Update on Clinical Management and Pathophysiology of Scleroderma

1. Subsets of Scleroderma
2. Antibody Associations
3. Management
4. Questions and Answers

Stephen Paget, MD: It is a real pleasure today to introduce Virginia Steen to you, who is a tenured professor at Georgetown University and has over the last many years offered to us most of our concepts about scleroderma as a systemic disorder, as a disorder of epithelial and vascular fibrotic changes, and also has been involved in most of the recent studies of penicillamine, Relaxin and other medications to try to affect the change of this illness. She is thought of an expert in this area and has continued her research, and it is a pleasure to have her here today.

Virginia Steen, MD: Thank you. I am very pleased to have gotten here. The last time I flew I got stuck in the airport for five hours with thunderstorms; so I'm glad we made it. We are going to talk today primarily about the clinical aspects because that is my area of expertise. But I would like to start with where we stand right now with the pathophysiology.

We know that the fibroblasts make an excessive amount of collagen and that there is a host of factors are stimulating the fibroblasts to make an excessive amount of collagen. We know the endothelial cell is involved, and there probably are factors in relationship there as well. We know that there probably are some genetic factors involved, particularly with the recent information from the Oklahoma Choctaw Indians, and a gene has been found but it is not clear whether that is the central factor.

We know that there are autoantibodies involved, , but they do not seem to have any direct relationship to the pathogenesis. They clearly seem to be more markers and are really the primary focus of where the genetic relationship is as far as HLA.

What we don't know, of course, is the initiating factor. We would like to think that it is some sort of environmental toxin because there are several other diseases that are scleroderma-like that are caused by such things, but in several epidemiological studies, there really is very little hint of a uniform etiology. Certainly it is possible, with the numerous autoantibodies, that there may be a specific different environmental or toxic relationship to different subsets of scleroderma patients.

Subsets of Scleroderma

One of the most important things that we need to understand is that there is a vast spectrum of patients with scleroderma and that we divide them into two major subsets. First of all, the limited scleroderma, which is the old CREST syndrome. Those patients have Raynaud's phenomena for years before they develop anything else. They'll get puffy fingers, and then they will have a minimal amount of joint and constitutional symptoms and their skin stays limited. It often doesn't even show up until 5 or 10 years after the onset of Raynaud's.

On the other hand, the diffuse scleroderma patients have a much more acute onset and lots of constitutional symptoms, arthralgias, and carpal tunnel syndrome; they have swollen hands, not just fingers, but whole swollen hands and legs and, consequently, they often go to many other doctors before they get to a rheumatologist because of the swollen legs. Their Raynaud's is often delayed. When you first see them they may not even have Raynaud's. The skin thickening starts at the fingers and works it way up through the arms and onto the trunk, and this whole thing happens within a relatively short time, usually within a couple of years, in contrast to the long duration characteristic of patients with limited scleroderma.

One physical examination finding, the tendon friction rubs that are distributed most frequently on the wrist, palm, and ankles, is a very specific finding for diffuse scleroderma for scleroderma in general. Friction rubs can be found in patients who don't have any skin thickening. They can just have very swollen, puffy hands or legs, and it can be very helpful early on in the disease in sorting out whether the patient is going to evolve to diffuse or limited scleroderma.

The organ system involvement in the two major subsets is important in the pulmonary fibrosis aspect. There really isn't any significant difference between limited and diffuse, although the diffuse tend to have more severe disease. With GI involvement, both of the esophagus and the small intestines, there is really no difference between the two groups, they are identical as far as their frequency and severity.

On the other hand, with pulmonary hypertension, isolated pulmonary vasculopathy type of hypertension occurs almost only in limited, and sclerodermal renal crisis occurs almost only in diffuse. Cardiac involvement occurs in both types of patients, with predominance in diffuse.

The natural history of these two, as I alluded to, is quite different. In limited scleroderma we see slowly developing skin involvement of long duration and then, after many, many years, malabsorption and pulmonary hypertension. In diffuse scleroderma, it is a much more acute onset -- lots of skin thickening early on and lots of internal organ involvement early on and stabilization, and then the question of how much, but some spontaneous improvement in skin.

This is from a study that I did looking at the timing of the onset of severe involvement. This is renal crisis, cardiomyopathy, arrhythmia, and pulmonary fibrosis with about less than 55%. Then we saw GI with hyperalimentation or pseudoobstruction and a skin score that was greater than 40. in the first three years of diffuse scleroderma patients. The vast majority of those people who are going to get these findings, anywhere from 60 to 80% of them, are going to get it within the first three years. Later, at 6 and 9 years, there are people that get these complications, but the frequency is much less.

