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Autoimmune Disease: Does Sex Matter?

Current Theories  With some exceptions, autoimmune diseases affect far more women than men. For some time, physicians and researchers have been asking why this is so. The most popular theory to date has been that female hormones set the stage for diseases such as systemic lupus erythematosus, Sjogren’s syndrome, and rheumatoid arthritis. But more recent research calls this theory into question-and suggests that there may be other reasons for the greater incidence of autoimmune disease in women, an issue sometimes referred to as sex predominance. Possible explanations may be roughly divided up into four areas:

(1) hormone theory,

(2) environmental factors,

(3) genetic influences, and

(4) whole organism factors.

Discussion of these potential causes is sometimes complicated by disagreement about the definition of an autoimmune disease. For the most part, however, there is general agreement that the following are autoimmune diseases: system lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, scleroderma, primary biliary cirrhosis, chronic active hepatitis, Graves disease, Goodpasture’s disease, hemolytic anemia, idiopathic thrombocytic purpura and Hashimoto’s thyroiditis. Other diseases that many physicians would put in this category include: ankylosing spondylitis, Lyme disease, pemphigus, vitiligo, myasthenia gravis, multiple sclerosis, and juvenile onset diabetes. A number of other illnesses may have features that are similar to those of autoimmune diseases, but they are not labeled as autoimmune diseases. Current Theories of Sex Predominance

1. Hormone Theory Hormone theory refers to the traditional belief that estrogen production puts women at a greater risk for developing an autoimmune disease. In tests conducted in the laboratory, estrogen has been demonstrated to make women’s immune systems “over-react” when compared to men’s. This finding supports the standard definition for lupus and other auto-immune diseases, in which the immune system is said to over-react to the body’s own tissues. It also appears to explain the ratio of incidence in a disease like lupus, in which 9 women get the disease for every 1 man. However, there are autoimmune diseases that occur more frequently in men than in women, including Goodpasture’s syndrome, in which the body creates antibodies that attack the lungs and kidneys. This disease occurs in 1 woman for every 3 men. Another problem with the hormone theory is disease severity. If women are more likely to develop lupus because they produce estrogen, they could be expected to become more seriously ill. But, overall, men and women with lupus experience the disease with the same range of severity. If estrogen were the deciding factor in who gets autoimmune diseases, it would also be reasonable to expect that similar diseases would have similar male-female ratios. However, there are a number of diseases that share characteristics with lupus (9:1) that have very different ratios, including Goodpasture’s disease (1:3), idiopathic thrombocytopenic purpura (2:1), and hemolytic anemia (2:1). If hormones and immune response are linked, then one could also expect women to react differently than men to infections and immunizations. However, there appears to be no significant difference. Moreover, hormonal changes that occur when menstruation begins, during pregnancy, and with menopause, do not seem to affect the course of autoimmune disease. Neither does the use of birth control pills or hormone replacement therapy.

2. Environmental Factors As these arguments against the role of hormones in explaining sex predominance and autoimmune disease have become more widely discussed, researchers are paying more attention to environmental factors. Some diseases that have been classified as autoimmune diseases are clearly caused by exposure to external toxins — medications or environmental pollutants. The differing roles of men and women at home and in the workplace help to explain who is exposed to these toxins. Scleroderma, for example, is seen disproportionately in male gold and coal miners who are exposed to high levels of silica. Drug-induced lupus is a long-recognized disease that occurred in the 1960s and 1970s, mostly in men who were given certain drugs to treat heart disease, and still occurs today, but less often since better drugs are available. Other examples of autoimmune disease caused by exposure include an epidemic of a disease that resembled scleroderma in Spain in the 1970s. In this case, 10,000 people, mostly women who were cooking at home with contaminated oil, developed the illness. While both men and women ate the cooked foods, women tasted the food as it was cooking, at a point when the heat had not yet destroyed the contaminant. By the time the food reached the table, the contaminant was destroyed, and no longer harmful. In another instance, men who cleaned manufacturing vats used to make polyvinyl chloride (the plastic that is used in so many products that we use on a daily basis) developed scleroderma. It was later found that they were exposed to a monomer in the air, a toxic chemical compound that joins with other compounds during heating to become polyvinyl chloride. The role of environmental factors may also be seen in children. In those under 12, for example, more boys develop Lyme disease than do girls. The reason for this difference can be found in the way children play. More boys play outside more of the time, and in doing so, increase their risk of exposure to disease-carrying ticks in wooded areas. (Looking at this example, one could come to the conclusion that a preference for a certain type of activity might be determined by hormones, which in turn could influence exposure to the environmental factor.) In an area of Brazil, a disease that closely resembles pemphigus foliaceus, an autoimmune skin disorder characterized by blisters, has been associated with a certain kind of black fly that lives near the river. Men who fished in this river were more likely to develop the disease than women who had less exposure to the flies. These examples support the idea that exposure to a toxin determines who will develop the disease, rather than the sex of the patient. Unfortunately, it does not yet help to explain female predominance in a disease like systemic lupus erythematosus. Researchers have looked at exposure to a number of products that women use with greater frequency, such as hair dye and lipstick, but have not identified any cause-and-effect link. The role of behavior can also be considered to influence the development of disease. Examples include osteoporosis, which can be modified by doing weight-bearing exercise. Coronary disease, including strokes and atherosclerosis, can be affected by changes in diet and reduction of cholesterol levels. And, injury-related osteoarthritis risk can be reduced by avoiding extreme sports. The risk of developing Reiter’s disease-a kind of reactive arthritis sometimes caused by venereal disease-can also be reduced by modifying behavior. It seems clear therefore, that behavior can cause illness, but we haven’t identified the specific behaviors involved with most autoimmune diseases.

