Nurse Practitioner:
doi: 10.1097/01.NPR.0000422207.69679.f5
Feature: AUTOIMMUNE DISEASES

The face of lupus

Weinstein, Patricia K. PhD, ARNP

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Author Information

Patricia K. Weinstein is an Associate Professor at the University of Central Florida, College of Nursing in Orlando, Fla.

The author has disclosed that she has no financial relationships related to this article.

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Abstract

Abstract: Systemic lupus erythematosus—a chronic, complex autoimmune disease without a defi nitive diagnostic test—often requires burdensome procedures to confi rm diagnosis. Nurse practitioners must understand lupus' clinical and serologic manifestations to make a diagnosis; some cases may not be identifi ed using only the American College of Rheumatology's criteria.

Systemic lupus erythematosus (SLE) is a chronic, relapsing autoimmune disorder with unpredictable manifestations that vary from patient-to-patient. Initially, individuals may present with symptoms such as fever, fatigue, and joint pain, that are common to many disorders, but unlike many diseases, there is no test to confirm diagnosis. Consequently, diagnosing SLE can be a challenge to even the most experienced clinician; the average time between initial presentation and definitive diagnosis is 2 years.1 Early diagnosis is essential to slow disease progression and prevent organ damage.

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The American College of Rheumatology (ACR) developed a set of diagnostic criteria for research purposes—not to specifically diagnose SLE.2,3 Critics claim the ACR's criteria may exclude nearly half of SLE patients.4 Nonetheless, without a specific biomarker or diagnostic test, clinicians frequently rely on the ACR's criteria to establish a diagnosis. A patient must meet at least 4 of the 11 criteria (either serially or simultaneously) during any interval of observation to be classified as having SLE (see ACR criteria for classification of SLE). Given the subsets that exist within five of the criteria, it would be possible to encounter 2,249 patients who meet the minimum four criteria before any two presented with identical symptoms.

The infrequency of lupus compounds the challenge of making a diagnosis. Estimates of prevalence rates in the United States range from 161,0005 to as high 1.5 million.6 SLE is even more infrequent in the male population with a 9:1 female-to-male ratio.6 Given the low prevalence of SLE in the general population, most primary care providers will not encounter patients with SLE on a frequent basis, thereby limiting their opportunity to observe many of SLE's less-common manifestations.7

Table ACR criteria f...
Table ACR criteria f...
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The eventual discovery of a biomarker may ease confirmation of disease, but until then, making an SLE diagnosis will remain a clinical challenge. Diagnosis should be determined by the overall clinical presentation and further informed by serologic studies/diagnostic procedures. Once SLE is suspected, referral to a rheumatologist is appropriate.8 Procedures such as skin, nerve, muscle, or renal biopsy by subspecialists are often necessary to make a firm diagnosis as well as to determine the extent of organ involvement.

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Assessment

SLE can affect any organ, which is reflected in its heterogeneity of clinical manifestations. A diagnosis of SLE is probable in patients who present with 4 or more of the 11 ACR criteria. However, this should not replace a thorough history, physical exam, or clinical judgment.

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History

The initial symptoms of SLE may be confused easily with those of other common disorders. Asking patients to describe what bothers them in their own words (rather than simply complete a symptom checklist) may help detect subtle signs and symptoms.9

While the onset of SLE is typically during the reproductive years, it may occur at any age. Late-onset SLE occurring at age 50 or later is less common and differs somewhat from that in younger patients. Arthritis and photosensitivity occur less often, female predominance decreases, and renal involvement is found in 42% to 52% of patients.10

Racial/ethnic background is important to ascertain. The incidence of SLE is two to three times higher in Black women than in non-Hispanic White women. It is suspected that just as many (if not more) Hispanic individuals have SLE than Blacks.6

Family history is often a tell-tale sign, as more than 12 different genes are associated with SLE. Approximately 10% to 20% of patients with SLE report having at least one first-degree relative who also has the disease.11