This is the survival here. You can see that, when you look at limited scleroderma from the time of the first Pittsburgh visit (and often times these are referrals and they are very sick), there still is a significant improvement in survival from the limited to the diffuse. If you take this same group of people only including patients who have two years of symptoms or less, obviously that is a very small group; we only have about 150 of those patients in the limited group. The difference is even greater when you take that from their first symptoms. So clearly the limited scleroderma patients overall have an outcome that is better, but some of their complications are just as bad if not worse.

Antibody Associations

These are the autoantibodies that I have spent a lot of time studying, because I think they really are very helpful in sorting out the different subsets. Unfortunately a lot of them are still not available. They are still research tools but when at least some of them are available, I think it is going to be helpful. Just starting over here is the limited group, those with anticentromere antibody, very few males, limited disease. Lots of the classical calcinosis and telangiectasias and then pulmonary hypertension.

Anti RNA polymerase-3, the overlap with myositis is interesting, with lots of calcinosis that might be related to their myositis, and they also interestingly have a lot of tuft resorption, which I hadn't realized -- the typical mixed connective disease with the typical findings. Anti-U3RNP is also a nucleolar antibody seen in high frequency in African Americans and in young; actually in Pittsburgh, we have a very small African American population, and I think we only had about 6% in our data base. And I now have about 23% in my Georgetown data base. So I am seeing an awful lot of these patients. They have both pulmonary fibrosis and pulmonary hypertension. I have an abstract showing that the pulmonary hypertension, that's the vasculopathy type of pulmonary hypertension, unlike the centromere patients, is associated with some pulmonary fibrosis. So it is really a bit confusing, but the degree of pulmonary hypertension is out of proportion to the degree of pulmonary fibros, and they also can get kidney disease. It may very well be, at least in my hypothesis, that one of the reasons that the African Americans have such severe disease in scleroderma is not so much the socioeconomic difference but because they have such a high proportion of this autoantibody that is associated with severe disease.

The Scl-70 is typically mostly in patients with diffuse disease, although there are some limited. Tuft resorption, ulcers, lots of pulmonary fibrosis--all over the world, this has been associated with pulmonary fibrosis. And the RNA polymerase 3 is almost exclusively associated with diffuse disease. Not much muscle disease. Not much lung, but lots of skin, most severe skin in our database and 25% of those patients will have renal crisis. So particularly when this assay becomes available, because it can give a speckled antinuclear antibody or really can be any pattern so trying to guess with an antinuclear antibody test alone is not helpful. There is not a lot of overlap here, but when the specific test is available identifying that population of patients, I think identifying them will be helped by knowing what autoantibody they have.

Management

Physical therapy consists of the typical "use it or lose it." A lot of people still do not order and insist on really aggressive--both active and passive--physical and occupational therapy, and I can't prove to you and I haven't figured out how to do a study (do you only use one hand?), but if you don't exercise you are going to lose your function and you can't get it back.

So all throughout the very early stages of the illness we really work very hard with the therapist to do very aggressive flexion and extension, particularly in the upper extremities, but, depending on severity, other joints as well. We use nonsteroidals. We use very low doses of steroids and we also use adequate analgesia, because if they have a lot of pain they are not going to exercise.

Moving on to the management of severe Raynaud's. I think we are all pretty comfortable with the usual calcium channel blockers, but when you have someone who has a severe ulceration and you are trying to optimize everything, you need to maximize the dose of calcium channel. You also need to do Doppler blood flow studies, particularly looking for some larger vessel disease. I remember my first patient, when I moved to the Washington area; Mike had a patient with ulnar blockage. That has been reported in several papers recently and can happen in scleroderma.

We do sympathetic blocks for maximum vasodilatation and pain, but my plastic surgeon does it through the hand rather than systemically. Another important thing is to control the pain with narcotics. Do not worry about whether they are going to become addicted. At this point your main goal is that they don't have a circle of pain and more spasm. Treat the infections. Local management of typical wound care with soaks and antibiotic and occlusive dressings.

Our plastic surgeons are doing digital sympathectomies, not just blocks but carefully peeling off all of the sympathetic fibers. There really have been some dramatic improvements in individual ulcers, much faster than usual, after this procedure. We have not done, I have not done an inter arterial injection for years, and the Iloprost and prostacyclin-here is not available, although in Europe they are using a lot of that for control.-- We have done studies on IV Iloprost, and it really seems to work very well, but it doesn't seem to be going to come to fruition here.