3. Genetic Influences Genetic differences between men and women have also been considered as an explanation for why one sex gets a disease more frequently than the other. Researchers have learned some interesting facts about these differences. Among them:

  1.  Every cell in every man’s body is different from every cell in every woman’s body-even those found in identical tissues (e.g., a man’s liver and a woman’s liver).
  2. There are huge differences in the DNA between the sexes, the cell membranes, and the way cells associate in the body. For example, every woman gets X chromosomes from her mother and her father. Every man gets X chromosomes from his mother only (he gets the Y chromosome from his father.) 
  3. Women who have been pregnant carry their baby’s cell
    s in their bloodstream even after they have given birth to their children-sometimes for decades. In normal women the cells drop dramatically after birth. In women with autoimmune diseases, the cells are often present at much higher numbers for a much longer period of time. These diseases include: scleroderma, primary biliary cirrhosis, Sjogren’s syndrome, and autoimmune thyroid disease. In women with thyroid nodules, the cells within the nodules have been found to be male cells, while the rest of the thyroid is made up of female cells.

As fascinating as this information is, scientists have not yet figured out its significance. But we can expect much more study of these phenomena.

4. Whole organism Issues Whole organism issues may also be a part of the picture-those that have nothing to do with sex or genes. For example, osteoporosis is, in large part dictated by body size. Very heavy people don’t get it, very thin people do. Moreover, tall, heavy people are less likely to have osteoporosis than are small, heavy people, since the disease relates to the size of the bones and how much calcium is lost from them. The likelihood of a woman developing breast cancer may be influenced by how many children she has, and Alzheimer’s disease appears to be linked with aging, although it is not understood whether it is part of the process itself, or something that takes 60 or 70 years to develop. Study of the aging process and autoimmune disease is underway as well. Can signs of the disease be detected in the bloodstream well before the patient has any symptoms? And, if so, are there ways to slow the progress of the disease or stop it? Looking at all of these factors, Dr. Lockshin concludes that a variety of factors may explain why more women get autoimmune diseases than do men. Why is there a 9 to 1 ratio in a disease like lupus? Why does rheumatoid arthritis occur in 2 women for every one man? Why do more men than women develop Goodpasture’s syndrome? It could be environment, hormones, behavior, genetic differences, or a combination of some or all of these factors. The information available to us now is part of a continuing discussion that promises to yield new ways of thinking about and approaching autoimmune disease over the coming decade and beyond.

Additional Reading If you are interested in reading more about the relationship between sex and disease, you may be interested in the following: Exploring the Biological Contributions to Human Health: Does Sex Matter? This book compiles a vast range of writings on the role of sex in a range of diseases, not just autoimmune illnesses. It is available for purchase or for free on-line at www.nap.edu/catalog/10028.html The X in Sex: How the X Chromosome Controls Our Lives by David Bainbridge. Available in bookstores and through on-line booksellers. Y: The Descent of Men by Steve Jones. Available in bookstores and through on-line booksellers. See the complete article on the Hospital for Special Surgery’s web site Summary prepared by Nancy Novick.

 
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Does ANA-negative lupus exist? What other labs are helpful when thinking of this diagnosis, and what if all of them are negative?

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The answer to the question depends on what is meant by lupus, and what is meant by ANA. To start with the definition of lupus: systemic lupus erythematosus (SLE) is one of many similar illnesses that affect young women and that cause arthritis, rashes, low white blood cell counts, low platelet counts, and kidney disease. (I’ll ignore, for this discussion, discoid [skin], drug-induced and neonatal lupus.) The features that unequivocally diagnose SLE are

(1) high titer anti-double stranded DNA antibody,

(2) anti-Sm (Smith) antibody,

(3) biopsy-proven kidney disease, or

(4) biopsy-proven skin disease.

