aspirin (81 mg) daily. At 1-month follow-up, her best-corrected visual acuity was 20/20 in each eye, and repeat Humphrey visual field was stable. Her right optic disc was diffusely pale with minimal residual edema.

FIG. 1: Right optic disc demonstrates pallid edema while the left disc is normal.

Given the paucity of cases, the potential role of TNF-α antagonists in the treatment of GCA is unclear. Interestingly, vasculitis has been reported to occur with use of TNF antagonists, mainly in the form of leukocytoclastic vasculitis (^10–12). One postulated mechanism for the development of vasculitis during the use of anti-TNF agents is direct drug toxicity to the vasculature. Other mechanisms include deposition of anti-TNF/TNF immune complexes in the vessel wall with induction of a type III hypersensitivity reaction, reaction of autoantibodies with endothelial cells, paradoxical increased vulnerability to granulomatous vasculitis due to TNF deficiency, and a TNF antagonist–induced switch from a Th1 to a Th2 T-lymphocyte response (¹¹). Whether any of these proposed mechanisms of vascular destruction underlie the development of GCA during use of TNF-α antagonists is unknown. While on long-term treatment with etanercept except for a 3-week drug holiday, our patient developed symptoms that, in retrospect, were most likely due to GCA. Although we cannot exclude the gap in therapy as a precipitating event of the patient's ischemic optic neuropathy, we believe this most likely was due to natural evolution of her disease process.

ACKNOWLEDGMENTS

The authors thank Haodong Xu, MD, of the Department of Pathology, University of Rochester Medical Center.