Is VZV the cause of GCA? AAS = CON NANOS March 5, 2018 ALFREDO A. SADUN, MD, PhD Flora Thornton Chair Doheny Eye Institute Vice-Chair of Ophthalmology, UCLA
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Gilden D, et al Neurol. Neuroimmunol Neuroinflamm. 2016 • Studied temporal artery (TA) biopsies • 104 were GCA+ (positive) • 100 were GCA- (negative) • 61 TA from (normal) at autopsy • Varicela-zoster virus (VZV) antigens found in 74% of GCA + • VZV antigens found in only 58% of GCA – • VZV antigens found in only 18% autopsy (nl) TA 4
What does the paper conclude? • 1) That VZV and histological changes may “help to explain disease (GCA) pathogenesis” • 2) GCA may result from trans-axonal transport of reactivated VZV from ganglia to TA wall. • 3) There may be a milder form of GCA both explaining • That inflammation may be restricted to the adventitia • That the GCA- cases had a 58% chance of VZV 5
Strengths of the paper • Many cases • A second form of controls (patients not even suspected of GCA) • A strong P value between the suspicion of GCA and VZV antibodies • A lot of work 6
What does the paper actually show? • VZV antigen, in comparison to autopsy cases, was • about 4 times more likely to be present in the vessel wall of GCA + cases • About 3.2 times more likely GCA- cases • VZV antigen near areas of adventitial inflammation 7
That VZV was • 4 X higher in TAB GCA + compared to controls • 3.2 X higher in TAB GCA – compared to controls • Makes sense if both had different forms of GCA But that 18% of autopsy cases showed VZV is very problematic unless we say that 18% of the elderly have subclinical VZV arteritis 8
There is no causal role of VZV in GCA • Association does not prove causality 9
There is no causal role of VZV in GCA • Association does not prove causality • Other studies did not find VZV in TAB specimens • Helweg-Larsen et al 0/13 GCA+ • Kennedy et al 0/15 • Rodriguez-Pla 0/50 10
There is no causal role of VZV in GCA • Lack of clinically supportive data • Only 4% of GCA was preceded by VZV (Rhee et al) 11
There is no causal role of VZV in GCA • Interventions to decrease VZV reactivation have not decreased rates of GCA • VZV vaccination have decreased VZV but not GCA 12
I had the chance to review a review paper in press by Kedar & Berger. They emphasize that Gilden et al is at level 5 class evidence. It does not warrant a sea change in our way of considering or treating GCA 13
Association does not prove causality • VZV may be an artifact of • Their staining process (remember J. Lawton Smith who published many different ophthalmological conditions with spirochetes (syphilis). • The altered immune state of GCA • A myriad of other possibilities 14
1969: Down a similar road for cause of uveitis • Treponema pallidum demonstrated in the aqueous humor of eyes with idiopathic uveitis • Silver stain • Retraction after it was noted that using the glass stopped bottle demonstrated spirochete like shavings of glass in every application 15
16
We’ve been down this road before in GCA • Burkholderia isolated from temporal arteries of 10 GCA • NANOS 2016 Bradley Katz et al presented: Absence of Bacteria in the Temporal Arteries of Patients with Giant Cell Arteritis. 18 TABs as f/u of previous linkage to Burkholderia 16S rRNA sequencing failed to identify any bacterial DNA 17
Why does it matter if VZV is the cause? If it were true we should be: • Treating GCA recurrence by adding antivirals • Be much less aggressive in the use of steroids or other immunosuppression • This is currently not warranted. 18
Conclusion: VZV is not the cause of GCA • At best, there is an association • A) Artifactual • B) Surrogate marker • C) Population at risk for both • At worst this is just the most recent premature conclusion in a series of studies purporting to find the underlying pathology of GCA. 19
We need to continue investigating the pathophysiology of this remarkable disease. • Since VZV is NOT the cause of GCA 20
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