The Many Faces of Lupus: An Expert Interview With Stephen Paget, MD

Helen Fosam, PhD

Disclosures

April 24, 2006

Editor's Note:

The importance of diagnosing systemic lupus erythematosus and its variants early in the course of disease cannot be overstressed. Medscape's Helen Fosam, PhD, Editorial Director of Rheumatology, interviewed Stephen Paget, MD, Chairman of the Division of Rheumatology at New York's Hospital for Special Surgery, on his perspective on early diagnosis of lupus, recognizing its unique presentations, and the primary care-specialist partnership in the diagnosis and treatment of this multifaceted disease.

Medscape: What are the most important issues facing rheumatologists in the care of patients with lupus?

Dr. Paget: The main issue is to try to normalize the life of people who have lupus so that their organs are not affected by the inflammatory and immunologic assault and to do it in the safest way possible. It is always a very careful balance with the medicines that we have to try to control the inflammation and not have negative effects upon the people who have the illness. The second most important issue is to find new and safe medications to control the immunologic process to allow patients with lupus to live both longer and happier lives.

Medscape: In terms of managing these issues, what's your advice to rheumatologists?

Dr. Paget: The most important thing with regard to the care of a patient with lupus is to develop a lifelong relationship and partnership with them in which there's a tremendous amount of trust and communication at all times. That also demands an appreciation of the person's illness -- its own personality -- as well as the personality of the person with the problem, so that you know what the impact of this illness is not only upon the person's body, but also on his or her life.

So once you are available and present and you develop this partnership, it's then mandatory to rapidly and effectively treat flares of the illness. Now each person's lupus is as individual and unique as the person's personality, name, and everything about them. So appreciating that uniqueness is key. Every person's lupus is different: different manifestations are occurring in a given person, they respond differently to therapy, their illness evolves in different ways at different times. Some people with lupus have a flare every 5 years and some constantly have active disease affecting one organ system or another, or presenting in one manner or another, and you have to be responsive to those. When you make your decisions therapeutically, it's usually based upon knowledge of the person, an understanding of how that flare is occurring at that time, and defining what their laboratory tests are to get a feel for the extent of the illness and its severity. Then you make therapeutic decisions that are equal in aggressiveness to the aggressiveness of the illness.

It's important to appreciate the fact that we're still treating the pathophysiology of the illness because we don't know its etiology. Back in the last century, we dealt with systemic illnesses such as tuberculosis, syphilis, and polio, and we didn't know very early on that they were infectious disorders, so they had the same type of unknown and strange nature to them as lupus does today. But because we were able to figure out that they were infectious illnesses and determine that antibiotics would be effective in treating them, the illnesses are for the most part gone. While that will eventually happen with lupus as we gain more knowledge about its immunology, its character, and its personality, right now, we're just treating the pathophysiology, meaning how the illness presents to us.

We know that lupus represents an overactive immune system, wherein the immune system of a person that is normally meant to fight off external infections is, unfortunately, for various genetic and other reasons, fighting against the person themselves. And so our job as rheumatologists is to reset the inflammatory and immunologic thermostat so it's not overreacting and causing tissue damage but rather is balanced. Therein lies the art and science of rheumatology: trying to choose the right medicine that will not only control the inflammation and stop tissue damage in a patient with lupus, but also will not leave them with severe side effects from the medicine. We have a broad armamentarium of medicines that are used for people with lupus. What you choose as therapy depends upon how that person's flare is presenting at that moment. If it's mild, then maybe mild medications can be used to calm the flare down. If it's severe, sometimes you have to bring out stronger medications. Unfortunately, today, those stronger medications can sometimes also hurt the person in the attempt to control the inflammatory process.

Medscape: You mentioned various medications; can you comment on the major classes that are currently used to treat lupus?

Dr. Paget: The medications that are now used for lupus are the following: the first group of medications is nonsteroidal anti-inflammatory medicines, such as naproxen, ibuprofen, and celecoxib. These are medications that are used for various types of arthritis and can be very effective in controlling milder manifestations of lupus, such as joint pain or inflammation, muscle pains, low-grade fever, and, sometimes, inflammation of the tissues around the heart and the lung. They are not disease-modifying drugs, meaning they do not change the natural history of the illness. They do have their own side effects, but they're generally mild. They are not effective for controlling the more severe manifestations, and could potentially exacerbate kidney disease, lung disease, heart disease, or brain disease.

