immune-mediated disorders, and a bit about post-infectious syndromes

May 17, 2002

Immunology is a large and complicated area of medicine that

interrelates with many other areas. So it's not surprising that a

number of immune-mediate (where the immune system contributes to the

disease) and infectious (where the immune system helps fight an anti-

microbial invasion) disorders were brought up under the immunology

umbrella. I think we're more likely to understand rosacea by

understanding immune-mediated activity rather than post-infectious

conditions, but I'll tell you what I know about both in relation to

local inflammation conditions like rosacea.

Regarding immune-mediated, one type is autoimmune disorders.

Autoimmunity is an immune response directed against an antigen within

the body. It is similar to an allergy, which is also an immune

response, but in allergies the antigen is foreign to the body and an

allergy only involves part of the immune system, the T-cells or B-

cells. One common misunderstanding and a key point: naturally

occurring autoantibodies are common in all healthy people, so the

mere presence of certain autoantibodies does not mean the person is

sick or has a disease. Even if a condition is diagnosed from blood

tests, it doesn't establish a cause-and-effect relationship, since

the autoantibodies may be the result, not the cause, of the disease

process.

I don't believe rosacea is an autoimmune disorder like some types of

thyroid disease, multiple sclerosis, or lupus but it seems to be

associated with other autoimmune disorders. The reason for the

association is not clear, but I think it's an important association

because it brings rosacea into the large family of immune-mediated

disorders.

Again regarding immune-mediated disorders, a large number of

compounds in the body stimulate or inhibit immune reactions. One

important group, cytokines, are proteins that help cells communicate

with one another and also sometimes regulate the immune system. A

complex cytokine network is involved in normal immune function, and

this network is comprised of positive and negative feedback loops

that enhance or suppress the immune (in this case, frequently

inflammatory) response. Many immune-mediated diseases (especially

connective tissue/rheumatic diseases) involve the abnormal regulation

of cytokines. Understanding how cytokines interact is a hot area for

reseach, and since they are often related to local inflammation may

ultimately prove helpful to rosaceans.

In particular, cytokines are in large part responsible for regulating

the production of groups of small molecule mediators of inflammation,

such as prostaglandins and leukotrienes. Understanding these small

immune-mediator molecules and how they relate with cytokinesis is

also a very active area of research. For example, we already know

that manipulation of prostaglandins are loosely associated with

exacerbations and remissions in some people's rosacea; for example,

it may be one of the mechanisms through which hormones affect rosacea

(although I would bet there are others).

There are also interactions between the immune system and the

neuropeptides such as NO and CRPG and all the rest that play a role

in vasodilation and pain perception. So there are ways to tie in the

vascular and pain components of rosacea, and research in those areas

may prove helpful as well.

Someone brought up scleroderma, and the unfortunate death of their

parent and concerns about having the condition themselves.

Scleroderma does show patterns of inheritance but in a very

complicated manner. Essentially, scleroderma is a multi-system

disorder involving immune activation, vascular damage, and excessive

synthesis of collagen. The cause of scleroderma seems to involve the

interplay between early immunological events and vascular changes,

inducing a population of activated fibrogenic fibroblasts that

produce the characteristic skin and inner organ changes. It's

enticing to speculate whether there are similar immunologic events in

rosacea, but they are certainly not the same vascular changes or skin

changes, and rosacea is not associated with inner organ changes, so

it's not that close a fit.

Raynaud's phenomenon is associated with scleroderma and other

connective tissue diseases, occlusive vascular disease, and some drug

effects, but as an isolated phenomenon Raynaud's is pretty common, so

most people don't have associated disorders. Raynaud's is an

exaggerated vascular response to cold temperature or emotional stress

manifest clinically by sharply demarcated color changes of the skin

of the digits, usually the fingers. As an isolated phenomenon, the

cause is abnormal local vasoconstriction regulated by the autonomic

nervous system -- so it's not immunologic-based. However, there is an

immune-mediated connection in that some people with Raynauds have

specific autoantibodies, which may or may not be related to the kinds

of immune activities found in connective tissue diseases.

All the above is pretty much distinct from the immune system's

involvement in combating infection disease. It's true that a post-

viral syndrome is often evoked to explain ongoing activity of some

part of the immune system immediately after fighting off a virus, but

most of those syndromes are very cleanly defined and have classic

symptoms. That doesn't entirely rule out other post-viral conditions,

of course, but nowadays that's a grab-bag theory that can explain any

disease or disorder. So rosacea may be a post-viral syndrome, but

from a practical perspective right now that doesn't help us

understand rosacea or anticipate a treatment plan. We need to learn

more about post-viral syndromes in general before we can relate it to

rosacea. Plus, the relationship may also be time coincidence, or it

may have to do with some other aspect of the infection unrelated to

the immune system.

I don't know what " glandular fever " refers to. I assume ME refers to

myalgic encephalitis, which historically was thought to be what they

called chronic fatigue syndrome (CFS) in the early part of the 20th

century. There is evidence of immune differences in patients with CFS

compared to healthy controls, but the importance of these changes is

unclear. These observations raise the possibility that some cases of

CFS are associated with a chronic inflammatory process (rosacea is a

chronic inflammatory condition), but the actual studies supporting

this are very inconsistent, and even when present are relatively

mild. Intuitively, I don't think that mainstream rosacea fits in well

here.

The NIH relates CFS and fibromyalgia, a common cause of chronic

musculoskeletal pain. Fibromyalgia is one of a group of soft tissue

pain disorders that affect muscles and soft tissues such as tendons

and ligaments. Importantly, neither fibromyalgia or CFS is associated

with tissue inflammation and the etiology of the pain and fatigue is

not thought to be immune-mediated. This is key: patients with

fibromyalgia and, in particular, those labeled to have chronic

fatigue syndrome, may be told or believe that their illness is caused

by an undiagnosed infection, but there's no direct evidence that

these syndromes are related to persistent infection or ongoing

immunologic abnormalities. Of course, these conditions may have begun

as a post-microbial syndrome. But I suspect the direct cause will be

found related to neurohormonal activity involving pain perception,

fatigue, abnormal sleep, and depression, since many (alas, not all)

respond to some form of therapy using tricyclic antidepressants and

serotonin reuptake inhibitors.

This is very, very confusing, heady stuff with an emphasis on

research as much or more than on clinical medicine, which explains

why I didn't go into immunology. I don't know that I have much

more to say about any of these.

I am intrigued by the whisper of immune-mediated pathology in

rosacea. I'm going to educate myself on this more, and will share

with the group anything interesting I uncover. I hope others will do

the same.

Marjorie

Marjorie Lazoff, MD

May 18, 2002

If someone's inflammatory rosacea is not responding to the usual

antibiotics at the maximum doses, and they don't want to take

accutane, and they have cultured and proven absence of gram negative

bacteria, then, it is likely an immunologic reaction creating pustules

and they should consider Dapsone, the antitiobitic with the highest

skin anti-inflammtory properties.

> Immunology is a large and complicated area of medicine that

> interrelates with many other areas. So it's not surprising that a

> number of immune-mediate (where the immune system contributes to

the

> disease) and infectious (where the immune system helps fight an

anti-

> microbial invasion) disorders were brought up under the immunology

> umbrella. I think we're more likely to understand rosacea by

> understanding immune-mediated activity rather than post-infectious

> conditions, but I'll tell you what I know about both in relation to

> local inflammation conditions like rosacea.

>

> Regarding immune-mediated, one type is autoimmune disorders.

> Autoimmunity is an immune response directed against an antigen

within

> the body. It is similar to an allergy, which is also an immune

> response, but in allergies the antigen is foreign to the body and

an

> allergy only involves part of the immune system, the T-cells or B-

> cells. One common misunderstanding and a key point: naturally

> occurring autoantibodies are common in all healthy people, so the

> mere presence of certain autoantibodies does not mean the person is

> sick or has a disease. Even if a condition is diagnosed from blood

> tests, it doesn't establish a cause-and-effect relationship, since

> the autoantibodies may be the result, not the cause, of the disease

> process.

>

> I don't believe rosacea is an autoimmune disorder like some types

of

> thyroid disease, multiple sclerosis, or lupus but it seems to be

> associated with other autoimmune disorders. The reason for the

> association is not clear, but I think it's an important association

> because it brings rosacea into the large family of immune-mediated

> disorders.

>

> Again regarding immune-mediated disorders, a large number of

> compounds in the body stimulate or inhibit immune reactions. One

> important group, cytokines, are proteins that help cells

communicate

> with one another and also sometimes regulate the immune system. A

> complex cytokine network is involved in normal immune function, and

> this network is comprised of positive and negative feedback loops

> that enhance or suppress the immune (in this case, frequently

> inflammatory) response. Many immune-mediated diseases (especially

> connective tissue/rheumatic diseases) involve the abnormal

regulation

> of cytokines. Understanding how cytokines interact is a hot area

for

> reseach, and since they are often related to local inflammation may

> ultimately prove helpful to rosaceans.

>

> In particular, cytokines are in large part responsible for

regulating

> the production of groups of small molecule mediators of

inflammation,

> such as prostaglandins and leukotrienes. Understanding these small

> immune-mediator molecules and how they relate with cytokinesis is

> also a very active area of research. For example, we already know

> that manipulation of prostaglandins are loosely associated with

> exacerbations and remissions in some people's rosacea; for example,

> it may be one of the mechanisms through which hormones affect

rosacea

> (although I would bet there are others).

