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Treatment of Systemic Lupus

Erythematosus: An Update

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MICHELLE PETRI, M.D., M.P.H., Johns Hopkins University School of Medicine, Baltimore,
Maryland
Am Fam Physician. 1998 Jun 1;57(11):2753-2760.
Systemic lupus erythematosus predominantly affects women and is more common in blacks.
Although survival rates have improved, over one half of patients with systemic lupus
erythematosus have permanent damage in one or more organ systems. Arthritis and cutaneous
manifestations are most common, but renal, hematologic and neurologic manifestations
contribute largely to morbidity and mortality. Treatment approaches emphasize using a
combination of drugs to minimize chronic exposure to corticosteroids.
Systemic lupus erythematosus has fascinated physicians for almost a century and remains the
prototypic autoimmune disease. Although it is estimated to affect one out of every 1,000 white
persons and one out of every 250 black women from 18 to 65 years of age,1 systemic lupus
erythematosus is certainly not the most common example of autoimmunity encountered by
physicians. Positive antinuclear antibodies are extremely common in the general population,
occurring in as many as 10 to 20 percent of young women.2 Localized autoimmune disorders,
such as autoimmune thyroid disease, are also much more common than systemic lupus
erythematosus.
Because systemic lupus erythematosus is a chronic disease, patients require extensive health
education in terms of their responsibility in managing their condition. This requires compliance
with office visits and medications, and lifestyle modifications to reduce or prevent associated

problems such as hyperlipidemia, obesity and hypertension. An ongoing partnership between the
primary care physician and the rheumatologist is essential in the long-term management of
patients with systemic lupus erythematosus.

Etiology and Pathophysiology

The cause of systemic lupus erythematosus remains elusive. Predisposing factors include genetic
factors (certain types of human leukocyte antigens and null complement alleles), environmental
factors including sun exposure, some drugs such as sulfa antibiotics, and hormonal factors.
Systemic lupus erythematosus is more common in blacks than in whites and is obviously more
common in women than in men (ratio: 9:1).3
The pathophysiology of systemic lupus erythematosus is not completely understood. The
production of abnormal antibodies by B cells remains the hallmark sign of lupus erythematosus.
Some of the autoantibodies, such as antidouble-stranded DNA and anti-Smith, are very specific
for systemic lupus erythematosus. Others, including anti-RNP, anti-Rho and anti-La, are also
present in other autoimmune diseases. Whether the B cells themselves are intrinsically abnormal
is a subject of current research. One of the underlying defects in systemic lupus erythematosus
may center on apoptosis, or programmed cell death. In patients with systemic lupus
erythematosus, cellular antigens exposed during apoptosis incite an immune response.4

Diagnostic Considerations
The diagnosis of systemic lupus erythematosus requires a thorough history, a physical
examination and laboratory tests, including a complete blood cell count, chemistry panel and
urinalysis. Serologic tests such as antinuclear antibodies, anti-Rho, anti-La, anti-RNP, anti-Sm,
anti-dsDNA and antiphospholipid antibodies are helpful to confirm the diagnosis. The American
College of Rheumatology (ACR) has developed criteria to classify patients with a diagnosis of
systemic lupus erythematosus for research studies (Table 1). Four of the 11 criteria must be met.5
These classification criteria are often helpful clinically, especially since they emphasize the
multisystemic nature of the disease.
View/Print Table
TABLE 1
Classification Criteria for Systemic Lupus Erythematosus*
Before a patient can be classified with systemic lupus erythematosus, at least four of the
following 11 disorders must be present:

Malar rash

Discoid rash

Photosensitivity

Oral ulcers

Arthritis

Serositis

Renal disorder

Neurologic disorder

Hematologic disorder

Immunologic disorder

Antinuclear antibodies

*According to information from the American College of Rheumatology.

