Lupus erythematosus

Systemic lupus erythematosus is a chronic, recurrent, potentially fatal multisystem inflammatory disorder that can be difficult to diagnose. (1,2) The disease has no single diagnostic marker; instead, it is identified through a combination of clinical and laboratory criteria. (3) Accurate diagnosis of systemic lupus erythematosus is important because treatment can reduce morbidity (4-11) and mortality, (12) particularly from lupus nephritis. This article reviews evidence-based recommendations for the diagnosis of systemic lupus erythematosus by primary care physicians.

Methods

We conducted a systematic evidence-based review of the published literature on systemic lupus erythematosus. After searching several evidence-based databases (Table 1), we reviewed the MEDLINE database using the PubMed search engine. Search terms included "lupus not discoid not review not case" and "lupus and treatment and mortality," with the following limits: 1996 to present, abstract available, human, and English language. One author reviewed qualifying studies for relevance and method.

When meta-analyses or systematic reviews were identified, they were used instead of the original research articles. For diagnosis, only studies with controls were included. Bibliographies from the articles were used to identify additional articles that we thought were important.

Results

PREVALENCE

Only one population-based screening study (13) of systemic lupus erythematosus was identified. This study reported a prevalence of 200 cases per 100,000 women (18 to 65 years of age) in England. One review (14) estimated the overall U.S. prevalence of definite systemic lupus erythematosus plus incomplete systemic lupus erythematosus (disease meeting only some diagnostic requirements for systemic lupus erythematosus) to be 40 to 50 cases per 100,000 persons.

No screening studies on the prevalence of systemic lupus erythematosus in children were identified. However, a review Article (15) reported that systemic lupus erythematosus is estimated to affect 5,000 to 10,000 U.S. children.

In the United States, systemic lupus erythematosus is reported to be more common in women, particularly black women, than in white men. (14,16) One U.S. retrospective study (16) of medical records found that the disease is diagnosed 23 times more often in black women than in white men. The prevalence of the disease is also higher in Hispanic and Asian Americans. (16) In addition, a familial predisposition to systemic lupus erythematosus has been identified. (17-19)

CLINICAL MANIFESTATIONS

Systemic lupus erythematosus most often manifests as a mixture of constitutional symptoms, with skin (Figure 1), musculoskeletal, and hematologic (mild) involvement (Table 2). (2,20,21) However, some patients present with predominantly hematologic, renal, or neuropsychiatric manifestations. (20)

Patients with systemic lupus erythematosus appear to be at high risk for coronary artery disease. (22-24) Infections, especially of the respiratory and urinary systems, also are common in patients with the disease and are difficult to distinguish from flares of lupus activity. (1,20)

The clinical manifestations of systemic lupus erythematosus are fundamentally the same in children and adults. (15) In two descriptive studies (25,26) of children with the disease, the most frequent manifestations were fever, rash, arthritis, alopecia, and renal involvement. Compared with adults, children have a higher incidence of malar rash, anemia, leukocytopenia, (27) and severe manifestations such as neurologic or renal involvement. (28)

MORBIDITY AND MORTALITY

Organ damage in systemic lupus erythematosus progresses over time. (29) A cohort study30 found that within seven years of diagnosis, 61 percent of patients developed clinically detectable organ damage, with neuropsychiatric (20.5 percent), musculoskeletal (18.5 percent), and renal (15.5 percent) organ systems most commonly affected. Remission of systemic lupus erythematosus is not uncommon but often is punctuated by flares. (31) In a six-year prospective cohort study, (23) disease flares occurred at a rate of 0.2 per year per patient.

Infections and diseases of the cardiovascular, renal, pulmonary, and central nervous systems are the most frequent causes of death in patients with systemic lupus erythematosus. (8,23,32-37) Since the 1950s, the five-year survival rate for patients with systemic lupus erythematosus has increased from 50 percent to a range of 91 to 97 percent. (8,23,32-34,38,39) It is not known how much of this increase in survival is due to improved management versus diagnosis of earlier and milder disease. Higher mortality rates are associated with seizures, lupus nephritis, and azotemia. (36,37,40)

Mortality rates for systemic lupus erythematosus are particularly high in children. In a retrospective study (26) of Brazilian children, overall mortality during 16 years of follow-up was 24 percent. Death occurred because of infection (58 percent), central nervous system disease (36 percent), and renal disease (7 percent). When disease onset was before the age of 15 years, renal involvement and hypertension predicted mortality.