[The American College of Rheumatology criteria are used to group similar patients together for research and treatment trials. They are classification criteria and are not meant to be used to make a diagnosis.]

The antibody tests must be accompanied by symptoms, since antibodies alone, with no symptoms, do not diagnose the disease. If a patient has symptoms plus diagnostic antibodies or biopsy proof of disease, the patient has SLE. If the patient lacks all four, the diagnosis is presumptive, even in the presence of illness.

There is no real consensus among physicians how best to describe symptomatic patients who lack all four of the unequivocal features. This writer diagnoses “lupus-like” illness, “mixed connective tissue disease,” “undifferentiated connective tissue disease,” and “forme fruste (meaning incipient, or hidden form) lupus”. Each has specific and separate meaning and describes different forms of illness. Most summaries report anti-DNA antibody in about half of patients, anti-Sm in about one-third, and ANA in 87-94% of patients with unequivocal SLE. Urowitz and Gladman cover this topic extensively in a textbook chapter[1]. In another textbook, Edworthy offers a complicated algorithm for diagnosis of lupus, using ANA titer, related antibodies, complement levels and symptoms to derive “diagnostic certainty”[2]. Still other text books discuss the uncertainties of serological testing without specifying frequencies of antibody negativity[3]. In this writer’s practice, as many as one-quarter of patients referred for suspect SLE fall into the not-quite-lupus category, while persons who have any one of the four unequivocal features listed above have SLE[4].

Some but not all physicians diagnose lupus, even ANA-negative lupus, in cases in which, to this author, another term would be preferable. Because the medical community does not agree, whether to diagnose a patient as having lupus or lupus-like disease is not a question of the physician’s being right or wrong; it is a question of a physician’s style. In either case, treatment options are the same.

Now, to the question of the meaning of ANA. The antinuclear antibody test is performed with different techniques in different laboratories; some techniques are more sensitive than others, such that one laboratory may find a (usually weak) positive test while another finds it negative. Some laboratories dilute 10-fold for screening (1:10), some as much as 100-fold (1:100), and some not at all. A commonly used method starts with a dilution of 1:10, then doubles with every successive dilution, so the next specimen tested is 1:20, then 1:40, 1:80, etc., the highest number positive being what the laboratory reports (for instance, 1:1280). Most lupus patients have sera that react at very high dilutions, essentially always more than 1:80, often more than 1:5120. Depending on the laboratory’s reporting habits, a test that is positive at 1:10 or even 1:40 may be called either negative or weakly positive. Most laboratories count 1:80 and higher as clearly positive. The point is that ANA-negative does not always precisely mean completely negative. Another point is that speckled (as opposed to diffuse or peripheral) ANA patterns do not read well in automated immunofluorescence tests, so may be reported as lower titer or negative than they would be if they were hand read by an experienced technician[5].

There is a further complication. The ANA is used to screen for lupus, not to diagnose it. This means that, for practical purposes, if the ANA is negative, lupus does not exist and no further testing need be done; indeed, some laboratories will not further screen sera that are ANA negative. If the ANA is positive, that means only that lupus is possible and that tests for antibody to double-stranded DNA, Sm (Smith), Ro/SSA (Sjogren’s syndrome A), La/SSB (Sjogren’s syndrome B), and RNP (ribonucleoprotein) must be performed to determine whether lupus is or is not present. Because of a variety of technical factors, it is possible to have a negative ANA but a positive specific antibody test, though this is very uncommon; for diagnosis a positive test for a specific antibody is more important than is a negative ANA test. Thus an “ANA-negative” person with strongly positive antibody to Sm would unequivocally have lupus (the author has seen many such patients). Because of this possibility, this writer, evaluating a new patient for lupus, usually simultaneously (to save time) tests for ANA, anti-DNA, anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-RNP, as well as for other abnormalities relative to the patient’s specific condition. That is, he does not completely discard the diagnosis if the ANA test is negative, though the diagnosis is much less likely.

Now another complication: all of the above applies to the evaluation of new symptoms in an untreated patient at a specific time. In a lupus patient-or in a patient with suspect lupus-tests change over time, either improving or worsening. Furthermore, tests often revert to normal during treatment. If the question, “Can an ANA-negative person have SLE?” is asked of a patient with established or treated disease, it may be impossible to confirm or refute the diagnosis-on the basis of blood tests alone-made years earlier, or in a patient taking high doses of prednisone or immunosuppressive drugs. In our recent cross-sectional study of atherosclerosis in SLE studying treated patients with disease of variable duration, at the time of study, 42% had anti-DNA antibody and 10% anti-Sm[6]. We did not specifically tabulate frequency of ANA.