The GI involvement, I think, develops because of other GI problems, but we certainly have benefited from the use of proton pump inhibitors in esophagitis. Our hypomotility problems are major now that Propulsid has been withdrawn. Our patients are not happy at all. Metaclopromide is just as not as good, it has a lot of side effects, and the company has not been very sympathetic. So I am not quite sure what we are going to do.

Some of the worst problems come from pseudoobstruction and malabsorption. I use a lot of antibiotics for bacterial overgrowth. I don't go through the craziness of trying to prove that malabsorption is bacterial overgrowth because I don't think there is a reliable method. I think people all have bacterial overgrowth in our disease. But using a variety of broad spectrum agents, Flagyl, Cipro, the old tetracycline and ampicillin as well, and di it in what I call it a creative way-- every day, every other day, two weeks on, two weeks off, three weeks on, one week off, whatever you can do to try to get control of the diarrhea.

Sometimes we use hyperalimentation to improve the nutritional status of the patients so that the bowel can now begin to work again. That works sometimes and buys us some time, and often the patients are able to come off the hyperalimentation and at least have a time where they don't have a lot of problems.

Another problem in the limited form of scleroderma is the large bowel involvement with severe constipation and obstipation, managed with all the regimens that you can come up with. There is no easy remedy. We use a lot of lactulose as a supplement here. Perforation, although it can occur, is rare but it's often missed, and you need to remember that a lot of these problems with the intestines are not associated with a severe pain; so don't just assume that if somebody has a lot of pain that it is just related to their scleroderma GI problem. And rectal problems have become a major difficulty for a lot of limited scleroderma patients. They have rectal prolapse but also have lots of seepage of stool, that they are very embarrassed about, which they describe as being diarrhea. So you have to make sure that you carefully question them as to whether they really have diarrhea or whether they are just losing some stool. The old Kegel exercises and official biofeedback that some rectal physicians do can be helpful in those circumstances.

Severe dysphagia,--fortunately, is not nearly as much a problem as we used to haveThe first thing we have to make sure it is not proximal dysphagia; there are patients who have proximal dysphagia more like myositis; many of them have overlap with not so much of myositis but of myopathy, the noninflammatory type of myopathy, and they do get some proximal involvement. Obviously, the proton pump inhibitors. I always like at that point to do a barium swallow or cinesophogram, mostly to look at whether there is a stricture or a severe dysmotility. I am not convinced that the GI people can do that with a scope, and so I like to see for myself which of these is the major problem. Often times, though, there is a complication of candida esophagitis; so the endoscopy is necessary and then you treat as you need to.

Moving on to the lung. Over the last 20 years, we have had a significant decrease in death from renal crisis, and we have had an increase in the frequency of pulmonary fibrosis. I'm sure all of you have noticed that these patients are increasingly becoming a problem. In addition to pulmonary fibrosis, we have some pleural effusions and pleural disease, a lot more pleural scarring than any actual symptoms. We can get bronchiectasis and spontaneous pneumothoraces in patients who have severe fibrosis and then other problems, including aspiration pneumonia and malignancy, need to be considered when you are evaluating someone with pulmonary involvement in scleroderma.

This is from a study in which we looked at patients with severe fibrosis, vital capacity of less than 55% of predicted. Patients who died had had a mean duration of scleroderma of almost ten years, but they only had symptoms for five years. So one might look at this data and say they didn't get their scleroderma lung disease and symptoms until late in their illness right before they died. But in reality when you look at that group of patients or a similar group of patients with severe fibrosis--we had 76 who had serial PFTs, at least two in the first four years--and you can see that the vast majority of loss in the vital capacity occurred in the first four years of the illness in spite of the fact that the symptomatic shortness of breath didn't occur late.

Often times, patients have vital capacities of 60 to 65%. They are not symptomatic, and then two years later their vital capacity is 60% and they are terribly symptomatic. So there is a threshold that is very important to recognize because you often can't go on one set of pulmonary function tests later in the course to know whether it is active disease or not.

Over the years we have been trying to define what is "active disease" in alveolitis. This is the original BAL data from five different centers. There was really pretty much of a gemish of increased cells, but there was no question that there was increased cellularity, and as it has turned out, the neutrophils are the predominant cell with the eosinophils complicating the issue.

Rick Silver's data. Compares the patients who had a normal BAL to those who had active alveolitis; the patients with alveolitis had more dyspnea, a lower vital capacity, a lower DLCO and a more progression of their pulmonary function tests over the next few years than those with the normal BAL.