>

> There are also interactions between the immune system and the

> neuropeptides such as NO and CRPG and all the rest that play a role

> in vasodilation and pain perception. So there are ways to tie in

the

> vascular and pain components of rosacea, and research in those

areas

> may prove helpful as well.

>

> Someone brought up scleroderma, and the unfortunate death of their

> parent and concerns about having the condition themselves.

> Scleroderma does show patterns of inheritance but in a very

> complicated manner. Essentially, scleroderma is a multi-system

> disorder involving immune activation, vascular damage, and

excessive

> synthesis of collagen. The cause of scleroderma seems to involve

the

> interplay between early immunological events and vascular changes,

> inducing a population of activated fibrogenic fibroblasts that

> produce the characteristic skin and inner organ changes. It's

> enticing to speculate whether there are similar immunologic events

in

> rosacea, but they are certainly not the same vascular changes or

skin

> changes, and rosacea is not associated with inner organ changes, so

> it's not that close a fit.

>

> Raynaud's phenomenon is associated with scleroderma and other

> connective tissue diseases, occlusive vascular disease, and some

drug

> effects, but as an isolated phenomenon Raynaud's is pretty common,

so

> most people don't have associated disorders. Raynaud's is an

> exaggerated vascular response to cold temperature or emotional

stress

> manifest clinically by sharply demarcated color changes of the skin

> of the digits, usually the fingers. As an isolated phenomenon, the

> cause is abnormal local vasoconstriction regulated by the autonomic

> nervous system -- so it's not immunologic-based. However, there is

an

> immune-mediated connection in that some people with Raynauds have

> specific autoantibodies, which may or may not be related to the

kinds

> of immune activities found in connective tissue diseases.

>

> All the above is pretty much distinct from the immune system's

> involvement in combating infection disease. It's true that a post-

> viral syndrome is often evoked to explain ongoing activity of some

> part of the immune system immediately after fighting off a virus,

but

> most of those syndromes are very cleanly defined and have classic

> symptoms. That doesn't entirely rule out other post-viral

conditions,

> of course, but nowadays that's a grab-bag theory that can explain

any

> disease or disorder. So rosacea may be a post-viral syndrome, but

> from a practical perspective right now that doesn't help us

> understand rosacea or anticipate a treatment plan. We need to learn

> more about post-viral syndromes in general before we can relate it

to

> rosacea. Plus, the relationship may also be time coincidence, or it

> may have to do with some other aspect of the infection unrelated to

> the immune system.

>

> I don't know what " glandular fever " refers to. I assume ME refers

to

> myalgic encephalitis, which historically was thought to be what

they

> called chronic fatigue syndrome (CFS) in the early part of the 20th

> century. There is evidence of immune differences in patients with

CFS

> compared to healthy controls, but the importance of these changes

is

> unclear. These observations raise the possibility that some cases

of

> CFS are associated with a chronic inflammatory process (rosacea is

a

> chronic inflammatory condition), but the actual studies supporting

> this are very inconsistent, and even when present are relatively

> mild. Intuitively, I don't think that mainstream rosacea fits in

well

> here.

>

> The NIH relates CFS and fibromyalgia, a common cause of chronic

> musculoskeletal pain. Fibromyalgia is one of a group of soft tissue

> pain disorders that affect muscles and soft tissues such as tendons

> and ligaments. Importantly, neither fibromyalgia or CFS is

associated

> with tissue inflammation and the etiology of the pain and fatigue

is

> not thought to be immune-mediated. This is key: patients with

> fibromyalgia and, in particular, those labeled to have chronic

> fatigue syndrome, may be told or believe that their illness is

caused

> by an undiagnosed infection, but there's no direct evidence that

> these syndromes are related to persistent infection or ongoing

> immunologic abnormalities. Of course, these conditions may have

begun

> as a post-microbial syndrome. But I suspect the direct cause will

be

> found related to neurohormonal activity involving pain perception,

> fatigue, abnormal sleep, and depression, since many (alas, not all)

> respond to some form of therapy using tricyclic antidepressants and

> serotonin reuptake inhibitors.

>

> This is very, very confusing, heady stuff with an emphasis on

> research as much or more than on clinical medicine, which explains

> why I didn't go into immunology. I don't know that I have much

> more to say about any of these.

>

> I am intrigued by the whisper of immune-mediated pathology in

> rosacea. I'm going to educate myself on this more, and will share

> with the group anything interesting I uncover. I hope others will

do

> the same.

>

> Marjorie

>

> Marjorie Lazoff, MD

May 18, 2002

If someone's inflammatory rosacea is not responding to the usual

antibiotics at the maximum doses, and they don't want to take

accutane, and they have cultured and proven absence of gram negative

bacteria, then, it is likely an immunologic reaction creating pustules

and they should consider Dapsone, the antitiobitic with the highest

skin anti-inflammtory properties.

> Immunology is a large and complicated area of medicine that

> interrelates with many other areas. So it's not surprising that a

> number of immune-mediate (where the immune system contributes to

the

> disease) and infectious (where the immune system helps fight an

anti-

> microbial invasion) disorders were brought up under the immunology

> umbrella. I think we're more likely to understand rosacea by

> understanding immune-mediated activity rather than post-infectious

> conditions, but I'll tell you what I know about both in relation to

> local inflammation conditions like rosacea.

>

> Regarding immune-mediated, one type is autoimmune disorders.

> Autoimmunity is an immune response directed against an antigen

within

> the body. It is similar to an allergy, which is also an immune

> response, but in allergies the antigen is foreign to the body and

an

> allergy only involves part of the immune system, the T-cells or B-

> cells. One common misunderstanding and a key point: naturally

> occurring autoantibodies are common in all healthy people, so the

> mere presence of certain autoantibodies does not mean the person is

> sick or has a disease. Even if a condition is diagnosed from blood

> tests, it doesn't establish a cause-and-effect relationship, since

> the autoantibodies may be the result, not the cause, of the disease

> process.

>

> I don't believe rosacea is an autoimmune disorder like some types

of

> thyroid disease, multiple sclerosis, or lupus but it seems to be

> associated with other autoimmune disorders. The reason for the

> association is not clear, but I think it's an important association

> because it brings rosacea into the large family of immune-mediated

> disorders.

>

> Again regarding immune-mediated disorders, a large number of

> compounds in the body stimulate or inhibit immune reactions. One

> important group, cytokines, are proteins that help cells

communicate

> with one another and also sometimes regulate the immune system. A

> complex cytokine network is involved in normal immune function, and

> this network is comprised of positive and negative feedback loops

> that enhance or suppress the immune (in this case, frequently

> inflammatory) response. Many immune-mediated diseases (especially

> connective tissue/rheumatic diseases) involve the abnormal

regulation

> of cytokines. Understanding how cytokines interact is a hot area

for

> reseach, and since they are often related to local inflammation may

> ultimately prove helpful to rosaceans.

>

> In particular, cytokines are in large part responsible for

regulating

> the production of groups of small molecule mediators of

inflammation,

> such as prostaglandins and leukotrienes. Understanding these small

> immune-mediator molecules and how they relate with cytokinesis is

> also a very active area of research. For example, we already know

> that manipulation of prostaglandins are loosely associated with

> exacerbations and remissions in some people's rosacea; for example,

> it may be one of the mechanisms through which hormones affect

rosacea

> (although I would bet there are others).

>

> There are also interactions between the immune system and the

> neuropeptides such as NO and CRPG and all the rest that play a role

> in vasodilation and pain perception. So there are ways to tie in

the

> vascular and pain components of rosacea, and research in those

areas

> may prove helpful as well.

>

> Someone brought up scleroderma, and the unfortunate death of their

> parent and concerns about having the condition themselves.

> Scleroderma does show patterns of inheritance but in a very

> complicated manner. Essentially, scleroderma is a multi-system

> disorder involving immune activation, vascular damage, and

excessive

> synthesis of collagen. The cause of scleroderma seems to involve

the

> interplay between early immunological events and vascular changes,

> inducing a population of activated fibrogenic fibroblasts that

> produce the characteristic skin and inner organ changes. It's

> enticing to speculate whether there are similar immunologic events

in

> rosacea, but they are certainly not the same vascular changes or

skin

> changes, and rosacea is not associated with inner organ changes, so

> it's not that close a fit.

>

> Raynaud's phenomenon is associated with scleroderma and other

> connective tissue diseases, occlusive vascular disease, and some

drug

> effects, but as an isolated phenomenon Raynaud's is pretty common,

so

> most people don't have associated disorders. Raynaud's is an

> exaggerated vascular response to cold temperature or emotional

stress

> manifest clinically by sharply demarcated color changes of the skin

> of the digits, usually the fingers. As an isolated phenomenon, the

> cause is abnormal local vasoconstriction regulated by the autonomic

> nervous system -- so it's not immunologic-based. However, there is

an

> immune-mediated connection in that some people with Raynauds have

> specific autoantibodies, which may or may not be related to the

kinds

> of immune activities found in connective tissue diseases.

>

> All the above is pretty much distinct from the immune system's

> involvement in combating infection disease. It's true that a post-

> viral syndrome is often evoked to explain ongoing activity of some

> part of the immune system immediately after fighting off a virus,

but

> most of those syndromes are very cleanly defined and have classic

> symptoms. That doesn't entirely rule out other post-viral

conditions,

> of course, but nowadays that's a grab-bag theory that can explain

any

> disease or disorder. So rosacea may be a post-viral syndrome, but

> from a practical perspective right now that doesn't help us

> understand rosacea or anticipate a treatment plan. We need to learn

> more about post-viral syndromes in general before we can relate it

to

> rosacea. Plus, the relationship may also be time coincidence, or it

> may have to do with some other aspect of the infection unrelated to

> the immune system.

