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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 ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 91, Number 5 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 514 Louis and Fernandes ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY 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 ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 91, Number 5 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