Diagnosis

The diagnosis of systemic lupus erythematosus is based on clinical and laboratory criteria. The criteria set developed by the American College of Rheumatology (ACR) is most widely used (Table 3). (41,42) An algorithm for the diagnosis of the disease is provided in Figure 2. (2,20,21,41,42)

[FIGURE 2 OMITTED]

In one study (41) that used patients with connective tissue diseases as the control group, the revised ACR diagnostic criteria for systemic lupus erythematosus were found to have an overall sensitivity of 96 percent and a specificity of 96 percent. Other studies (21,32,43) have reported sensitivities ranging from 78 to 96 percent and specificities ranging from 89 to 100 percent. The ACR criteria may be less accurate in patients with mild disease. (21)

Elevation of the antinuclear antibody (ANA) titer to 1:40 or higher is the most sensitive of the ACR diagnostic criteria. More than 99 percent of patients with systemic lupus erythematosus have an elevated ANA titer at some point, (21,41) although a significant proportion of patients may have a negative ANA titer early in the disease. (2) However, the ANA test is not specific for systemic lupus erythematosus. A study41 involving 15 international laboratories found that ANA tests in the general population were positive in 32 percent of persons at a 1:40 dilution and in 5 percent of persons at a 1:160 dilution. Rates of positive ANA tests were not affected by age up to 60 years (the upper age limit of the study).41

In the absence of systemic lupus erythematosus, the most common reason for a positive ANA test is the presence of another connective tissue disease. Diseases that often are associated with a positive ANA test include Sjogren's syndrome (68 percent of affected patients), scleroderma (40 to 75 percent), rheumatoid arthritis (25 to 50 percent), and juvenile rheumatoid arthritis (16 percent). (20) An ANA test also can be positive in patients with fibromyalgia. In patients with diseases other than systemic lupus erythematosus, ANA titers usually are lower, and the immunofluorescent pattern is different. (20)

Rates of positive ANA tests are affected by the prevalence of systemic lupus erythematosus in the population. Specifically, false-positive rates will be higher in populations with a low prevalence of the disease, such as primary care patients. Because of the high false-positive rates at 1:40 dilution, ANA titers should be obtained only in patients who meet specific clinical criteria (discussed in the clinical recommendations section of this article). When ANA titers are measured, laboratories should report ANA levels at both 1:40 and 1:160 dilutions and should supply information on the percentage of normal persons who are positive at each dilution. (41)

Interpretation of ANA titers is similar in children. An ANA titer of less than 1:40 is useful for ruling out systemic lupus erythematosus (sensitivity of 98 percent). However, an ANA titer of 1:40 or higher has a positive predictive value of only 10 percent because of the common occurrence of high ANA titers in children.44

Clinical Recommendations

The ACR recommends ANA testing in patients who have two or more unexplained signs or symptoms listed in Table 2. (2,20,21) [Reference 2--Evidence level C, consensus/expert guidelines] Because of the high rate of false-positive ANA titers, testing for systemic lupus erythematosus with an ANA titer or other autoantibody test is not indicated in patients with isolated myalgias or arthralgias in the absence of these specific clinical signs.45 Under most circumstances, a persistently negative ANA titer (less than 1:40) can be assumed to rule out systemic lupus erythematosus. (41)

A normal-range ANA titer in the context of organ system involvement that suggests systemic lupus erythematosus should prompt a work-up for alternative diagnoses. If no other cause is identified, the diagnosis of ANA-negative systemic lupus erythematosus and consultation with a rheumatologist should be considered. If patients with a normal ANA titer develop new clinical features that are consistent with systemic lupus erythematosus, ANA testing should be repeated. (46) [Evidence level C, consensus/expert guidelines]

According to a guideline from the College of American Pathologists (CAP), no further laboratory tests are necessary in patients who meet diagnostic criteria for systemic lupus erythematosus and also have a positive ANA test result. (46)