Adapted with permission from Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield
NF, et al. The 1982 revised criteria for classification of systemic lupus erythematosus. Arthritis
Rheum 1982; 25:12717.
Systemic lupus erythematosus is a disease that continues to evolve over time. Thus, a patient
who presents with skin and joint disease remains at risk for renal disease even after having lupus
erythematosus for decades. Continued monitoring, even when the disease appears to be clinically
inactive, is essential. It is very important that a partnership be established between the primary
care physician, the rheumatologist and any other physicians caring for the patient. This
partnership has been summarized in the guidelines from the ACR.6

The major challenge for physicians managing patients with lupus erythematosus is to treat the
active phase without allowing the treatment itself to cause long-term damage. This intent has led
to a major change in treatment approach, with the goal of limiting corticosteroid exposure, if
possible. As a result, physicians are now less reluctant to turn to immunosuppressive drugs such
azathioprine (Imuran) or cyclophosphamide (Cytoxan). Treatment for active systemic lupus
erythematosus differs, depending on the organ systems involved and disease severity. Current
treatment often includes a combination of drugs.

Musculoskeletal Manifestations
At some point, over 90 percent of patients with systemic lupus erythematosus have
polyarthralgias or polyarthritis because of the disease. Nonsteroidal anti-inflammatory drugs
(NSAIDs) remain the mainstay of treatment in these patients, especially those who have mild
polyarthralgias or polyarthritis (Table 2). It is preferable to avoid the more gastrotoxic NSAIDs,
because patients with systemic lupus erythematosus may require NSAID treatment for years and
may use NSAIDs in conjunction with other drugs such as corticosteroids, which increases the
risk of gastric injury. In addition, NSAIDs may adversely affect renal function, a special concern
because 50 percent of patients with systemic lupus erythematosus develop associated nephritis.
View/Print Table
TABLE 2
Treatment of Polyarthritis in Patients with Systemic Lupus Erythematosus
Drug

Comment

NSAIDs

Avoid gastrotoxic NSAIDs; counter with cytoprotective therapy

Antimalarials

Hydroxychloroquine (Plaquenil) is the antimalarial drug used most often in

the United States; ophthalmologic monitoring is recommended every six to
12 months

Glucocorticoids

Individual joints may benefit from intra-articular injection of

triamcinolone (Aristospan); severe polyarthritis flare-ups may be treated
with intravenous pulse therapy consisting of 1,000 mg of
methylprednisolone (Solumedrol) daily for three days; use of prednisone
for maintenance therapy should be limited to 10 mg or less daily

Immunosuppressive Methotrexate (Rheumatrex) or azathioprine (Imuran) can be used as

drugs
steroid-sparing drugs; methotrexate cannot be used during pregnancy

NSAIDs = nonsteroidal anti-inflammatory drugs.

Antimalarial agents, especially hydroxychloroquine (Plaquenil), are frequently used in the
treatment of polyarthritis. Hydroxychloroquine is very safe; only 1 percent of patients using it
develop retinopathy. Retinopathy as a result of hydroxychloroquine use is usually reversible
when the drug is discontinued.
In spite of NSAID and antimalarial therapy, some patients require corticosteroids to control
severe polyarthritis. An extremely severe flare-up of polyarthritis can be treated with intravenous
methylprednisolone sodium succinate (A-Methapred, Solu-Medrol), 1,000 mg administered over
90 minutes, given daily for three days. This therapy will usually abruptly stop the flare, allowing
the patient to stay on a low-maintenance dosage of prednisone. If the maintenance dosage of
prednisone is greater than 10 mg per day, additional steroid-sparing drugs can be added to the
regimen. Low dosages of methotrexate (Rheumatrex), such as 7.5 mg given orally once per
week, are extremely effective. It is now standard practice to use folic acid to counter some of the
minor side effects of methotrexate.7 Patients taking methotrexate should abstain from alcohol,
because combined use increases the risk of cirrhosis.
Additional musculoskeletal complications of systemic lupus erythematosus include osteonecrosis
and osteoporosis (Table 3). Osteonecrosis, also called avascular necrosis of bone, occurred in 14
percent of patients in one study.8
View/Print Table
TABLE 3
Musculoskeletal Complications of Systemic Lupus Erythematosus
Osteonecrosis (avascular necrosis of bone)