>

> I don't know what " glandular fever " refers to. I assume ME refers

to

> myalgic encephalitis, which historically was thought to be what

they

> called chronic fatigue syndrome (CFS) in the early part of the 20th

> century. There is evidence of immune differences in patients with

CFS

> compared to healthy controls, but the importance of these changes

is

> unclear. These observations raise the possibility that some cases

of

> CFS are associated with a chronic inflammatory process (rosacea is

a

> chronic inflammatory condition), but the actual studies supporting

> this are very inconsistent, and even when present are relatively

> mild. Intuitively, I don't think that mainstream rosacea fits in

well

> here.

>

> The NIH relates CFS and fibromyalgia, a common cause of chronic

> musculoskeletal pain. Fibromyalgia is one of a group of soft tissue

> pain disorders that affect muscles and soft tissues such as tendons

> and ligaments. Importantly, neither fibromyalgia or CFS is

associated

> with tissue inflammation and the etiology of the pain and fatigue

is

> not thought to be immune-mediated. This is key: patients with

> fibromyalgia and, in particular, those labeled to have chronic

> fatigue syndrome, may be told or believe that their illness is

caused

> by an undiagnosed infection, but there's no direct evidence that

> these syndromes are related to persistent infection or ongoing

> immunologic abnormalities. Of course, these conditions may have

begun

> as a post-microbial syndrome. But I suspect the direct cause will

be

> found related to neurohormonal activity involving pain perception,

> fatigue, abnormal sleep, and depression, since many (alas, not all)

> respond to some form of therapy using tricyclic antidepressants and

> serotonin reuptake inhibitors.

>

> This is very, very confusing, heady stuff with an emphasis on

> research as much or more than on clinical medicine, which explains

> why I didn't go into immunology. I don't know that I have much

> more to say about any of these.

>

> I am intrigued by the whisper of immune-mediated pathology in

> rosacea. I'm going to educate myself on this more, and will share

> with the group anything interesting I uncover. I hope others will

do

> the same.

>

> Marjorie

>

> Marjorie Lazoff, MD

May 18, 2002

If someone's inflammatory rosacea is not responding to the usual

antibiotics at the maximum doses, and they don't want to take

accutane, and they have cultured and proven absence of gram negative

bacteria, then, it is likely an immunologic reaction creating pustules

and they should consider Dapsone, the antitiobitic with the highest

skin anti-inflammtory properties.

> Immunology is a large and complicated area of medicine that

> interrelates with many other areas. So it's not surprising that a

> number of immune-mediate (where the immune system contributes to

the

> disease) and infectious (where the immune system helps fight an

anti-

> microbial invasion) disorders were brought up under the immunology

> umbrella. I think we're more likely to understand rosacea by

> understanding immune-mediated activity rather than post-infectious

> conditions, but I'll tell you what I know about both in relation to

> local inflammation conditions like rosacea.

>

> Regarding immune-mediated, one type is autoimmune disorders.

> Autoimmunity is an immune response directed against an antigen

within

> the body. It is similar to an allergy, which is also an immune

> response, but in allergies the antigen is foreign to the body and

an

> allergy only involves part of the immune system, the T-cells or B-

> cells. One common misunderstanding and a key point: naturally

> occurring autoantibodies are common in all healthy people, so the

> mere presence of certain autoantibodies does not mean the person is

> sick or has a disease. Even if a condition is diagnosed from blood

> tests, it doesn't establish a cause-and-effect relationship, since

> the autoantibodies may be the result, not the cause, of the disease

> process.

>

> I don't believe rosacea is an autoimmune disorder like some types

of

> thyroid disease, multiple sclerosis, or lupus but it seems to be

> associated with other autoimmune disorders. The reason for the

> association is not clear, but I think it's an important association

> because it brings rosacea into the large family of immune-mediated

> disorders.

>

> Again regarding immune-mediated disorders, a large number of

> compounds in the body stimulate or inhibit immune reactions. One

> important group, cytokines, are proteins that help cells

communicate

> with one another and also sometimes regulate the immune system. A

> complex cytokine network is involved in normal immune function, and

> this network is comprised of positive and negative feedback loops

> that enhance or suppress the immune (in this case, frequently

> inflammatory) response. Many immune-mediated diseases (especially

> connective tissue/rheumatic diseases) involve the abnormal

regulation

> of cytokines. Understanding how cytokines interact is a hot area

for

> reseach, and since they are often related to local inflammation may

> ultimately prove helpful to rosaceans.

>

> In particular, cytokines are in large part responsible for

regulating

> the production of groups of small molecule mediators of

inflammation,

> such as prostaglandins and leukotrienes. Understanding these small

> immune-mediator molecules and how they relate with cytokinesis is

> also a very active area of research. For example, we already know

> that manipulation of prostaglandins are loosely associated with

> exacerbations and remissions in some people's rosacea; for example,

> it may be one of the mechanisms through which hormones affect

rosacea

> (although I would bet there are others).

>

> There are also interactions between the immune system and the

> neuropeptides such as NO and CRPG and all the rest that play a role

> in vasodilation and pain perception. So there are ways to tie in

the

> vascular and pain components of rosacea, and research in those

areas

> may prove helpful as well.

>

> Someone brought up scleroderma, and the unfortunate death of their

> parent and concerns about having the condition themselves.

> Scleroderma does show patterns of inheritance but in a very

> complicated manner. Essentially, scleroderma is a multi-system

> disorder involving immune activation, vascular damage, and

excessive

> synthesis of collagen. The cause of scleroderma seems to involve

the

> interplay between early immunological events and vascular changes,

> inducing a population of activated fibrogenic fibroblasts that

> produce the characteristic skin and inner organ changes. It's

> enticing to speculate whether there are similar immunologic events

in

> rosacea, but they are certainly not the same vascular changes or

skin

> changes, and rosacea is not associated with inner organ changes, so

> it's not that close a fit.

>

> Raynaud's phenomenon is associated with scleroderma and other

> connective tissue diseases, occlusive vascular disease, and some

drug

> effects, but as an isolated phenomenon Raynaud's is pretty common,

so

> most people don't have associated disorders. Raynaud's is an

> exaggerated vascular response to cold temperature or emotional

stress

> manifest clinically by sharply demarcated color changes of the skin

> of the digits, usually the fingers. As an isolated phenomenon, the

> cause is abnormal local vasoconstriction regulated by the autonomic

> nervous system -- so it's not immunologic-based. However, there is

an

> immune-mediated connection in that some people with Raynauds have

> specific autoantibodies, which may or may not be related to the

kinds

> of immune activities found in connective tissue diseases.

>

> All the above is pretty much distinct from the immune system's

> involvement in combating infection disease. It's true that a post-

> viral syndrome is often evoked to explain ongoing activity of some

> part of the immune system immediately after fighting off a virus,

but

> most of those syndromes are very cleanly defined and have classic

> symptoms. That doesn't entirely rule out other post-viral

conditions,

> of course, but nowadays that's a grab-bag theory that can explain

any

> disease or disorder. So rosacea may be a post-viral syndrome, but

> from a practical perspective right now that doesn't help us

> understand rosacea or anticipate a treatment plan. We need to learn

> more about post-viral syndromes in general before we can relate it

to

> rosacea. Plus, the relationship may also be time coincidence, or it

> may have to do with some other aspect of the infection unrelated to

> the immune system.

>

> I don't know what " glandular fever " refers to. I assume ME refers

to

> myalgic encephalitis, which historically was thought to be what

they

> called chronic fatigue syndrome (CFS) in the early part of the 20th

> century. There is evidence of immune differences in patients with

CFS

> compared to healthy controls, but the importance of these changes

is

> unclear. These observations raise the possibility that some cases

of

> CFS are associated with a chronic inflammatory process (rosacea is

a

> chronic inflammatory condition), but the actual studies supporting

> this are very inconsistent, and even when present are relatively

> mild. Intuitively, I don't think that mainstream rosacea fits in

well

> here.

>

> The NIH relates CFS and fibromyalgia, a common cause of chronic

> musculoskeletal pain. Fibromyalgia is one of a group of soft tissue

> pain disorders that affect muscles and soft tissues such as tendons

> and ligaments. Importantly, neither fibromyalgia or CFS is

associated

> with tissue inflammation and the etiology of the pain and fatigue

is

> not thought to be immune-mediated. This is key: patients with

> fibromyalgia and, in particular, those labeled to have chronic

> fatigue syndrome, may be told or believe that their illness is

caused

> by an undiagnosed infection, but there's no direct evidence that

> these syndromes are related to persistent infection or ongoing

> immunologic abnormalities. Of course, these conditions may have

begun

> as a post-microbial syndrome. But I suspect the direct cause will

be

> found related to neurohormonal activity involving pain perception,

> fatigue, abnormal sleep, and depression, since many (alas, not all)

> respond to some form of therapy using tricyclic antidepressants and

> serotonin reuptake inhibitors.

>

> This is very, very confusing, heady stuff with an emphasis on

> research as much or more than on clinical medicine, which explains

> why I didn't go into immunology. I don't know that I have much

> more to say about any of these.

