The Genetic Basis of Lupus
Lupus is an illness in which the immune system appears to have gotten confused. Instead of attacking viruses, bacteria or cancer cells – which is what it's there to do – the immune system attacks the person's own body.
The evidence that lupus is a genetic disease is quite clear. Lupus runs in families. If you have lupus, there's a five percent chance that one of your siblings will get the disease.
If you are a non-identical twin, the chances are about the same as for a sister, suggesting that nothing major happens in the womb to cause lupus. But if you are an identical twin – and your twin has lupus – the chances go up to 57 percent that you will develop the disease. Thus, there is strong evidence for a genetic basis, but it is clearly not a simple genetic basis.
If just one gene you could inherit always caused lupus, at least one out of four siblings should get lupus, considering the classic laws of genetics. Some people who are related to lupus patients have various lupus-like symptoms, suggesting that they have acquired “incomplete lupus” without developing the full-blown disease.
So how do we explain that? And, since identical twins are genetically identical, why does lupus affect only 57 percent of identical twins? We're just beginning to understand that there are several possible explanations.
Multiple Genes Involved
The first important concept is that more than one gene may be involved. One-fourth of your siblings should inherit any one gene, but if three, four or more different genes need to be inherited together, this doesn't explain why both identical twins don't get the disease, since they inherit the same genes.
A concept that could explain why some identical twins of lupus patients are spared is called gene penetrance. This means that you can have a gene – and that gene may cause you to be susceptible to a disease – but the illness still doesn't show up. This is possible because something in the environment is needed to get the disease started. This environment can be either outside your body or inside your body, which is greatly influenced by infections or toxins, or even your other genes. The idea that a certain gene could be there – but not expressing itself completely – is called “incomplete penetrance.”
A third concept, developed in recent years, is that there are cases where genes actually change or rearrange themselves in the body after the first cell divides at the moment of creation. So even identical twins can end up with somewhat different genes that develop later, after they have separated from each other in the womb, or after birth. This can be true for certain genes that have to do with the immune system.
The Role of Genes
What do we know about lupus that helps us to understand the roles of genes? First, there is the predominance of women to men who get the disease. It seems likely that this has to do with a direct effect of hormones on the immune system. Female hormones may help create the environment that allows a lupus gene to penetrate.
Much research is being done to identify the genes that lupus patients share. The ones that are best understood are a series of genes which regulate how the immune system works and where and when it might attack.
These genes are part of the network that is involved in tissue typing. They allow the immune system to recognize and attack foreign invasions from viruses, bacteria, or cancer cells, and to distinguish them from things that should not be attacked, such as parts of the body or tissue-typed organ transplants.
If you were looking for a defective gene that causes lupus, major histocompatibility complex (MHC) genes, whose normal function is to regulate immune responsiveness, would be good candidates since the immune system in lupus gets confused into attacking a person's own body. And, in fact, MHC genes are shared by many lupus patients.
How Genes Work
How do these genes work? They make proteins that act very much like the Lord Chamberlain to a very paranoid queen. Imagine a world in your bloodstream that is rather like medieval times with lots of small castles, each inhabited by a different queen, each queen waited on by a special court made up of one Lord Chamberlain and a lot of little soldiers.
If an infection enters the bloodstream, an invading particle will be picked up by a special Lord Chamberlain, who is genetically programmed to recognize it. He takes the particle back to his own castle and formally presents it to the queen as if it were the ambassador from a foreign country. The queen takes one look at the particle, shouts, “Off with its head!” – and all sorts of things start to happen.
First, immune-fighting cells get made. Then little proteins called antibodies get made. These are like little soldiers who specifically know how to recognize that original invading particle. So they leave cells and run around the blood stream attacking anything that looks to them like the particle.
If they get confused and think your kidney or joints look like an invading particle, then you might develop lupus. But the antibodies would never have started attacking if the Queen hadn't started shouting. And the Queen would have kept quiet if the Lord Chamberlain hadn't brought the particle into her castle.