Testing for antibody to double-stranded DNA antigen (anti-dsDNA) and antibody to Sm nuclear antigen (anti-Sm) may be helpful in patients who have a positive ANA test but do not meet full criteria for the diagnosis of systemic lupus erythematosus. Anti-dsDNA and anti-Sm, particularly in high titers, have high specificity for systemic lupus erythematosus, although their sensitivity is low. Therefore, a positive result helps to establish the diagnosis of the disease, but a negative result does not rule it out.46 The CAP guideline recommends against testing for other autoantibodies in ANA-positive patients, because there is little evidence that these tests are of benefit. (46)

The ACR recommends that primary care physicians consider a rheumatology referral for patients with characteristic signs and symptoms of systemic lupus erythematosus (Table 2) (2,20,21) and a positive ANA test, particularly if these patients have more than mild or stable disease. (2) [Reference 2--Evidence level C, consensus/expert guidelines]

The authors indicate they do not have any conflicts of interest. Sources of funding: this project was partially funded by the Delaware Division of Public Health, grant number PSC0432.

The authors thank Cheryl Mongillo and Teresa Gill Cirillo for assistance in preparing the manuscript.

Table 1

Resources Used for an Evidence-Based Review of the Literature on

Systemic Lupus Erythematosus

American College of Physicians Journal Club (http://www.acpjc.org)

National Guideline Clearinghouse Database (http://www.guideline.gov)

Agency for Healthcare Research and Quality

Database (http://www.ahcpr.gov)

Turning Research into Practice Database

(http://www.tripdatabase.com)

Cochrane Database of Systematic Reviews (http://www.cochrane.org)

British National Health Service Centre for Reviews and Dissemination

(http://www.york.ac.uk/inst/crd/)

REFERENCES

(1.) Edworthy SM. Clinical manifestations of systemic lupus erythematosus. In: Ruddy S, Harris ED, Sledge CB, Kelley WN, eds. Kelley's Textbook of rheumatology. 6th ed. Philadelphia: Saunders, 2001:1105-19.

(2.) Guidelines for referral and management of systemic lupus erythematosus in adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum 1999;42:1785-96.

(3.) Petri M. Treatment of systemic lupus erythematosus: an update. Am Fam Physician 1998;57:2753-60.

(4.) Meinao IM, Sato EI, Andrade LE, Ferraz MB, Atra E. Controlled trial with chloroquine diphosphate in systemic lupus erythematosus. Lupus 1996;5:237-41.

(5.) Molina JF, McGrath H Jr. Longterm ultraviolet-A1 irradiation therapy in systemic lupus erythematosus. J Rheumatol 1997;24:1072-4.

(6.) McGrath H, Martinez-Osuna P, Lee FA. Ultraviolet-A1 (340-400 nm) irradiation therapy in systemic lupus erythematosus. Lupus 1996;5:269-74.

(7.) Dammacco F, Della Casa Alberighi O, Ferraccioli G, Racanelli V, Casatta L, Bartoli E. Cyclosporine-A plus steroids versus steroids alone in the 12-month treatment of systemic lupus erythematosus. Int J Clin Lab Res 2000;30:67-73.

(8.) Carneiro JR, Sato EI. Double blind, randomized, placebo controlled clinical trial of methotrexate in systemic lupus erythematosus. J Rheumatol 1999; 26:1275-9.

(9.) Alvarez-Nemegyei J, Cobarrubias-Cobos A, Escalante-Triay F, Sosa-Munoz J, Miranda JM, Jara LJ. Bromocriptine in systemic lupus erythematosus: a double-blind, randomized, placebo-controlled study. Lupus 1998;7:414-9.

(10.) Pollak VE, Pirani CL, Kark RM. Effect of large doses of prednisone on the renal lesions of and life span of patients with lupus glomerulonephritis. J Lab Clin Med 1961;57:495-511.

(11.) Bansal VK, Beto JA. Treatment of lupus nephritis: a meta-analysis of clinical trials. Am J Kidney Dis 1997;29:193-9.

(12.) Bellomio V, Spindler A, Lucero E, Berman A, Santana M, Moreno C, et al. Systemic lupus erythematosus: mortality and survival in Argentina. A multicenter study. Lupus 2000;9:377-81.