>

> I am intrigued by the whisper of immune-mediated pathology in

> rosacea. I'm going to educate myself on this more, and will share

> with the group anything interesting I uncover. I hope others will

do

> the same.

>

> Marjorie

>

> Marjorie Lazoff, MD

May 18, 2002

Marjorie,

A big thank you for posting this. Many on the list have said time and

time again that they think rosacea is an immune-related disorder.

It's great to hear it from a physician!

On a somewhat related note, I read in last month's issue of

Scientific American (May '02) that researchers at Harvard believe

that Atherosclerosis (heart disease) is caused by inflammation which

causes the bad cholesterol to form in the arteries. They think there

is a gene that causes this inflammation to occur.

Here is a url to the site:

http://www.sciam.com/2002/0502issue/0502currentissue.html .

Unfortunately, you have to pay to read that particular article. If

anyone is interested, I can scan the article and post it in our files

on our site. Just let me know.

Thanks,

Matija

> Immunology is a large and complicated area of medicine that

> interrelates with many other areas. So it's not surprising that a

> number of immune-mediate (where the immune system contributes to

the

> disease) and infectious (where the immune system helps fight an

anti-

> microbial invasion) disorders were brought up under the immunology

> umbrella. I think we're more likely to understand rosacea by

> understanding immune-mediated activity rather than post-infectious

> conditions, but I'll tell you what I know about both in relation to

> local inflammation conditions like rosacea.

>

> Regarding immune-mediated, one type is autoimmune disorders.

> Autoimmunity is an immune response directed against an antigen

within

> the body. It is similar to an allergy, which is also an immune

> response, but in allergies the antigen is foreign to the body and

an

> allergy only involves part of the immune system, the T-cells or B-

> cells. One common misunderstanding and a key point: naturally

> occurring autoantibodies are common in all healthy people, so the

> mere presence of certain autoantibodies does not mean the person is

> sick or has a disease. Even if a condition is diagnosed from blood

> tests, it doesn't establish a cause-and-effect relationship, since

> the autoantibodies may be the result, not the cause, of the disease

> process.

>

> I don't believe rosacea is an autoimmune disorder like some types

of

> thyroid disease, multiple sclerosis, or lupus but it seems to be

> associated with other autoimmune disorders. The reason for the

> association is not clear, but I think it's an important association

> because it brings rosacea into the large family of immune-mediated

> disorders.

>

> Again regarding immune-mediated disorders, a large number of

> compounds in the body stimulate or inhibit immune reactions. One

> important group, cytokines, are proteins that help cells

communicate

> with one another and also sometimes regulate the immune system. A

> complex cytokine network is involved in normal immune function, and

> this network is comprised of positive and negative feedback loops

> that enhance or suppress the immune (in this case, frequently

> inflammatory) response. Many immune-mediated diseases (especially

> connective tissue/rheumatic diseases) involve the abnormal

regulation

> of cytokines. Understanding how cytokines interact is a hot area

for

> reseach, and since they are often related to local inflammation may

> ultimately prove helpful to rosaceans.

>

> In particular, cytokines are in large part responsible for

regulating

> the production of groups of small molecule mediators of

inflammation,

> such as prostaglandins and leukotrienes. Understanding these small

> immune-mediator molecules and how they relate with cytokinesis is

> also a very active area of research. For example, we already know

> that manipulation of prostaglandins are loosely associated with

> exacerbations and remissions in some people's rosacea; for example,

> it may be one of the mechanisms through which hormones affect

rosacea

> (although I would bet there are others).

>

> There are also interactions between the immune system and the

> neuropeptides such as NO and CRPG and all the rest that play a role

> in vasodilation and pain perception. So there are ways to tie in

the

> vascular and pain components of rosacea, and research in those

areas

> may prove helpful as well.

>

> Someone brought up scleroderma, and the unfortunate death of their

> parent and concerns about having the condition themselves.

> Scleroderma does show patterns of inheritance but in a very

> complicated manner. Essentially, scleroderma is a multi-system

> disorder involving immune activation, vascular damage, and

excessive

> synthesis of collagen. The cause of scleroderma seems to involve

the

> interplay between early immunological events and vascular changes,

> inducing a population of activated fibrogenic fibroblasts that

> produce the characteristic skin and inner organ changes. It's

> enticing to speculate whether there are similar immunologic events

in

> rosacea, but they are certainly not the same vascular changes or

skin

> changes, and rosacea is not associated with inner organ changes, so

> it's not that close a fit.

>

> Raynaud's phenomenon is associated with scleroderma and other

> connective tissue diseases, occlusive vascular disease, and some

drug

> effects, but as an isolated phenomenon Raynaud's is pretty common,

so

> most people don't have associated disorders. Raynaud's is an

> exaggerated vascular response to cold temperature or emotional

stress

> manifest clinically by sharply demarcated color changes of the skin

> of the digits, usually the fingers. As an isolated phenomenon, the

> cause is abnormal local vasoconstriction regulated by the autonomic

> nervous system -- so it's not immunologic-based. However, there is

an

> immune-mediated connection in that some people with Raynauds have

> specific autoantibodies, which may or may not be related to the

kinds

> of immune activities found in connective tissue diseases.

>

> All the above is pretty much distinct from the immune system's

> involvement in combating infection disease. It's true that a post-

> viral syndrome is often evoked to explain ongoing activity of some

> part of the immune system immediately after fighting off a virus,

but

> most of those syndromes are very cleanly defined and have classic

> symptoms. That doesn't entirely rule out other post-viral

conditions,

> of course, but nowadays that's a grab-bag theory that can explain

any

> disease or disorder. So rosacea may be a post-viral syndrome, but

> from a practical perspective right now that doesn't help us

> understand rosacea or anticipate a treatment plan. We need to learn

> more about post-viral syndromes in general before we can relate it

to

> rosacea. Plus, the relationship may also be time coincidence, or it

> may have to do with some other aspect of the infection unrelated to

> the immune system.

>

> I don't know what " glandular fever " refers to. I assume ME refers

to

> myalgic encephalitis, which historically was thought to be what

they

> called chronic fatigue syndrome (CFS) in the early part of the 20th

> century. There is evidence of immune differences in patients with

CFS

> compared to healthy controls, but the importance of these changes

is

> unclear. These observations raise the possibility that some cases

of

> CFS are associated with a chronic inflammatory process (rosacea is

a

> chronic inflammatory condition), but the actual studies supporting

> this are very inconsistent, and even when present are relatively

> mild. Intuitively, I don't think that mainstream rosacea fits in

well

> here.

>

> The NIH relates CFS and fibromyalgia, a common cause of chronic

> musculoskeletal pain. Fibromyalgia is one of a group of soft tissue

> pain disorders that affect muscles and soft tissues such as tendons

> and ligaments. Importantly, neither fibromyalgia or CFS is

associated

> with tissue inflammation and the etiology of the pain and fatigue

is

> not thought to be immune-mediated. This is key: patients with

> fibromyalgia and, in particular, those labeled to have chronic

> fatigue syndrome, may be told or believe that their illness is

caused

> by an undiagnosed infection, but there's no direct evidence that

> these syndromes are related to persistent infection or ongoing

> immunologic abnormalities. Of course, these conditions may have

begun

> as a post-microbial syndrome. But I suspect the direct cause will

be

> found related to neurohormonal activity involving pain perception,

> fatigue, abnormal sleep, and depression, since many (alas, not all)

> respond to some form of therapy using tricyclic antidepressants and

> serotonin reuptake inhibitors.

>

> This is very, very confusing, heady stuff with an emphasis on

> research as much or more than on clinical medicine, which explains

> why I didn't go into immunology. I don't know that I have much

> more to say about any of these.

>

> I am intrigued by the whisper of immune-mediated pathology in

> rosacea. I'm going to educate myself on this more, and will share

> with the group anything interesting I uncover. I hope others will

do

> the same.

>

> Marjorie

>

> Marjorie Lazoff, MD

May 18, 2002

Marjorie,

A big thank you for posting this. Many on the list have said time and

time again that they think rosacea is an immune-related disorder.

It's great to hear it from a physician!

On a somewhat related note, I read in last month's issue of

Scientific American (May '02) that researchers at Harvard believe

that Atherosclerosis (heart disease) is caused by inflammation which

causes the bad cholesterol to form in the arteries. They think there

is a gene that causes this inflammation to occur.

Here is a url to the site:

http://www.sciam.com/2002/0502issue/0502currentissue.html .

Unfortunately, you have to pay to read that particular article. If

anyone is interested, I can scan the article and post it in our files

on our site. Just let me know.

Thanks,

Matija

> Immunology is a large and complicated area of medicine that

> interrelates with many other areas. So it's not surprising that a

> number of immune-mediate (where the immune system contributes to

the

> disease) and infectious (where the immune system helps fight an

anti-

> microbial invasion) disorders were brought up under the immunology

> umbrella. I think we're more likely to understand rosacea by

> understanding immune-mediated activity rather than post-infectious

> conditions, but I'll tell you what I know about both in relation to

> local inflammation conditions like rosacea.

>

> Regarding immune-mediated, one type is autoimmune disorders.

> Autoimmunity is an immune response directed against an antigen

within

> the body. It is similar to an allergy, which is also an immune

> response, but in allergies the antigen is foreign to the body and

an

> allergy only involves part of the immune system, the T-cells or B-

> cells. One common misunderstanding and a key point: naturally

> occurring autoantibodies are common in all healthy people, so the

> mere presence of certain autoantibodies does not mean the person is

> sick or has a disease. Even if a condition is diagnosed from blood

> tests, it doesn't establish a cause-and-effect relationship, since

> the autoantibodies may be the result, not the cause, of the disease

> process.