Occurs in 14 percent of patients with systemic lupus erythematosus

Most commonly affects the hip joints

Early detection requires MRI

Core decompression of bone is an effective treatment in early stages of the disease

Osteoporosis

Occurs in 64 percent of patients with systemic lupus erythematosus

Osteoporosis of the lumbar spine is associated with the highest dosage of prednisone and the
cumulative effects of prednisone

Calcium, vitamin D, calcitonin and bisphosphonates are effective treatments (even in

premenopausal women with osteoporosis)

MRI = magnetic resonance imaging.

The major risk factors for osteonecrosis include a prednisone dosage greater than 20 mg per day
for one month or longer, and the presence of Raynaud's disease or vasculitis.8 Avascular necrosis
of bone, if detected early by magnetic resonance imaging (MRI), can often be effectively treated
with core decompression of bone, an orthopedic procedure.9 Patients with osteonecrosis who
present at later stages usually require a total joint replacement. The early detection of avascular
necrosis of bone usually requires an MRI scan of the hip.
The same study reported that only 35 percent of premenopausal women with lupus
erythematosus had normal bone mineral density.8 Screening for osteoporosis may be indicated in
these patients because premenopausal osteoporosis can be effectively treated with calcium,
vitamin D, bisphosphonates and/or calcitonin salmon (Calcimar, Miacalcin, Salmonine).
Guidelines from the ACR have suggested the use of estrogen supplementation in premenopausal
women with corticosteroid-induced osteoporosis, but this therapy has not yet been shown to be
safe in patients with systemic lupus erythematosus.10 Ultimately, the risk of osteoporosis can be
minimized or avoided by limiting patient exposure to corticosteroids.

Cutaneous Manifestations
Over 90 percent of patients with systemic lupus erythematosus eventually have a cutaneous
manifestation of the disease, including malar rash, discoid lupus erythematosus, alopecia or
aphthous stomatitis. The usual therapy for cutaneous lupus erythematosus is strict use of sun
block, judicious use of topical steroids (although fluorinated topical steroids should not be used
on the face) and antimalarial therapy (Table 4). Some patients with very severe cases of discoid
lupus erythematosus may not respond adequately to the usual dosage of hydroxychloroquine,
which is 400 mg per day for a normal-sized adult. Quinacrine, in a dosage of 100 mg per day,
can be added without increasing the risk of retinopathy, or the patient can be switched to
chloroquine HCl (Aralen), in a dosage of 250 mg per day.
View/Print Table
TABLE 4

Management of Cutaneous Lupus Erythematosus

Treatment agent

Comment

Sun block

Blocks both UVA and UVB radiation

Antimalarials

Use of combination antimalarial therapy (hydroxychloroquine [Plaquenil]

and quinacrine) or chloroquine (Aralen), which has more risk of
retinopathy, is sometimes necessary

Dapsone

G6PD status should be checked

Retinoids

Avoid using in pregnant women

Corticosteroids

Use of corticosteroids may be necessary as part of initial therapy for

severe discoid lupus or for lupus vasculitis; intradermal corticosteroids are
helpful for individual discoid lesions, especially in the scalp

Immunosuppressive Methotrexate (Rheumatrex) or azathioprine (Imuran) is used as steroiddrugs

sparing drug

Thalidomide
(Synovir)

One of the most effective drugs for treatment of discoid lupus, but
teratogenicity and neuropathy will limit its acceptance and use

UVA = ultraviolet A; UVB = ultraviolet B; G6PD = glucose-6-phosphate dehydrogenase.

