Giant Cell Arteritis Review

David M Katz, MDBethesda Neurology, LLC

Neuro-Ophthalmology and Neurology3202 Tower Oaks Blvd, Suite 330

N Bethesda, MD 20852301-540-2700

September 7, 2014

Giant cell arteritis, aka Temporal Arteritis Demographics

• Most common in Caucasian females• Female-to-Male ratio >3:1• Incidence: 30/100,000• Median age at diagnosis: 72 years• Cause: unknown

Hoffman GS, Langord CA, Weyand CM, Goronzy JJ. Inflammatory diseases of blood vessels, 2nd ed. Wiley-Blackwell, 2012.

GCA Symptoms• New onset headache (constant, dull, achy pain): 60-90%• Scalp tenderness to touch (temples or occiput): 40-70%• Polymyalgia rheumatica (achy shoulders/hips): 50%• Jaw/tongue claudication (pain or fatigue with chewing): 30-50%• Limb claudication (ex. calf pain with walking): 5-15%• Systemic symptoms (weight loss, fatigue, anorexia): 20-50%• Permanent vision loss: 15%• Transient vision loss: 20%• Diplopia: 10%• Always get STAT ESR and non-cardiac CRP in patients with anterior ischemic

optic neuropathy (AION), branch or central retinal artery occlusion, amaurosis fugax or diplopia if > 50 years of age. Write your cell number on order sheet and also give your number to the patient. Also give them a prescription for prednisone.

• Hoffman GS, Langord CA, Weyand CM, Goronzy JJ. Inflammatory diseases of blood vessels, 2nd ed. Wiley-Blackwell, 2012.

GCA Signs• ESR >50 in 90% (normal ESR for males is age/2, for

females is age+10/2)• ESR >100 in 60%• Non-cardiac CRP >2x normal in 90%• Anemia in 30%• Elevated WBC in 20-30%• Elevated platelet count in 20-30%• Elevated anti-cardiolipin IgG Ab in 30-50% • Absent temporal artery pulse in 40%• Diplopia in 10%• Weight loss in 40%• Fever in 20%

GCA “Rule of Thirds”

• 1/3 of GCA patients will lose vision, and 2/3 have warning signs >1 week prior to permanent vision loss– Of the GCA patients with vision loss:

• 1/3 will go blind within 1 day, if untreated• 1/3 within 1 week, if untreated• 1/3 within 1 month, if untreated

GCA related vision loss

• Arteritic anterior ischemic optic neuropathy (AAION) occurs in 80-90% of cases

• Posterior ischemic optic neuropathy (PION) occurs in 15%, and when seen is pathognomonic for GCA

• CRAO in 3%• Patchy choroidal non-perfusion on FA is also

pathognomonic for GCA due to inflammation of retinal and optic nerve head vessels. This is never seen with NAION or CRAO.

Optic Nerve Vascular Supply (optic nerve head perfused by small posterior ciliary

vessels, not the CRA)

GCA pathology

• GCA preferentially affects small and medium sized arteries that have a muscular layer, not intracranial internal carotid arteries. Therefore, GCA patients rarely suffer strokes.

• A positive temporal artery biopsy (TABx) typically shows inflammation of the intima and medial layers, more so than advential layer with disruption of the internal elastic lamina.

Temporal Artery BiopsyPositive Negative

NAION vs AAION

• Mean age=57• Va>20/60 in 50%• Hyperemic disc swelling• Small or absent cup• Second eye involvement in 1/7 at

5 years

• Cup unchanged once edema resolves

• FA shows late disc leakage• Cotton wool spots and retinal

infarcts are very rare

• Mean age=72• Va<20/220 in 70%• Pallid disc swelling• Cups of any size• Second eye involvement in 1/3:

1/3 within 1 day, 1/3 within 1 week and 1/3 within 1 month

• Cup enlarges once edema resolves

• FA shows late disc leakage and delayed choroidal perfusion

• Cotton wool spots very common

AAION A: severe pallid swelling

B: patchy choroidal non-perfusion on FA

NAIONhyperemic disc swelling

AAION (GCA) NAION

“To biopsy, or not to biopsy, that is the question”

• American College of Rheumatology (ACR) in 1990 published guidelines for GCA to help decide who needed a TABx.

• If at least 3 of these 5 were positive, ACR quoted a sensitivity of 94% and specificity of 91% for GCA:– Age > 50– New headache– Temporal artery tenderness or loss of pulse– ESR > 50– Abnormal TABx

“The rest of the story”

• Wills Eye Hospital in 2012 used the ACR criteria and their GCA cases from 2001-06 of 112 patients

• 9 patients were negative by ACR criteria alone, but had positive TABx• 46% of GCA cases would have been missed by ACR criteria if TABx had

not been done (only 2 of 5 criteria met without TABx)• 28% of TABx negative patients met ACR criteria for GCA• Bottom line: TABx recommended for essentially all cases, unless

gravely ill or refuse TABx. (if a lowly neurologist (me) did them in the office under local anesthesia during neuro-oph fellowship and no complications occurred, how difficult/risky can it be for the patient?)