The second group of medications is antimalarial drugs, such as hydroxychloroquine or quinacrine. These are disease-modifying drugs and are very well tolerated and can change the natural history of the disease. Thus, all patients with lupus are treated with antimalarial drugs, such as hydroxychloroquine, which appear to control inflammation in the joints, can control fatigue, and can sometimes prevent internal-organ flares. They have the added positive of controlling skin disease, decreasing cholesterol, and also thinning the blood, all of which can be very, very helpful in patients with lupus.

The next group of drugs is corticosteroids, the most common of which is prednisone. Steroids are the classical double-edged sword: on the one hand, they're very powerful controllers of inflammation, but they can lead to side effects, especially when given in high doses for long periods of time. The side effects can include swelling of the body, osteonecrosis with damage to bone, osteoporosis, high blood pressure, mood changes, and infections. The most important thing here is for a patient with lupus to be followed by a rheumatologist, because they really understand the balance and the right way to give this medication so that the patient's lupus flare is controlled and the patient is not then subject to the severe side effects that can occur. Steroids can be given orally or intravenously, and some patients will receive what's called pulse steroid therapy; this is very high dose intravenous medication that is sometimes necessary for life- and organ-threatening disease.

The next group of drugs is called immunosuppressive drugs. These are also cancer chemotherapy drugs but we in rheumatology use them in lower doses than in patients with cancer. The most commonly used of these drugs are azathioprine (also called Imuran) and methotrexate. These drugs can be given orally and can be very effective with more severe types of lupus in which there is internal organ damage or in patients who do not respond to antimalarial drugs, nonsteroidal anti-inflammatories, or steroids. The real "cruise missile," the real strong drug that has been used over the years, is cyclophosphamide, also called Cytoxan. This drug is often brought in when there's very severe internal organ damage or inflammation such as kidney, brain, heart, or lung disease. It can be a very effective drug when used along with steroids in controlling tissue damage. Unfortunately, it, too, can lead to side effects, such as infection, hair loss, infertility, bladder bleeding or hemorrhage, and, also, the development of cancers. There are 2 new drugs that have come about recently; one is called CellCept or mycophenolate mofetil; it's an oral medication that some clinical investigators have shown to be as effective as cyclophosphamide for the treatment of kidney disease, but without as many side effects. And the new important drug that's come out recently is Rituxan or rituximab, a drug that was previously used for non-Hodgkin's lymphoma and can now be tremendously effective in those patients who have responded to none of the medicines that I've mentioned before, including mycophenolate. There are now trials ongoing in both kidney lupus and non-kidney lupus to see when rituximab can and should be used and how it should be balanced with other therapy in controlling very severe lupus.

Medscape: Is early diagnosis and early aggressive treatment important for managing lupus?

Dr. Paget: Yes what's very important for the readers to understand is that the outcome of all autoimmune diseases -- whether it's lupus, rheumatoid arthritis, scleroderma, dermatomyositis, or Sjogren syndrome, or the vasculitides -- are always much better when the disease is diagnosed and treated early. And it's also important not only to diagnose and treat it early but to have these patients seen and cared for by rheumatologists who understand the balance that I mentioned before, who understand the characteristics of the illness, and also the characteristics of the medicines used for it because they can best craft a regimen that is both effective and safe. It's important to appreciate that medical students and internal medicine trainees do not usually get very good education in the area of autoimmune diseases and types of arthritis. They may not know what they're dealing with, but it's important in those patients who have prolonged fevers and arthritis and internal organ damage and fatigue and problems like that for internists to appreciate that lupus is a possible diagnosis and they should move those patients quickly to rheumatologists and partner with them in improving the lives of patients with lupus. It's very important to realize that rheumatologists are not going to steal their patients but rather coordinate the care with the primary care physician. Another very key fact is that lupus, as with rheumatoid arthritis, has a spillover effect onto other parts of the body. So the inflammatory process of lupus spills over onto blood vessels -- including coronary arteries -- leading to premature atherosclerosis; and onto bones, leading to osteoporosis. Thus, it is absolutely vitally important to have a global approach to lupus as doctors do for diabetes. So you have to control the inflammation so that it doesn't spill over onto other organs. You have to give a baby aspirin to prevent coronary artery disease, you have to control high blood pressure and diabetes, you have to control obesity and stop smoking, and you have to have a zero tolerance for the inflammatory process, and treat like you would diabetes with tight control of the disease, always carefully balancing the pluses and minuses of the medications that are used for the treatment of the disease.

Medscape: What's the prognosis for patients treated for lupus?

Dr. Paget: The prognosis of patients with lupus has profoundly improved over the past 50 years for many reasons: (1) greater recognition early on of the disease; (2) our general medical knowledge of how to treat high blood pressure, diabetes, osteoporosis, infections, etc.; and (3) there's greater recognition and more rheumatologists available who understand the illness so that today a patient with lupus can live, with 90% assurance, for more than 20 years. And this is profoundly different than the 1950s and 1960s, when the 5- or 10-year survival rate was 15% or 20%.