Environmental factors play a role in the onset of SLE. Inquiry should be made about provocative factors such as exposure to sunlight, tobacco use, situational stress, infections (particularly Epstein-Barr virus and streptococcal infections), chemical toxins, and medications.12 Skin lesions may develop shortly after UV exposure (or up to 3 weeks later) and persist for months. Consequently, patients may not recognize the effects of UV-exposure as disease-related. Sun exposure may also induce or exacerbate systemic symptoms.13

Patients may relate a history of recurrent infections—particularly lung, skin, and urine—and should be asked about any bleeding or clotting problems. Petechiae and ecchymoses may be related to thrombocytopenia. Thrombotic events may indicate the presence of antiphospholipid antibodies (aPLs), although the risk of thrombosis is higher in SLE than for the general population independent of aPLs.14

Constitutional symptoms such as fever, fatigue, and weight loss occur in 50% to 100% of patients and may be unrelated to any specific organ involvement. Fever is usually low-grade, rarely exceeding 102° F (38.8° C). Weight loss is less common and may be related to anorexia or gastrointestinal symptoms.9

Fatigue is the most frequent complaint and can occur acutely with lupus flares. No lab values correlate with fatigue, and most often, fatigue is unrelated to activity.15

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Mucocutaneous

Four of the 11 ACR SLE criteria are mucocutaneous.3 Skin manifestations occur in 70% to 80% of patients at some time in their lives and are classified into three subsets: acute, subacute, and chronic.13 Acute cutaneous lupus erythematosus most often presents as facial erythema, but it is the classical “butterfly” or malar rash that spans the cheeks and nasal bridge, sparing the nasolabial folds that are most commonly associated with SLE (see Classic butterfly rash).13 A woman of childbearing age who presents with a rash, fever, and joint aches should raise a high level of suspicion for SLE. The rash can occur anywhere on the body and may include blisters. Onset is abrupt, can last for hours or days, and most often heals without scarring. Photosensitive dermatitis may also be reported.10 Subacute cutaneous lupus erythematosus (SCLE) usually presents as annular lesions that are particularly sensitive to UV light but heal without scarring.13 SCLE also may manifest as thick, scaly lesions most commonly on the knees that are similar in formation and appearance to psoriasis; many patients with SCLE have systemic disease. Chronic cutaneous lupus erythematosus (CCLE) such as discoid occurs infrequently with SLE. Discussion of CCLE subtypes is beyond the scope of this article; however, information is available at http://dermnetnz.org/immune/cutaneous-lupus.html.

Scarring or nonscarring alopecia occurs in 20% to 30% of patients.13 Thinning with short, broken hairs in the frontal areas of the scalp is common. Raynaud phenomenon is observed in approximately 30% of SLE patients, may occur years before other manifestations, does not correlate with disease activity, and is rarely associated with permanent damage.9 Livedo reticularis may also be observed.16

Nearly 70% of patients with cutaneous lupus report photosensitivity, which often precedes other disease manifestations.17 UV injury, by both natural and artificial light, induces apoptosis and necrosis of keratinocytes, which in turn causes the release of chemokines and extracellular self-DNA.

Oral ulcers are the mucosal counterparts of skin lesions and are similarly classified;18 scarring is usually absent because of better mucosal regeneration compared to the skin. The most common mucosal presentation is the oral discoid lesion. Distribution is usually asymmetric, whereas oral lichen planus is almost always symmetric. Lip manifestations include discoid lesions and diffuse cheilitis. Oral manifestations can occur in isolation or in association with skin lesions, be acute or chronic, painful, or asymptomatic.

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Ocular

Fundoscopy should be part of the physical exam, as retinal vasculitis can occur.9 Its presence is marked by narrow, sheathed retinal arterioles with white exudates next to the vessels. Blurring of the optic disk margins may indicate pseudotumor cerebri, a central nervous system (CNS) manifestation associated with intracranial hypertension, cerebral venous thrombosis, or corticosteroid withdrawal.19 Optic neuritis is unusual but should be considered if loss of vision has occurred. Other ocular manifestations include dry eye, infiltrative keratitis, scleritis, episcleritis, and orbital inflammation.20