Because chloroquine therapy carries an increased risk of retinopathy compared with
hydroxychloroquine therapy, patients taking it should undergo ophthalmologic monitoring every
three months. In patients who cannot tolerate antimalarials, dapsone or retinoids are additional
therapeutic choices. It is important that glucose-6-phosphate dehydrogenase status be checked in
black patients before they begin dapsone therapy. Retinoids should not be used in patients who
may become pregnant. Patients with very severe cutaneous lupus erythematosus, including lupus
vasculitis, may require high dosages of corticosteroids. If the maintenance dosage of
corticosteroids is greater than 10 mg per day, the addition of steroid-sparing agents, such as
methotrexate or azathioprine, should be considered. One of the most effective drugs in the
treatment of cutaneous lupus erythematosus, including discoid lupus erythematosus, is

thalidomide (Synovir); however, because of its teratogenic effects and the increased risk of
peripheral neuropathy in patients taking it, this agent will probably never have widespread use.

Renal Manifestations
One of the major worries for physicians and patients with systemic lupus erythematosus is lupus
nephritis (Table 5). Overall, 50 percent of patients with systemic lupus erythematosus have some
manifestation of lupus nephritis; this figure reached 75 percent in black patients who were
followed prospectively by the author.
View/Print Table
TABLE 5
Characteristics of Lupus Nephritis
Occurs in approximately 50 percent of patients with systemic lupus erythematosus

More common in black people

Renal biopsy can be helpful in identifying the activity of lupus nephritis and the degree of
chronicity (scarring)

Cyclophosphamide (Cytoxan) is more effective than corticosteroids alone for the treatment of
severe forms of lupus nephritis (diffuse proliferative glomerulonephritis)
Not all lupus nephritis is severe. Patients with milder forms, including mesangial
glomerulonephritis and focal proliferative glomerulonephritis, may respond to corticosteroid
therapy alone or with steroid-sparing drugs such as azathioprine. However, the patient with
rapidly progressive lupus nephritis, with diffuse proliferative glomerulonephritis on biopsy, or
severe proteinuria and active urine sediment, will initially need high-dose corticosteroid therapy
and should be a candidate for cyclophosphamide therapy. Clinical trials at the National Institutes
of Health have been instructive in the development of protocols for the administration of
cyclophosphamide with minimal long-term toxicity.11 Cyclophosphamide, in a dosage of 750 to
1,000 mg per m2 body surface area, is well tolerated when given in conjunction with
prehydration, mesna ([Mesnex injection], which binds acrolein, a toxic cyclophosphamide
metabolite) to avoid hemorrhagic cystitis, and antiemetics. Patients receiving this therapy may
later be at risk for the development of malignancies, but the risk of leukemia and lymphoma
appears to be very small. Premature ovarian failure is a significant complication and occurs in up
to 60 percent of women over 30 years of age.12 Even with aggressive therapy, renal lupus leads

to major morbidity and is a major cause of mortality in patients with systemic lupus
erythematosus.

Central Nervous System Manifestations

The central nervous system manifestations of systemic lupus erythematosus can present in many
forms and are often difficult to diagnose (Table 6). No gold standard diagnostic test currently
exists. Characteristic abnormalities are frequently found on brain MRI, lumbar puncture and
electroencephalogram. Psychosis and seizures are usually easy to diagnose and respond well to
antipsychotics or anticonvulsants, as well as to corticosteroid treatment for systemic lupus
erythematosus. However, many patients with systemic lupus erythematosus present with
cognitive function difficulties, making it a challenge for the physician to differentiate between
what is related to active lupus erythematosus, what is related to corticosteroid treatment, and
what may be related to depression or chronic fatigue syndrome. Fibromyalgia, a musculoskeletal
syndrome characterized by generalized pain, fatigue and a variety of associated symptoms, is
found in as many as 30 percent of patients with systemic lupus erythematosus and is frequently
associated with chronic fatigue. Patients with central nervous system manifestations of lupus
erythematosus who present with status epilepticus, organic brain syndrome or coma can be
treated with intravenous methylprednisolone pulse therapy. Patients with severe or resistant
symptoms may also require treatment with intravenous cyclophosphamide and/or
plasmapheresis. However, it is usually necessary to rule out other conditions that may mimic
central nervous system manifestations of systemic lupus erythematosus, including infection and
toxic metabolic states.
View/Print Table
TABLE 6
Neurologic Manifestations of Systemic Lupus Erythematosus
Psychosis