If the pathologist reports “normal meninges” on your TABx, you went too deep…

Temporal artery biopsy findings in GCA

• Thickening of the intima, necrosis of the internal elastic lamina and media and lymphocytic infiltration of the vessel wall with giant cells are seen acutely.

• Biopsies of patients on steroids >1 week will still show disruption of the internal elastic lamina but fewer or no lymphocytes or giant cells, termed healed arteritis.

• A temporal artery biopsy specimen > 2.5 cm confirms the diagnosis in >90% of cases. If negative, a contralateral biopsy has a yield of <5%.

If all GCA patients had these obviously prominent vessels we

would never miss a case

“To biopsy unilaterally vs. bilaterally, that is the follow up

question”

• One study from Wills Eye Hospital and another from Wilmer Eye Hospital both showed that a unilateral > 2.5 cm TABx is adequate.

• 1 case out of 90 at each center had a positive TABx only on one side.

GCA treatment

• Steroids should be started immediately upon suspecting the diagnosis, i.e., “shoot first and ask questions later.” If highly suspicious, have them go directly to the lab, then directly to the pharmacy and take 100 mg in the pharmacy while awaiting the ESR and CRP results.

• IV methylprednisolone 1g/d x3-5 days may be indicated if loss of vision <24 hours based on anecdotal evidence

• High dose prednisone (80-100 mg/d) is an alternative to IV steroids in some patients

• After 48 hours, visual improvement after starting steroids is rare (<5%) but dramatically lowers risk to contralateral eye

• TABx will remain abnormal for at least 7 days after starting high dose steroids, so no rush to biopsy. Even months later, healed arteritis will remain (disruption of internal elastic lamina)

Potential new treatments for GCA

• Tocilizumab (Actemra) is approved for RA and blocks interleukin-6 5 patients with GCA all were able to taper steroids quickly but the follow up

period was only 4 months

• Methotrexate and azathioprine (Imuran) have shown mixed results as steroid sparing agents in GCA

• Etanercept (Enbrel) a TNF alpha inhibitor used to treat RA and psoriasis lowered the total steroid dose at 1 year in a group of 17 steroid dependant GCA patients.

• Hoffman GS, Langord CA, Weyand CM, Goronzy JJ. Inflammatory diseases of blood vessels, 2nd ed. Wiley-Blackwell, 2012 months)• Seitz, et al. Swiss Medical Weekly. 141:1-4, 2011

Could GCA be due to an infection?

• Univ of Utah group tested 10 patients with biopsy-proven GCA for a strain of Burkholderia Pseudomallei (BP) in the TABx and serum. 9/10 were positive, 2/2 with negative TABx were neg for BP and 16/16 controls were negative for BP.

• They then cultured BP from serum and TABx specimens of 4 positive patients and found that BP activated dendritic cells and macrophages to produce multinucleated giant cells in vitro, the pathognomonic finding in a TABx.

What is Burkholderia Pseudomallei?

• BP causes melioidosis, aka Whitmore’s disease.• A tropical infection seen in SE Asia and northern

Australia. Most common in rice farmers• Found in contaminated soil and water• Signs and symptoms, usually <2-4 weeks after exposure:

cough, fever, headache, anorexia, abdominal pain, joint and muscle pain (similar to GCA symptoms but not vision loss)

• BP septicemia fatal in 90% if untreated, 50% with antibiotics – CDC, 2012

DeDomenico I, Koenig C, Katz B, et al. A murine model of GCA: infection with a BP-like strain treated with steroids and antibiotics. Platform presentation, Feb 2012, NANOS meeting

Burkholderia Pseudomallei: gram negative, aerobic, motile, rod-shaped bacterium

DeDomenico I, Koenig C, Katz B, et al. A murine model of GCA: infection with a BP-like strain treated with steroids and antibiotics. Platform presentation, Feb 2012, NANOS meeting

(LPS: lipopolysaccharide)

Antibiotics for GCA?

• A murine model of BP induced GCA:• 24 mice received intraperitoneal injection of BP– 6 then received steroids alone– 6 received steroids and minocycline– 6 received minocycline alone– 6 received no therapy

Antibiotics for GCA?

• 6/6 untreated mice became ill, 3/6 died <30 hrs• 4/6 treated with minocycline alone survived >30

hrs• 5/6 treated with steroids alone survived >30 hrs• 6/6 treated with steroids and minocycline

survived >30 hrs• At necropsy, the control and steroid treated

mice had extensive bacterial burden, the minocycline treated mice did not.