The answer to the question, “Does ANA-negative lupus exist?” is technically “yes”, with a large number of buts, and ifs, and whens. Another answer is that the question is not very important. It is never critical to say definitively that a given patient does or does not have lupus. What is important is to evaluate the current symptoms, to put the symptoms into an overall context that includes blood tests, duration of symptoms, other illnesses, and medications, and to develop a treatment plan based on the total information rather than on a blood test alone.

See the complete article on the Hospital for Special Surgery’s web site

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[1] Urowitz MB, Gladman DD. Antinuclear antibody-negative systemic lupus erythematosus. In: Lahita, RG. Systemic Lupus Erythematosus, 3rd Edition. San Diego: Academic Press; 1999. p. 319-324. [2] Edworthy SM. Clinical manifestations of systemic lupus erythematosus. In: Ruddy S, Harris ED III, Sledge CB, editors. Kelley’s Textbook of Rheumatology, 6th ed. Philadelphia: W.B. Saunders; 2001. p. 1105-1124. [3] Koopman WJ. Arthritis and Allied Conditions. Philadelphia: Lippincott Williams & Wilkins; Philadelphia. p 1445-1502. [4] Lahita RG, The clinical presentation of systemic lupus erythematosus. In: Lahita, RG. Systemic Lupus Erythematosus, 3rd ed. San Diego: Academic Press; 1999. p. 325-336. [5] Fritzler MJ. Immunofluorescent antinuclear antibody test. In: Rose NR, de Macario E, Fahey JL, Friedman H, Penn GM, editors. Manual of Clinical Laboratory Immunology. Washington: American Society for Microbiology; 1992. p. 724-729. [6] Roman MJ, Sha
nker B-A, Davis A, Lockshin MD, Sammaritano L, Simantov R, Crow MK, Schwartz JE, Paget SA, Devereux RB, Salmon JE. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus: a case-control study. N Engl J Med;349:2399-2406

 
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Update on Antiphospholipid Antibody – In-Depth Overview for Physicians

Grand Rounds
Michael D. Lockshin

I want to give you both an overview of the antiphospholipid antibody syndrome and update the audience on things that happened at the recent meeting in Tours, France, which gave some of the most current and up-to-date information on the syndrome. I am also going to give you some speculations about the future.

The basic definition of the syndrome has been around for more than a decade now and has consisted of recurrent thromboses, venous or arterial, recurrent pregnancy losses (I will have more to say about that in just a few minutes), the presence of an antibody, a diagnostic antibody within a family of antibodies, not a single antibody, and some people will add another major component which is the catastrophic vascular occlusion syndrome. The clinical manifestations can be very dramatic and they happen in young people. This is one of the first patients I ever saw here at this hospital, probably 20 years ago, before we had a diagnosis of the antiphospholipid syndrome. This is a young lady, 21 years old at the time, who had multiple cerebral infarcts and a known lupus anticoagulant. I have used the term here now, which we did not have then, of antiphospholipid antibody syndrome or PAPS. This also is a MRI, one of the earliest versions of the MRI, demonstrating diffuse white matter disease and infarctive disease in a 33-year-old man whose presenting manifestations were dementia and occipital blindness. This is a more common manifestation; this is a lady whom I saw just about two weeks ago, a 42-year-old woman who had multiple UBOs (or just diffuse areas of hyperintensity) scattered throughout her brain-you can see them along here or in contrast along here-and forgetful episodes with some hints of dementia but very little else as a manifesting symptom. You can also see abrupt and severe vascular occlusion. This was a spontaneous event in the lady who ended up developing gangrene of three of her extremities before the catastrophic syndrome was stopped by plasmapheresis, and who survived this event despite the severity of what happened.