This is the other technique that we have been using, because of the problem with doing BALs, particularly in the community. And it is really not so much that they don't know how to do the BAL and do the fluid, but their technicians don't know how to read the macrophages; so you get the slide that says there are 85% polys in the BAL and it doesn't help very much. So we used high resolution CT scans, and this haziness here called 'ground glass appearance,' which is particularly at the periphery and the bases but can be anywhere in the lung, has been shown to correlate with the development of fibrosis and with the progression of the disease and response to treatment. So we have been able to use this as a marker. What has happened over the last ten years is that Cytoxan has become the favorite treatment. Rick Silver and I were doing similar time periods (his was prospective and mine was retrospective), and we both came up with the same data: the group with Cytoxan had significant improvement in their vital capacity over the first two years of treatment. This is unlike high dose prednisone, unlike other immunosuppressive agents, unlike D-penicillamine, and unlike those that weren't treated. This was all retrospective. No blindding, no control, no nothing.

Then, over the long term, again only the Cytoxan group had a significant improvement over the five year time period, with a vital capacity going from 50 to 60%, in contrast to the other groups. There now are probably 10 different studies that have shown at least some response to Cytoxan. The most recent one was Barbara White's, and she didn't have as much improvement but she had a lot of stabilization in her patients, and the thing she had which most of us haven't had is a group of untreated patients with alveolitis. This was not blinded, not controlled. These were, for one reason or another, people who didn't get treated even though they had alveolitis and none of those people improved or stabilized.

So we now have a multicenter, placebo-controlled, NIH funded, Cytoxan study which has been very hard to recruit for, and we have changed some of the criteria to open it up a lot. But if you have any patients with scleroderma that you think might have active alveolitis, I think probably the closest center is Dr. Seibold in New Jersey. I don't think there is anybody in New York doing it.

We will move on to look at what the DLCO meant. This study was precipitated by lots of physicians who felt that the DLCO was the precursor of severe pulmonary fibrosis and who were being very aggressive in treating with a lot of strong drugs, patients who had isolated decrease in vital capacity. That wasn't my experience; so I looked at a group of 73 patients who had normal vital capacities but a decreased DLCO and then, on followup almost five years later, they still had a normal vital capacity and actually their DLCOs improved. But when you look at the patterns they had, more than half of them either remained with the DLCO reduction or became normal. The other half had changes in their pattern. There were about a quarter who developed restrictive disease but only two of the 20 patients ,or 2 out of the 73 people, developed a vital capacity of less than 55% or what I use as severe fibrosis. Some of them developed obstructive disease, and most of those were smokers.

The interesting thing was that there was a significant increase in the frequency of the isolated pulmonary hypertension. This number is for the whole group. If you only look at those patients who had limited scleroderma, it is up to 20%; so that we know that the limited scleroderma patients are the most likely to get the pulmonary hypertension and this looks like it's a predictive factor. This is the kind of pulmonary hypertension I am talking about with the severe, noninflammatory, thickened intimal proliferation without a lot of fibrosis.

This was an early study that we did looking at a small group of pulmonary hypertension patients. Their mean DLCO at the time of pulmonary hypertension was 39%; 65% of them had less than 45. We are talking about a low DLCO, with similar amounts of fibrosis and a similar degree of vital capacity changes.

This is echocardiograms. Anywhere from a third to 64% of patients who have elevated PA pressures on echo. We don't see that kind of frequency of this severe, deadly type of pulmonary hypertension. So I haven't been quite sure how to interpret this data, but I am a little concerned that people are going to find out that they have a little bit of elevation in their PA pressures and go off the deep end thinking they are going to die of this pulmonary hypertension.

So I did a study which looked at 106 pulmonary hypertension cases and matched controls, all since about 1985 so they could have calcium channel blockers, matched them for age, type of scleroderma, disease onset, disease duration, the mean date of the first visit. And in these 42 patients who developed pulmonary hypertension after their first visit ,we matched them to that time factor, we call it a matching time and we designated a similar matching time for the controls. We looked at both the DLCO and the PA echo pressures prior to the development of the pulmonary hypertension. In the cases, the mean DLCO about five years before was 52% of predicted in contrast to the controls in whom it was 81% of predicted, whereas the PA Pressure was 34 versus 29 which was not significant although there was a trend.