Medscape: You mentioned earlier that treatment needs to be individualized; how do patients differ in terms of their disease presentation?

Dr. Paget: There are many faces of lupus. The most common manifestations of lupus are constitutional symptoms, such as fatigue, weight loss, and fever; another set is the musculoskeletal presentation, with arthralgias or arthritis or myalgias or muscle inflammation and weakness. It can affect the pleura and the pericardium and patients can present with pericarditis or pleuritis with chest pain on deep breathing. It can affect the internal organs such as the heart and the lung and the central or peripheral nervous system or the kidney. It can affect the internal organs in the abdomen, including the liver, the spleen, the pancreas, and the intestines. So it has many different faces. And in a given person with lupus it can either always present in exactly the same manner or, every time they flare, they can present in a different way. The flares usually do have a memory to them so that patients know they're flaring, for example, when they start to lose their hair and develop low-grade fevers and fatigue and weight loss and joint pain or a skin rash. Another patient's lupus may only be manifested by seizures or a stroke. Other patients may develop kidney failure with swelling and high blood pressure. So the way in which you define that is you keep the doors of communication open, and they tell you the symptoms that they have when they call you on the phone or they e-mail you. You then examine them and you do various blood and urine tests, immunologic tests, such as an antinuclear antibody (ANA), or an anti-DNA antibody, or complement levels. And all of these, including imaging techniques, such as a chest x-ray, computed tomography (CT) scans, or magnetic resonance imaging (MRI), are put together in a very unique individual clinical equation, that lets you know if there's a flare, what organs or tissues are involved in the flare, and how extensive and severe the flare is, and that gives you the idea of what therapies may be needed.

Medscape: In terms of management, do the same techniques and principles apply for both children and adults?

Dr. Paget: Yes, exactly the same principles apply. Obviously, children have a much longer life ahead of them and thus you have to be very, very careful with regard to the medications you choose and the doses you decide upon, specifically with regard to the damage to bone, the ability of steroids, for example, to cause problems with growth; and the emotional and educational and social problems that may affect children with lupus. So children should be treated by pediatric rheumatologists in concerted partnership with their general pediatrician. There are specific issues with regard to childhood that differ from those of older folks, although the therapies are often the same. Different therapies may have to take into consideration the different immune systems. For example, rituximab may have very different effects in very young children and should be avoided. While we would like to avoid the use of cyclophosphamide in young children, its use has to be balanced with its, potential for causing sterility or infertility, and it is often used in the setting of severe organ inflammation and damage. But, in general, the approach is the same; it's a global approach that demands the close communication between physician and patient and, in the case of children, their parents, while always carefully balancing the pluses and minuses of the medication in a given person.

Medscape: With respect to the diagnosis, you mentioned a series of different tests; is there a menu of tests that must be followed to conclusively diagnose lupus?

Dr. Paget: When you're making a diagnosis of lupus you have to appreciate that the diagnosis is predominantly a clinical one wherein the laboratory tests are helpful and supportive in making diagnostic or therapeutic decisions. The first possibility of lupus should be considered by all physicians in patients who have persistent signs of inflammation, including fevers, fatigue, and weight loss; or manifestations of joint inflammation, skin rash, hair loss, or internal organ problems. And they also have to appreciate that some of these symptoms and signs can overlap with those of patients who have infections or cancer. Thus, you have to be an astute clinician to try to rule those out as quickly as possible and then come to the possibility that lupus is present. Often, once physicians encounter these types of multisystem presentations that I just mentioned, they will rule out infection and cancer and then do some screening tests like an ANA -- and if that test is abnormal or elevated they'll then do a more specific lupus test, such as an anti-DNA antibody. If that's abnormal in the context of a multisystem illness as I described, the diagnosis is nearly assured once you've ruled out infection and cancer. At that point, you'll do general screening tests such as a complete blood count because patients with lupus can often have a low white blood cell count, they're anemic, and they can have a low platelet count. You also have to screen for organ damage, so you look at liver function tests, kidney function tests, and you look at a urinalysis to see if there are red blood cells or protein. You would also do immunologic tests such as complement levels -- C3 and C4. Often, in the setting of kidney disease or immune complex disease, not only would the ANA be positive and the anti-DNA be high but the complement levels are low because these proteins get involved in the immune process and get consumed. And so you put all of these clinical and laboratory tests together to try to form a personal tapestry for a person. Once you've made that definition, sometimes, more sophisticated tests are necessary such as an MRI of the brain or an ultrasound of the kidney or a CT scan of the abdomen. You may even need to do organ biopsies such as a kidney biopsy or a lung biopsy; these can give extra information with regard to how that organ is doing and could also guide you with regard to the therapy that may be needed.

