Download Review of systemic lupus erythematosus

Vol. 91 No. 5 May 2001
ORAL SURGERY
ORAL MEDICINE
ORAL PATHOLOGY
MEDICAL MANAGEMENT UPDATE
Editor: James R. Hupp
Review of systemic lupus erythematosus
Patrick J. Louis, DDS, MD,a and Rui Fernandes, DMD, MD,b Birmingham, Ala
UNIVERSITY OF ALABAMA AT BIRMINGHAM
(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:512-6)
Systemic lupus erythematosus (SLE) is a chronic
inflammatory autoimmune disease of unknown cause.
This disease occurs most commonly in women of
childbearing age and ranges in severity from a mild
disease, with rash and arthritis complications, to a
devastating illness, with renal failure and profound
nervous system disturbances.
SLE has a variable course and prognosis. It is characterized by periods of relative quiescence and exacerbations that may involve any organ or tissue in various
combinations (Table I). The prevalence of SLE varies
throughout the world. In North America and northern
Europe, SLE occurs in about 40 persons per 100,000.
Distinct immunologic abnormalities—in particular,
antinuclear, anticytoplasmic, and antiphospholipid
antibodies—develop in patients with SLE. In addition
to the persistent risk of disease flares, permanent organ
system damage develops in more than half of SLE
patients. This damage progresses over time and is
usually more severe in African-American patients than
in white patients. Although the prognosis for persons
with SLE has improved dramatically in the last 4
decades, mortality remains a major concern. The
mortality rate among patients with SLE is at least 3
times that of the general population. Survival rates are
approximately 80% at 10 years after diagnosis and
approximately 65% at 20 years. Deaths early in the
course of SLE are usually attributed to active disease
and infections, but deaths that occur later in the disease
Table I. Clinical features of SLE*
System
Constitutional
Musculoskeletal
Skin
Renal
Gastrointestinal
Pulmonary
Cardiac
Reticuloendothelial
Hematologic
aAssociate
Professor and Director, Oral and Maxillofacial Surgery
Residency Program, Department of Oral and Maxillofacial Surgery,
Schools of Medicine and Dentistry.
bResident, Oral and Maxillofacial Surgery.
Received for publication Jan 4, 2001; accepted for publication Jan 8,
2001.
Copyright © 2001 by Mosby, Inc.
1079-2104/2001/$35.00 + 0 7/13/114153
doi:10.1067/moe.2001.114153
512
Neuropsychiatric
*Adapted from reference 5.
Feature
Fatigue
Fever (in the absence of infection)
Weight loss
Arthritis, arthralgias
Myositis
Butterfly rash
Photosensitivity
Mucous membrane lesion
Purpura
Alopecia
Raynaud’s phenomenon
Urticaria
Vasculitis
Hematuria
Proteinuria
Casts
Nephrotic syndrome
Nausea, vomiting
Abdominal pain
Pleurisy
Pulmonary parenchyma
Pulmonary hypertension
Pericarditis
Endocarditis
Myocarditis
Lymphadenopathy
Splenomegaly
Hepatomegaly
Anemia
Thrombocytopenia
Leukopenia
Psychosis
Seizures
Organic brain syndrome
Transverse myelitis
Cranial neuropathies
Peripheral neuropathies
Louis and Fernandes 513
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Table II. 1997 update of the 1982 American College of Rheumatology classification criteria for systemic lupus
erythematosus*
Item
Malar rash
Discoid rash
Photosensitivity
Oral ulcers
Nonerosive arthritis
Pleuritis or pericarditis
Renal disorder
Neurologic disorder
Hematologic disorder
Immunologic disorder
Positive antinuclear antibody
Definition
Fixed erythema, flat or raised, over malar eminences, sparing the nasolabial folds
Erythematous raised patches with adherent keratotic scaling and follicular plugging: Atrophic scarring may
occur in older lesions
Skin rash as a result of unusual reaction to sunlight, by patient history or observed by physician
Oral or nasopharyngeal ulceration, usually painless, observed by a physician
Involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion
A. Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion
OR
B. Pericarditis—documented by electrocardiogram or rub or evidence of pericardial effusion
A. Persistent proteinuria >0.5 g per day or >3+ if quantitation not performed
OR
B. Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed
A. Seizures in absence of offending drugs or known metabolic derangement (eg, uremia, ketoacidosis, or
electrolyte imbalance)
OR
B. Psychosis—in absence of offending drugs or known metabolic derangement (eg, uremia, ketoacidosis, or
electrolyte imbalance)
A. Hemolytic anemia with reticulocytosis,
B. Leukopenia <4000/mm3 on >2 occasions,
C. Lymphopenia <1500/mm3 on >2 occasions,
OR
D. Thrombocytopenia <100,000/mm3 in absence of offending drugs
A. Anti-DNA: antibody to native DNA in abnormal titer,
B. Anti-Sm: presence of antibody to Sm nuclear antigen,
OR
C. Positive finding of antiphospholipid antibodies based on (1) abnormal serum level of IgG or
immunoglobulin M (IgM) anticardiolipin antibodies, (2) positive test result for lupus anticoagulant by
means of standard method, or (3) false-positive test result for at least 6 months and confirmed by
Treponema pallidum immobilization or fluorescent treponemal antibody absorption test
Abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time
in absence of drug
*Adapted from reference 6.
