Information contributed by Douglas White, MD, PhD, Division Chief, Rheumatology, Gundersen Health System, Onalaska, Wisconsin; and the Lupus Foundation of America.

Chances are, if you are reading this, that you or someone you love has been diagnosed with systemic lupus erythematosus (SLE). It’s also quite likely that this is not the first material you’ve read on the topic. Indeed, there are many excellent discussions of this disease with an abundance of patient-oriented and scientific information and free advice from doctors and patients familiar with SLE. (A few of our favorites are listed below.) Unfortunately, much of the readily available information about SLE is either too vague and general to be meaningful to a particular patient, or too bogged down in scientific lingo to be helpful. Our aim then is to strike a balance and offer information about SLE that will advance patients’ understanding without overwhelming them with medicalese.

What is SLE?  The War Analogy
Much of what we understand about the immune system can be explained by analogy to the armed forces. In this analogy, your immune system is the sum total of the Army, Navy, Air Force and Marines. Germs (bacteria, viruses, etc.) that cause disease are the enemy. It’s immediately clear with this analogy that it would be misleading and an oversimplification to think of the immune system as either “on” or “off”. Like the armed forces, the immune system is a complex web of interacting components that is capable of graded responses. Furthermore, your immune system makes use of distinct branches at different times depending on the threat, and so part of the immune system may be quiet while another is highly active. Also like a good army, a finely tuned immune system knows when to shut down a response and trigger healing pathways in order to avoid excess collateral damage. When an enemy (especially one who has invaded your home soil) has been defeated, it’s counter productive to continue bombing. In this analogy, SLE is caused by environmental triggers and genetic defects that prompt distinct branches of the armed forces to over react or prevent them from shutting down an immune response in a timely fashion. But, again, it can be misleading to think of the immune system in a person with SLE as simply “hyperactive”. (People with SLE don’t enjoy extra protection from infectious agents.) Rather, derangements in one or more branch of the immune system appear to cause uncoordinated or poorly controlled immune responses with resultant damage to different organs at different times. In this analogy, treatment for SLE is aimed at blunting one or more branches of the immune system. The vast majority of treatments for SLE target broad domains of the immune system while some newer therapies (such as belimumab) attempt to target specific components of the immune system more narrowly.

Limitations of the War Analogy
For hundreds of years, sterility has been associated with health and safety. (This tenet, while currently being revisited by scientists, still dominates the marketing of hand soap in the United States.) The greatest limitation of the war analogy then, as it is usually conceived in the sterility-is-good-for-you era, is the fact that all humans are colonized inside and out by billions of micro-organisms, even in health. These passengers (and their genes) are variously referred to as “normal flora”, the “microbiome” (bacteria), the “virome” (viruses), etc. Most micro-organisms in and on our bodies do not pose a threat and therefore shouldn’t be thought of as the enemy. Indeed, these micro-organisms are beneficial (and necessary for normal health) when present in appropriate numbers in the appropriate anatomic space at the appropriate time. But the same micro-organisms, when present in larger numbers, or in the wrong location, or at the wrong stage of development can be deadly. It’s now clear that the normal immune system not only co-exists and interacts with billions of micro-organisms, but is shaped and sculpted by them. The concept that many diseases, including SLE, might be caused by disruptions in the immune system that stem from an imbalance in the components or location of our normal flora is an area of active research.

ANA and SLE
ANA stands for “antinuclear antibody” and is a blood test. This blood test is frequently (and misleadingly) referred to by doctors and patients alike as a “lupus test”. One of the most important things to understand about SLE is that a patient with a positive (abnormal) ANA test does not necessarily have SLE. The list of conditions associated with a positive ANA is long (see below) and includes normal healthy people. On the other hand, properly performed (HEp-2) ANA test, is highly valuable in ruling out SLE. That is to say, if a patient’s ANA test comes back negative (normal) then she or he almost certainly does not have SLE.

ANA testing is a topic of great confusion because the ANA test has not always been so reliable. Not long ago, medical schools correctly taught that approximately 20% of SLE patients would have a negative ANA. Fortunately, the methodology behind the test has improved and so the test is now much more sensitive. Unfortunately, there are labs that still perform less reliable (and less expensive) versions of the ANA test, sometimes without making this clear to ordering physicians, and so the confusion is propagated (see the ACR’s position statement here on this topic).