>

> I don't believe rosacea is an autoimmune disorder like some types

of

> thyroid disease, multiple sclerosis, or lupus but it seems to be

> associated with other autoimmune disorders. The reason for the

> association is not clear, but I think it's an important association

> because it brings rosacea into the large family of immune-mediated

> disorders.

>

> Again regarding immune-mediated disorders, a large number of

> compounds in the body stimulate or inhibit immune reactions. One

> important group, cytokines, are proteins that help cells

communicate

> with one another and also sometimes regulate the immune system. A

> complex cytokine network is involved in normal immune function, and

> this network is comprised of positive and negative feedback loops

> that enhance or suppress the immune (in this case, frequently

> inflammatory) response. Many immune-mediated diseases (especially

> connective tissue/rheumatic diseases) involve the abnormal

regulation

> of cytokines. Understanding how cytokines interact is a hot area

for

> reseach, and since they are often related to local inflammation may

> ultimately prove helpful to rosaceans.

>

> In particular, cytokines are in large part responsible for

regulating

> the production of groups of small molecule mediators of

inflammation,

> such as prostaglandins and leukotrienes. Understanding these small

> immune-mediator molecules and how they relate with cytokinesis is

> also a very active area of research. For example, we already know

> that manipulation of prostaglandins are loosely associated with

> exacerbations and remissions in some people's rosacea; for example,

> it may be one of the mechanisms through which hormones affect

rosacea

> (although I would bet there are others).

>

> There are also interactions between the immune system and the

> neuropeptides such as NO and CRPG and all the rest that play a role

> in vasodilation and pain perception. So there are ways to tie in

the

> vascular and pain components of rosacea, and research in those

areas

> may prove helpful as well.

>

> Someone brought up scleroderma, and the unfortunate death of their

> parent and concerns about having the condition themselves.

> Scleroderma does show patterns of inheritance but in a very

> complicated manner. Essentially, scleroderma is a multi-system

> disorder involving immune activation, vascular damage, and

excessive

> synthesis of collagen. The cause of scleroderma seems to involve

the

> interplay between early immunological events and vascular changes,

> inducing a population of activated fibrogenic fibroblasts that

> produce the characteristic skin and inner organ changes. It's

> enticing to speculate whether there are similar immunologic events

in

> rosacea, but they are certainly not the same vascular changes or

skin

> changes, and rosacea is not associated with inner organ changes, so

> it's not that close a fit.

>

> Raynaud's phenomenon is associated with scleroderma and other

> connective tissue diseases, occlusive vascular disease, and some

drug

> effects, but as an isolated phenomenon Raynaud's is pretty common,

so

> most people don't have associated disorders. Raynaud's is an

> exaggerated vascular response to cold temperature or emotional

stress

> manifest clinically by sharply demarcated color changes of the skin

> of the digits, usually the fingers. As an isolated phenomenon, the

> cause is abnormal local vasoconstriction regulated by the autonomic

> nervous system -- so it's not immunologic-based. However, there is

an

> immune-mediated connection in that some people with Raynauds have

> specific autoantibodies, which may or may not be related to the

kinds

> of immune activities found in connective tissue diseases.

>

> All the above is pretty much distinct from the immune system's

> involvement in combating infection disease. It's true that a post-

> viral syndrome is often evoked to explain ongoing activity of some

> part of the immune system immediately after fighting off a virus,

but

> most of those syndromes are very cleanly defined and have classic

> symptoms. That doesn't entirely rule out other post-viral

conditions,

> of course, but nowadays that's a grab-bag theory that can explain

any

> disease or disorder. So rosacea may be a post-viral syndrome, but

> from a practical perspective right now that doesn't help us

> understand rosacea or anticipate a treatment plan. We need to learn

> more about post-viral syndromes in general before we can relate it

to

> rosacea. Plus, the relationship may also be time coincidence, or it

> may have to do with some other aspect of the infection unrelated to

> the immune system.

>

> I don't know what " glandular fever " refers to. I assume ME refers

to

> myalgic encephalitis, which historically was thought to be what

they

> called chronic fatigue syndrome (CFS) in the early part of the 20th

> century. There is evidence of immune differences in patients with

CFS

> compared to healthy controls, but the importance of these changes

is

> unclear. These observations raise the possibility that some cases

of

> CFS are associated with a chronic inflammatory process (rosacea is

a

> chronic inflammatory condition), but the actual studies supporting

> this are very inconsistent, and even when present are relatively

> mild. Intuitively, I don't think that mainstream rosacea fits in

well

> here.

>

> The NIH relates CFS and fibromyalgia, a common cause of chronic

> musculoskeletal pain. Fibromyalgia is one of a group of soft tissue

> pain disorders that affect muscles and soft tissues such as tendons

> and ligaments. Importantly, neither fibromyalgia or CFS is

associated

> with tissue inflammation and the etiology of the pain and fatigue

is

> not thought to be immune-mediated. This is key: patients with

> fibromyalgia and, in particular, those labeled to have chronic

> fatigue syndrome, may be told or believe that their illness is

caused

> by an undiagnosed infection, but there's no direct evidence that

> these syndromes are related to persistent infection or ongoing

> immunologic abnormalities. Of course, these conditions may have

begun

> as a post-microbial syndrome. But I suspect the direct cause will

be

> found related to neurohormonal activity involving pain perception,

> fatigue, abnormal sleep, and depression, since many (alas, not all)

> respond to some form of therapy using tricyclic antidepressants and

> serotonin reuptake inhibitors.

>

> This is very, very confusing, heady stuff with an emphasis on

> research as much or more than on clinical medicine, which explains

> why I didn't go into immunology. I don't know that I have much

> more to say about any of these.

>

> I am intrigued by the whisper of immune-mediated pathology in

> rosacea. I'm going to educate myself on this more, and will share

> with the group anything interesting I uncover. I hope others will

do

> the same.

>

> Marjorie

>

> Marjorie Lazoff, MD

May 18, 2002

Marjorie,

A big thank you for posting this. Many on the list have said time and

time again that they think rosacea is an immune-related disorder.

It's great to hear it from a physician!

On a somewhat related note, I read in last month's issue of

Scientific American (May '02) that researchers at Harvard believe

that Atherosclerosis (heart disease) is caused by inflammation which

causes the bad cholesterol to form in the arteries. They think there

is a gene that causes this inflammation to occur.

Here is a url to the site:

http://www.sciam.com/2002/0502issue/0502currentissue.html .

Unfortunately, you have to pay to read that particular article. If

anyone is interested, I can scan the article and post it in our files

on our site. Just let me know.

Thanks,

Matija

> Immunology is a large and complicated area of medicine that

> interrelates with many other areas. So it's not surprising that a

> number of immune-mediate (where the immune system contributes to

the

> disease) and infectious (where the immune system helps fight an

anti-

> microbial invasion) disorders were brought up under the immunology

> umbrella. I think we're more likely to understand rosacea by

> understanding immune-mediated activity rather than post-infectious

> conditions, but I'll tell you what I know about both in relation to

> local inflammation conditions like rosacea.

>

> Regarding immune-mediated, one type is autoimmune disorders.

> Autoimmunity is an immune response directed against an antigen

within

> the body. It is similar to an allergy, which is also an immune

> response, but in allergies the antigen is foreign to the body and

an

> allergy only involves part of the immune system, the T-cells or B-

> cells. One common misunderstanding and a key point: naturally

> occurring autoantibodies are common in all healthy people, so the

> mere presence of certain autoantibodies does not mean the person is

> sick or has a disease. Even if a condition is diagnosed from blood

> tests, it doesn't establish a cause-and-effect relationship, since

> the autoantibodies may be the result, not the cause, of the disease

> process.

>

> I don't believe rosacea is an autoimmune disorder like some types

of

> thyroid disease, multiple sclerosis, or lupus but it seems to be

> associated with other autoimmune disorders. The reason for the

> association is not clear, but I think it's an important association

> because it brings rosacea into the large family of immune-mediated

> disorders.

>

> Again regarding immune-mediated disorders, a large number of

> compounds in the body stimulate or inhibit immune reactions. One

> important group, cytokines, are proteins that help cells

communicate

> with one another and also sometimes regulate the immune system. A

> complex cytokine network is involved in normal immune function, and

> this network is comprised of positive and negative feedback loops

> that enhance or suppress the immune (in this case, frequently

> inflammatory) response. Many immune-mediated diseases (especially

> connective tissue/rheumatic diseases) involve the abnormal

regulation

> of cytokines. Understanding how cytokines interact is a hot area

for

> reseach, and since they are often related to local inflammation may

> ultimately prove helpful to rosaceans.

>

> In particular, cytokines are in large part responsible for

regulating

> the production of groups of small molecule mediators of

inflammation,

> such as prostaglandins and leukotrienes. Understanding these small

> immune-mediator molecules and how they relate with cytokinesis is

> also a very active area of research. For example, we already know

> that manipulation of prostaglandins are loosely associated with

> exacerbations and remissions in some people's rosacea; for example,

> it may be one of the mechanisms through which hormones affect

rosacea

> (although I would bet there are others).

