A. Introduction

1. Systemic Inflammatory Disease
   1. Primarily affects large arteries (above the diaphragm)
   2. Typically associated with systemic symptoms and polyarthralgias
2. Epidemiology
   1. Usually affects persons >50 years old; mean age = 70 years
   2. Incidence in persons >50 years old is ~20/100,000 persons per year
   3. May be more prevalent in northern climates
   4. Very high incidence (~1% per year) in persons >80 years old
3. Greatest concern is potential for acute blindness
   1. Thoracic aortic aneurysms also concerning
   2. Myocardial infarctions have occasionally been reported
4. Long term survival of patients with GCA is same as that of general population

B. Symptoms

1. Common
   1. Headache, often unilateral, may be abrupt: 77%
   2. Jaw claudication (worse with chewing): 50%
   3. Scalp pain
   4. Constitutional Symptoms (inflammatory, see below): ~50%
   5. Polymyalgia rheumatica (PMR) symptoms: 35%
   6. Visual Symptoms: >30%
2. Visual Symptoms
   1. 30-50% of patients have visual symptoms
   2. Ameurosis fugax quite common
   3. Up to 40% have visual loss
   4. Posterior cilliary artery is most commonly involved in cases of visal loss (75-100%)
   5. Central retinal artery involved in up to 50% of cases
   6. Elevated platelet count is a major risk factor for visual loss in GCA [5]
3. PMR
   1. Low grade fever with fatigue
   2. Aching and stiffness in trunk and mainly proximal muscle groups
   3. PMR in patients >70 years with abrupt headache or jaw claudication is likely GCA
4. Constitutional Symptoms [10]
   1. Due to systemic Inflammation
   2. Anorexia
   3. Weight loss
   4. Malaise, Weakness, Myalgeas
   5. Fever: ~25%
   6. Anemia (chronic inflammatory type)
   7. Night sweats
   8. Fatigue - common
5. Uncommon Symptoms
   1. Stroke, memory loss (dementia), hallucinations
   2. Raynaud's Phenomenon
   3. Occipital Headache [8]
   4. Abdominal pain and dysphagia
   5. Myocardial infarction
   6. Pulmonary infiltrates
   7. Respiratory Symptoms: dry cough, sore throat, tongue pain
   8. Fever of unknown origin
   9. Upper and lower extremity claudication [8]
   10. Mononeuritis multiplex (especially of brachial plexus)
   11. Shortness of breath [10]
6. Aortic Involvement [9]
   1. More common in Takayasu Arteritis than GCA
   2. Overall, however, GCA patients >50 years have ~27% incidence of large-artery disease
   3. Cilitations, valve insufficiency, and aneurysms (thoracic and abdominal) do occur
   4. ~18% of GCA patients >50 years have aortic aneurysms or dissection
   5. Risk for thoracic aneurysms17X higher in GCA compared with age matched controls
   6. Abdominal aneurysm rate ~2X higher in GCA than controls
   7. Risk for aortic dissection increased in patients with hypertension
   8. Large artery disease develops late in GCA, usually after 10 years with disease
   9. Aortic disease may also occur in Cogan Syndrome
   10. Aortitis can be caused by a variety of other syndromes as well

C. Pathophysiology [1,3,11]

1. Systemic inflammatory Disease
   1. Initiated by dendritic cells in vessel walls
   2. Activated dendritic cells produce chemokines CCL19 and CCL21, attracts other cells
   3. Dendritric cells also produce IL6 and IL18 which stimulate T cells
   4. Dendritic cells activate incoming CD4+ T cells through MHC Class II and coactivators
   5. CD4+ T lymphocytes initiate a Type 1 T helper response (IL18 dependent)
   6. T cells and macrophages typically cause granulomas in vessel wall
   7. Causes vessel wall damage including apoptosis, fibrosis with stensoses and/or aneurysms
2. T Lymphocytes in GCA
   1. Oligoclonal T cell expansions in peripheral blood lymphocytes of GCA patients
   2. CD4+ T helper cell populations implicated
   3. CD8+ T cells are decreased in peripheral blood
   4. Increased association with HLA-DRB1*04 and DRB1*01
3. Cytokine patterns of vasculitic lesions [11]
   1. IL-1ß, IL-6 and TGF-ß1 mRNA present in GCA as well as PMR lesions
   2. GCA lesions had both IFN gamma (IFNg) and IL-2 mRNA production
   3. PMR lesions had only IL-2, without IFNg
   4. Suggests signficant differences (? correlation with symptoms) between GCA and PMR