Partial list of conditions associated with a positive ANA test:
• Normal healthy people, especially women
• SLE
• Sjogren’s
• Myositis
• Drug-induced lupus
• Systemic Sclerosis
• Hashimoto’s thyroiditis
• Hepatitis
• Inflammatory bowel disease
• Psoriasis
• Tuberculosis
• Cancer
• Multiple Sclerosis
• Myasthenia Gravis
• Certain types of transplants

Potential causes of SLE
Like all scientifically rooted discussions of the cause of SLE, our comments on the topic start with a very important declaration: The cause(s) of SLE is/are not known. Perhaps the discussion should stop there because, quite frankly, nearly everything that follows is speculation. But the conversation almost never ends there. Patients and their families really want an answer. And scientists really want to provide one. And so we present our best hypothesis: that an environmental trigger (viruses seem to be the best candidates) in genetically susceptible individuals (a number of suceptibility genes have been identified), starts a cascade of events that culminate in SLE. In the broadest of terms, this hypothesis may well turn out to be correct. But there are huge gaps that need to be filled and the unfolding of the story will undoubtedly reveal unexpected plot twists.

In the meantime, as you hunt for an answer to the cause of SLE, we urge you to beware two major pitfalls that have led to many a misunderstanding and emotional let down. The first is reporting on individual scientific papers. One fundamental requirement of the scientific method is reproducibility and so no individual scientific finding is given full credence until it has been confirmed and corroborated by other scientists (it’s not good enough for the first scientist to get the same result three times in a row in her own lab). In this light, the hype that often accompanies public reporting on individual scientific papers is nearly always premature and overstated with trailing comments about the need for future research drowned out by headlines proclaiming a breakthrough. Ironically, even the scientists add fuel to this fire by employing workers at major medical schools whose job it is to make sure that announcements of high-profile papers are widely disseminated.

The second is the distinction between correlation and causation. At some level, we are all aware of the dangers of jumping to conclusions about the cause of an event just because it is correlated with something else. (That’s what makes this example so funny.) Nonetheless, when we do not have a sound understanding of a how a system works (as is often the case in medicine), the temptation is strong and has led to deadly consequences (for example, when we assumed that suppressing an abnormal heart rhythm would improve survival after a heart attack (see here for more information).

The Outlook (Prognosis) for People with SLE
The first thing to know about the prognosis of SLE is that the spectrum of disease burden among affected individuals is very broad. Some patients with bona fide SLE will have a mild course, find their symptoms relatively easy to treat with oral medications, live a normal lifespan and die of something else. Others will not be so lucky. For reasons that are still not clear, SLE in African Americans and Hispanics is more severe than it is in Caucasians. Though there is no cure for SLE, there has been tremendous progress over the last decades and survival rates have improved dramatically. In 1953, the 5-year survival of SLE was estimated at approximately 50%. By 2008, that number had jumped to 96% (Ippolito and Petri, 2008. Breban M et al 1991). And while part of this improvement is due clarifications in the definition of SLE (and thus the inclusion of milder cases), much of his has to do with improvements in the treatment for SLE as well as the infections and other problems (“co-morbidities”) that come with SLE.

SLE and the Nervous System
SLE can affect almost any part of the body and seems to affect the nervous system in a third or more of patients.  There are several terms doctors use to describe this: neuropsychiatric lupus (NPSLE), neurocognitive dysfunction, or central nervous system lupus (CNS lupus).  We emphasize them here because many SLE patients find nervous system symptoms among the most difficult to understand, explain to others, treat and tolerate.

The nervous system has three parts, any of which may be affected by SLE.

• The central nervous system (CNS)—The brain and spinal cord.
• The peripheral nervous system (PNS)—The network of nerves that connects the brain and spinal cord to the rest of the body, and gives skin and muscles the signals needed for sensation and movement.
• The autonomic nervous system (ANS)—Allows communication between spinal and peripheral nerves and the brain and internal organs, and controls functions like breathing, blood flow, and heart rate.

People with SLE can experience a number of complications when their nervous system is affected. The symptoms may come on suddenly or may come and go, but they will vary depending upon the location and extent of the tissue injury. These symptoms also can be present in other diseases, so diagnosing lupus-related nervous system disorders is often difficult.

Various diagnostic tools are used to determine whether SLE is the cause of nervous system problems:

• Brain scans — magnetic resonance imaging (MRI) and computed tomography (CT)
• Electroencephalograms (to capture the electrical pattern of brain activity)
• Lumbar puncture (aka spinal tap, to examine fluid in the spinal column)
• Behavioral and cognitive testing

Depending on the symptoms, a variety of medications are available to treat lupus-related nervous system disorders, including non-steroidal anti-inflammatory drugs, antimalarials, and steroids. Your response to treatment may be rapid or gradual over several months.  For many people with lupus, nervous system involvement is completely reversible.