Seizures

Organic brain syndrome

Stroke

Cognitive function abnormalities

Transverse myelopathy

Mononeuritis multiplex

Cardiovascular Manifestations
One of the major complications of systemic lupus erythematosus is premature or accelerated
atherosclerosis (Table 7). This complication is one of the causes of later mortality, in the
perimenopausal and early postmenopausal years. It is also a major cause of morbidity. Studies
conducted worldwide have suggested that somewhere between 6 and 10 percent of patients with
systemic lupus erythematosus have clinically recognized premature atherosclerosis.13 When
screening studies are performed, the prevalence appears to be even greater, approaching 40
percent. The pathogenesis of premature atherosclerosis is almost certainly multifactorial and
includes direct effects of the disease and side effects of treatment. Longitudinal regression
analyses14 have shown that increasing the dosage of prednisone increases serum cholesterol,
weight and blood pressure. Patients with systemic lupus erythematosus have higher levels of
homocysteine, a known risk factor for atherosclerosis.15 Intervention, in the form of both
lifestyle modifications and pharmacologic therapy, may be appropriate in young women with
systemic lupus erythematosus and these risk factors for atherosclerosis.
View/Print Table
TABLE 7
Characteristics of Premature Atherosclerosis
Present in 6 to 10 percent of patients with systemic lupus erythematosus

Associated with duration of disease

Corticosteroid treatment increases the levels of cardiovascular risk factors, including weight,
blood pressure, cholesterol and homocysteine levels
Antiphospholipid antibody syndrome is one of the most common causes of acquired
hypercoagulability in the general population and is much more common in patients with
systemic lupus erythematosus (Table 8). About one half of patients with systemic lupus
erythematosus make antiphospholipid antibodies, including anticardiolipin antibody and lupus
anticoagulant. These antibodies often fluctuate over time, as does disease activity in general.
Patients who have antiphospholipid antibodies have an increased risk of antiphospholipid

antibody syndrome, a hypercoagulable state that can present with venous thrombosis, arterial
thrombosis, recurrent pregnancy loss or thrombocytopenia.
View/Print Table
TABLE 8
Characteristics of Antiphospholipid Antibody Syndrome
50 percent of patients with systemic lupus erythematosus manufacture antiphospholipid
antibodies but often do so intermittently and at low titer

The two clinically important antiphospholipid antibodies are lupus anticoagulant and
anticardiolipin antibody

Presentations of antiphospholipid antibody syndrome include thrombosis, recurrent or late

pregnancy loss, and thrombocytopenia

Long-term management of patients who have had a thrombotic event resulting from
antiphospholipid antibody syndrome includes high-intensity warfarin (Coumadin) therapy (INR
of 3 to 4)

INR = International Normalized Ratio.

The diagnosis of antiphospholipid antibody syndrome requires one of the four clinical
presentations mentioned previously and the presence of either lupus anticoagulant or moderateor high-titer anticardiolipin antibody. In patients with systemic lupus erythematosus, the presence
of lupus anticoagulant appears to be more specific for the syndrome than the presence of
anticardiolipin antibodies,16 but high-titer anticardiolipin antibody of the IgG or IgM class is
also a risk factor.
Patients with systemic lupus erythematosus who have already had a manifestation of
antiphospholipid antibody syndrome require treatment. Patients who have had venous or arterial
thrombosis appear to benefit from maintenance therapy with high-intensity (International
Normalized Ratio of 3 to 4) warfarin (Coumadin).17 Women who have had recurrent pregnancy
loss in the first trimester, or even one second- or third-trimester loss, have a greater chance of a
successful pregnancy if given heparin and low-dose aspirin therapy.18 Patients with
antiphospholipid antibody syndrome who also have thrombocytopenia cannot be safely treated
with either heparin or warfarin, unless their platelet count remains above 50,000 103 per mm3
(50 109 per L).