Medscape: Can you comment on the different subtypes or variants of lupus?

Dr. Paget: There are various subtypes of lupus. Neonatal lupus, wherein the mother has lupus and the child in utero gets some of the antibodies that cross the placenta, can lead to the child having a rash or a low platelet count at birth. Usually, in that situation, once those antibodies are cleared from the child, the child does not then develop lupus, and the problems that I just mentioned go away. In a small group of children born to mothers with lupus, and specifically to mothers with RoLa autoantibodies, the child could develop heart block that can be permanent. There's a type of lupus called discoid lupus in which patients develop disc-shaped scaling and redness of parts of their skin. On biopsy of that skin, they're found to have specific abnormalities that are consistent with discoid lupus. Only rarely does discoid lupus go on to develop into systemic lupus. With systemic lupus erythematosus, a patient has the propensity to develop inflammation and immunologic insults to any part of their body because it's a systemic disease and the problems are disseminated through the blood. In any given person, it's difficult to know why a specific organ or organ system or tissue abnormalities occur; nobody knows why that is. It may be genetically defined. But one person with lupus may just have joint inflammation and skin rash and fatigue for their whole life and thus you choose medicines to control those. Another patient may have kidney disease and brain disease as their major manifestations. Another may have skin disease, fatigue, and seizures. Nobody knows why individuals have individual characteristics of lupus but whatever it is, you define it in the manner that I mentioned and you treat it depending upon the major clinical manifestations that you find.

Medscape: What about lupus nephritis -- how common is it?

Dr. Paget: Lupus nephritis is one of the more feared and severe manifestations of lupus. About 40% to 50% of patients with lupus develop kidney disease. About 30% to 40% of those develop the more severe type of kidney disease that can lead to kidney failure. You have to define whether your patient has kidney disease, how bad it is, and how aggressive the therapy needs to be. That usually is determined by the physical examination, laboratory tests, and often a kidney biopsy. Those give you the idea of how severe the manifestation is and how aggressive you need to be to control it.

Medscape: Many patients will probably see their primary care physicians first. What's your view on how best to involve primary care physicians in care of patients with lupus?

Dr. Paget: The primary care physician is all-important; first of all, they're on the frontline. It's not at all uncommon today to hear of people who have had lupus for 4 or 5 years, and who have been branded as having emotional problems or an infection or some endocrine problem. They've lived with this for years without receiving the right diagnosis. So a key thing is for the primary care, frontline physician to make the diagnosis as early as possible and then send the patient to the rheumatologist and partner with them.

I can't tell you how many times I've had patients who've said, "Thank God, doctor, that you told me I had lupus; I thought I had cancer, I thought I had some horrible infection, and even though you've told me that I have this illness that can be bad, just knowing allows me to feel better about it. I now have some control over the illness because I can understand it and read about it."

Medscape: So do you agree that educating primary care physicians on this disease is very important?

Dr. Paget: It is so important and we in other institutions focus a lot on this. You know we have the Cornell medical students in New York and we try to teach them, and we also have the New York Presbyterian interns and residents and we try to teach them, because the frontline physicians can make all the difference. They can make the diagnosis early so you can prevent problems or they can refer the patients early so you can stop the problems in their tracks. Without that, patients are on their own and the disease has its way with them.

Medscape: Looking ahead in terms of emerging therapies, are there any in the horizon?

Dr. Paget: Yes, there are extraordinary new therapies; the one I mentioned before is rituximab. This is a drug that's been used over the past 7 or 8 years for non-Hodgkin's lymphoma and it has an effect upon B lymphocytes that are important immunologic cells in the development of lupus. There are 2 main studies that are going on to try to determine the rightful place of rituximab in the treatment of lupus. But I can tell you that in the past few years we have had patients who did not respond or broke through steroids, cyclophosphamide, mycophenolate mofetil, and all of the medicines I mentioned and the thing that made a difference was rituximab. There are other similar types of drugs that affect the immune system and strike a good balance between suppressing the immune system but not causing side effects, so that the future does look brighter. The most important thing, though, is research, research, research; finding the actual cause of lupus so that, just as tuberculosis and polio and syphilis and rheumatic fever were controlled, so, too, will be lupus. Abatacept, also called Orencia, is another medicine that affects T lymphocytes, which also play a role, in conjunction with the B cell, in causing the inflammatory process.

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