course are often caused by atherosclerotic vascular
disease. Therapy, especially long-term high-dose
glucocorticoid treatment, can contribute to myopathy,
osteoporosis, hypertension, diabetes, atherosclerotic
vascular disease, infections, and death. Timely and
aggressive therapy, however, can delay or prevent
morbidity and organ failure and is cost-effective.
PATHOGENESIS
SLE is considered to be the prototypical human
autoimmune disease mediated by pathogenic immune
complexes. Persons with this disorder spontaneously
produce autoantibodies that react with a variety of
cellular and extracellular constituents, including DNA
and other nucleic acids, nucleoproteins, cytoplasm
components, cell surface antigens, and matrix components. These immunoglobulins participate in the formation of immune deposits, initiating an inflammatory
response that often causes cell death and organ failure.
Genetic, immunologic, hormonal, and environmental
factors are involved in its pathogenesis.
There are 2 hypotheses to explain the number of
different antibodies seen in SLE. One is that antibodyforming B lymphocytes are stimulated in a relatively
nonspecific fashion, in so-called polyclonal B-cell activation. The other is that the immune response in SLE
is specifically stimulated by antigens. A genetic factor
in the pathogenesis of SLE is strongly supported by
studies in human beings in whom and animals in which
SLE spontaneously develops. The evidence in human
beings points to a gene or genes linked to the HLA-DR
and HLA-DQ loci in the class II immune response
complex. The predisposition to SLE has been studied
in twins; dizygotic pairs have a concordance rate
similar to that for other family members. However, the
rate is still 6 to 8 times greater than that for unrelated
persons. Environmental factors, such as ultraviolet rays
and exposure to tobacco and aromatic amines, have
been shown to play a role in the pathogenesis of SLE.
DRUG-INDUCED LUPUS
A number of drugs can cause a disorder resembling
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May 2001
SLE—most of them infrequently. Procainamide is
responsible for the majority of cases. The clinical
manifestations of drug-related SLE, including arthralgias, maculopapular rash, serositis, fever, anemia, and
leukopenia, are relatively mild. The antinuclear antibody (ANA) test usually shows a homogeneous
staining pattern; the pattern is caused by antibody
reacting to nuclear histones. Antihistone antibody
production is characteristic of drug-induced lupus, but
these antibodies are not specific for the syndrome.
Antinative DNA is almost never detected. Patients with
drug-induced lupus erythematosus may also have
antiphospholipid antibodies and their thromboembolic consequences. Drug-induced lupus usually
subsides 4 to 6 weeks after treatment when the
causative agent is stopped, but the ANA test can
remain positive for 6 to 12 months. Drugs capable of
causing a lupus-like syndrome do not seem to aggravate primary SLE.
anemia, leukopenia, lymphopenia, and thrombocytopenia. These abnormalities may reflect the nonspecific effects of inflammation on bone marrow function,
as well as the beginning of the production of specific
antibodies to blood cell elements. Because these
abnormalities improve as a disease is controlled,
they provide a quick way to determine the need for
therapy or to evaluate its efficacy. The presence of
proteinuria, as well as an active sediment with red
blood cells and cellular casts, points to active
glomerulonephritis.
INITIAL EVALUATION: MAKING THE
DIAGNOSIS
Due to multisystem involvement and its protean manifestations, the diagnosis of SLE may be difficult. SLE
should be suspected in any patient who has features
affecting 2 or more organ systems as listed in Table I.
The American College of Rheumatology has published
criteria for the classification of patients as having SLE
(Table II). Although the criteria were designed to ensure
that SLE patients reported in the literature do in fact
have the disease, they are also useful in evaluating individual patients. If a patient has, at any time in his or her
medical history, 4 of the 11 criteria documented, the
diagnosis of SLE can be made with approximately 95%
specificity and 85% sensitivity. If the patient meets
fewer than 4 criteria, SLE diagnosis is possible; but the
diagnosis depends on clinical judgment. If the ANAs are
negative, there is a low probability that the patient has
SLE. Patients with positive ANA alone—without organ
system involvement or typical laboratory findings—are
unlikely to have SLE.
