An In-Depth Overview of Systemic Lupus Erythematosus

1. Definition
2. Pathogenesis
3. Clinical Presentation
4. Laboratory Findings
5. Differential Diagnosis
6. Initial Treatment
7. Long-term Management Issues
8. Prognosis
9. When to Seek Referral to a Specialist
10. Annotated Bibliography

Lupus is an autoimmune illness in which parts of the immune system, which normally protect you from outside invaders, run amok and attack parts of your body.

Lupus has several forms:

• systemic lupus erythematosus (SLE), which can affect the skin and other organs throughout the body, including abnormalities in the blood;
• discoid lupus, which only affects the skin, causing a scarring rash (although subacute cutaneous lupus also primarily affects the skin);
• subacute cutaneous lupus is a form of systemic lupus in which a characteristic rash predominates, indicators in the blood are strongly positive, but involvement of other organs is usually mild;
• drug-induced lupus, which is relatively rare and disappears when the offending drug (such as hydralazine and procaine amide) is discontinued;
• neonatal lupus, which occurs in infants of women with specific blood test abnormalities.

(This article will focus primarily on SLE, with brief discussion of neonatal lupus in the section below on pregnancy.)

Although SLE is a chronic disease that usually lasts a lifetime, many patients have periods of flare (when symptoms worsen) and remission (when symptoms lessen or disappear).

SLE affects women nine times as often as men, blacks four times as often as whites, and is most likely to arise between the ages of 15 and 45. The reasons for this distribution are unknown.

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Differential diagnosis and management of the various signs and symptoms differ depending on whether the patient is newly diagnosed and untreated or the patient has been treated for many years. (See Boumpas in bibliography below.) Two recent American textbooks for physicians present extensively referenced and detailed discussion of all aspects of these illnesses. (See Wallace and Lahita.)

II. Pathogenesis

Pathogenesis refers to the origin and development of a disease. The actual cause of SLE is unknown, but research has suggested some interesting theories.

Lupus nephritis - inflammation of the kidney in people with lupus - is the model doctors use for explaining the pathogenesis of SLE. However, principles that explain lupus nephritis may not apply to other manifestations of lupus - such as lupus arthritis, rash, fever, alopecia (hair loss), thrombocytopenia (abnormally low platelets in the blood), heart valve problems, or neurologic disease (such as memory problems or seizures).

Research (especially that involving twins and families) suggests that genetics may be significantly involved in predisposing you to SLE. Further, some evidence suggests that infections of some kind-we don't know which-may be involved.

A particularly attractive theory suggests that failure to process the products of an immune response (the garbage managing aspect of immunity) is defective in SLE patients. This theory suggests that, in genetically predisposed people, that is, people whose bodies don't do a good job of managing the garbage, some external agent (such as a drug or virus) produces garbage that stays in the blood stream and triggers their immune system to develop antibodies (the germ-fighting agents in your blood) that cause inflammation - which damages their own tissue even more.

III. Clinical Presentation

A. New diagnosis

The classical patient with SLE is easy to recognize: a young woman with fever, swollen lymph glands, a butterfly-shaped rash on her face, arthritis - in the same small joints on both sides of her body, hair loss, chest pain, and protein in the urine.

Hair loss, particularly frontal, with short, broken hairs, is common.

Alopecia in SLE. Click Thumbnail to Enlarge

However, most patients have symptoms in only one or two body areas at the onset of SLE. In order of frequency, following are the common symptoms of lupus.

1. Arthritis (inflammation indicated by heat, redness, and swelling) in multiple small joints - such as those of the hands and wrists - which may be fleeting or sustained and, on occasion, look like rheumatoid arthritis;

2. Malaise, fatigue, low grade fevers (sometimes high fever), and weight loss - called "constitutional" symptoms;

3. Rashes (simply erythema - redness - of the skin or, more often raised rashes) that characteristically involve the central area of the face (called a malar rash), the hairline, the "shawl" area and backs of the upper arms, the finger tips, and the base of nails;

4. Hair loss (alopecia), particularly in the front of the head - with short, broken hair;

5. Kidney (renal) disease, such as nephritis (inflammation of the kidney) and glomerulonephritis (inflammation of the glomeruli filters in the kidney) which may be detected by the presence of protein in your urine;

6. Blood (hemotologic) abnormalities, anemia, leukopenia, and cytopenia;

7. Chest pains, usually due to inflammation of the pericardium (the sac that surrounds your heart) or the pleura (the membrane that surround the lungs) - called pericarditis and pleuritis;

8. Oral ulcers in the mouth that are usually painless;

9. Neuropsychiatric problems, such as headache, memory problems, mood disorders, confusion, psychosis, seizure, and stroke;

10. Abdominal pain.

Hard palate ulcer in SLE (arrow). Click Thumbnail to Enlarge

Other problems that may occur later in the course of SLE are rarely seen when the disease is initially diagnosed. These include: myelopathy (a disorder of the spinal cord), myocarditis (inflammation of the middle layers of the walls of the heart), lung problems such as pulmonary hypertension or pneumonitis, and acute psychosis.

