Re: Dr. Lerner and Nitric Oxide Experiments

May 17, 2002

Adam, that's an intellectually sophisticated observation. It may well

be that NO isn't as involved in rosacea-induced flushing as

originally hypothesized, or it may be that imperfect research and/or

imperfect topical preparations are delaying the transition from basic

science to practical clinical benefits. There are other possibilities

as well.

I have another theory, although I say this with full realization of

my limited knowledge base, that I'm probably totally wrong.

That's the thing with theories -- they sound great but they're a dime

a dozen to create, and unless they're proven they mean nothing

compared to another good theory.

Anyway, with that disclaimer, here's my thinking at present: after

reading the stories here, learning more on a number of levels, and

thinking about it over the past few months, I'm coming to believe

that rosacea is primarily an immune-mediated disorder, not primarily

a vascular disorder.

Let me explain by way of this example: if I were to hit your face

hard, strike your cheek several times, in short order your cheek

would turn red and begin to hurt: the skin on your cheek would begin

to flush and burn. We both know that the cause of the flush wasn't

something out of the blue, wasn't something due to vascular problems -

- your cheek's flush and pain is a normal response to the skin being

stimulated, " injured " by my slaps.

Now, imagine if you didn't know that I slapped you -- you were asleep

or drunk or something -- and woke up with a flushed, painful cheek.

You would try to attribute that flush to something -- food, the

weather, the UV lights in the club the night before, stress at work --

and, failing to do that, you would think you had a primary flushing

disorder.

A slap is a pretty obvious stimuli to a flush, but what if there was

something just as likely to induce a flush but wasn't so obvious?

What if an immune-related substance was inside the dermis layer of

the cheek -- something that would irritate like a slap, but

painlessly at first and from within? This unknown substance would

release a cascade of chemical reactions typical for soon-to-be-

inflammed skin: it would attract increased blood flow to the local

area, pain and swelling and itching might develop, and as the pores

responded to the inflammation within a day or so pustules and papules

would develop as well. The cheek would flush not because of a primary

vascular abnormality but because of something that tripped an

immunologic reaction, a reaction that included vascular dilation.

What are the features of this hidden substance that we theorize is

immunologically active (meaning that it capable of initiating the

immunologic cascade, as described in the above paragraph)? For

starters, it would be disproportionally represented in fair skinned

people -- others could get it too, but we're talking generalities

here. It would slowly manifest over one or more decades -- again a

generality, but typically true. Also as a generality, many would

respond to 6-12 week course of antibiotics which is thought to be

anti-inflammatory; indeed, it's responsive to many anti-inflammatory

agents. Finally, the myriad of manifestations could be explained by

individual variance within the common immune active pathway -- some

with more flushing than others, some with itching, many with papules

but not everyone, etc. None of these sound like problems with food or

problems with stress management -- fair-skinned people don't differ

from others to account for these difference, for example.

But a genetic cause for the inflammation could account for all this,

some aberrant gene that now codes for a substance that goes to the

dermis of the central face and stimulates some part of the immune

sytem.

Perhaps the gene is located close enough to the genes that control

skin pigment so that the two traits would travel together most but

not all of the time. Or, the aberrant gene is present in many people,

but those with fair skin are for some reason especially sensitive to

immune aberration. The gene need not, in fact would not be expected

to follow classic Mendelian genetics. It might be inducible by other

factors, or only partially expressed. A primary immunologic disorder

also nicely accounts for the association (not causal, but observed co-

pairing) of rosacea with other immune-related disorders, many of

which are also thought to have a genetic basis.

So, that's how I would explain why the research on neuropeptides

doesn't seem to be panning out. Neuropeptides are likely involved but

may not be the primary culprit causing facial flushing, it may *not*

be that repeated dilations lead to vascular wall injury, causing

immune active substances already present in the blood to leak into

the dermis of the central face. It may be the other way around --

immune active substances already in the dermis activate NO synthase

to increase NO production and cause vasodilation, along with the

other immune responses. As a dependent rather than causal agent, NO

synthase would probably have to be completely shut down, not just

decreased as would be the case if it were more active or present in

too high amounts, as the vascular theory explains. Shutting it down

completely may be very hard to do, because of all the compensatory

mechanisms that would prevent complete breakdown of vasodilation.

I don't have nearly enough knowledge to defend this, but I know many

people favor rosacea as primarily an immunologic disorder with

thinking along this line. When I first learned about rosacea I

didn't buy it, but now, increasingly, I do. This group is

disproportionally, almost exclusively, favoring the vascular theory

so we don't talk about other mainstream medical theories much.

Marjorie

Marjorie Lazoff, MD

May 17, 2002