(13.) Johnson AE, Gordon C, Hobbs FD, Bacon PA. Undiagnosed systemic lupus erythematosus in the community. Lancet 1996;347:367-9.

(14.) Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778-99.

(15.) Lehman TJ. Systemic onset juvenile rheumatoid arthritis. Retrieved March 20, 2003, from http://www. uptodate.com/physicians/rheumatology_toclist.asp.

(16.) McCarty DJ, Manzi S, Medsger TA Jr, Ramsey-Goldman R, LaPorte RE, Kwoh CK. Incidence of systemic lupus erythematosus. Race and gender differences. Arthritis Rheum 1995;38:1260-70.

(17.) Gourley IS, Cunnane G, Bresnihan B, FitzGerald O, Bell AL. A clinical and serological comparison of familial and non-familial systemic lupus erythematosus in Ireland. Lupus 1996;5:288-93.

(18.) Grennan DM, Parfitt A, Manolios N, Huang Q, Hyland V, Dunckley H, et al. Family and twin studies in systemic lupus erythematosus. Dis Markers 1997;13:93-8.

(19.) Gray-McGuire C, Moser KL, Gaffney PM, Kelly J, Yu H, Olson JM, et al. Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16-15.2. Am J Hum Genet 2000;67:1460-9.

(20.) Schur PH. General symptomatology and diagnosis of systemic lupus erythematosus in adults. Retrieved March 20, 2003, from http://www.upto date.com/physicians/rheumatology_toclist.asp.

(21.) Gilboe IM, Husby G. Application of the 1982 revised criteria for the classification of systemic lupus erythematosus on a cohort of 346 Norwegian patients with connective tissue disease. Scand J Rheumatol 1999;28:81-7.

(22.) Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jansen-McWilliams L, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997;145:408-15.

(23.) Jonsson H, Nived O, Sturfelt G. Outcome in systemic lupus erythematosus: a prospective study of patients from a defined population. Medicine [Baltimore] 1989;68:141-50.

(24.) Rahman P, Urowitz MB, Gladman DD, Bruce IN, Genest J Jr. Contribution of traditional risk factors to coronary artery disease in patients with systemic lupus erythematosus. J Rheumatol 1999;26:2363-8.

(25.) Singh S, Kumar L, Khetarpal R, Aggarwal P, Marwaha RK, Minz RW, et al. Clinical and immunological profile of SLE: some unusual features. Indian Pediatr 1997;34:979-86.

(26.) Marini R, Costallat LT. Young age at onset, renal involvement, and atrial hypertension are of adverse prognostic significance in juvenile systemic lupus erythematosus. Rev Rhum Engl Ed 1999;66:303-9.

(27.) Rood MJ, ten Cate R, van Suijlekom-Smit LW, den Ouden EJ, Ouwerkerk FE, Breedveld FC, et al. Childhood-onset systemic lupus erythematosus: clinical presentation and prognosis in 31 patients. Scand J Rheumatol 1999;28:222-6.

(28.) Carreno L, Lopez-Longo FJ, Monteagudo I, Rodriguez-Mahou M, Bascones M, Gonzalez CM, et al. Immunological and clinical differences between juvenile and adult onset of systemic lupus erythematosus. Lupus 1999;8:287-92.

(29.) Gladman DD, Goldsmith CH, Urowitz MB, Bacon P, Fortin P, Ginzler E, et al. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index for systemic lupus erythematosus international comparison. J Rheumatol 2000;27:373-6.

(30.) Rivest C, Lew RA, Welsing PM, Sangha O, Wright EA, Roberts WN, et al. Association between clinical factors, socioeconomic status, and organ damage in recent onset systemic lupus erythematosus. J Rheumatol 2000;27:680-4.

(31.) Schur PH. Overview of the therapy and prognosis of systemic lupus erythematosus in adults. Retrieved March 20, 2003, from http://www.upto date.com/physicians/rheumatology_toclist.asp.

(32.) Stahl-Hallengren C, Jonsen A, Nived O, Sturfelt G. Incidence studies of systemic lupus erythematosus in southern Sweden: increasing age, decreasing frequency of renal manifestations and good prognosis. J Rheumatol 2000;27:685-91.