Central Nervous System (CNS)
When lupus affects your central nervous system, many symptoms may occur, including:

• Headaches
• Confusion
• Fatigue
• Depression
• Seizures
• Strokes
• Vision problems
• Mood swings
• Difficulty concentrating

Lupus Fog or Cognitive Dysfunction
As many as half of all people with lupus describe feelings of confusion, fatigue, memory loss, and difficulty expressing their thoughts. This collection of symptoms is termed cognitive dysfunction, although many people with lupus call it “lupus fog.” Cognitive dysfunction most often affects people with mild to moderately active lupus. The causes of these symptoms, and the reasons the symptoms tend to come and go, remain unknown but some of the best research in this area is being done by Dr. Betty Diamond in Manhasset, NY. Living with cognitive dysfunction can be very frustrating. However, you can learn to improve your concentration and lessen confusion and memory loss with a variety of coping skills, including puzzles, games, biofeedback, using a daily appointment calendar, and balancing daily activities to reduce stress.

Lupus Headache
Compared with the general population, people with lupus may be twice as likely to experience migraine-like lupus headaches, commonly known as lupus headaches. The features of lupus headaches are similar to migraines and may be seen more often in people who also have Raynaud’s phenomenon. However, headaches can also be caused by vasculitis, a symptom of active lupus due to inflammation of the blood vessels. If you are experiencing headaches that are not improved by an over-the-counter headache medication, be sure to tell your doctor.

Medication Side Effects
Medications used to treat lupus can cause side effects that are similar to the symptoms of CNS lupus. If you have symptoms of CNS lupus you should consult a rheumatologist or neurologist who can determine which symptoms are side effects of medication and which are due to lupus. The drugs most known for causing symptoms like those of CNS lupus are:

• Non-steroidal anti-inflammatory drugs (NSAIDs) – May cause headache, dizziness, confusion, and in rare instances, meningitis-like symptoms
• Antimalarials – Very high doses (not usually given for lupus) may cause manic behavior, seizures, psychosis
• Corticosteroids – May cause agitation, confusion, mood swings, psychosis, depression
• Anti-hypertensive medications – May cause depression or loss of sex drive

A serious form of lupus called CNS vasculitis may occur when there is inflammation of the blood vessels of the brain. Characterized by high fevers, seizures, psychosis, and meningitis-like stiffness of the neck, CNS vasculitis is the most dangerous form of lupus involving the nervous system and usually requires hospitalization and high doses of corticosteroids to suppress the inflammation.

Peripheral Nervous System (PNS)
The nerves of the peripheral nervous system control motor responses and sensation, so symptoms of numbness or tingling, or inability to move a part of your body, may be the result of lupus affecting these nerves. Known as peripheral neuropathies, symptoms of PNS nerve damage are caused by inflammation or compression of the nerves due to swelling in the tissue around them. The types of symptoms you might experience include:

• Vision problems
• Facial pain
• Ringing in the ears
• Dizziness
• Drooping of an eyelid
• Carpel tunnel syndrome

Autonomic Nervous System (ANS)
The autonomic nervous system regulates many of the body’s functions that happen almost automatically: heart rate, blood pressure, feeling hot or cold, bladder and bowel functions, release of adrenalin, breathing, sweating, and muscle movement. Lupus can cause these nerve signals to be overactive, which can lead to a wide range of symptoms:

• Numbness
• Burning
• Tingling
• Mental confusion
• Headaches
• Gastrointestinal problems such as nausea, vomiting, constipation, or diarrhea

Raynaud’s phenomenon is a condition of ANS involvement caused by inflammation of nerves or blood vessels. Blood vessels in the hands and feet go into spasm and restrict blood flow, usually as a reaction to cold temperatures, with the tips of the fingers or toes turning red, white, or blue. Raynaud’s can also cause pain, numbness, or tingling in fingers and/or toes. People who have Raynaud’s phenomenon are advised to avoid cold conditions when possible, and may have to wear gloves or mittens when in air-conditioned surroundings.

Livedo reticularis and palmar erythema are two other skin disorders that may affect you if you have autonomic nerve damage. Both of these conditions can cause a bluish, lacelike mottling under your skin, especially on your legs, giving your skin a “fishnet” look.

Sources for more information

http://www.rheumatology.org/practice/clinical/patients/diseases_and_conditions/lupus.asp
http://www.uptodate.com/contents/systemic-lupus-erythematosus-sle-beyond-the-basics
http://www.hopkinslupus.org/lupus-info/