The way in which I got into studying this syndrome was with the pregnancies. This again, is a relatively old slide, demonstrating in a patient population with lupus and primary antiphospholipid antibody syndrome alone, the risk to pregnancy of having the antibody going from no antibody present (under 16 IgG antiphospholipid antibody units) to high titer on the first blood test drawn during the index pregnancy. In the green bars are women who have not been pregnant before. The yellow bars are women who have had prior losses, and you can see that in this group of patients the history of a prior fetal loss and a high titer antibody gave an over 80% probability of losing the current pregnancy. There was stepwise increment from negative titers but it was also true that the history of a prior loss even in women who had negative antibody titers also predicted loss at about a 2:1 ratio, that is, a prior loss plus the high titer antibody. Predicted losses in a woman who had never been pregnant but who had high titer antibody had about a 40% probability of losing that pregnancy. I guess it does not show well on this slide, but one of the characteristics also is livedo reticularis. This, in a better projection, shows rather striking livedo. It is characteristic of many patients and is distinct from a more hard livedo, as you see, here referred to as livedo racemosa, a point made by Jean-Charles Piette from France, that is different and that occurs in patients with vasculitis. There is a good paper by him in the recent Journal of Autoimmunity that describes the differences between the two types of livedo that occur, the one with antiphospholipid antibody and the one with vasculitis. This is one of the severe manifestations occurring in a young woman with the catastrophic syndrome. Those of you who recognize the histology will recognize this as myocardium. This is a coronary artery that has completely occluded and was the cause of her death. Again, I do not remember her precise age, but she was in her thirties. You will note the characteristic pathology, which is a totally bland thrombus like this, with no signs of inflammation, no vasculitis whatsoever within the coronary vessels. This is another patient, a young man who was well known to many of the physicians here. This is his aortic valve, along here, with this huge excrescence that led to severe aortic insufficiency and eventual valve replacement in this man, and also, mitral valve replacement. This is another manifestation of the syndrome that occurs in patients who have had the disease for some period of time. In the catastrophic syndrome, a relatively rare but dramatic event that can occur is the sudden onset of adrenal failure associated with hemorrhage around the adrenal glands. The hemorrhage occurs after infarction of the adrenal glands and is the cause for sudden hypotension, severe nausea, and back pain in patients with the antiphospholipid antibody syndrome; this slide given to me by Ware Branch shows extensive hemorrhage around both adrenal glands. …

See the complete article on the Hospital for Special Surgery’s web site

 
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When should patients with antiphospholipid antibody be treated with long-term anticoagulation, and how high should the INR be?

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Michael D. Lockshin

Currently, the recommendation for asymptomatic patients who have antiphospholipid antibody (regardless of titer) is that they not be treated. One retrospective study, conducted here at HSS, looked at women who had been identified because of fetal loss and were/were not treated with aspirin; the results suggested that aspirin protects against future clotting events[1]. The primary author, Doruk Erkan, MD, is now engaged in a prospective study through the national registry (APSCORE) to verify the findings.

I don’t believe that anyone would treat asymptomatic patients with warfarin or heparin. Michelle Petri, MD, of Johns Hopkins Medical Center, advises hydroxychloroquine[2].

With regard to the INR, the best information comes from the a double-blind, prospective study by Crowther in The New England Journal of Medicine in 2003, which stated that, for uncomplicated antiphospholipid syndrome patients who have not previously failed anticoagulation, an INR of 2.5 is as effective as are higher INRs[5]. This paper reduces a recommendation previously made by Khamashta in 1995 for an INR of greater than 3[3],and a subsequent update raising (without justification, in this reviewer’s mind) the recommended INR to 3.5[4]. In the Crowther study, the recommendation applied equally to patients with venous and with arterial clots.

Many authorities also prescribe a baby aspirin as well.

See the complete article on the Hospital for Special Surgery’s web site
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[1] Erkan D, Merrill JT, Yazici Y, Sammaritano L, Buyon JP, Lockshin MD. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin. Arthritis Rheum. 2001 Jun;44(6):1466-7.

[2] Petri M. Treatment of the antiphospholipid antibody syndrome: progress in the last five years? Curr Rheumatol Rep. 2000 Jun;2(3):256-61.

[3] Khamashta MA, Hughes GR. Antiphospholipid antibodies and antiphospholipid syndrome. Curr Opin Rheumatol. 1995 Sep;7(5):389-94. Review.

[4] Ruiz-Irastorza G, Khamashta MA, Hunt BJ, Escudero A, Cuadrado MJ, Hughes GR. Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5. Arch Intern Med. 2002 May 27;162(10):1164-9.

[5] Crowther M A, Ginsberg J S, Julian J, Denburg J, Hirsh J, et al. A Comparison of Two Intensities of Warfarin for the Prevention of Recurrent Thrombosis in Patients with the Antiphospholipid Antibody Syndrome. New Engl J Med 2003 Sep 18; 349:1133-1138.

 
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Vaccinations and Rheumatic Disease

Special Report

Common questions about vaccinations for patients with rheumatic disease fall into four categories:

1. Does vaccination cause rheumatic disease?
2. Does vaccination worsen rheumatic disease?
3. Is vaccination effective in rheumatic disease?
4. Are vaccinations dangerous for someone with rheumatic disease?

Because there are many types of vaccinations (see Table below), many different vaccination schedules, and many differences among patients with rheumatic diseases, definitive answers are few. However, a number of specific studies permit general answers. In general, those answers are:

1. Vaccination does not cause rheumatic disease.

2. Vaccinations do not worsen rheumatic disease.

3. Vaccinations are generally effective in patients who are not taking high doses of prednisone or immunosuppressive drugs.