So I have been very impressed and insistent that the DLCO makes a major difference. This was a small group of patients on whom we had serial DLCOs dating back from 15 years prior to the diagnosis. I think you can see that that group of patients had decreased DLCO each five year time period where as the non PHT patients had stabilization. So this is the group that is going to get pulmonary hypertension, and this is the group that we need to focus on as far as treatment goes. This is the survival, and this is why we have to do something with this group of patients, because, until recently, these patients all died.

I'm skipping around here. This is another technique, which I think will be very helpful. These are stress echos. This is an interesting paper with inherited primary pulmonary hypertension in which they now know what the gene is, and so they took asymptomatic patients from relatives who had the gene and they did stress echos. Of the 14 patients who had a normal resting PA pressure, but a high PA pressure with exercise, all fourteen had the gene, whereas in the patients who had the normal exercise there were only two. So this may very well be a better technique, and we are looking at it in our patients.

The treatment of this in the past few years. as you know. has been helped by the development by the use of continuous infusion of Prostacyclin; this is the improvement in the 6 minute walk time in these patients. But recently there has been a new drug that is an endothelial receptor blocker and potent vasoconstrictor. The effect in the pulmonary vessels, the vasoconstriction, depends on the size of the vessels, and it seems that the size of the vessels that are involved, and are particularly affected by experimental PHT, are associated with the increased endothelia, as well as correlating with the PVR in primary pulmonary hypertension patients, and in scleroderma. As of my abstract this year, endothelin 1 is increased. This drug (which is in the fast track by the FDA and I believe that their review is September 9th) results in a significant improvement walk time in comparison to the placebo group, that had a deterioration in the walk time.

So this is really a very exciting, good drug, not only because it improved walk time, it improved cardiac index, decreased arterial pressure, vascular resistance, but the most important thing is that it is a pill twice a day that only causes an occasional headache. So it is really well tolerated. It is obviously too soon to know about survival. These studies were only four months in duration but certainly, the increased walk time -- we are excited about this.

Lung cancer is an important thing in patients with severe fibrosis. Often times patients will come in with more symptoms, with pleural effusions, with changes on their chest x-ray, and everybody just attributes that to more fibrosis, but this is increased epidemiologically in our patients. Again it is most often in long-standing patients with severe fibrosis in both limited and diffuse, rarely if ever in centromere patients, because they don't get a lot of fibrosis. Cancer usually presents as an acute deterioration, although we have found patients that have cancer by doing a high resolution CT scan. It's not the best study, but when you are doing that, looking for problems, you sometimes see the tumor. It can be all types. Most of it is unrelated to smoking, and like all lung cancers, survival is bad. But the key thing here is to look for it and to think about it.

Heart disease: as I mentioned, cardiomyopathy is most frequent in diffuse scleroderma. Arrhythmia is common in both groups, but the diffuse tends to be more of the severe ventricular problems and the limited tends to be more conduction defects and atrial problems. We don't know what causes these other than that there are fibrotic changes and there are some ischemic changes, particularly exercise and cold-induced changes, but we don't know where the defect in the heart is, and that makes it difficult because none of the vessels are really significantly involved. Treatment of all of these, at this point, really is just treatment of the manifestations, and we depend on the cardiologist to give us a hint with that.

Moving on to our success story, at this point, with renal crisis. I don't think I need to go through this in this group--severe malignant hypertension, rapidly progressive creatinine. Often, even after the blood pressure is controlled, the creatinine continues to go up. Almost half the patients will have a microangiopathic hemolytic anemia and thrombocytopenia, and since I have been at Georgetown, there have been three obvious scleroderma patients who have been transferred to Georgetown because they have "TPP" and the doctors in the other hospitals didn't even look at the patient to see that they had scleroderma.

Congestive heart failure and pericardial effusions are common both before the onset, as well as at the time of crisis. The predictive factors of renal crisis: we have known for a while that it is early diffuse scleroderma with rapidly progressive skin disease, lots of anemia, not necessarily microangiopathic anemia but just anemia in general, new cardiac events. I told you about the polymerase-3 antibodies and we will talk about this in a minute. But surprisingly, the blood pressure, the creatinine, even the pathology and the anti-Scl 70 do not predict the development of it.

Interestingly in a recent study that I've done, 1.6% of people have an unexplained serum creatinine who haven't had renal crisis. As far as steroids, when I did a case control of the renal crisis patients, and this again was because of the un-supported stories that high dose steroids cause renal crisis, I must say that, through my early years in this disease, I really thought that was just because people were sick and they got higher dose steroids. It took me quite a few years to figure out how to do this study. So we matched people for reasons of developing renal crisis and reasons for receiving high dose steroids, whether it is skin score, tendon rubs, or muscle involvement, and they were very closely matched.