B. Established diagnosis

Patients with SLE follow three types of courses: chronic active, relapsing-remitting, and long-remitting. The chronic active form is most common, accounting for about half of patient-years.

A common mistake in treating a patient with known SLE is to attribute any deterioration in health in a patient to lupus activity. Attribution of a complication to active SLE should always occur by exclusion, after infection, drug reaction, atherosclerosis, and neoplasm have been ruled out. Even arthritis in a lupus patient may be due to infection or to osteonecrosis. Osteoporosis with fracture may be a cause of extremity or back pain.

IV. Laboratory Findings

A. Routine blood, urine, and biochemical tests

If your doctor thinks you may have lupus, your initial evaluation is likely to include a series of blood tests - complete blood count (CBC), sedimentation rate (a measure of inflammation), chemistry profile, lipid profile - and urinalysis. If the urinalysis is abnormal, your doctor may have you collect your urine for 24 hours and do a test called creatinine clearance to further check your kidney function. Other available tests add to general information about the patient but are not critical for management unless indicated by specific symptoms.

B. Serological (blood) tests

A number of immunological "markers" of lupus can be detected in blood. To diagnose lupus definitively, your doctor will check for: antinuclear antibody (ANA), which is, for practical purposes, always positive, and is used as a screening test (a negative ANA excludes lupus), anti-double-stranded DNA antibody, anti-Sm (which stands for anti-Smith) antibody, either of which confirms the diagnosis, and - to check for possible kidney problems - complement (as C3, C4, and/or CH50).

If your doctor knows or suspects that you have had a blood clot or a miscarriage, checks for anticardiolipin antibody and lupus anticoagulant (antiphospholipid antibody) are helpful. If a woman is contemplating pregnancy, in addition to antiphospholipid antibody, tests for antibody to Ro/SSA and La/SSB can help predict if your baby may develop neonatal lupus.

V. Differential Diagnosis

Many different diseases can cause symptoms similar to those of SLE. Differential diagnosis is the process by which the physician figures out which one is causing your problems. This is important because diseases that may cause such symptoms are often treated in a very different manner from SLE.

A. Confusing other diseases

Infections such as mononucleosis (sometimes called "the kissing disease"), HIV, endocarditis (inflammation of the membrane lining the heart), and strep after-effects (such as rheumatic fever and kidney problems) resemble SLE. Some types of cancer, including lymphoma and leukemia, may cause lupus-like symptoms. The rash of rosacea is easy to confuse with that of SLE, as is antibiotic-induced photosensitivity. Although thrombocytopenia (low levels of platelets in the blood) can be caused by SLE, it may also occur as an adverse effect of some drugs or after a strep infection or other causes. What distinguishes lupus from some of these problems is the ability of lupus to cause abnormalities in multiple organs at the same time.

B. Overlap diseases

Some lupus patients have symptoms that overlap those of other diseases, such as rheumatoid arthritis, scleroderma, dermatomyositis, Sjogren's syndrome, or systemic vasculitis (inflammation of the blood vessels). In such patients, the diagnostic label is less important than are the symptoms and organ systems involved because treatment is directed to specific abnormalities of specific organ systems.

C. ACR Criteria and how to use them

The American College of Rheumatology has devised Classification Criteria for SLE (See Table 1). When a patient has any four of the following, she is said to have SLE: malar rash; discoid rash; photosensitivity; oral ulcers; non-erosive arthritis; pleuritis or pericarditis; renal disorder; neurologic disorder; hematologic disorder; anti-DNA, anti-Sm, or antiphospholipid antibody; and antinuclear antibody.

