Which one of the following has been shown to be an effective treatment target for Giant - PowerPoint Presentation

Slide1

Which one of the following has been shown to be an effective treatment target for Giant Cell Arteritis?

Interleukin 1

Interleukin 6Interleukin 17Tumor Necrosis Factor α Tumor Growth Factor β

2. Which one of the following is one the key player in formation of granuloma in Giant Cell Arteritis? Interleukin 1 Interleukin 6Interleukin 17Tumor Necrosis Factor α Tumor Growth Factor β

PATHOPHYSIOLOGY OF GCA

Granulomatous inflammation with abundant CD4+ T cells, macrophages, and giant cells involving

large- and medium-sized arteries

is the histopathologic hallmark of GCA. CD4+ T cells in GCA lesions mainly demonstrate two effector phenotypes:T helper (Th)1— producing interferon gamma (INFɣ) Th17—producing interleukin (IL) 17. INFɣ and IL-17 orchestrate downstream events resulting in

granuloma formation, monocyte recruitment, and differentiation of monocytes into macrophages and multinucleated giant cells

In addition, patients with GCA have a defective population of regulatory T cells (

Tregs

) that express a

hypofunctional variant of the master regulatory transcription factor Foxp3 (so called Foxp3∆2 Tregs) and produce IL-17PATHOPHYSIOLOGY OF GCAIL-6 is a key contributor to GCA pathogenesis. This cytokine not only drives the polarization of CD4+ T cells toward the Th17 phenotype, but it also suppresses the differentiation and function of Tregs. Moreover, IL-6 participates in the activation of monocytes and macrophages, and induces endothelial cells to acquire the pro-inflammatory phenotype necessary to traffic these and other leukocytes to the sites of inflammation.The result of arterial wall inflammation in GCA is either structural damage that may lead to dilatation (eg

, aortic aneurysm) or edema and remodeling (eg, intimal hyperplasia) that may lead to stenosis ultimately resulting in vessel occlusion and tissue ischemia.The superficial temporal arteries are involved in most patients, but GCA can affect other arteries. A clear majority of strokes in GCA are due to occlusion in the posterior circulation and the vertebral arteries. Involvement of the intra-cranial arteries is exceedingly rare.Stroke can occur in 1.5 to 7% of patients with GCA. A previous ischemic event in GCA is the strongest predictor of subsequent event, as are lower inflammatory markers, and the presence of cardiovascular risk factors: If stroke occurs, it is usually within one month of diagnosis and may be prevented by the initiation of glucocorticoid therapy.

Most GCA-positive TAs contained VZV in skip areas that correlated with adjacent GCA pathology, supporting the hypothesis that VZV triggers GCA immunopathology.

Antiviral

treatment may confer additional benefit to patients with GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.

PATHOPHYSIOLOGY OF GCA

Diagnosis of GCA

ESR

Most useful testHigher in GCA than other vasculitidesAlmost always>50 mm/h ( ACR diagnostic Criteria ) Normal in 10% of patientsCRPUseful when ESR<40 mm/hRF/Anti-CCP/ANA should be negativeTA biopsy (TAB)DiagnosticUS shows “halo sign”, 75% sensitivity, 83% specificityPET scan89% sensitivity, 95% specificityMore reliable than other imaging studies

3

. Vision

loss in GCA is most commonly due to

arteritic anterior ischemic optic neuropathy (AAION) secondary to occlusion of which arteries? Posterior ciliary Central retinal (CRAO) Branch retinal (BRAO)

Superficial temporal Choroidal The reported incidence of visual symptoms in GCA ranges from 12% to 70%, and permanent vision loss can occur in as many as 1 in 6 new patients prior to the initiation of corticosteroid therapy: - Visual loss caused by GCA can be partial or complete, uni- or bilateral. - Transient visual loss often develops into permanent loss if treatment is delayed. Vision loss experienced with GCA is rarely reversible. - Newly recognized GCA should be considered a true ophthalmologic emergency. - Patients with low levels of inflammatory markers are more likely to experience visual loss.  Vision loss in GCA is most commonly due to

arteritic

anterior ischemic optic neuropathy (

AAION

) secondary to occlusion of the

posterior ciliary arteries

that perfuse the

head of the optic nerve

. Less frequent mechanisms include:

central retinal artery (CRAO) and branch retinal artery (BRAO) occlusions

On

fundoscopic

examination,

AAION

is characterized by a pale (“

chalk white”)

and swollen optic disc.