The Lord Chamberlain (who is an MHC molecule) may be shared by many lupus patients and may be one of primary genes that put people at risk. The Queen (who is called the I Cell Receptor) and the antibodies are examples of immune genes that can rearrange themselves after the beginning of life, so they may or may not be shared exactly in families, even by identical twins. This could explain why an identical twin of a lupus patient might have more risk of developing lupus than another sister, but not a 100 percent risk.
Self-Attacking Genes
But why do lupus patients carry these genes that can start an attack on their own bodies – and what prevents other people from doing the same thing? In order to have a diverse ability to recognize and protect the body from diverse infections over a lifetime, everybody has some genes capable of making proteins that attack their own organs.
However, immune cells go through a complex educational process early in life in the thymus gland, where they are taught to recognize the difference between “us” and “them” – and what sorts of invaders it is appropriate to attack. Those that misbehave and threaten to attack parts of their own bodies are usually simply killed off by a process called apoptosis. But the well-behaved immune cells “graduate” from the thymus and are allowed to enter the bloodstream.
A gene which regulates the system that eliminates self-attacking cells in the thymus gland is defective in some mice with a lupus-like illness. The jury is still out on whether this is the fact in human lupus – but many researchers are now considering the possibility.
I cannot go into all the other genes that seem to put people at increased risk for lupus. But one important set of genes gives rise to special inflammatory proteins called complement proteins. These proteins act something like the artillery used by the antibody soldiers when they attack, and defects to some of the complement genes have been described in lupus and lupus-like illnesses.
Continued Research Needed
In summary, lupus is a complicated disease with a complicated genetic basis. It involves several genes we know of, and probably more not yet identified, that are important to regulating appropriate immune activity.
There are two reasons why continued research into the causes and genetic basis of lupus is very important – first and foremost, to improve the care of lupus patients. Although treatments are better than 20 years ago, and we encourage lupus patients to have optimism for a fairly normal life, people still die from lupus or from side effects of the medications. And others become very ill and suffer major organ damage. Patient care could be better if we knew more.
Second, what we learn by studying lupus has profound implications for better understanding and treatment for many other diseases. This point should not be forgotten when writing to Congresspersons or fundraising for the Lupus Foundation.
Lupus research provides a large picture window into the mysteries of the immune system and will very likely contribute to the understanding and treatment of AIDS, heart disease, cancer, diabetes and many other diseases. This research includes the one disease that costs more than any other – and affects everyone on earth – the process of aging itself.
By Joan T. Merrill, MD, St. Luke's-Roosevelt Hospital Center, New York City. Reprinted with permission from the newsletter of the SLE Foundation, New York.
=========================================================== This information is for"informational purposes" and is not meant to be used for medical diagnosis. Alwaysconsult your physician on matters such as this.
Tuesday, March 13, 2007
Difficult-to-Manage Lupus
Difficult-to-Manage Lupus
Having treated over 2,000 lupus patients over the last 20 years, I was intrigued when the editor of Lupus Update asked me to write about “Difficult to Manage Lupus.” After all, isn't all lupus difficult to manage? However, there are certain situations that are more difficult to manage than others. Ten patient cases are presented here:
When not to overtreat? Resistant non-organ-threatening disease?
A patient with Systemic Lupus Erythematosus (SLE) has persistently active rashes, fevers, fatigue and pain on taking a deep breath despite nonsteroidals and Plaquenil. There is no evidence for heart, lung, liver, central nervous system, hematologic or renal involvement. There are circumstances when certain treatments often do more harm than good if oral steroids or methotrexate are added in this situation, so I might try a few other things first. Consider increasing Plaquenil, consider DHEA, use very high dose nonsteroids or a local one-time only steroid boost.
Cyclophosphamide (Cytoxan) resistant lupus nephritis
Fifteen to twenty percent of all individuals with SLE have lupus in their kidneys and biopsies showing proliferative disease. With no treatment, they will be on dialysis within 2-3 years. Although Cytoxan is the treatment of choice for them, this toxic therapy does not work or wears off 30-40 percent of the time. What do I do? My options include: consider adding azathioprine (Imuran) to the Cytoxan and continue treatments; add plasmapheresis or pulse-dose steroids; or substitute nitrogen mustard for Cytoxan. Consider rebiopsying the patient and make sure that the renal lesion is reversible. Sometimes, it's better to let a patient go on to dialysis and transplant them than treat them further. Newer treatments may be utilized: cyclosporin, mycophenolate mofetil (CellCept) or tacrillimus (Prograf, FK 506). Drug trials with LJP394 and Biogen's antiCD40 ligand are available at selected medical centers.