Other serologic tests may have a higher predictive
value than ANA and thus may aid in the diagnosis
of SLE or related connective tissue disease. Hightiter immunoglobulin G (IgG) antibodies to doublestranded DNA and antibodies to the Smith antigen
(anti-Sm) are usually specific for SLE. Antibodies to
RNA proteins (anti-RNP, anti-Ro, anti-La) and to
phospholipids (anticardiolipin) occur in SLE and
other connective tissue diseases, as does hypocomplementemia.
Two simple laboratory tests are highly informative
measures of disease activity: complete blood count and
urinalysis. Active lupus is frequently characterized by
Mucosal involvement
Oral lesions are found in approximately 21% of
patients with SLE. Although any mucosal surface can
be affected by SLE, the most common areas of
involvement are the mouth and lips. The lesions can
be similar to those found in persons with discoid
lupus erythematosus (DLE), or there may be more
specific erosive lesions. Cutaneous and mucosal
lesions of the face are the most prominent findings in
DLE. Oral lesions are found in approximately 24% of
patients with DLE. These lesions are generally
described as annular leukoplakic areas or erythematous erosions. Chronic lesions that present as leukoplakic patches may also occur with few other symptoms. Lesions may present diffusely throughout the
oral cavity, including on the buccal mucosa and on the
tongue, palate, and lips. They may also present as a
prominent marginal gingivitis.
Treatment
Due to the multisystem involvement, varied clinical
presentation, and severity of SLE, the treatment must
be tailored to meet the patient’s needs. A detailed
assessment of the patient and a comprehensive characterization of the systems involved should be
completed to establish the goals of therapy. Therapy
usually involves nonsteroidal antiinflammatory drugs
(NSAIDs), corticosteroids, antimalarial agents, and
immunosuppressive drugs. These drugs may be used
alone or in combination.
Arthritis and serositis are often controlled with
NSAIDs or aspirin. Use of these agents requires vigilance on the part of the physician because they can
worsen renal function or produce hepatitis. Chloroquine
and hydroxychloroquine, antimalarial agents, are generally used if arthritis symptoms are not completely
controlled with NSAIDs. An assessment of glucose-6phosphate dehydrogenase activity is recommended
before initiation because these drugs can precipitate
hemolytic anemia in enzyme-deficient patients.
Pleurisy and pericarditis caused by inflammation of
the serosa generally present as chest pain and shortness
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Louis and Fernandes 515
of breath. If NSAIDs fail to completely control these
symptoms, then corticosteroids should be considered.
Before initiating steroid therapy, infection and thromboembolic phenomena should be excluded. Patients
with SLE are prone to both of the aforementioned
pathologies, and they can also present with chest pain
and shortness of breath.
Cutaneous manifestations are generally responsive to
topical applications of fluorinated corticosteroids or
antimalarial agents. Severe discoid lupus and cutaneous vasculitis usually necessitate the use of systemic
corticosteroids. Protection from sun exposure is essential for all patients.
Patients with thrombocytopenia and hemolytic
anemia usually respond to steroid therapy. When this is
not effective, the use of immunosuppressive agents
should be considered. A splenectomy is generally
avoided in patients with SLE because they are prone to
bacteremias.
There are no absolute guidelines for the management
of lupus nephritis. Some studies have demonstrated
that a regimen that includes cyclophosphamide is more
effective in preserving renal function than treatment
with glucocorticoids alone. High-pulsed doses of
cyclophosphamide given intravenously at monthly
intervals appear to be as effective as lower daily dose
oral therapy and less toxic to the bladder. The use of
renal biopsy to classify the extent of involvement has
helped to guide therapy.
The treatment of central nervous system manifestations is empirical and uncertain. Diffuse central nervous
system manifestations probably reflect primary
angiopathy. However, thromboembolic events caused
by antiphospholipid antibodies must be ruled out.
Angiopathy is usually treated with high-dose oral and
intravenous glucocorticoids. Cyclophosphamides may
also be beneficial. Thromboembolic phenomena must
be treated with anticoagulant therapy.
should be considered—especially for patients with low
white blood cell counts and for those undergoing
immunosuppressive therapy.
DENTAL AND SURGICAL CONSIDERATIONS
Before embarking on elective or emergent dental or
surgical care, the physician must give some consideration to the possible complications associated with the
treatment of SLE patients.
Cardiovascular system
Libman-Sacks endocarditis (nonbacterial verrucous
endocarditis) has been reported to be as high as 50% at
autopsy of SLE patients. Microscopic injury to the
valvular endothelium may not cause audible turbulence
but still may act as a nidus for microbial seeding during
transient bacteremia. However, a controversy still
exists as to whether routine antibiotic prophylaxis
should be recommended. Antibiotic prophylaxis
Immune system
Although certain aspects of the immune system of
the patient with SLE may be hyperactive, protective
immunity may be suboptimal. Most medications used
to treat patients with SLE further compromise the
immune system. Thus, the patient may be susceptible
to infection or shock, or both. Steroid supplementation should be considered for those taking adrenally
suppressive doses of corticosteroids. Elective treatment should be deferred for patients with low
absolute neutrophil counts. Antibiotic prophylaxis
must be considered for patients who might be immunosuppressed.