Optic disc edema may be accompanied by disc hemorrhage, retinal whitening, or cotton wool spots.

Fluorescein angiography is also a valuable diagnostic tool in GCA with eye involvement and demonstrates areas of choroidal

hypoperfusion

.

4

. In

GCA patients who treated with steroid ,

elevation of inflammatory markers without clinical manifestations of disease activity (flare) can occur in :  < 5 % of patients < 10 % of patients< 25 of patients

> 50% of patients > 75% of patients Disease flare Defined based on clinical manifestations .An isolated elevation of the inflammatory markers is not considered a disease flare Most disease flares in steroid-treated patients also present with increased inflammatory markers (ESR and/or CRP) In steroid -treated patients, disease flares with normal inflammatory markers can occur in up to 35% of the patients In steroid -treated patients, elevation of inflammatory markers without clinical manifestations of disease activity can occur in > 50% of patients

In

Tocilizumub

-treated

patients, inflammatory markers normalize and become unreliable for disease activity

monitoring.

Steroid non-responsive GCA

Possible side effects of Tocilizumab (TCZ) may include infection, infusion and hypersensitivity reactions, leucopenia/neutropenia, thrombocytopenia, dyslipidemia, and bowel perforation

Contra-indications for the use of TCZ include :active infection untreated latent tuberculosisabsolute neutrophil count (ANC) < 2000/mm3 platelet counts < 100,000/mm3 AST or ALT > 1.5 times the upper limit of normal, and history of diverticulitis. Tocilizumab(ACTEMRA)Humanized anti IL-6 receptor monoclonal antibody and binds specifically to IL-6 receptors.Recommended laboratory monitoring while

on TCZ is as follows

5. Which

one of the following features in NOT the indication for obtaining vascular imaging in patients with GCA ?

A. Claudication

B. Transient Visual loss C. Pulse deficits D. BruitsE. BP asymmetry

Imaging modalities to assess for luminal and mural changes suggesting Large Vessel Vasculitis (LVV) include CTA, MRI/MRA, PET/CT and PET/CTA Vascular imaging should be obtained in patients with clinical evidence suggesting LVV (eg, claudication, pulse deficits, bruits, BP asymmetry) Serial vascular imaging (eg, every 12 months) should be performed in patients with previously documented LVV (eg, aortic aneurysm) The role of vascular imaging for the assessment of disease activity and response to treatment has not been established

Vascular surgery consultation is recommended for

T

horacic

aortic aneurysm > 4 cm or Abdominal aneurysms > 5 cm6. Which of the following finding is the indication for vascular surgery consultation in patient with GCA? Thoracic aortic aneurysm with any size

Abdominal aortic aneurysms with any sizeThoracic aortic aneurysm > 2 CmAbdominal aortic aneurysm > 5 CmNone of those

7. Case

simulation practice :

73 years old male with new onset of left sided headache started 2 days ago . He has visual blurriness with his headache. No fever or jaw claudication.

Initial work up at emergency room was negative CT scan and ESR of 68 with CRP 5.5 . He denies jaw claudication and no limb claudication. His vital sign are normal and he denies any fever and chills. He complains of loss of appetite.His exam shows severe tenderness on left temporal area with normal

ophthalmoscopic exam. His CBC shows:High dose oral steroid ( 1mg/ kg ) started and patient was sent for urgent left temporal artery Biopsy which performed next day . On day #7 , patient has been seen for biopsy result which was negative . His patient continues with minimal relied and in exam he continues to have scalp tenderness on left temporal area with no change in his exam. His repeat las showed ESR of 59 with CRP of 6.7 . His CBC is:Next step ?

Bilateral

TABx

91% negative predictive valueOnly when proper biopsy is negative85% + in proper unilateral TAB Negative in patchy/segmental involvementNegative in superficial occipital artery involvementOnly 3%-5% additional informationAortic arch syndromeNegative TA biopsy in 40% of patientsNeeds CTA/MRA for diagnosisAlways do Congo red to r/out amyloidosis