Refractory chronic cutaneous lupus with no systemic disease
A patient has lupus rashes covering 70 percent of the body, but their ANA is negative and all blood work is normal. Plaquenil has not helped. I have had some success with: switching from Plaquenil to Chloroquine and adding quinacrine, retinoids such as Accutante or Soriatene; antileprosy drugs including thalidomide, clofazimine or dapsone; topical nitrogen mustard or BCNU.
Lifestyle-altering central nervous system (CNS) symptoms with a normal MRI scan of the brain and blood tests showing slight activity
When my patients complain about not thinking clearly, severe headaches and profound fatigue, the issue is raised as to whether it could be vasculitis of the CNS. True CNS vasculitis in SLE is usually obvious (e.g., fevers, meningitis-like picture, psychosis, seizures), and responds to high dose steroids. But could the patient have “subclinical vasculitis?” In fact, this is rare and most often the symptoms are due to abnormal blood flow to the brain due to a dysfunction of the autonomic nervous system and / or the dysfunction of chemicals known as cytokines (interleukins, interferons, etc.). I frequently order a SPECT scan (which might include antineural antibodies) and antiribosomal P antibodies and a spinal tap. Make sure that your doctor obtains LE cells, oligoclonal bands, antineuronal antibodies and IgG synthesis rate in addition to the usual determinations.
Cognitive impairment in patients without CNS vasculitis
How do we treat the patient in number 4 (above) who does not have vasculitis? Interventions are useful that improve the blood flow to the brain regulated by the autonomic nervous system (which controls the dilation or constriction of blood vessels, thus regulating our pulse and blood pressure), such as: biofeedback, relaxation techniques, cognitive therapy and counseling. Additionally, serotonin boosters (Prozac, Zoloft, Paxil) may help give a patient more energy and clarity. Antimalarials (Plaquenil, quinacrine) and DHEA can be useful. Steroids may seem to help at first but make things worse in the long run and should be avoided unless there is evidence for inflammation.
More than one miscarriage in a patient without anticardiolipin antibodies
Antiphospholipid antibodies and the circulating lupus anticoagulant can cause miscarriages. Most primary care doctors stop the workup after obtaining a negative anticardiolipin antibody and circulating anticoagulant test and don't treat the patient. On the other hand, aggressive reproductive immunologists unnecessarily treat patients with expensive and toxic approaches such as heparin, prednisone and intravenous gamma globulin for subsequent pregnancies which would be successful in any case. Active lupus by itself can cause miscarriages. I'm in the middle. I check for three to four different phospholipid antibodies, Protein C, Protein S, antithrombin III, Factor V Leiden mutation, BDRL and kaolin PTTs.
Is the muscle and joint aching a lupus flare or fibromyalgia?
Fibromyalgia can be as discomforting as lupus-associated inflammation but is made worse by corticosteroids. It is important not to inappropriately treat. I generally only treat symptoms of lupus with higher doses of anti-inflammatory medicine when there is objective evidence of joint swelling (synovitis), a high CPK (muscle enzyme), a high sed rate or CRP (blood tests for inflammation), low C3 complement or high anti-DNA. Lacking this, sometimes I have had to resort to obtaining a bone scan to assess if somebody with profound musculoskeletal discomfort and SLE is inflamed or experiencing a flare or fibromyalgia. The latter is treated with tricyclics, serotonin boosters and muscle relaxants and is seen in 25 percent of lupus patients.
The patients with non-organ threatening disease who want to treat their disease “naturally”
Twenty percent of patients with non-organ threatening disease will evolve organ threatening disease over five years, but this percentage decreases to five percent with two years of Plaquenil. No herb or spice has been shown to be specifically effective for SLE, and studies are sorely needed. None of these preparations, marketed as nutritional supplements to avoid FDA regulation, are standardized. Avoid believing testimonials and only rely on peer-reviewed published controlled studies. Let the buyer beware.