>

> There are also interactions between the immune system and the

> neuropeptides such as NO and CRPG and all the rest that play a role

> in vasodilation and pain perception. So there are ways to tie in

the

> vascular and pain components of rosacea, and research in those

areas

> may prove helpful as well.

>

> Someone brought up scleroderma, and the unfortunate death of their

> parent and concerns about having the condition themselves.

> Scleroderma does show patterns of inheritance but in a very

> complicated manner. Essentially, scleroderma is a multi-system

> disorder involving immune activation, vascular damage, and

excessive

> synthesis of collagen. The cause of scleroderma seems to involve

the

> interplay between early immunological events and vascular changes,

> inducing a population of activated fibrogenic fibroblasts that

> produce the characteristic skin and inner organ changes. It's

> enticing to speculate whether there are similar immunologic events

in

> rosacea, but they are certainly not the same vascular changes or

skin

> changes, and rosacea is not associated with inner organ changes, so

> it's not that close a fit.

>

> Raynaud's phenomenon is associated with scleroderma and other

> connective tissue diseases, occlusive vascular disease, and some

drug

> effects, but as an isolated phenomenon Raynaud's is pretty common,

so

> most people don't have associated disorders. Raynaud's is an

> exaggerated vascular response to cold temperature or emotional

stress

> manifest clinically by sharply demarcated color changes of the skin

> of the digits, usually the fingers. As an isolated phenomenon, the

> cause is abnormal local vasoconstriction regulated by the autonomic

> nervous system -- so it's not immunologic-based. However, there is

an

> immune-mediated connection in that some people with Raynauds have

> specific autoantibodies, which may or may not be related to the

kinds

> of immune activities found in connective tissue diseases.

>

> All the above is pretty much distinct from the immune system's

> involvement in combating infection disease. It's true that a post-

> viral syndrome is often evoked to explain ongoing activity of some

> part of the immune system immediately after fighting off a virus,

but

> most of those syndromes are very cleanly defined and have classic

> symptoms. That doesn't entirely rule out other post-viral

conditions,

> of course, but nowadays that's a grab-bag theory that can explain

any

> disease or disorder. So rosacea may be a post-viral syndrome, but

> from a practical perspective right now that doesn't help us

> understand rosacea or anticipate a treatment plan. We need to learn

> more about post-viral syndromes in general before we can relate it

to

> rosacea. Plus, the relationship may also be time coincidence, or it

> may have to do with some other aspect of the infection unrelated to

> the immune system.

>

> I don't know what " glandular fever " refers to. I assume ME refers

to

> myalgic encephalitis, which historically was thought to be what

they

> called chronic fatigue syndrome (CFS) in the early part of the 20th

> century. There is evidence of immune differences in patients with

CFS

> compared to healthy controls, but the importance of these changes

is

> unclear. These observations raise the possibility that some cases

of

> CFS are associated with a chronic inflammatory process (rosacea is

a

> chronic inflammatory condition), but the actual studies supporting

> this are very inconsistent, and even when present are relatively

> mild. Intuitively, I don't think that mainstream rosacea fits in

well

> here.

>

> The NIH relates CFS and fibromyalgia, a common cause of chronic

> musculoskeletal pain. Fibromyalgia is one of a group of soft tissue

> pain disorders that affect muscles and soft tissues such as tendons

> and ligaments. Importantly, neither fibromyalgia or CFS is

associated

> with tissue inflammation and the etiology of the pain and fatigue

is

> not thought to be immune-mediated. This is key: patients with

> fibromyalgia and, in particular, those labeled to have chronic

> fatigue syndrome, may be told or believe that their illness is

caused

> by an undiagnosed infection, but there's no direct evidence that

> these syndromes are related to persistent infection or ongoing

> immunologic abnormalities. Of course, these conditions may have

begun

> as a post-microbial syndrome. But I suspect the direct cause will

be

> found related to neurohormonal activity involving pain perception,

> fatigue, abnormal sleep, and depression, since many (alas, not all)

> respond to some form of therapy using tricyclic antidepressants and

> serotonin reuptake inhibitors.

>

> This is very, very confusing, heady stuff with an emphasis on

> research as much or more than on clinical medicine, which explains

> why I didn't go into immunology. I don't know that I have much

> more to say about any of these.

>

> I am intrigued by the whisper of immune-mediated pathology in

> rosacea. I'm going to educate myself on this more, and will share

> with the group anything interesting I uncover. I hope others will

do

> the same.

>

> Marjorie

>

> Marjorie Lazoff, MD

May 18, 2002

You're welcome, Matija.

There's been lots of talk about the inflammatory nature of

atherosclerosis, which is related not only to heart disease but to

stroke and peripheral vascular disease as well. I'm not aware of any

genetic research related to this, but I suppose we're going to be

hearing a lot about genes over the coming decade.

I would be interested in reading the article. I love the Scientific

American graphics, so if you can scan those too, that would be

wonderful.

Marjorie

Marjorie Lazoff, MD

> > Immunology is a large and complicated area of medicine that

> > interrelates with many other areas. So it's not surprising that a

> > number of immune-mediate (where the immune system contributes to

> the

> > disease) and infectious (where the immune system helps fight an

> anti-

> > microbial invasion) disorders were brought up under the

immunology

> > umbrella. I think we're more likely to understand rosacea by

> > understanding immune-mediated activity rather than post-

infectious

> > conditions, but I'll tell you what I know about both in relation

to

> > local inflammation conditions like rosacea.

> >

> > Regarding immune-mediated, one type is autoimmune disorders.

> > Autoimmunity is an immune response directed against an antigen

> within

> > the body. It is similar to an allergy, which is also an immune

> > response, but in allergies the antigen is foreign to the body and

> an

> > allergy only involves part of the immune system, the T-cells or B-

> > cells. One common misunderstanding and a key point: naturally

> > occurring autoantibodies are common in all healthy people, so the

> > mere presence of certain autoantibodies does not mean the person

is

> > sick or has a disease. Even if a condition is diagnosed from

blood

> > tests, it doesn't establish a cause-and-effect relationship,

since

> > the autoantibodies may be the result, not the cause, of the

disease

> > process.

> >

> > I don't believe rosacea is an autoimmune disorder like some types

> of

> > thyroid disease, multiple sclerosis, or lupus but it seems to be

> > associated with other autoimmune disorders. The reason for the

> > association is not clear, but I think it's an important

association

> > because it brings rosacea into the large family of immune-

mediated

> > disorders.

> >

> > Again regarding immune-mediated disorders, a large number of

> > compounds in the body stimulate or inhibit immune reactions. One

> > important group, cytokines, are proteins that help cells

> communicate

> > with one another and also sometimes regulate the immune system. A

> > complex cytokine network is involved in normal immune function,

and

> > this network is comprised of positive and negative feedback loops

> > that enhance or suppress the immune (in this case, frequently

> > inflammatory) response. Many immune-mediated diseases (especially

> > connective tissue/rheumatic diseases) involve the abnormal

> regulation

> > of cytokines. Understanding how cytokines interact is a hot area

> for

> > reseach, and since they are often related to local inflammation

may

> > ultimately prove helpful to rosaceans.

> >

> > In particular, cytokines are in large part responsible for

> regulating

> > the production of groups of small molecule mediators of

> inflammation,

> > such as prostaglandins and leukotrienes. Understanding these

small

> > immune-mediator molecules and how they relate with cytokinesis is

> > also a very active area of research. For example, we already know

> > that manipulation of prostaglandins are loosely associated with

> > exacerbations and remissions in some people's rosacea; for

example,

> > it may be one of the mechanisms through which hormones affect

> rosacea

> > (although I would bet there are others).

> >

> > There are also interactions between the immune system and the

> > neuropeptides such as NO and CRPG and all the rest that play a

role

> > in vasodilation and pain perception. So there are ways to tie in

> the

> > vascular and pain components of rosacea, and research in those

> areas

> > may prove helpful as well.

> >

> > Someone brought up scleroderma, and the unfortunate death of

their

> > parent and concerns about having the condition themselves.

> > Scleroderma does show patterns of inheritance but in a very

> > complicated manner. Essentially, scleroderma is a multi-system

> > disorder involving immune activation, vascular damage, and

> excessive

> > synthesis of collagen. The cause of scleroderma seems to involve

> the

> > interplay between early immunological events and vascular

changes,

> > inducing a population of activated fibrogenic fibroblasts that

> > produce the characteristic skin and inner organ changes. It's

> > enticing to speculate whether there are similar immunologic

events

> in

> > rosacea, but they are certainly not the same vascular changes or

> skin

> > changes, and rosacea is not associated with inner organ changes,

so

> > it's not that close a fit.

> >

> > Raynaud's phenomenon is associated with scleroderma and other

> > connective tissue diseases, occlusive vascular disease, and some

> drug

> > effects, but as an isolated phenomenon Raynaud's is pretty

common,

> so

> > most people don't have associated disorders. Raynaud's is an

> > exaggerated vascular response to cold temperature or emotional

> stress

> > manifest clinically by sharply demarcated color changes of the

skin

> > of the digits, usually the fingers. As an isolated phenomenon,

the

> > cause is abnormal local vasoconstriction regulated by the

autonomic

> > nervous system -- so it's not immunologic-based. However, there

is

> an

> > immune-mediated connection in that some people with Raynauds have

> > specific autoantibodies, which may or may not be related to the

> kinds

> > of immune activities found in connective tissue diseases.