4. Vaccinations are not dangerous for persons with rheumatic disease, except: live-virus and bacterium vaccinations are dangerous for, and are contraindicated in, patients who take high doses of prednisone or immunosuppressive drugs, or who have very low white blood cell counts or are otherwise immunocompromised.

References to medical articles (below) can provide readers with information on specific rheumatic diseases. references to medical articles are attached. Detailed information about vaccinations, including immunization schedules and doses are available from the National Centers for Disease Control, Advisory Committee On Immunization Practices (CDC, ACID), which provides a comprehensive website. What follows are brief answers to questions patients with rheumatic disease may ask. …

See the complete article on the Hospital for Special Surgery’s web site

 
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Might herbals or other dietary supplements affect antiphospholipid syndrome or clotting risk, especially in patients treated with Coumadin? What about progesterone in postmenopausal patients with APS?

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Michael D. Lockshin

The antiphospholipid syndrome (APS) causes excessive blood clotting, leading to strokes, heart attacks, and pulmonary emboli (clots in the lungs). It also causes pregnancies to fail, because of clots in the placenta.

While much is known about the syndrome, what actually triggers a clot at a specific time in an individual patient is unknown. Similarly, there are no definitive studies on the effect of herbals and other supplements on the initial occurrence of APS or on its worsening or improving when such supplements are taken. Indeed, with the large number of supplements available, the absence of standardization in their formulation and manufacture, and the differing doses with which they are used, the absence of such information is not very surprising.

Once a patient is diagnosed with APS, however, he or she is often prescribed warfarin (Coumadin) or a form of heparin (such as Lovenox or Fragmin) taken orally or injected daily to stop the abnormal clotting from recurring. In doses too high, the effect of these drugs is to cause hemorrhage. The body normally has redundant systems to prevent hemorrhage, so patients taking the appropriate dose of medicines that interfere with one type of clotting are still reasonably safe if, for example, they cut themselves because other ways to form clots are available. However, the dose must be constantly monitored to be certain that a patient is in a safe zone. That’s where taking herbal supplements may be dangerous.

According to a publicly available listing of drug interactions[1], the following is a minimum list of alternative medicines that interact with prescribed anticoagulants by increasing risk of bleeding: androgens, German chamomile, coQ10, danshen (red sage, saliva root), dong quai (Chinese angelica), evening primrose oil, fenugreek, feverfew, fish oils, flaxseed, garlic, ginger, ginko biloba, ginseng, grape seed, green tea, horse chestnut seed, milk thistle, quinine, red clover, red yeast, St. John’s wort, willow bark.

Other alternative therapies may increase the risk of clotting. Vitamin K counteracts Coumadin; vitamin preparations or diet supplements that include vitamin K increase the risk of clotting in patients taking Coumadin (but not in those using heparin or antiplatelet drugs like aspirin or Plavix).

Thus the major risk of herbals and other supplements to patients with antiphospholipid syndrome is interference with treatment rather than worsening the disease.

The same cannot be said for estrogen. Estrogen, in the form of postmenopausal treatment or oral contraception, including patches, increases a woman’s tendency to clot. Therefore, estrogen can provoke clotting in patients with APS, whether they are being treated with anticoagulants or not. Most specialists in the field advise against taking this hormone.

Progesterone, also used for contraception, amenorrhea, in some pregnancy situations, and in post-menopausal therapy, is probably safe for patients with APS. In fact, the literature on this topic is remarkably old and sparse[2], but information from the SELENA study of lupus patients may be available soon. Excessive clotting is a listed side-effect of drugs of the progesterone class.

Most experts in the field prefer that patients with APS use no estrogen or progesterone supplements until better information is available. In our small study of infertile women with APS undergoing artificial ovarian stimulation to achieve pregnancy, no APS-related complications of hormone treatment occurred[3].

Therefore, the take-home message is simple: both hormones and herbal and other dietary supplements may change one’s risk for clotting or, in some cases, bleeding. The best advice for APS patients is to use such products with extreme caution, if at all.

See the complete article on the Hospital for Special Surgery’s web site

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[1] ePocrates RxPro, www.epocrates.com

[2] Comp PC, Zacur HA. Contraceptive choices in women with coagulation disorders. Am J Obstet Gynecol. 1993 Jun;168(6 Pt 2):1990-3.

[3] Guballa N, Sammaritano L, Schwartzman S, Buyon J, Lockshin MD. Ovulation induction and in vitro fertilization in systemic lupus erythematosus and antiphospholipid syndrome. Arthritis Rheum. 2000 Mar;43(3):550-6.|

 
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How should proliferative glomerulonephritis with crescent formation be treated in young women with SLE? Will low-dose pulse cyclophosphamide (Cytoxan) and/or mycophenolate mofetil (CellCept) do the job while preserving fertility?