These criteria classify groups of patients for clinical studies and do not diagnose individual patients. In individual patients, the diagnosis of lupus is fully sustainable with fewer criteria. For instance, a patient who has high titer antinuclear antibody and lupus glomerulonephritis on biopsy, but who has no other symptoms, clearly has lupus even though she has only two criteria. Conversely, a patient with rheumatoid arthritis might have antinuclear antibody, hemolytic anemia or thrombocytopenia, proteinuria, and pleurisy-more than four criteria-and not have lupus. Hence the ACR Criteria should not be used to exclude or confirm the diagnosis of lupus in an individual patient.

VI. Initial Treatment

A. Indications to Treat

If you don't have any symptoms, you may not need treatment - except when laboratory tests reveal proteinuria, hematuria (protein or blood in the urine) or severe thrombocytopenia (<50,000/mm3). Anti-DNA antibody and complement should be monitored, but do not by themselves demand treatment if there are no associated clinical findings of disease activity.

Treatment includes non-steroidal anti-inflammatory drugs (NSAIDs), drugs originally developed for malaria (but which help lupus), and low dose corticosteroids (such as 20 mg prednisone per day or less). You only need doses that suppress your symptoms if you have arthritis, fever, rash, lymphadenopathy, anemia, and/or serositis.

But more aggressive therapy (higher dosing) is needed if you have nephritis and neurologic disease. High dose corticosteroid and immunosuppressive drugs are appropriate for systemic flare, glomerulonephritis, severe thrombocytopenia, neurologic disease, and vasculitis. Life-threatening disease requires use of all available treatments, including experimental drugs and procedures.

B. Drugs

1. NSAIDs. These drugs help ease pain and prevent inflammation. NSAIDs are generally useful for patients with myalgia (muscle aches), arthralgia (joint aches), arthritis (inflammation of joints), and serositis, and are occasionally useful for control of low-grade fever (under 101^o). More than a dozen traditional NSAIDs are available, such as ibuprofen (brand names include Motrin, Advil). No specific NSAID is preferred.

Occasional lupus patients develop renal insufficiency, hepatitis, or high fever and sterile meningitis when given NSAIDs, especially (but not exclusively) indomethacin or ibuprofen. In patients with thrombocytopenia, newer NSAIDs called COX-2 inhibitors are preferred because of their lack of effect on platelets. Celecoxib (Celebrex) should not be used in patients who are allergic to sulfonamides, a common problem in SLE patients.

2. Sunscreens. Approximately one-third of lupus patients are photosensitive, i.e., become ill (not just rash) after sun exposure. These patients benefit from use of high-grade sunscreens, SPF 15 or higher. In addition, you should try to avoid being out in the sun for extended periods between 10 am and 4 pm in the spring and summer.

3. Antimalarials. These drugs modulate the immune system in ways that are not understood. Patients with arthralgias, malaise, fatigue, or rash often respond well to hydroxychloroquine (Plaquenil) at 200-400 mg/day. This drug can also help prevent flares. Its effects usually take three months to be seen. Very rarely, patients taking hydroxychloroquine develop a problem in the eyes called retinopathy. Although recent data have questioned the existence of hydroxychloroquine retinopathy, retinal monitoring is still advised. Depending on your dose and how long you have been taking it, Your doctor is likely to advise seeing an ophthalmologist every six months to a year. Discontinuation of hydroxychloroquine may cause severe disease exacerbation. Rarely, hydroxychloroquine causes darkening of the skin, like a suntan.

4. Corticosteroids. Corticosteroids are synthetic versions of a hormone produced by your adrenal glands. They help suppress inflammation. High dose oral corticosteroid (60 mg/day of prednisone or equivalent) for four to six weeks, followed by taper (gradual reduction of dosage) over several months, is the gold-standard treatment for patients with systemic flare, glomerulonephritis, severe thrombocytopenia, vasculitis, and neurologic disease of any type except antiphospholipid antibody-associated stroke. Lower doses of corticosteroid are used for symptomatic treatment of patients not responding to NSAIDs and/or antimalarials. Bolus intravenous steroid is methylprednisolone (Solu-Medrol), 1000 mg, given over 30 minutes daily for three consecutive days has been used to treat acute SLE since the 1970s. However, there is little research to support this practice - except for inducing remission in patients with glomerulonephritis. Most specialists use bolus steroid for control of other lupus manifestations; some use it monthly in lieu of daily oral steroid. There are no systematic studies proving that one regimen is better than the other. (Long-term use of corticosteroids increases the risk of developing osteoporosis.)