C. Diagnosis [1,2]

1. Temporal artery biopsy required for diagnosis
2. High Clinical Suspicion
   1. Elderly patients with new onset headaches, scalp pain, other symptoms
   2. High erythrocyte sedimentation rate (ESR)
   3. Disease has high morbidity if untreated (blindness, heat attack, stroke, other)
   4. Treatment is highly effective
   5. Therefore, low threshold for temporal artery biopsy (see below)
   6. Any patient with moderate or high clinical suspicion should undergo biopsy to rule out GCA
3. Radiographic Evaluation
   1. Sensitivity and specificity of abnormal findings on ultrasound are ~70% and 80% [12]
   2. Temporal artery ultrasound does not increase diagnostic accuracy of clinical exam [13]
   3. With ~10% pretest probability of GCA , negative ultrasound rules out disease [12]
   4. Chest radiograph may be useful to screen for thoracic aneurysms
   5. Positron emission tomography (18F-glucose) can show inflammation of aorta in GCA [14]
   6. Magnetic resonance angiography (MRA) or CT with contrast can show large vessel disease
4. Elevated inflammatory markers
   1. Elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP)
   2. >90% have ESR >40mm/hr; majority have ESR >80mm/hr
   3. About10% of patients will have ESR<30mm/hr
   4. C-Reactive Protein (CRP) may be elevated in ~25% of the patients with normal ESR [3]
   5. IL-6 elevations are probably most sensitive but test not always available [2]
5. Hematology
   1. Leukocytosis
   2. Anemia - chronic disease type; mild to moderate
   3. Thrombocytemia (acute phase reaction)
6. Uncommon Laboratory Findings
   1. Renal Disease: albuminuria
   2. Abnormal liver function tests
   3. Syndrome of inappropriate antidiuretic hormone
   4. Microangiopathic hemolytic anemia
7. Other causes of systemic symptoms and increased ESR should be evaluated
   1. Multiple Myeloma
   2. Other Neoplasms: especially lymphomas
   3. Bacterial Endocarditis
   4. Autoimmune disorders: other vasculitis, systemic lupus
   5. Other chronic infections including osteomyelitis, tuberculosis
8. Temporal Artery Biopsy
   1. Multiple biopsies of the temporal artery may be required
   2. 4-5cm of vessel should be obtained for adequate evaluation
   3. Bilateral biopsies should be done if initial biopsy is negative and suspicion is high
   4. Long term glucocorticoids probably invalidate biopsy results
   5. However, 7-14 days of high dose glucocorticoids probably do not affect biopsy findings

D. Pathology

1. Temporal Artery Biopsy [10]
   1. Sensitivity of single biopsy (adequate specimen at least 3cm): 80%
   2. Sensitivity of double biopsy: 95%
   3. Specificity is nearly100%
   4. Atherosclerotic Disease is a very common finding in most biopsy series
   5. All patients with symptoms of PMR and possible vasculitis should undergo biopsy
2. Classic Histology
   1. Focal granulomatous inflammation with multinucleated giant cells in ~50% of cases
   2. Usually affects cranial vessels, temporal and occipital arteries
   3. Carotids and/or aorta itself may be involved
   4. Severe forms have other regions of body affected including coronary arteries
3. Non-Classical Histology
   1. Mixed-cell inflammatory infiltrate
   2. Lymphocytes and other mononuclear cells
   3. Giant cells not present
   4. Rare neutrophils and eosinophils
4. Rare patients have small vessel vasculitis surrounding a normal temporal artery [2]