Coagulation system
Thrombocytopenia is usually present to a mild
degree and not clinically significant in most cases of
SLE. However, on occasion, thrombocytopenia may be
severe. In addition, circulating anticoagulant may be
present.
Inhibitors are most commonly directed against factor
VIII, but they may interact at many levels of the coagulation cascade. In addition, the inhibitors methotrexate, cyclophosphamide, and azathioprine may also
suppress marrow function. A platelet count and coagulation studies should be obtained before embarking on
procedures that can result in significant bleeding.
Renal system
Renal failure is generally a prominent feature of
SLE. If renal failure is present, an adjustment of
medication dosages must be considered. The adjustment is usually based on kidney function. If the patient
is undergoing dialysis, an adjustment of treatment
times should proceed as it does in the management of
any patient with renal failure.
Drug considerations
Some drugs may cause a lupus-like syndrome or
exacerbate a preexisting disease, although this is rare.
Sulfonamide, penicillin, and NSAIDs that are commonly used in dentistry are some of the drugs that have
been implicated.
SUGGESTED READING
1. Mills JA. Medical progress: systemic lupus erythematosus. N
Engl J Med 1994;330:1871-9.
2. Arnett FC, Reveille JD. Genetics of systemic lupus erythematosus. Rheum Dis Clin North Am 1992;18:865-92.
3. Pisetsky DS, Gilkeson G, St Clair EW. Systemic lupus erythematosus. Diagnosis and treatment. Med Clin North Am 1997;81:
113-28.
516 Louis and Fernandes
4. Rasaratnam I, Ryan PF. Systemic lupus erythematosus. Med J
Aust 1997;166:322-7.
5. 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;42:1785-96.
6. Hochberg MC. Updating the American College of Rheumatology
revised criteria for the classification of systemic lupus erythematosus [letter]. Arthritis Rheum 1997;25:1271-7.
7. Mounzer KC, DiNubile MJ. Prophylactic use of antibiotics and
vaccines in patients with rheumatologic disorders. Rheum Dis
Clin North Am 1997;23:259-75.
8. Greenberg MS. Immunologic diseases. In: Lynch MA, Brightman
VJ, Greenberg MS, editors. Burkett’s oral medicine: diagnosis
and treatment. 9th ed. Philadelphia: Lippincott; 1994.
9. Callen JP. Mucocutaneous changes in patients with lupus erythematosus: the relationship of these lesions to systemic disease.
Rheum Dis Clin North Am 1988;14:81-97.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
May 2001
10. Steinberg AD, Steinberg SC. Long-term preservation of renal
function in patients with lupus nephritis receiving treatment that
includes cyclophosphamide versus those treated with prednisone
only. Arthritis Rheum 1991;34:945-50.
11. Boumpas DT, Austin HA III, Vaughn EM, Klippel JH, Steinberg
AD, Yarboro CH, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in
severe lupus nephritis. Lancet 1992;340:741-5.
Reprint requests:
Patrick J. Louis, DDS, MD
Associate Professor and Director
Oral and Maxillofacial Surgery Residency Program
Department of Oral and Maxillofacial Surgery
Schools of Medicine and Dentistry
University of Alabama at Birmingham
1919 7th Ave S
Birmingham, AL 35294
Abstract
Review of severe osteoradionecrosis treated by surgery alone or surgery with postoperative hyperbaric
oxygenation
A. Maier, A. Gaggl, H. Klemen, et al
British Journal of Oral and Maxillofacial Surgery 2000;38:173-6.
This article reports the results of a clinical study of 41 patients with mandibular osteoradionecrosis. Patients were
divided into research arms to receive either post resection (of the radiation-damaged bone) hyperbaric oxygen (HBO)
treatment, repeated debridement and clindamycin, or debridement and clindamycin without HBO. Assignment to
HBO and no HBO groups was based on the availability of HBO at participating institutions. It is unclear from the
article what means were used to standardize debridement protocols and success criteria.
The authors found that patients receiving HBO not only did not receive a benefit, but also had poorer outcomes
than did those not receiving HBO. The authors concede that the study numbers are relatively low but conclude that
HBO should not be recommended for treatment of severe osteoradionecrosis after an initial resectioning of the
involved mandible. They do appear to recommend following the protocol of preoperative and postoperative HBO for
prevention and preresection of osteoradionecrosis.
James R. Hupp
DMD, MD, JD, MBA