5. Immunosuppressives. Immunosuppressive drugs tamp down your immune system - some parts of which are over-active when you have lupus. Cyclophosphamide (Cytoxan), azathioprine (Imuran), methotrexate (Rheumatrex or Trexall), cyclosporine (Sandimmune or Neoral), and mycophenolate mofetil (Cellcept) are the immunosuppressive drugs most commonly used in SLE. The three most common situations that lead to prescribing immunosuppressives are:

• you have diffuse proliferative or membranoproliferative glomerulonephritis; research has clearly shown that these drugs preserve kidney function;
• you don't get adequate benefit from low to moderate doses of corticosteroids;
• you respond to corticosteroids but have been unable to reduce your dose below 20 mg of steroid per day.

Intravenous cyclophosphamide, usually given once a month for six months, and then every three months for 24 more months, is the most effective and proven regimen for treating severe lupus nephritis, although other dose schedules may be effective. Azathioprine (100-150 mg per day), cyclosporine (2.5 mg/kg/d of Neoral), and mycophenolate mofetil (1-2 grams per day) are likely as effective but less well-established in clinical trials. Methotrexate (up to 20 mg per week) is primarily used for intractable arthritis.

6. Anticoagulation. Some people with SLE who have antiphospholipid antibodies are more likely to develop blood clots (thromboses) and need anticoagulant therapy to prevent them. Anticoagulation with warfarin or heparin is indicated for patients with recurrent thromboses due to antiphospholipid antibody, but usually not for vascular occlusion due to vasculitis. Heparin is appropriate for pregnant patients who have had repeated miscarriages due to antiphospholipid antibody. If you are taking warfarin, you will need frequent blood tests to make sure you are at the right dose and not at risk for either clots or excessive bleeding. Enoxaparin (Lovenox) and dalteparin (Fragmin) are forms of heparin that are more convenient and safer than standard heparin (but much more expensive); these drugs have also been used successfully for anticoagulation but have not been formally studied in clinical trials.

C. Experimental Approaches

1. Intravenous immunoglobulin, given daily for two to three consecutive days each month, is clearly, though temporarily, useful for patients with severe thrombocytopenia. It also may aid recovery in patients who have recurrent miscarriages or vasculitis. It sometimes is the only agent usable in patients with severe infection and active disease, in whom high dose corticosteroids and immunosuppressive agents are relatively contraindicated by the infection.

2. Dehydroepiandrosterone (DHEA) is widely known to the lay public, and many patients take small doses (25 to 50 mg/day). In clinical trials, 200 mg/day offered a small benefit to a subset of patients, but the drug form known as prasterone has yet not received FDA approval for treating SLE.

3. Vitamins are taken by most patients, but the benefit of any specific vitamin is unknown. Patients taking methotrexate require folic acid to reduce the risk of side effects. All patients taking corticosteroids should take vitamin D and calcium to help prevent osteoporosis. Antioxidants may be useful, particularly for patients at risk for early atherosclerosis.

No agent among the new biologics has yet emerged as an effective therapy for SLE, though many are now under test.

VII. Long-term Management Issues

A. Lupus nephritis

Between one-third and one-half of lupus patients develop kidney disease; those with high levels of anti-DNA antibody and low serum complement levels are most at risk. Lupus nephritis is likely when urinary protein, erythrocytes, or leukocytes (in the absence of infection) occur, or when creatinine clearance falls; your doctor can monitor you for this problem with blood and urine tests. Because other problems - such as kidney stones, obstruction, infection, and neoplasm (cancer) - can cause the same signs, they must be excluded before treatment. Although lupus nephritis can occur in patients with normal urinalyses and normal renal function, if serum complement is normal, important disease is unlikely.

When to do a kidney biopsy
A kidney biopsy is appropriate when the results will change treatment. The most common reason for a biopsy is new discovery of a modest proteinuria or celluria with normal, near normal, or recently changed creatinine clearance. A patient with normal urinalysis and renal function is not a candidate for biopsy, since the likelihood of a kidney lesion that needs treatment is low. Biopsy also is not appropriate in a patient with rapidly progressive renal failure, severe proteinuria, or cellular casts, since immediate aggressive therapy is mandatory. However, in a patient with rapidly progressive disease, a biopsy to assess whether any salvageable kidney remains may occasionally be appropriate; the results of the biopsy may justify a change in treatment.

Types of lupus glomerulonephritis
By biopsy criteria, the following types of lupus glomerulonephritis are recognized.