We looked at the frequency of high dose steroids in the six months prior to the development of renal crisis or prior to the development of the first visit in the controls (since we use very little steroids in our patients we felt that we had to use the control at their first visit). I think you can see the cases have three times the amount, at the ratio of almost three, in comparison to the controls, a figure which was statistically significant. Now I am not saying that high dose steroid cause it. I'm not saying that you can't ever use high dose steroids. I'm just saying, please, be very cautious. Don't use it cavalierly. The most common cause for the use of steroids in this group of patients was "because they had scleroderma and they had swollen hands" and they were just immediately given 60 mg of Prednisone. None of these cases were given steroids because of severe lung involvement.

This is the outcome with ACE inhibitors, which has made such a major difference in our treatment of this complication. It has really dramatically changed. This is the original study which has been expanded to more than 150 now. But the frequency of good outcome is almost identical. The patients with good outcomes--more than half of them have a good outcome. Some of them don't ever have dialysis. Some of them have temporary dialysis and still, even with the 150 treated, there is a greater percentage of those who come off dialysis within the next 18 months. I think I am finally convincing some of the nephrologists that that actually happens.

We still have a significant amount of early deaths. Most of these are because the patients aren't started early. They are not identified as having renal crisis. They are started on the wrong medication, w. But we have to continue to work better and identify patients at risk and get them started earlier.

This is the outcome, as you see this group that went on to dialysis, they came off of dialysis and five years later or ten years later, they still have very good creatinine. Only 6% of the patients that were either on no dialysis or temporary dialysis have had over the next ten years to go onto dialysis at a later time. The survival in this group is very close to the survival of scleroderma diffuse patients.

Questions and Answers

Question: Dr. Steen you mentioned the success of Cytoxan early in the study. What kind of systemic problems are in those patients who have been treated with Cytoxan and had such good results?

Virginia Steen, MD: Those are primarily for lung involvement. So the outcome for survival is also very good, despite some poor outcome and persistent dialysis patients. I think if we are very aggressive with treatment and catch them early on that we can do very well. I might point out one more thing, that in the past year I have had ten patients treated with angiotensin receptor blockers (ARBS) who have not faired well at all and, again, I have an abstract about this that describes how either they were started on it and it didn't control, the patients were switched to it and they lost control ,and a couple of patients it was added and they had to go on to dialysis. So be careful with the ARBS.

There is my unexplained BUN and creatinine that, in 669 patients followed for over ten years, was very very small. Don't just assume that an elevated creatinine is due to scleroderma. If they haven't had renal crisis, you have to look carefully to make sure there are no other causes for that creatinine.

Okay, moving on to the potpourri of different medications that have been used in this disease. Gerry Rodnan used to say " no drug has been proven ineffective until its been tried in scleroderma". We've looked at a variety of things that have been looked at before but, unfortunately, we still do not have any significant treatment.

These are the recent clinical trials that have been done. We'll start at the bottom. Methotrexate; one-year trial, no significant difference in cutaneous manifestations. Photopheresis, one year study, no difference. This is Relaxin, the first study, the six-month study where it was very exciting that there was a significant difference just at 6 months. As you know, in the repeat study with three times as many patients, there was absolutely no difference in any of the groups. The penicillamine study was completed a couple of years ago. Both groups improved but there was no difference. There was a little bit of a problem in this study as far as I'm concerned, and I guess you know that I am a proponent of penicillamine, but half of the people withdrew from this study. The people withdrew from the treatment group, withdrew because of toxicity, and the people that withdrew, many of them withdrew from the placebo because of a failure to respond.

The people that they were left with, I think that you can see have milder disease than some of these other studies, and some of their improvement occurred early even at three and six months. In contrast to our patients--this was retrospectively looked at during the same time period, the same criteria--we had 49 patients who had two skin scores. Our mean first skin score was 29 in comparison to 20. At the end of six months most of our patients had an increase in their skin score going from 29 to 33, where the study didn't have anything. But it's two years, our patients went from a skin score to 18 which was a 37% decrease, and two-thirds had greater than 25%. I think that's quite a bit different.

When I look at all of our patients in the last ten years, two-thirds of my patients have had a 50% improvement by two years in their skin thickening and they have had improved survival compared to our other patients. This is not controlled. It's anecdotal and it doesn't stand for anything according to most people, but if there is that good a result with those patients, treating them very early, I am just a little concerned about throwing that out completely.

