Detroit, November, 1995 An antibody traditionally associated with rheumatic autoimmune diseases such as lupus, has been identified as a common thread in families where at least one member suffers from an autoimmune disorder associated with high levels of the antibody.

      The research, conducted by investigators at Yale University School of Medicine and St. Mary Hospital in Waterbury, Connecticut, was published in the November issue of the American Journal of Medicine.

      The antibody, known as the antiphospholipid antibody (APL), is one of a class of antibodies referred to as auto-antibodies. Common to autoimmune diseases, auto-antibodies are proteins produced by the body to attack itself, rather than invading viruses and bacteria. APL is made to fight certain good body fats called lipids. When the level of APL is high and these proteins float freely throughout the blood, a disease state occurs. The antiphospholipid antibody syndrome (APS) is associated with recurrent clotting events (thrombosis) including premature stroke, repeated miscarriages, phlebitis, venous thrombosis (clot in the vein) and pulmonary thromboembolism (blockage of an artery found in the lung due to a clot that has traveled from a vein). It is also associated with low platelet or blood elements that prevent bleeding.

      Recently, however, even more disease states have been linked with APL including premature heart attack, migraine headaches, various cardiac valvular abnormalities, skin lesions, diseases that mimic multiple sclerosis, vascular diseases of the eye that can lead to visual loss and blindness, and early peripheral vascular disease that can result in amputations of the extremities and digits.

      The St. Mary/Yale study looked at 23 individual family members with APS, 87 of their blood relatives, 18 spouses and 37 controls. Overwhelmingly, it found clustering of the APL antibody in families. Of the 87 blood relatives, some 50 — or nearly 60% — had auto-antibodies, compared with only one spouse. Approximately 33 percent or one-third had antiphospholipid antibodies, while another 37 percent had other auto-antibodies, such as anti-nuclear antibodies. None of the controls tested positive.

      The study also found that more relatives had suffered from one of the manifestations of APS than did either the spouses or controls. Indeed, several relatives were found to have either lupus (4) or lupus-like syndrome (4), premature stroke (2), recurrent fetal loss (3), recurrent thrombosis (1) or thrombocytopenia (2).

      While the study is relatively small, it is supported by other previous studies that suggest APL antibodies may actually be genetically transmitted from family member to family member, from generation to generation, said Thomas Greco, M.D., assistant clinical professor of medicine, Yale University School of Medicine, and chief, Section of Inflammatory Diseases, St. Mary Hospital, who conducted the research, along with Nahum Goldberg, M.D., and Ann Marie Kelly, M.D. More important, the APL antibody may be associated with one disease process in one family member and yet another disease process in another family member, he added.

      Collaborative studies looking into whether the various disease states may possibly occur in increased frequency in family members who carry the proteins are currently being planned by St. Mary, Yale University, and Duke University School of Medicine. In addition, other universities may participate in the joint research effort.

      Previous independent research at Duke led by Michael Seldin, M.D., Ph.D., associate professor, supports this new data. Dr. Seldin team found strong evidence for genetic transmission of APS in analyses of 12 different families. Preliminary modeling in these studies has suggested the possibility that inheritance of this disease may be due to a single dominant genetic defect with variability in disease penetrance. The workers in collaboration with Dr. Greco and other centers have initiated a study of the gene patterns in families with APL. It is hoped that this gene hunting study will ultimately define the genetic defect(s) in this disease.

      Recent data presented by French researchers at the October meeting of the American College of Rheumatology also support the findings of Drs. Greco, Goldberg and Kelly. In a study on families with antiphospholipid antibodies, many relatives were found to have diseases related to these proteins as well as many other immunologic diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome, Crohn disease, multiple sclerosis, low platelets (ITP), thyroid disease and others.

      Dr. Greco pointed out that while the prevalence of these proteins among the patients nationwide is relatively low (between 1 and 2 percent), for given families it may be very high — as high as one in every two family members. If an APL inheritance pattern can be firmly established in future studies, the good news is that we may be able to prevent premature stroke, heart attack, recurrent miscarriage and the other APL-associated diseases by performing simple and inexpensive tests and taking more thorough family histories, explained Dr. Greco. It may be premature to say, but APL may end up being one of the common threads that ties together all of the seemingly unrelated 80 known autoimmune diseases, said Virginia T. Ladd, president of the American Autoimmune Related Diseases Association (AARDA).

      She said large studies of patients with neurologic autoimmune diseases such as multiple sclerosis and myasthenia gravis, endocrine autoimmune diseases such as thyroid, juvenile and type 1 diabetes, and rheumatic autoimmune diseases including rheumatoid arthritis, lupus, scleroderma and Sjogren syndrome, need to be conducted to confirm this theory. If it turns out that APL is a common factor in autoimmune diseases, then the next step for researchers is to begin looking for an autoimmune gene.