> >

> > All the above is pretty much distinct from the immune system's

> > involvement in combating infection disease. It's true that a post-

> > viral syndrome is often evoked to explain ongoing activity of

some

> > part of the immune system immediately after fighting off a virus,

> but

> > most of those syndromes are very cleanly defined and have classic

> > symptoms. That doesn't entirely rule out other post-viral

> conditions,

> > of course, but nowadays that's a grab-bag theory that can explain

> any

> > disease or disorder. So rosacea may be a post-viral syndrome,

but

> > from a practical perspective right now that doesn't help us

> > understand rosacea or anticipate a treatment plan. We need to

learn

> > more about post-viral syndromes in general before we can relate

it

> to

> > rosacea. Plus, the relationship may also be time coincidence, or

it

> > may have to do with some other aspect of the infection unrelated

to

> > the immune system.

> >

> > I don't know what " glandular fever " refers to. I assume ME refers

> to

> > myalgic encephalitis, which historically was thought to be what

> they

> > called chronic fatigue syndrome (CFS) in the early part of the

20th

> > century. There is evidence of immune differences in patients with

> CFS

> > compared to healthy controls, but the importance of these changes

> is

> > unclear. These observations raise the possibility that some cases

> of

> > CFS are associated with a chronic inflammatory process (rosacea

is

> a

> > chronic inflammatory condition), but the actual studies

supporting

> > this are very inconsistent, and even when present are relatively

> > mild. Intuitively, I don't think that mainstream rosacea fits in

> well

> > here.

> >

> > The NIH relates CFS and fibromyalgia, a common cause of chronic

> > musculoskeletal pain. Fibromyalgia is one of a group of soft

tissue

> > pain disorders that affect muscles and soft tissues such as

tendons

> > and ligaments. Importantly, neither fibromyalgia or CFS is

> associated

> > with tissue inflammation and the etiology of the pain and fatigue

> is

> > not thought to be immune-mediated. This is key: patients with

> > fibromyalgia and, in particular, those labeled to have chronic

> > fatigue syndrome, may be told or believe that their illness is

> caused

> > by an undiagnosed infection, but there's no direct evidence that

> > these syndromes are related to persistent infection or ongoing

> > immunologic abnormalities. Of course, these conditions may have

> begun

> > as a post-microbial syndrome. But I suspect the direct cause will

> be

> > found related to neurohormonal activity involving pain

perception,

> > fatigue, abnormal sleep, and depression, since many (alas, not

all)

> > respond to some form of therapy using tricyclic antidepressants

and

> > serotonin reuptake inhibitors.

> >

> > This is very, very confusing, heady stuff with an emphasis on

> > research as much or more than on clinical medicine, which

explains

> > why I didn't go into immunology. I don't know that I have

much

> > more to say about any of these.

> >

> > I am intrigued by the whisper of immune-mediated pathology in

> > rosacea. I'm going to educate myself on this more, and will share

> > with the group anything interesting I uncover. I hope others will

> do

> > the same.

> >

> > Marjorie

> >

> > Marjorie Lazoff, MD

May 18, 2002

You're welcome, Matija.

There's been lots of talk about the inflammatory nature of

atherosclerosis, which is related not only to heart disease but to

stroke and peripheral vascular disease as well. I'm not aware of any

genetic research related to this, but I suppose we're going to be

hearing a lot about genes over the coming decade.

I would be interested in reading the article. I love the Scientific

American graphics, so if you can scan those too, that would be

wonderful.

Marjorie

Marjorie Lazoff, MD

> > Immunology is a large and complicated area of medicine that

> > interrelates with many other areas. So it's not surprising that a

> > number of immune-mediate (where the immune system contributes to

> the

> > disease) and infectious (where the immune system helps fight an

> anti-

> > microbial invasion) disorders were brought up under the

immunology

> > umbrella. I think we're more likely to understand rosacea by

> > understanding immune-mediated activity rather than post-

infectious

> > conditions, but I'll tell you what I know about both in relation

to

> > local inflammation conditions like rosacea.

> >

> > Regarding immune-mediated, one type is autoimmune disorders.

> > Autoimmunity is an immune response directed against an antigen

> within

> > the body. It is similar to an allergy, which is also an immune

> > response, but in allergies the antigen is foreign to the body and

> an

> > allergy only involves part of the immune system, the T-cells or B-

> > cells. One common misunderstanding and a key point: naturally

> > occurring autoantibodies are common in all healthy people, so the

> > mere presence of certain autoantibodies does not mean the person

is

> > sick or has a disease. Even if a condition is diagnosed from

blood

> > tests, it doesn't establish a cause-and-effect relationship,

since

> > the autoantibodies may be the result, not the cause, of the

disease

> > process.

> >

> > I don't believe rosacea is an autoimmune disorder like some types

> of

> > thyroid disease, multiple sclerosis, or lupus but it seems to be

> > associated with other autoimmune disorders. The reason for the

> > association is not clear, but I think it's an important

association

> > because it brings rosacea into the large family of immune-

mediated

> > disorders.

> >

> > Again regarding immune-mediated disorders, a large number of

> > compounds in the body stimulate or inhibit immune reactions. One

> > important group, cytokines, are proteins that help cells

> communicate

> > with one another and also sometimes regulate the immune system. A

> > complex cytokine network is involved in normal immune function,

and

> > this network is comprised of positive and negative feedback loops

> > that enhance or suppress the immune (in this case, frequently

> > inflammatory) response. Many immune-mediated diseases (especially

> > connective tissue/rheumatic diseases) involve the abnormal

> regulation

> > of cytokines. Understanding how cytokines interact is a hot area

> for

> > reseach, and since they are often related to local inflammation

may

> > ultimately prove helpful to rosaceans.

> >

> > In particular, cytokines are in large part responsible for

> regulating

> > the production of groups of small molecule mediators of

> inflammation,

> > such as prostaglandins and leukotrienes. Understanding these

small

> > immune-mediator molecules and how they relate with cytokinesis is

> > also a very active area of research. For example, we already know

> > that manipulation of prostaglandins are loosely associated with

> > exacerbations and remissions in some people's rosacea; for

example,

> > it may be one of the mechanisms through which hormones affect

> rosacea

> > (although I would bet there are others).

> >

> > There are also interactions between the immune system and the

> > neuropeptides such as NO and CRPG and all the rest that play a

role

> > in vasodilation and pain perception. So there are ways to tie in

> the

> > vascular and pain components of rosacea, and research in those

> areas

> > may prove helpful as well.

> >

> > Someone brought up scleroderma, and the unfortunate death of

their

> > parent and concerns about having the condition themselves.

> > Scleroderma does show patterns of inheritance but in a very

> > complicated manner. Essentially, scleroderma is a multi-system

> > disorder involving immune activation, vascular damage, and

> excessive

> > synthesis of collagen. The cause of scleroderma seems to involve

> the

> > interplay between early immunological events and vascular

changes,

> > inducing a population of activated fibrogenic fibroblasts that

> > produce the characteristic skin and inner organ changes. It's

> > enticing to speculate whether there are similar immunologic

events

> in

> > rosacea, but they are certainly not the same vascular changes or

> skin

> > changes, and rosacea is not associated with inner organ changes,

so

> > it's not that close a fit.

> >

> > Raynaud's phenomenon is associated with scleroderma and other

> > connective tissue diseases, occlusive vascular disease, and some

> drug

> > effects, but as an isolated phenomenon Raynaud's is pretty

common,

> so

> > most people don't have associated disorders. Raynaud's is an

> > exaggerated vascular response to cold temperature or emotional

> stress

> > manifest clinically by sharply demarcated color changes of the

skin

> > of the digits, usually the fingers. As an isolated phenomenon,

the

> > cause is abnormal local vasoconstriction regulated by the

autonomic

> > nervous system -- so it's not immunologic-based. However, there

is

> an

> > immune-mediated connection in that some people with Raynauds have

> > specific autoantibodies, which may or may not be related to the

> kinds

> > of immune activities found in connective tissue diseases.

> >

> > All the above is pretty much distinct from the immune system's

> > involvement in combating infection disease. It's true that a post-

> > viral syndrome is often evoked to explain ongoing activity of

some

> > part of the immune system immediately after fighting off a virus,

> but

> > most of those syndromes are very cleanly defined and have classic

> > symptoms. That doesn't entirely rule out other post-viral

> conditions,

> > of course, but nowadays that's a grab-bag theory that can explain

> any

> > disease or disorder. So rosacea may be a post-viral syndrome,

but

> > from a practical perspective right now that doesn't help us

> > understand rosacea or anticipate a treatment plan. We need to

learn

> > more about post-viral syndromes in general before we can relate

it

> to

> > rosacea. Plus, the relationship may also be time coincidence, or

it

> > may have to do with some other aspect of the infection unrelated

to

> > the immune system.

> >

> > I don't know what " glandular fever " refers to. I assume ME refers

> to

> > myalgic encephalitis, which historically was thought to be what

> they

> > called chronic fatigue syndrome (CFS) in the early part of the

20th

> > century. There is evidence of immune differences in patients with

> CFS

> > compared to healthy controls, but the importance of these changes

> is

> > unclear. These observations raise the possibility that some cases

> of

> > CFS are associated with a chronic inflammatory process (rosacea

is

> a

> > chronic inflammatory condition), but the actual studies

supporting

> > this are very inconsistent, and even when present are relatively

> > mild. Intuitively, I don't think that mainstream rosacea fits in

> well

> > here.