This is what is going on now. I am sure you are familiar with the thalidomide study at Rockefeller. I have not seen any objective data. I have seen some laboratory and some immunological data, but the best I have heard from Dr. Oliver is that the hair grows back on the arms. This is an oral collagen study by; there are six centers or seven centers around the country. People are very excited about this. I think it's only because it's one of the main ones available now. The original preliminary data was not exciting to me, but they did get it funded by NIH and we're gung-ho for anything that can get funded.

Minocycline. I'm sure you heard the controversy about it. It's based on 11 patients, 6 of whom completed a year of the drug and four of whom were "cured." And then the bone marrow transplant issue. Dan Furst actually presented at the National Scleroderma Foundation meeting this weekend, and it is going to be very, very hard to interpret that data because, yes, he took very sick people, but not all sick people die, and he is talking about doing a controlled trial with high dose Cytoxan as the control arm for the bone marrow transplant.

Other things that have been looked at and sometimes used, cyclosporine. I looked at FK-506, and it works great, except the toxicity is unmanageable. Enbrel (I'm sure Remicade is back there, too), but Enbrel had a group of patients, I think it was 12 or 15; there were some that responded -- not dramatic. Again, interferon has been used and is still being looked at-- pretty wide spectrum of responses, but I suppose it is still in the game plan. Halofuginone is a thing they put in chicken feed. People are working with this, trying to get FDA approval to look at that. I haven't heard very much about PUVA recently. The photophoresis people were trying to say that was helpful for a while, and I have only seen this in the literature.

So we keep working and even if we haven't managed to make a major effect on the disease as a whole, we have certainly done a lot for the different manifestations, and we are all geared up and ready to come up with the right drug. And I hope I have convinced you that it is not a hopeless disease. Thank you.

Question: Ginny, nice talk. I have two questions. One is that Steve had mentioned that we are not seeing a lot of new scleroderma, but I have seen actually several patients of a type that you didn't describe. They come in very much undifferentiated connective tissue disease, arthritis, rash, fevers, things like that. Most of them have been anti-Ro positive and, over two to three years, turn into scleroderma. That has puzzled me because I haven't heard that discussed. That was the first question and second, what do you think about Lee Nelson's work?

Virginia Steen, MD: The first one is easier to answer. Somewhere between 5 and 10% of the patients who have anti-Ro, and they are mostly limited disease patients who have Sjögren's like symptoms, and we have very few patients that have had fevers. We have some, but they have really mostly been RNP patients and I can look in the computer, but that doesn't ring any bells.

As far as we know, micro-chimera theories, I think that any theory of the pathogenesis of scleroderma has to somehow or other take into account all the different subsets, and at this point she can only account for women who have had children, and you've got men, you've got women who have never had children, and then she sort of comes up with other explanations. These findings are seen in lots of lupus patients. They are found in normals. Maybe it will turn into something, but I just haven't been convinced at this point that that is the direction where we are going to go.

They keep talking about how graft versus host disease is scleroderma. It is not scleroderma. It is very different from scleroderma. It's scleroderma-like but, if anything, it's more like fascitis and lupus profundus and that kind of family of things. It's not scleroderma. So I have had several levels of difficulty with it.

Question: There were some old studies which showed that when you transplant skin from normal part of the body to the sclerodermal area, the skin became sclerodermatous. How does one account for that sort of thing?

Virginia Steen, MD: Because there are factors that are stimulating the fibroblasts to turn on. They are completely normal fibroblasts, and whatever it is, is turning the fibroblasts on to make the excessive amount of collagen.

Question: So the problem is not all systemic, although certain organs get involved right? Because to take the normal skin and put in on the bad areas, that becomes sclerodermatous.

Virginia Steen, MD: Right. It is a systemic disease, but one aspect of it as far as what happens in the skin is a local phenomenon.

Question: The other question is do you think penicillamine changes the course of pulmonary disease?

Virginia Steen, MD: No I really don't. I mean I wrote that years ago, but I really don't think so.

Question: Virginia I have a few questions. First of all, to whom do you give penicillamine and when are you triggered to do so?

Virginia Steen, MD: I only give it to patients with early diffuse scleroderma who are developing more skin involvement. If somebody is two years down the road and has totally stabilized their skin involvement, I'll watch them, and if they don't progress at all I won't give to them.

Question: Should all patients with scleroderma be put on ACE inhibitors prophylactically?