Published on May 28, 2003 by in For Physicians

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Decision-making in such young women can be difficult and among the most agonizing – for both patient and physician. It usually requires a very prolonged conversation with the patient and her immediate family, whether parents or significant other. While such women clearly need treatment – and preservation of fertility is obviously desired – it is very difficult to know the best option.

 We use one of three options in these circumstances:

1. administer full-dose cyclophosphamide (with prednisone) and hope for the best;

2. administer prednisone and mycophenolate, although there is a little controversy as to whether this is as effective as cyclophosphamide; or

3. pretreat the patient with leuprolide acetate (Lupron) and administer prednisone and cyclophosphamide, although it makes young women pretty miserable and it must be continued for the full duration of treatment.

None of these options is ideal. The usual solution is number 2. Low-dose cyclophosphamide would not be helpful. The Europeans (English and French, in separate investigations) have published on “low-dose” cyclophosphamide in uncontrolled trials, but their definition of low-dose is 0.5 g per meter squared every two weeks, rather than the NIH protocol of 1.0 g per meter squared every month – so I don’t get the point of it all. It seems to me the total cyclophosphamide dose is more or less the same, and they have provided no additional data regarding fertility or other critical information.

 See the complete article on the Hospital for Special Surgery’s web site

 
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How has the treatment of psoriatic arthritis changed over the last 5 years? Where do you see it going in the next 2 years?

Published on May 19, 2003 by in For Physicians

Ask the Expert

Several aspects of psoriatic arthritis make it hard to answer questions about its treatment succinctly.

First, there are at least three forms of psoriatic arthritis: in some patients it looks very much like rheumatoid arthritis, in others like ankylosing spondylitis, and in still others only the end joints of the fingers (and, usually, the fingernails) are involved. What may work for one type of psoriatic arthritis may not for another.

Second, although most doctors think all inflammatory rheumatic diseases are autoimmune, it has been very hard to identify specific problems with the immune system in patients with psoriasis or psoriatic arthritis. Since most treatments for autoimmune disease change the function of specific parts of the immune system, it is hard to know which function to identify as a potential target when you are not even certain that the immune system has gone awry.

Third, compared to rheumatoid arthritis, psoriatic arthritis is fairly uncommon. It is an ‘orphan’ disease, and most treatments that are tried have been borrowed from another disease rather than specifically developed for psoriatic arthritis.

That said, much has happened in the last few years. For at least the past two decades, the standard treatment for psoriatic arthritis has included nonsteroidal anti-inflammatory drugs, sulfasalazine and, in more severe cases, methotrexate or cyclosporin. Corticosteroid drugs such as prednisone have not been very effective. Methotrexate, the most effective, has the added advantage that it treats the skin condition as well as the joints, but even with it many patients failed to respond well. Drugs useful in treating the skin disease, such as acitretin (Soriatane), sometimes work in refractory cases but are often toxic.

About 5 years ago the dramatic success in rheumatoid arthritis of the new class of drugs called biologics, specifically inhibitors of a small chemical called tumor necrosis factor alpha led to trials of these drugs in psoriatic arthritis. In brief, TNF alpha inhibitors — etanercept (Enbrel) and infliximab (Remicade) – work extremely well in many patients with psoriatic arthritis of all three types[1],[2],[3]. Adalimumab (Humira) is a very recently released similar drug that may be expected to work as well. These drugs may work by inhibiting TNF alpha or by breaking the inflammatory cycle in a different way. TNF alpha inhibitors also appear to protect bone from being eaten away[4]. In clinical trials, these drugs reduce inflammation and prevent deterioration over several years, and they improve skin disease as well.

As a result of success with TNF alpha inhibitors, other biologics, which have different effects on the immune system, are now under trial[5],[6],[7]. The down side is that all of these drugs are extremely expensive, that they are injectable rather than available in pill form, and that their major side effect is that they make recipients susceptible to certain kinds of infections. Otherwise they are not particularly difficult to take. Specific information about these drugs can be found elsewhere on this website.

The details of how these biologics affect the immune system is less important than the fact that they do work in psoriatic arthritis. In doing so, they teach us that the immune system is abnormal in psoriatic arthritis, that very specific abnormalities can be corrected, and that the development of treatments based on an immunological theory of this disease is valid. Thus, in the next several years, we can expect to see many more immunologically active drugs – largely biologics – developed for and tried in psoriatic arthritis. With luck, one or more of the new drugs will be inexpensive, orally administered, side-effect free, and possibly even curative.

See the complete article on the Hospital for Special Surgery’s web site
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[1] Braun J, Sieper J. Role of novel biological therapies in psoriatic arthritis : effects on joints and skin. BioDrugs. 2003;17(3):187-99.