Hematologic Lupus
Anemia in patients with systemic lupus erythematosus is most often associated with chronic
disease or is related to iron deficiency. Classic autoimmune hemolytic anemia can present
acutely (and severely) or as a chronic condition. Severe hemolytic anemia is treated initially with
intravenous methylprednisolone, 1,000 mg per day for three days.
Leukopenia, which frequently occurs in patients with systemic lupus erythematosus, is usually
not severe (i.e., white blood cell count of less than 1,000 103 per mm3 [1.0 109 per L]) and
rarely requires treatment. Thrombocytopenia, if stable, and if the platelet count remains above
50,000 103 per mm3 (50 109 per L), should not be associated with bleeding unless the patient
has an additional coagulation defect. Severe, life-threatening thrombocytopenia is treated with
high-dose intravenous methylprednisolone but may also require intravenous immunoglobulin
therapy. The long-term management of patients with severe thrombocytopenia may also include
danazol (Danocrine), vincristine (Oncovin), immunosuppressive drugs and, in rare instances,
splenectomy.

Pregnancy in Women with Systemic Lupus Erythematosus

Twenty years ago, women with systemic lupus erythematosus were often told not to become
pregnant. Today, most women with lupus erythematosus can have a successful pregnancy,
although the potential for maternal and fetal complications does exist (Table 9). Patients who
require warfarin or cyclophosphamide therapy should not become pregnant because of the
teratogenic potential of these drugs. Some patients with lupus erythematosus who have the antiRho and anti-La antibodies do have a higher risk of congenital heart block in the fetus. Patients
with antiphospholipid antibody syndrome have an increased risk of pregnancy loss and may
require heparin and low-dose aspirin therapy to have a successful pregnancy.
Patients with active lupus erythematosus and renal disease, or those who require higher dosages
of prednisone (greater than 20 mg per day) have an increased risk of preterm birth.19 In spite of
these obstacles, prenatal management that is based on a partnership between a rheumatologist
and an obstetrician who has experience with high-risk pregnancies usually results in a successful
outcome.
View/Print Table
TABLE 9
Pregnancy-Associated Complications in Women with Systemic Lupus Erythematosus
Pregnancy loss

Early losses are usually due to active lupus erythematosus or unknown factors

Second- or third-trimester losses are usually due to antiphospholipid antibody syndrome

Congenital heart block

Mother usually has both anti-Rho and anti-La antibodies

Most babies survive, but some have important morbidity

Monitoring the next pregnancy with serial four-chamber fetal echocardiograms may allow early
detection of fetal heart block

Preterm birth

Risk factors include active lupus erythematosus, maintenance therapy using prednisone dosages
of more than 20 mg daily, renal disease and hypertension

Increased risk of premature rupture of the membranes

Pre-eclampsia may be difficult to differentiate from renal flare caused by systemic lupus
erythematosus
The Author
Michelle Petri, M.D., M.P.H., is an associate professor of medicine at Johns Hopkins University
School of Medicine, Baltimore, where she is also the director of the Lupus Center and the
Hopkins Lupus Cohort Study. Dr. Petri received a medical degree from Harvard Medical School,
Boston. After training in internal medicine at Massachusetts General Hospital, Boston, she
completed fellowships in rheumatology, and allergy and immunology at the University of
California, San Francisco, School of Medicine.
Address correspondence to Michelle Petri, M.D., M.P.H., Division of Rheumatology, Johns
Hopkins University School of Medicine, 1830 E. Monument St., Suite 7500, Baltimore, MD
21205. Reprints are not available from the author.

REFERENCES

show all references

1. Scopelitis E. Systemic lupus erythematosis. In: Hurst JW, ed. Medicine for the practicing
physician. 3d ed. Boston: Butterworth-Heinemann, 1992....

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