My eight-year-old daughter has aches and a positive ANA. Should I be worried?
Ten percent of women with SLE will have a daughter with the disease, and two percent a son with it. Twenty percent with SLE will have an offspring with an autoimmune disorder (most commonly autoimmune thyroid disease). Fifty percent of children of lupus patients have a positive ANA. Girls who are prepubertal develop lupus very rarely. Their positive ANA is inherited and their aches are usually due to growing pains. We usually advise against ANA or antibody testing unless there is objective evidence for a problem such as a fever, swollen joints or rash.
The 70-year-old woman with a diagnosis of new-onset lupus
Ten percent of the population develops ANAs as they age. When senior citizens are found to have a positive ANA and have a high sedimentation rate and joint aches, they often come to rheumatologists with a diagnosis of lupus. In reality, the overwhelming majority do not have the disease. Polymyalgia rheumatica, fibromyalgia, rheumatoid arthritis and particularly Sjogren's syndrome need to be ruled out.
By Daniel J. Wallace, MD, Clinical Professor of Medicine, UCLA School of Medicine. Reprinted with permission from the Maryland Lupus Foundation. Dr. Wallace is the author of “The Lupus Book: A Guide for Patients and their Families”.
=========================================================== This information is for"informational purposes" and is not meant to be used for medical diagnosis. Alwaysconsult your physician on matters such as this.
Having treated over 2,000 lupus patients over the last 20 years, I was intrigued when the editor of Lupus Update asked me to write about “Difficult to Manage Lupus.” After all, isn't all lupus difficult to manage? However, there are certain situations that are more difficult to manage than others. Ten patient cases are presented here:
When not to overtreat? Resistant non-organ-threatening disease?
A patient with Systemic Lupus Erythematosus (SLE) has persistently active rashes, fevers, fatigue and pain on taking a deep breath despite nonsteroidals and Plaquenil. There is no evidence for heart, lung, liver, central nervous system, hematologic or renal involvement. There are circumstances when certain treatments often do more harm than good if oral steroids or methotrexate are added in this situation, so I might try a few other things first. Consider increasing Plaquenil, consider DHEA, use very high dose nonsteroids or a local one-time only steroid boost.
Cyclophosphamide (Cytoxan) resistant lupus nephritis
Fifteen to twenty percent of all individuals with SLE have lupus in their kidneys and biopsies showing proliferative disease. With no treatment, they will be on dialysis within 2-3 years. Although Cytoxan is the treatment of choice for them, this toxic therapy does not work or wears off 30-40 percent of the time. What do I do? My options include: consider adding azathioprine (Imuran) to the Cytoxan and continue treatments; add plasmapheresis or pulse-dose steroids; or substitute nitrogen mustard for Cytoxan. Consider rebiopsying the patient and make sure that the renal lesion is reversible. Sometimes, it's better to let a patient go on to dialysis and transplant them than treat them further. Newer treatments may be utilized: cyclosporin, mycophenolate mofetil (CellCept) or tacrillimus (Prograf, FK 506). Drug trials with LJP394 and Biogen's antiCD40 ligand are available at selected medical centers.
Refractory chronic cutaneous lupus with no systemic disease
A patient has lupus rashes covering 70 percent of the body, but their ANA is negative and all blood work is normal. Plaquenil has not helped. I have had some success with: switching from Plaquenil to Chloroquine and adding quinacrine, retinoids such as Accutante or Soriatene; antileprosy drugs including thalidomide, clofazimine or dapsone; topical nitrogen mustard or BCNU.
Lifestyle-altering central nervous system (CNS) symptoms with a normal MRI scan of the brain and blood tests showing slight activity
When my patients complain about not thinking clearly, severe headaches and profound fatigue, the issue is raised as to whether it could be vasculitis of the CNS. True CNS vasculitis in SLE is usually obvious (e.g., fevers, meningitis-like picture, psychosis, seizures), and responds to high dose steroids. But could the patient have “subclinical vasculitis?” In fact, this is rare and most often the symptoms are due to abnormal blood flow to the brain due to a dysfunction of the autonomic nervous system and / or the dysfunction of chemicals known as cytokines (interleukins, interferons, etc.). I frequently order a SPECT scan (which might include antineural antibodies) and antiribosomal P antibodies and a spinal tap. Make sure that your doctor obtains LE cells, oligoclonal bands, antineuronal antibodies and IgG synthesis rate in addition to the usual determinations.