[2] Anandarajah AP, Ritchlin CT. Etanercept in psoriatic arthritis. Expert Opin Biol Ther. 2003 Feb;3(1):169-77.

[3] Yazici Y, Erkan D, Lockshin MD. Etanercept in the treatment of severe, resistant psoriatic arthritis: continued efficacy and changing patterns of use after two years.Clin Exp Rheumatol. 2002 Jan-Feb;20(1):115.

[4] Ritchlin CT, Haas-Smith SA, Li P, Hicks DG, Schwarz EM. J Clin Invest 2003 Mar;111(6):821-31. Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest. 2003 Mar;111(6):821-31.

[5] Kraan MC, van Kuijk AW, Dinant HJ, Goedkoop AY, Smeets TJ, de Rie MA, Dijkmans BA, Vaishnaw AK, Bos JD, Tak PP. Alefacept treatment in psoriatic arthritis: reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum. 2002 Oct;46(10):2776-84.

[6] Utset TO, Auger JA, Peace D, Zivin RA, Xu D, Jolliffe L, Alegre ML, Bluestone JA, Clark MR. Modified anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial.J Rheumatol. 2002 Sep;29(9):1907-13.

[7] McInnes IB, Illei GG, Danning CL, Yarboro CH, Crane M, Kuroiwa T, Schlimgen R, Lee E, Foster B, Flemming D, Prussin C, Fleisher TA, Boumpas DT. IL-10 improves skin disease and modulates endothelial activation and leukocyte effector function in patients with psoriatic arthritis. J Immunol. 2001 Oct 1;167(7):4075-82.

 
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Is there any difference in the prognosis of SLE patients who are diagnosed and treated early versus late in the disease?

Ask the Expert 

The biggest problem in answering this is the definition of ‘early’ and ‘late’ lupus. Some patients have very minor symptoms that persist for years and need almost no treatment; others are very sick from the outset of their very first symptoms.

Most people use the term ‘early’ to denote time, but in lupus the issue is probably one of severity. Clearly, the sooner the disease is recognized, and the sooner treatment is initiated, the less damage will occur. However, early treatment does not necessarily prevent later flares. Patients with SLE follow three types of courses: chronic active (accounting for about half of patient-years), relapsing-remitting, and long-remitting.

There’s also the concern about what sort of treatment is indicated. In some cases, that means corticosteroids; in others, immunosuppressives are needed, and in still others, anticoagulants. All have dangers associated with them, and it is a judgment call whether to use them or not in given circumstances. For example, even management of asymptomatic patients with anti-cardiolipin antibody is still controversial.

There is, in fact, so much variability in the treatment of an individual lupus patient that I cannot provide a clear answer about early or late treatment. However, I do not know of any research suggesting that early treatment prevents later serious flares.

(For further treatment information, see Dr. Lockshin’s Blog – Comment In-Depth Topic Review on SLE.)

See this article on the Hospital for Special Surgery’s web site

 
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Update on Smallpox and Flu Vaccinations

At this time of year, patients with lupus, rheumatoid arthritis, and other autoimmune diseases always ask, “Should I get a flu vaccination?” At this time in our history, many patients are also asking, “Should I get a smallpox vaccination?” These questions are really about three more general questions: 

  • Are patients with autoimmune diseases unusually susceptible to flu or smallpox?
  • Can patients with autoimmune diseases be adequately protected if they do receive a vaccination?
  • Is the vaccine safe, in the sense that it can either cause autoimmune disease to worsen or can cause complications by itself?

The brief answers, which are different depending on the disease and vaccine, are:

1. Patients taking immunosuppressive drugs, including prednisone or other corticosteroids, and those with lung and/or kidney disease, are unusually susceptible to flu.

Although little is known about susceptibility to smallpox, based on what happens with the related varicella virus (which causes chickenpox and shingles), patients on immunosuppressive drugs will likely be at high risk for severe disease if they are exposed to smallpox.

For both diseases, the increased risk includes patients taking: corticosteroids, such as prednisone and methylprednisolone (Medrol); immunosuppressive drugs, such as methotrexate (Rheumatrex, Trexall), azathioprine (Imuran), mycophenolate mofetil (CellCept), cyclophosphamide (Cytoxan), leflunomide (Arava), cyclosporine (Sandimmune, Neoral) and similar drugs; and biologics, such as the TNF-alpha inhibitors infliximab (Remicade) and etanercept (Enbrel) and the IL-1 inhibitor anakinra (Kineret).

2. Flu vaccine successfully protects patients with rheumatic disease, if they are not taking high doses of immunosuppressive drugs.

3. Flu vaccine does not worsen rheumatic disease and is generally well tolerated by rheumatic disease patients.

See the complete article on the Hospital for Special Surgery’s web site

 
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