> >

> > The NIH relates CFS and fibromyalgia, a common cause of chronic

> > musculoskeletal pain. Fibromyalgia is one of a group of soft

tissue

> > pain disorders that affect muscles and soft tissues such as

tendons

> > and ligaments. Importantly, neither fibromyalgia or CFS is

> associated

> > with tissue inflammation and the etiology of the pain and fatigue

> is

> > not thought to be immune-mediated. This is key: patients with

> > fibromyalgia and, in particular, those labeled to have chronic

> > fatigue syndrome, may be told or believe that their illness is

> caused

> > by an undiagnosed infection, but there's no direct evidence that

> > these syndromes are related to persistent infection or ongoing

> > immunologic abnormalities. Of course, these conditions may have

> begun

> > as a post-microbial syndrome. But I suspect the direct cause will

> be

> > found related to neurohormonal activity involving pain

perception,

> > fatigue, abnormal sleep, and depression, since many (alas, not

all)

> > respond to some form of therapy using tricyclic antidepressants

and

> > serotonin reuptake inhibitors.

> >

> > This is very, very confusing, heady stuff with an emphasis on

> > research as much or more than on clinical medicine, which

explains

> > why I didn't go into immunology. I don't know that I have

much

> > more to say about any of these.

> >

> > I am intrigued by the whisper of immune-mediated pathology in

> > rosacea. I'm going to educate myself on this more, and will share

> > with the group anything interesting I uncover. I hope others will

> do

> > the same.

> >

> > Marjorie

> >

> > Marjorie Lazoff, MD

May 18, 2002

You're welcome, Matija.

There's been lots of talk about the inflammatory nature of

atherosclerosis, which is related not only to heart disease but to

stroke and peripheral vascular disease as well. I'm not aware of any

genetic research related to this, but I suppose we're going to be

hearing a lot about genes over the coming decade.

I would be interested in reading the article. I love the Scientific

American graphics, so if you can scan those too, that would be

wonderful.

Marjorie

Marjorie Lazoff, MD

> > Immunology is a large and complicated area of medicine that

> > interrelates with many other areas. So it's not surprising that a

> > number of immune-mediate (where the immune system contributes to

> the

> > disease) and infectious (where the immune system helps fight an

> anti-

> > microbial invasion) disorders were brought up under the

immunology

> > umbrella. I think we're more likely to understand rosacea by

> > understanding immune-mediated activity rather than post-

infectious

> > conditions, but I'll tell you what I know about both in relation

to

> > local inflammation conditions like rosacea.

> >

> > Regarding immune-mediated, one type is autoimmune disorders.

> > Autoimmunity is an immune response directed against an antigen

> within

> > the body. It is similar to an allergy, which is also an immune

> > response, but in allergies the antigen is foreign to the body and

> an

> > allergy only involves part of the immune system, the T-cells or B-

> > cells. One common misunderstanding and a key point: naturally

> > occurring autoantibodies are common in all healthy people, so the

> > mere presence of certain autoantibodies does not mean the person

is

> > sick or has a disease. Even if a condition is diagnosed from

blood

> > tests, it doesn't establish a cause-and-effect relationship,

since

> > the autoantibodies may be the result, not the cause, of the

disease

> > process.

> >

> > I don't believe rosacea is an autoimmune disorder like some types

> of

> > thyroid disease, multiple sclerosis, or lupus but it seems to be

> > associated with other autoimmune disorders. The reason for the

> > association is not clear, but I think it's an important

association

> > because it brings rosacea into the large family of immune-

mediated

> > disorders.

> >

> > Again regarding immune-mediated disorders, a large number of

> > compounds in the body stimulate or inhibit immune reactions. One

> > important group, cytokines, are proteins that help cells

> communicate

> > with one another and also sometimes regulate the immune system. A

> > complex cytokine network is involved in normal immune function,

and

> > this network is comprised of positive and negative feedback loops

> > that enhance or suppress the immune (in this case, frequently

> > inflammatory) response. Many immune-mediated diseases (especially

> > connective tissue/rheumatic diseases) involve the abnormal

> regulation

> > of cytokines. Understanding how cytokines interact is a hot area

> for

> > reseach, and since they are often related to local inflammation

may

> > ultimately prove helpful to rosaceans.

> >

> > In particular, cytokines are in large part responsible for

> regulating

> > the production of groups of small molecule mediators of

> inflammation,

> > such as prostaglandins and leukotrienes. Understanding these

small

> > immune-mediator molecules and how they relate with cytokinesis is

> > also a very active area of research. For example, we already know

> > that manipulation of prostaglandins are loosely associated with

> > exacerbations and remissions in some people's rosacea; for

example,

> > it may be one of the mechanisms through which hormones affect

> rosacea

> > (although I would bet there are others).

> >

> > There are also interactions between the immune system and the

> > neuropeptides such as NO and CRPG and all the rest that play a

role

> > in vasodilation and pain perception. So there are ways to tie in

> the

> > vascular and pain components of rosacea, and research in those

> areas

> > may prove helpful as well.

> >

> > Someone brought up scleroderma, and the unfortunate death of

their

> > parent and concerns about having the condition themselves.

> > Scleroderma does show patterns of inheritance but in a very

> > complicated manner. Essentially, scleroderma is a multi-system

> > disorder involving immune activation, vascular damage, and

> excessive

> > synthesis of collagen. The cause of scleroderma seems to involve

> the

> > interplay between early immunological events and vascular

changes,

> > inducing a population of activated fibrogenic fibroblasts that

> > produce the characteristic skin and inner organ changes. It's

> > enticing to speculate whether there are similar immunologic

events

> in

> > rosacea, but they are certainly not the same vascular changes or

> skin

> > changes, and rosacea is not associated with inner organ changes,

so

> > it's not that close a fit.

> >

> > Raynaud's phenomenon is associated with scleroderma and other

> > connective tissue diseases, occlusive vascular disease, and some

> drug

> > effects, but as an isolated phenomenon Raynaud's is pretty

common,

> so

> > most people don't have associated disorders. Raynaud's is an

> > exaggerated vascular response to cold temperature or emotional

> stress

> > manifest clinically by sharply demarcated color changes of the

skin

> > of the digits, usually the fingers. As an isolated phenomenon,

the

> > cause is abnormal local vasoconstriction regulated by the

autonomic

> > nervous system -- so it's not immunologic-based. However, there

is

> an

> > immune-mediated connection in that some people with Raynauds have

> > specific autoantibodies, which may or may not be related to the

> kinds

> > of immune activities found in connective tissue diseases.

> >

> > All the above is pretty much distinct from the immune system's

> > involvement in combating infection disease. It's true that a post-

> > viral syndrome is often evoked to explain ongoing activity of

some

> > part of the immune system immediately after fighting off a virus,

> but

> > most of those syndromes are very cleanly defined and have classic

> > symptoms. That doesn't entirely rule out other post-viral

> conditions,

> > of course, but nowadays that's a grab-bag theory that can explain

> any

> > disease or disorder. So rosacea may be a post-viral syndrome,

but

> > from a practical perspective right now that doesn't help us

> > understand rosacea or anticipate a treatment plan. We need to

learn

> > more about post-viral syndromes in general before we can relate

it

> to

> > rosacea. Plus, the relationship may also be time coincidence, or

it

> > may have to do with some other aspect of the infection unrelated

to

> > the immune system.

> >

> > I don't know what " glandular fever " refers to. I assume ME refers

> to

> > myalgic encephalitis, which historically was thought to be what

> they

> > called chronic fatigue syndrome (CFS) in the early part of the

20th

> > century. There is evidence of immune differences in patients with

> CFS

> > compared to healthy controls, but the importance of these changes

> is

> > unclear. These observations raise the possibility that some cases

> of

> > CFS are associated with a chronic inflammatory process (rosacea

is

> a

> > chronic inflammatory condition), but the actual studies

supporting

> > this are very inconsistent, and even when present are relatively

> > mild. Intuitively, I don't think that mainstream rosacea fits in

> well

> > here.

> >

> > The NIH relates CFS and fibromyalgia, a common cause of chronic

> > musculoskeletal pain. Fibromyalgia is one of a group of soft

tissue

> > pain disorders that affect muscles and soft tissues such as

tendons

> > and ligaments. Importantly, neither fibromyalgia or CFS is

> associated

> > with tissue inflammation and the etiology of the pain and fatigue

> is

> > not thought to be immune-mediated. This is key: patients with

> > fibromyalgia and, in particular, those labeled to have chronic

> > fatigue syndrome, may be told or believe that their illness is

> caused

> > by an undiagnosed infection, but there's no direct evidence that

> > these syndromes are related to persistent infection or ongoing

> > immunologic abnormalities. Of course, these conditions may have

> begun

> > as a post-microbial syndrome. But I suspect the direct cause will

> be

> > found related to neurohormonal activity involving pain

perception,

> > fatigue, abnormal sleep, and depression, since many (alas, not

all)

> > respond to some form of therapy using tricyclic antidepressants

and

> > serotonin reuptake inhibitors.

> >

> > This is very, very confusing, heady stuff with an emphasis on

> > research as much or more than on clinical medicine, which

explains

> > why I didn't go into immunology. I don't know that I have

much

> > more to say about any of these.

> >

> > I am intrigued by the whisper of immune-mediated pathology in

> > rosacea. I'm going to educate myself on this more, and will share

> > with the group anything interesting I uncover. I hope others will

> do

> > the same.

> >

> > Marjorie

> >

> > Marjorie Lazoff, MD

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