• Normal biopsy.
• Mesangial nephritis (immune complexes and some inflammatory cells in the mesangium). Long-term prognosis for maintenance of kidney function is good.
• Focal proliferative (inflammatory cells in segments of glomeruli, few glomeruli involved, immune complex deposits subendothelial or subepithelial). Long-term prognosis is good, but this lesion often progresses to more severe forms.
• Diffuse proliferative (inflammatory cells throughout the glomeruli, many glomeruli involved, crescents present, subendothelial immune complex deposits present). Long-term prognosis is poor.
• Membranous (non-inflammatory, thickened glomerular basement membranes, subepithelial deposits). This lesion is characterized by severe proteinuria and gradual deterioration of renal function, but is considered to have a fair prognosis.
• Membranoproliferative (combination of the preceding two). Prognosis is poor.

A revised classification of lupus nephritis is underway.

Renal failure
Despite advances in therapy, lupus nephritis causes renal failure in a minority of patients. Of those entering dialysis during an acute flare, one-third will be able to discontinue dialysis within the first year. The remaining two-thirds, and those suffering gradual deterioration of renal function over several years, do not recover normal kidney function; however, they tolerate dialysis and kidney transplantation well. Despite statements to the contrary, active lupus does occur in patients on dialysis. Symptoms of lupus flare in dialysis patients are different from those of early disease; low-grade fevers and failure-to-thrive syndromes predominate. A rising level of anti-DNA antibody is the best confirmation of active lupus in a patient on dialysis. Ordinarily, low dose oral corticosteroid is sufficient to control the flare.

B. Flares

Flares of lupus in individual patients tend to repeat themselves. That is, a patient whose prior flares have been characterized by arthritis and rash is likely to have similar future flares. However, the disease does change over time. So some patients may develop rheumatoid-like arthritis or scleroderma-like skin. Although nephritis develops early in the illness in most patients who will have nephritis, it may nonetheless develop later on in those who have not had it earlier.

C. Organ dysfunction and failure (non-renal)

After many years of disease, some SLE patients develop hypertension, accelerated atherosclerosis, valvular heart disease, and renal failure. Systemic vasculitis also tends to be a late complication. Patients with antiphospholipid antibody develop arterial and venous thromboses and valvular heart disease. Atherosclerosis is most likely in patients who have continuing, low-grade disease activity.

Low blood counts, early kidney disease, and high blood pressure are the only complications of lupus that do not cause symptoms until they are advanced. All lupus patients should therefore have periodic blood counts, urine tests and routine measurement of blood pressure to check for these complications. New onset high blood pressure often reflects worsening kidney disease. High blood pressure should be treated vigorously, since hypertension itself damages kidney function. Patients should be self-aware and report to their physicians any other symptoms that might indicate further complications.

Rising anti-DNA antibody and falling complement levels are rough but unspecific guides to impending flares, especially kidney. Chest pain, shortness of breath, or reduced exercise tolerance, even in patients in their 30s, should alert the physician to the development of coronary artery disease due to vasculitis or accelerated atherosclerosis, or to the occurrence of pulmonary hypertension. These complications, too, are treatable.

D. Pregnancy

Pregnancy is possible in most patients with lupus. Complications are frequent; all patients must be considered high risk. In pregnancy or planned pregnancy, referral to a physician who specializes in treating such patients is always appropriate. Patients with antiphospholipid antibody are at risk for pregnancy loss; patients with anti-Ro/SSA and anti-La/SSB antibodies are at risk for delivering a child with neonatal lupus.

Rash of Neonatal Lupus

E. Hormones: oral contraceptive pills, estrogen replacement therapy

Controlled clinical trials recently completed will definitively answer the question of whether oral contraceptive and post-menopausal estrogen replacement therapies are safe for lupus patients. Early estimates suggest that both are safe in patients who do not have high levels of antiphospholipid antibody. Since there is a risk of inducing thrombosis in those with high levels of antiphospholipid antibody, levels should be assessed before prescribing such drugs.

VIII. Prognosis

Prognosis is a forecast about the likely course of a disease. The severity of lupus varies widely - from trivial to rapidly lethal. Kidney and brain disease worsen an individual patient's prognosis more than do arthritis, rash, or other organ problems. The good news is that ten-year survival of all patients is more than 80%. However, disabilities are common. Long-term complications include: kidney failure, accelerated atherosclerosis (with myocardial infarction - heart attack - and stroke), cardiac and respiratory failure (including pulmonary hypertension), and osteoporosis and other complications of (corticosteroid) therapy. Active SLE and infection cause the majority of early deaths; atherosclerosis and renal failure are prominent causes of late death.