E. Treatment

1. Generally low threshold to treat in appropriate clinical setting
   1. Major problem is that high doses of glucocorticoids are required in GCA
   2. These agents may have significant side effects, particularly in older persons
   3. Risk of visual loss, however, requires that therapy be started early and GCA ruled out
   4. Strongly recommend that biopsy be done if GCA is moderately or highly likely [6]
   5. Glucocorticoid with methotrexate should be strongly considered [15]
   6. However, data with "steroid sparing" agents is not terribly strong [3]
2. Prednisone
   1. Usually initiate therapy at 40 to 60mg per day oral until symptoms resolve
   2. Some recommend higher doses if any visual complications occurring
   3. Strongly consider 125-250mg IV methylprednisolone x 1-3 days for visual symptoms
   4. Probably require several days for full action (must block macrophage activation)
   5. Symptoms usually resolve within 1-3 days
3. Prednisone Taper
   1. Reduce prednisone to 20-40mg / day for 4-6 weeks (reduce by 5mg/week)
   2. At 20mg/day, reduce by 2.5mg every two weeks
   3. If methotrexate (MTX) is used, prednisone may be completely withdrawn
   4. If MTX is not used, reduce prednisone to 5-10mg/day for 1-2 years
   5. After 1-2 years, with ESR in normal range, gradually taper prednisone off
   6. Alternating day prednisone therapy is not effective in GCA
   7. Dapsone has also been used as a glucocorticoid sparing agent [5]
4. Methotrexate (MTX) [15,16]
   1. Used for disease modifying and "steroid-sparing" activity
   2. Strongly consider oral MTX 10mg/week (use IM injection if oral not tolerated)
   3. Initiate MTX at time of initial glucocorticoid treatment in high risk patients
   4. MTX permited complete taper of prednisone and reduces disease recurrence [15]
   5. MTX use leads to ~25% reduction in total prednisone dosage over 24 months [15]
   6. These results were not confirmed in a major multinational study, where MTX added to standard prednisone did not reduce relapse or cumulative glucocorticoid dose [16]
5. Monitoring Inflammation
   1. Monitor ESR (or CRP and/or IL-6 levels) closely to insure ESR <40mm/hr
   2. Goal is ESR < 40mm/hr (CRP < 5mg/L) on lowest possible prednisone dose
   3. IL-6 levels may be most sensitive marker of systemic inflammation
6. Tumor Necrosis Factor Alpha (TNFa) Blockade [2,4]
   1. Anti-TNFa Ab, infliximab (Remicade®) has shown activity in steroid-resistant GCA [2]
   2. However, in a randomized trial, maintenance therapy with infliximab following steroid- induced remission of no benefit, and may be harmful [4]
   3. Infliximab also of no benefit, with possible harm, in treatment of PMR [6]
7. Health Maintenance on Glucocorticoids
   1. Vaccinations should be up to date
   2. Osteoporosis should be prevented with at least calcium + vitamin D
   3. Strongly consider additional prevention with concommitant bisphosphonate therapy
   4. MTX use in initial therapy leads to reduction in total prednisone dose over 2 years
8. Visual Symptoms
   1. Thrombocytosis with acute visual loss is a risk factor for permanent visual loss
   2. Glucocorticoids may not be effective alone for severe visual loss
   3. High-dose methylprednisolone (up to 1000mg/d) has been advocated for visual problems
   4. Consider addition of antiplatelet agents to glucocorticoids [4]

References

1. Salvarani C, Cantini F, Hunder GG. 2008. Lancet. 372(9634):234
2. Shmerling RH. 2006. JAMA. 295(21):2525
3. Weyand CM and Goronzy JJ. 2003. NEJM. 349(2):160
4. Hoffman GS, Cid MC, Rendt-Zagar KE et al. 2007. Ann Intern Med. 146(9):621
5. Liozon E, Herrmann F, Ly K, et al. 2001. Am J Med. 111(3):211
6. Salvarani C, Macchioni P, Manzini C, et al. 2007. Ann Intern Med. 146(9):631
7. Ronthal M, Gonzalez RG, Smith RN, Frosch MR. 2003. NEJM. 349(2):170 (Case Record)
8. Docken WP and Marx EJ. 2002. NEJM. 347(4):272 (Case Record)
9. Nuenninghoff DM, Hunder GG, Christianson TJ, et al. 2003. Arthritis Rheum. 48(12):3522
10. Kay J, Finn DS, Stone JR. 2006. NEJM. 354(6):623 (Case Record)
11. Weyand CM, Schonberger, Oppitz U, 1997. Arthritis Rheum. 40(1):40
12. Karassa FB, Matsagas MI, Schmidt WA, Ioannidas JPA. 2005. Ann Intern Med. 142(5):359
13. Salvarani C, Silingardi M, Ghirarduzzi A, et al. 2002. Ann Intern Med. 137(4):232
14. Blockmans D, Stroobants S, Maes A, Mortelmans L. 2000. Am J Med. 108(3):246
15. Jover JA, Hernandez-Garcia C, Morado IC, et al. 2001. Ann Intern Med. 134(2):106
16. Hoffman GS, Cid MC, Hellmann DB, et al. 2002. Arthritis Rheum. 46(5):1309