Cognitive impairment in patients without CNS vasculitis
How do we treat the patient in number 4 (above) who does not have vasculitis? Interventions are useful that improve the blood flow to the brain regulated by the autonomic nervous system (which controls the dilation or constriction of blood vessels, thus regulating our pulse and blood pressure), such as: biofeedback, relaxation techniques, cognitive therapy and counseling. Additionally, serotonin boosters (Prozac, Zoloft, Paxil) may help give a patient more energy and clarity. Antimalarials (Plaquenil, quinacrine) and DHEA can be useful. Steroids may seem to help at first but make things worse in the long run and should be avoided unless there is evidence for inflammation.
More than one miscarriage in a patient without anticardiolipin antibodies
Antiphospholipid antibodies and the circulating lupus anticoagulant can cause miscarriages. Most primary care doctors stop the workup after obtaining a negative anticardiolipin antibody and circulating anticoagulant test and don't treat the patient. On the other hand, aggressive reproductive immunologists unnecessarily treat patients with expensive and toxic approaches such as heparin, prednisone and intravenous gamma globulin for subsequent pregnancies which would be successful in any case. Active lupus by itself can cause miscarriages. I'm in the middle. I check for three to four different phospholipid antibodies, Protein C, Protein S, antithrombin III, Factor V Leiden mutation, BDRL and kaolin PTTs.
Is the muscle and joint aching a lupus flare or fibromyalgia?
Fibromyalgia can be as discomforting as lupus-associated inflammation but is made worse by corticosteroids. It is important not to inappropriately treat. I generally only treat symptoms of lupus with higher doses of anti-inflammatory medicine when there is objective evidence of joint swelling (synovitis), a high CPK (muscle enzyme), a high sed rate or CRP (blood tests for inflammation), low C3 complement or high anti-DNA. Lacking this, sometimes I have had to resort to obtaining a bone scan to assess if somebody with profound musculoskeletal discomfort and SLE is inflamed or experiencing a flare or fibromyalgia. The latter is treated with tricyclics, serotonin boosters and muscle relaxants and is seen in 25 percent of lupus patients.
The patients with non-organ threatening disease who want to treat their disease “naturally”
Twenty percent of patients with non-organ threatening disease will evolve organ threatening disease over five years, but this percentage decreases to five percent with two years of Plaquenil. No herb or spice has been shown to be specifically effective for SLE, and studies are sorely needed. None of these preparations, marketed as nutritional supplements to avoid FDA regulation, are standardized. Avoid believing testimonials and only rely on peer-reviewed published controlled studies. Let the buyer beware.
My eight-year-old daughter has aches and a positive ANA. Should I be worried?
Ten percent of women with SLE will have a daughter with the disease, and two percent a son with it. Twenty percent with SLE will have an offspring with an autoimmune disorder (most commonly autoimmune thyroid disease). Fifty percent of children of lupus patients have a positive ANA. Girls who are prepubertal develop lupus very rarely. Their positive ANA is inherited and their aches are usually due to growing pains. We usually advise against ANA or antibody testing unless there is objective evidence for a problem such as a fever, swollen joints or rash.
The 70-year-old woman with a diagnosis of new-onset lupus
Ten percent of the population develops ANAs as they age. When senior citizens are found to have a positive ANA and have a high sedimentation rate and joint aches, they often come to rheumatologists with a diagnosis of lupus. In reality, the overwhelming majority do not have the disease. Polymyalgia rheumatica, fibromyalgia, rheumatoid arthritis and particularly Sjogren's syndrome need to be ruled out.
By Daniel J. Wallace, MD, Clinical Professor of Medicine, UCLA School of Medicine. Reprinted with permission from the Maryland Lupus Foundation. Dr. Wallace is the author of “The Lupus Book: A Guide for Patients and their Families”.
=========================================================== This information is for"informational purposes" and is not meant to be used for medical diagnosis. Alwaysconsult your physician on matters such as this.
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