(33.) Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients. European Working Party on Systemic Lupus Erythematosus. Medicine [Baltimore] 1999;78:167-75.

(34.) Mok CC, Lau CS, Chan TM, Wong RW. Clinical characteristics and outcome of southern Chinese males with systemic lupus erythematosus. Lupus 1999;8:188-96.

(35.) Koh ET, Seow A, Leong KH, Chng HH. SLE mortality in an oriental population. Lupus 1997;6:27-31.

(36.) Jacobsen S, Petersen J, Ullman S, Junker P, Voss A, Rasmussen JM, et al. A multicentre study of 513 Danish patients with systemic lupus erythematosus. II. Disease mortality and clinical factors of prognostic value. Clin Rheumatol 1998;17:478-84.

(37.) Blanco FJ, Gomez-Reino JJ, de la Mata J, Corrales A, Rodriguez-Valverde V, Rosas JC, et al. Survival analysis of 306 European Spanish patients with systemic lupus erythematosus. Lupus 1998;7:159-63.

(38.) Uramoto KM, Michet CJ Jr, Thumboo J, Sunku J, O'Fallon WM, Gabriel SE. Trends in the incidence and mortality of systemic lupus erythematosus, 1950-1992. Arthritis Rheum 1999;42:46-50.

(39.) Urowitz MB, Gladman DD, Abu-Shakra M, Farewell VT. Mortality studies in systemic lupus erythematosus. Results from a single center. III. Improved survival over 24 years. J Rheumatol 1997; 24:1061-5.

(40.) Ward MM. Hospital experience and expected mortality in patients with systemic lupus erythematosus: a hospital level analysis. J Rheumatol 2000; 27:2146-51.

(41.) Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-7.

(42.) Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [Letter]. Arthritis Rheum 1997;40:1725.

(43.) Ferraz MB, Goldenberg J, Hilario MO, Bastos WA, Oliveira SK, Azevedo EC, et al. Evaluation of the 1982 ARA lupus criteria data set in pediatric patients. Committees of Pediatric Rheumatology of the Brazilian Society of Pediatrics and the Brazilian Society of Rheumatology. Clin Exp Rheumatol 1994;12:83-7.

(44.) Malleson PN, Sailer M, Mackinnon MJ. Usefulness of antinuclear antibody testing to screen for rheumatic diseases. Arch Dis Child 1997;77:299-304.

(45.) Guidelines for the initial evaluation of the adult patient with acute musculoskeletal symptoms. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996;39:1-8.

(46.) Kavanaugh A, Tomar R, Reveille J, Solomon DH, Homburger HA. Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens. American College of Pathologists. Arch Pathol Lab Med 2000; 124:71-81.

JAMES M. GILL, M.D., M.P.H., is director of the Health Services Research Group and associate program director of the family practice residency program at Christiana Care Health Services, Wilmington, Del. Dr. Gill received a medical degree from the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, and a master of public health degree from Johns Hopkins University, Baltimore.

ANNA M. QUISEL, M.D., is a family practice and urgent care physician in the Newark, Del., area. Dr. Quisel graduated from the University of Washington School of Medicine, Seattle, and completed a family practice residency at Christiana Care Health Services.

PETER V. ROCCA, M.D., is a rheumatologist in private practice in Wilmington, Del. Dr. Rocca received his medical degree from Georgetown University School of Medicine, Washington, D.C. He completed an internal medicine residency at Christiana Care Health Services and a rheumatology fellowship at Georgetown University School of Medicine.

DENE T. WALTERS, M.D., is emeritus chairman of the Department of Family and Community Medicine and emeritus program director of the family practice residency program at Christiana Care Health Services. Dr. Walters is a graduate of the University of Pennsylvania School of Medicine, Philadelphia.

Address correspondence to James M. Gill, M.D., M.P.H., Christiana Care Health Services, 1401 Foulk Rd., Wilmington, DE 19803 (e-mail: Jgill@christianacare.org). Reprints are not available from the authors.

COPYRIGHT 2003 American Academy of Family Physicians
COPYRIGHT 2003 Gale Group