      According to AARDA, approximately 50 million Americans,(20 percent of the population or one in five people) suffers from an autoimmune disease. Of these, the majority are women; some estimates say that 75 percent of those affected — well over 30 million people — are women. Autoimmunity is the underlying cause of all autoimmune diseases and the leading cause of chronic illness. While these illnesses cannot be cured, they can be treated.

      AARDA is the nation only organization dedicated to raising awareness of the early warning signs of autoimmune diseases, bringing a national focus to autoimmunity as a major health issue, and promoting a collaborative effort among researchers to find a cure for all autoimmune diseases.

Profiles — Families with APL

     The Frey Family — Several years ago, Jennie Frey, one of the patients in Dr. Greco study, suffered severe headaches, arthralgia (joint pain) and tested positive for the antiphospholipid antibody (APL). In her workup she was found to have multiple small strokes on her MRI scan. While in care, her daughter was hospitalized and had a stroke. Other physicians who had been caring for her discontinued her Coumadin after a year and she had a second stroke. In Dr. Greco first family study, he found that not only was this daughter (age 31) suffering from the APL syndrome (APS), but that a second daughter who had pregnancy loss has APLs. In addition, a third daughter also has auto-antibodies in her serum.

      The Santiago Family — Amarilis Santiago is a young woman who, in her teens, developed ITP (the low platelet syndrome associated with APLs). She was treated for that and then developed ischemia (gangrene) of her finger and toe. She then developed deep venous thrombosis and phlebitis of her leg. Later, she had a major lung clot and recurrent lung clots — despite aggressive therapy — and required a filter placed in her inferior vena cava to prevent further clotting and stroke, and further pulmonary emboli.

      The Santiago family, like the Frey, was one of the families in Dr. Greco study. Amarilis mother, Mrs. Santiago, tested positive for APLs. She also has experienced joint pain, myalgia, headaches, but has not yet had any major events.

      Amarilis brother has not been as lucky. In the early 90, while at the Groton Submarine base, he developed ITP (low platelet), the exact same disease process that Amarilis had developed. He was sent to Bethesda Naval Hospital where he tested positive for other auto-antibodies, and upon further evaluation was diagnosed with aplastic anemia. After conferring with Dr. Greco about the other family members medical history, a bone marrow transplant was ruled out by the Bethesda physicians. Instead, they treated him with high doses of corticosteroid and were able to reverse the aplastic anemia. While he recovered from that, he has since developed other medical problems, including a lupus-like illness.

     The Morgan Family — Sister Morgan is a nun at the Abbey of Regina Laudis in Waterbury, Connecticut. She was diagnosed with a multiple sclerosis-like illness. Because of atypical presentations for her neurologic syndrome, she was evaluated by Dr. Greco and found to have APLs antibodies (two types). Multiple sclerosis-like illnesses have not been described in patients with APLs and work is being done currently to further study this patient population. While not part of Dr. Greco study, his team has seen her father, who was suffering from weakness, joint pain and swelling. At first, his platelet count, which normally is 150,000 to 250,000, was 1,000. He suffered from thrombocytopenia (low platelet count), a disease that is well established as a primary marker for the APS. He also had APLs. Hence, both the daughter and father had APLs and both had different disease processes. Mr. Morgan had numerous hospitalizations over the next year. Over that period, a classic picture of APS, with thrombocytopenia , positive lupus anticoagulant and anticardiolipin antibodies (two types of APLs). He then developed a perforated nasal septum. Currently in Dr. Greco care, he is doing well on a therapy that includes cortisone therapy and cytoxic (anticancer) agents.

     The Berardi Family — Anthony Berardi is a husband and father and has been a patient of Dr. Greco for many years. He has had cutaneous skin lupus erythematosus and some other features of systemic lupus erythematosus (SLE), but has been healthy enough to maintain his job as an electrician. His daughter developed juvenile rheumatoid arthritis and had been followed by Dr. Greco. She has also had pregnancy loss and has tested positive for APLs. Her gynecologist has been notified and she has been started on treatment with aspirin therapy throughout the current pregnancy (standard therapy now for one pregnancy loss with APL). Recently, Mr. Berardi developed dizzy spells, numbness of his face, and symptoms suggestive of a transient ischemic episode (compromised blood flow to his brain). Based on his daughter history, he was tested for APLs recently and tested positive. He is being treated with Coumadin in order to prevent further strokes. (The strokes have been documented on MRIs). Another family member recently died with systemic lupus erythematosus.

      AARDA PRESS RELEASE 11/95 - Study in American Journal of Medicine, Nov. 1995 Issue.