Virginia Steen, MD: There is data against it, but there is no data to support that. They did that; they prophylactically gave people ACE inhibitors, and of their 33 renal crisis patients, 19 of them were on ACE inhibitors at the time they developed renal crisis. The way to explain that is the dose that you would use prophylactically is not enough to overcome the renal crisis episode. It is not enough to turn it off. There is something that triggers that and overcomes the low dose of ACE inhibitors, and some of the people might have a lot of trouble tolerating ACE inhibitors, and if you have theories that decreased perfusion contributes to the development of it, I haven't reached that.

Question: When do people move into your clinical protocols for alveolitis, pulmonary hypertension, where you start to put them through the workup. What the symptoms or findings that trigger that?

Virginia Steen, MD: Somebody that I'm following, since we know that, again, early disease, Scl-70 positive, whether they have diffuse or limited, are at the greatest risk. I will do serial pulmonary function tests, and if they have an abnormal pulmonary function test, I'll get an HRCT. If there is any discrepancy either between the change in the pulmonary function test levels, the pulmonary function test,or the HRCT, I'll get a BAL and base it on the tie-breaking. If they are both consistent with alveolitis, I will go ahead and treat them. Of course, now I am trying to submit them to the protocol and that is pretty much the protocol. The protocol is actually fairly easy to get into. You have to have a vital capacity of less than 85%. You have to have some dyspnea, and you have to have either ground glass or 3% neutrophils.

Question: I didn't see on your final list of potential therapies blocking of TGF-beta or pro-fibrotic cytokines.

Virginia Steen, MD: Certainly the TGF data is the new kid on the block, and that's like six months and hasn't gotten to my slide yet. But it is really only animal data. I think there may be one small phase 1 study that has said it was tolerable, but we don't know whether it's effective. The pro-fibrotic, anti fibrotic things -- that is where you would think the money is. The only anti-fibrotic that I have had experience with is Pirfenidone, which I'm not even sure what it is, but it was used by the pulmonary people to look at fibrosis ,and it was sort of an iffy type thing. The kidney people are looking at it in renal sclerosis, and the liver people are looking at it in cirrhosis. It really hasn't gone anywhere. Barry Gruber did about ten patients a couple of years ago and wasn't real excited about its effectiveness. All of us have talked to different biotech companies about one or another of these things that they have, wondering if scleroderma should be one of the things they are directing at.

Unfortunately, as usual, the companies focus on the big diseases and we get lost, but we keep plugging along.

Question: Dr. Steen you know what I am going to ask probably better than anybody else I can think of. But you know very well that regional blood flows have been examined in patients over many years, whether it's pulmonary blood flow, renal blood flow or the peripheral blood flow in the skin, Raynaud's phenomenon and so on. So many people have thought that there is a primary problem in the vasculature that accounts for fibrosis and everything else later on as it goes on. Shouldn't the drugs that you use or hope that you can use, be focused on that. If you believe prior work for example that the ischemic phenomena occur and produce abnormal antibodies, etc,. why should we be using drugs and focusing on drugs like Relaxin, when that is not really the primary problem. The primary problem is in the endothelial cell or don't you think it's in the endothelial cell?

Virginia Steen, MD: There is no question that there is a problem in the endothelial cell. The question is whether that is a primary problem, whether the effects of the changes in the endothelial cell are secondary and thus cause the problem in the kidneys. I mean there are so many interchanges here.

Question: But you remember Paul Cannon's study, a long time ago. When you put your hand in cold water, renal blood flow went like that.

Virginia Steen, MD: There is no question that that's primary because, it may not be completely but its primarily because the vessels are thickened. There is intimal proliferation; we've documented that in so many things. There probably is a super-reactivity as well, but that isn't overcome by the kind of vasodilators that we have. Now the things like the endothelial agents that can unconstrict theoretically the pulmonary vessels, and that is sort of going in that way.

Question: Paul Cannon's study did that. He didn't know anything about nitric oxide.

Virginia Steen, MD: No I know that.

Question: He didn't know anything about endothelian-1.

Virginia Steen, MD: No. but it makes sense. You were looking at Raynaud's type of things in the kidney. I mean you know that. I think we need more progress.

Question: Do you see any difference in the long-term outcome of scleroderma between patients with positive ANAs and negative ANAs?

Virginia Steen, MD: At this point, there are only about 5% of patients that don't have a positive ANA and, in my antibody study, I included them at first and it was such a gemish of people. There were some limited. There were some diffuse. There was just a little bit of everything. They didn't fit into any one category, and I didn't even include them and consequently their survival is sort of in between everything.