IX. When to Seek Referral to a Specialist

The American College of Rheumatology has suggested the following reasons for a primary care physician to refer a suspected lupus patient to a rheumatologist:

• To confirm a diagnosis;
• To assess disease activity and severity;
• To provide general disease management;
• To manage uncontrolled disease;
• To manage organ involvement or life-threatening disease;
• To manage/prevent treatment toxicities
• In other specific circumstances, including antiphospholipid syndrome, pregnancy, and surgery.

In lupus patients, life-threatening disease manifestations may be heart, blood, brain, lungs, kidneys, or generalized systemic. Severe other organ system disease may occur in the joints, skin, and gastrointestinal tract. Referral is appropriate for any severe manifestation of disease, forecasts of likely outcomes and life-planning, for pregnancy, for milder disease that does not respond to therapy, and for any circumstance in which the patient or the physician is uncomfortable with current diagnosis or management. It is particularly important to consider, and seek advice on, new or unexpected developments in an otherwise stable patient. Often the rheumatologist is the first to suspect that the new event is not due to active lupus but is an independent, usually infectious, event.

X. Annotated Bibliography

1. DiGeronimo TF and Paget SA. New Hope for People with Lupus: Your Friendly, Authoritative Guide to the Latest in Traditional and Complementary Solutions. Prima Communications. This paperback, available through your bookstore, is co-authored by the physician-in-chief of Hospital for Special Surgery.
   
   
2. Boumpas DT, Austin HA III, Fessler BJ, Balow JE, Klippel JH, Lockshin MD. Systemic lupus erythematosus: Emerging concepts. Part 1: Renal, neuropsychiatric, cardiovascular, pulmonary, and hematologic disease. Ann Intern Med 1995;122:940-940, and,
   
   
3. Boumpas DT, Fessler BJ, Austin HA III, Balow JE, Klippel JH, Lockshin MD. Systemic lupus erythematosus: Emerging concepts. Part 2: dermatologic and joint disease, the antiphospholipid antibody syndrome, pregnancy and hormonal therapy, morbidity and mortality, and pathogenesis. Ann Intern Med 1995;123:42-53. These two articles summarize the important new information in almost all aspects of lupus up to the moment of publication. Important advances since these articles were published are: emergence of new criteria and more formal classification systems for various complications of lupus and initial case reports (but no definitive controlled clinical trials) on use of biologics and other new therapies.
   
   
4. Lahita RG (editor). Systemic Lupus Erythematosus. 3rd edition. San Diego:Academic Press, 1998. One of two major American textbooks, covering all aspects of lupus.
   
   
5. Wallace DJ, Hahn BH (editors). Dubois' Lupus Erythematosus. 5th edition. Baltimore:Williams & Wilkins, 1997. One of two major American textbooks, covering all aspects of lupus.
   
   
6. Barr SG, Zonana-Nacach A, Magder LS, Petri M. Patterns of disease activity in systemic lupus erythematosus. Arthritis Rheum 1999;42:2682-2688. This paper makes an important point: lupus is less an intermittent than a chronically present disease. The implications are that treatment should not be considered transient, but when initiated may be for very long periods of time.
   
   
7. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis Rheum. 1999; 42:1785-1796 This article is the 'official word' of the American College of Rheumatology on referral. The article itself tries to be a mini-textbook. It covers most essential issues and is a good quick reference for 1999 thinking on most import lupus issues.
   
   
8. Tsakonas E, Joseph L, Esdaile JM, Choquette D, Senecal JL, Cividino A, Danoff D, Osterland CK, Yeadon C, Smith CD. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. Lupus. 1998;7:80-85.
   
   
9. Van Vollenhoven RF, Engleman EG, McGuire JL. Dehydroepiandrosterone in systemic lupus erythematosus: results of a double-blind, placebo-controlled randomized clinical trial. Arthritis Rheum. 1995;38:1826-1831. This paper represents the strongest evidence favoring use of this drug. The apparent benefits are marginal at best.
   
   
10. Petri M. Hopkins Lupus Cohort. 1999 update. Rheum Dis Clin North Am. 2000 May;26(2):199-213 A review of a large, well analyzed clinical experience, focusing on atherosclerosis.
    
    

Also see the patient education pamphlets published by The SLE Foundation and the Lupus Foundation of America.