Diagnosis of Systemic Lupus Erythematosus

Am Fam Physician. 2003 Dec 1;68(11):2179-2187.

Systemic lupus erythematosus is a multisystem inflammatory disease that is often difficult to diagnose. Before the diagnosis can be established, four of 11 clinical and laboratory criteria must be met. Antinuclear antibody titer is the primary laboratory test used to diagnose systemic lupus erythematosus. Because of the low prevalence of the disease in primary care populations, the antinuclear antibody titer has a low predictive value in patients without typical clinical symptoms. Therefore, as specified by the American College of Rheumatology, this titer should be obtained only in patients with unexplained involvement of two or more organ systems. Pa tients with an antinuclear antibody titer of 1:40 and characteristic multiorgan system involvement can be diagnosed with systemic lupus erythematosus without additional testing; however, patients with an antibody titer of 1:40 who fail to meet full clinical criteria should undergo additional testing, including tests for antibody to doublestranded DNA antigen and antibody to Sm nuclear antigen. While an antinuclear antibody titer of less than 1:40 usually rules out systemic lupus erythematosus, patients with persistent, characteristic multisystem involvement may be evaluated for possible antinuclear antibody–negative disease.

Systemic lupus erythematosus is a chronic, recurrent, potentially fatal multisystem inflammatory disorder that can be difficultto 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 morbidity411 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.

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/)

TABLE 1   Resources Used for an Evidence-Based Review of the Literature on Systemic Lupus Erythematosus

View Table

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/)

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 study13 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 review14 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 article15 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 study16 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

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

FIGURE 1.

TABLE 2
Clinical Features of Systemic Lupus Erythematosus

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

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 studies25,26 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.8,23,3237 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.8,23,3234,38,39 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 study26 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

TABLE 3
American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

Diagnosis of Systemic Lupus Erythematosus

FIGURE 2.

An algorithm for the diagnosis of systemic lupus erythematosus (SLE). (ANA = antinuclear antibody; ACR = American College of Rheumatology; antidsDNA = antibody to double-stranded DNA antigen; anti-Sm = antibody to Sm nuclear antigen)

Information from references 2,20,21,41, and 42.

View Large

Diagnosis of Systemic Lupus Erythematosus


FIGURE 2.

An algorithm for the diagnosis of systemic lupus erythematosus (SLE). (ANA = antinuclear antibody; ACR = American College of Rheumatology; antidsDNA = antibody to double-stranded DNA antigen; anti-Sm = antibody to Sm nuclear antigen)

Information from references 2,20,21,41, and 42.

Diagnosis of Systemic Lupus Erythematosus


FIGURE 2.

An algorithm for the diagnosis of systemic lupus erythematosus (SLE). (ANA = antinuclear antibody; ACR = American College of Rheumatology; antidsDNA = antibody to double-stranded DNA antigen; anti-Sm = antibody to Sm nuclear antigen)

Information from references 2,20,21,41, and 42.

In one study41 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 studies21,32,43 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 Sjögren'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 [Reference2—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. AntidsDNA 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 [Reference2—Evidence level C, consensus/expert guidelines]

The Authors

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.

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.

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 nonfamilial 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.uptodate.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. Agespecific 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.uptodate.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.


Copyright © 2003 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions and/or permission requests.

Want to use this article elsewhere? Get Permissions


Article Tools

  • Download PDF
  • Print page
  • Share this page
  • AFP CME Quiz

Information From Industry

More in Pubmed

Navigate this Article