• Could the relationship between the BP bacteria and GCA be similar to the relationship between H. pylori infection and peptic ulcer disease?

• Rheumatologists have used minocycline for many years to treat RA and lupus based on anecdotal evidence. Perhaps they were treating an unknown bacterial infection that stimulated the immune system to attack the joints in RA.

A cautionary tale from the law offices of Dewey, Cheatham and Howe

• 2004 Medical Malpractice Settlement Report

• 83-year old woman suffers acute vision loss in both eyes one week apart.• The plaintiff is an 83 year old with a past medical history of chronic open angle glaucoma and cataracts. On 9/10/02 , she woke up

and could not see out of her left eye. (The plaintiff never regained any vision in her left eye, and the plaintiff was making no claim for any loss of vision in her left eye.) She went to see the defendant ophthalmologist who documented that the plaintiff had no

pain, no fever, no weight loss, no masseter claudication, and no scalp tenderness. However, upon exam, he found that the plaintiff's optic nerve was swollen with hemorrhage. He questioned the diagnosis of non-arteritic optic neuropathy , and

he ordered a CBC (complete blood count), ESR (erythrocyte sedimentation rate), and planned to see the plaintiff again in two weeks. There is no documentation present that he ordered a C-reactive protein (CRP), or that he instructed the plaintiff to return immediately for any visual difficulty with her right eye.

• One week later, the plaintiff was admitted with acute vision loss in her right eye. Initial lab work revealed an

elevated ESR of 66, and an elevated CRP of 1.86 (normal range 0.08-0.80). The treating physicians believed that the plaintiff's clinical history and evaluation were suspicious for temporal arteritis and started her on intravenous steroid therapy. On 9/18/02, a

temporal artery biopsy was performed and subsequent pathologic analysis confirmed the diagnosis of temporal arteritis (giant cell arteritis).

• The plaintiff alleged that the defendant ophthalmologist was negligent when he failed to order a CRP, and when he failed to inform the plaintiff to return immediately if she experienced any changes in her right eye. The plaintiff further alleged that if the CRP was elevated, the accepted standard of care required that the ophthalmologist immediately admit the plaintiff to the hospital for the initiation of intravenous steroid therapy, and to order a temporal artery biopsy to confirm or definitively rule out the diagnosis of temporal arteritis.

• The defendant claimed that he complied in all respects with the applicable standard of care, and that nothing he did or failed to do caused

the plaintiff's blindness. The defense further contended that steroids are not proven to be effective in treating temporal arteritis, and that to have any chance of being even somewhat effective, they must be given immediately after the onset of symptoms, an impossibility given that the symptoms were first associated with vision loss in the plaintiff's left eye. The defense was prepared to call two experts to testify that nothing could have been done to save the vision in the plaintiff's right eye.

How much did the case settle for in an 83-year-old with bilateral blindness?• A: nothing, the ophthalmologist was right• B: $25,000, a “nuisance settlement” given her

age• C: $100,000 given her age/short life

expectancy• D: $1,000,000

Highlights• Giant cell arteritis is a major cause of permanent vision loss

and quick action with high dose steroids often prevents bilateral blindness.

• The key presenting symptoms and signs include: headache, jaw pain, fatigue, scalp tenderness, severe monocular vision loss with pallid optic disc edema, a central retinal artery occlusion or a normal fundus exam, and an elevated ESR and non-cardiac CRP.

• A significant number of patients do not present will all these findings so have a low index of suspicion and order an ESR/CRP/CBC STAT in all patients presenting with AION, PION, BRAO, CRAO, diplopia or amaurosis fugax.

• PS GCA patients only come in on Friday afternoons and Holiday weekends…

Bibliography• DeDomenico I, Koenig C, Katz B, et al. A murine model of

GCA: infection with a BP-like strain treated with steroids and antibiotics. Platform presentation, Feb 2012, NANOS meeting San Antonio, TX

• Hoffman G, Langord C, Weyand C, et al. Inflammatory diseases of blood vessels, 2nd ed. Wiley-Blackwell, 2012)

• Hall J, Volpe N, Galetta S, et al. The role of unilateral temporal artery biopsy. Ophthalmol:110(3):543-8, 2003

• Ray-Chaudhuri N, Kine D, Tijani O, et al. Effect of prior steroid treatment on temproal artery biopsy findings in GCA. BJO:86(5):530-2, 2002

• Boyev L, et al. Efficacy of unilateral vs. bilateral temporal artery biopsies for diagnosis of GCA. AJO:128:211-5,1999

Thank you

David M Katz, MDBethesda Neurology, LLC

3202 Tower Oaks BlvdSuite 330

N Bethesda, MD 20852301-540-2700