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Musculoskeletal

Up to 90% of patients experience transitory arthritis and arthralgia.21 The arthritis is usually symmetrical, nonerosive, nonprogressive, and nondeforming. It initially occurs in the small joints of the hands and wrist and may involve large joints but spares the spine. Occasionally, patients will develop chronic synovitis with reducible deformity that may first lead to an incorrect diagnosis of rheumatoid arthritis (RA). If osteonecrosis occurs, it is most commonly in the hip and late in the disease. Patients may complain of generalized myalgia and muscle weakness, but myositis is rare. About a third of SLE patients also have fibromyalgia, which like lupus, has a high prevalence of positive antinuclear antibody (ANA) and female predominance.14

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Renal

Kidney involvement is a hallmark of SLE with lupus nephritis being a harbinger of poor outcome.22 About one-third to one-half of patients have renal involvement that is diagnosed by the presence of proteinuria (dipstick 3+, greater than 500 mg/24 hour).14 Definitive assessment of renal injury is determined by renal biopsy.8

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Cardiovascular

The most common cardiovascular presentation is pericarditis.9 Symptoms can be severe or mild and last for just hours or weeks; tamponade is rare. When a young female patient presents with dyspnea and pleuritic chest pain, SLE should be included in the differential diagnosis.

Premature and accelerated atherosclerosis is a leading cause of morbidity and mortality in lupus. SLE patients have a 7-to-10-fold increased risk of cardiovascular disease. This is especially pronounced in younger women whose risk for myocardial infarction may be greater than 50-fold compared to non-SLE controls.23 Chronic inflammation and immune dysregulation contribute to the prematurity and acceleration of atherosclerosis. Consequently, a diagnosis of atherosclerotic disease in a woman under 45 should warrant investigation into the possibility of an underlying autoimmune disorder.

Classic butterfly ra...
Classic butterfly ra...
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Conduction defects, such as first- and second-degree heart blocks and bundle-branch blocks, may be transient or persistent. Myocarditis, verrucous endocarditis (Libman-Sacks), and coronary arteritis are rare but should be red flags for SLE.14

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Pulmonary

Pleuritis is the most common pulmonary presentation.14 Pleural effusion, which may be secondary to other processes such as infection or pulmonary embolism, is not unusual. Less commonly, chronic diffuse interstitial lung disease occurs. Acute lupus pneumonitis is an abrupt febrile pneumonitic illness characterized by pleuritic chest pain, cough, hemoptysis, and dyspnea in which infection has been ruled out; it has a 50% mortality and is marked by decreasing hematocrit and pulmonary infiltrates.24 Pulmonary hypertension presents similarly to idiopathic pulmonary hypertension but with a higher incidence of concomitant Raynaud phenomenon. The risk of pulmonary embolism is increased in patients with aPLs.25

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Gastrointestinal

Gastrointestinal symptoms are not included in the ACR criteria but are the initial presentation in many patients.16 Among common complaints are dysphagia, anorexia, nausea, vomiting, and diarrhea. Abdominal distension, pain, and tenderness may signal mesenteric vasculitis or thrombosis. Hepatomegaly may be found in active disease, and approximately 1/3 of patients have mildly elevated liver enzymes.

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Neuropsychiatric

Neuropsychiatric involvement may present as seizures, psychosis, stroke, coma, meningitis, transverse myelitis, or peripheral neuropathy. In addition, 28% of manifestations appear before or near the time of SLE diagnosis.26 Cognitive dysfunction (fuzzy thinking or memory deficit) is the most common neurologic manifestation present in up to 80% of patients 10 years after diagnosis.25 Although many patients complain of headache, their overall incidence—both migraine and tension type—in SLE patients is similar to that in the general population.27 CNS lupus/vasculitis/cerebritis is the most serious syndrome associated with SLE. It is rare but appears usually early in the disease and presents with fever, seizures, nuchal rigidity, and psychotic or bizarre behavior. Lupus myelitis is another serious complication whose presentations range from weakness or difficulty in moving one limb to paraplegia.28

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Lymphoid

Lymphadenopathy is common but nonspecific.29 Nodes are typically nontender, shotty, and 3 to 4 cm in size. It is not uncommon for lymphoma to be suspected when lymphadenopathy is the presenting symptom. Splenomegaly also may be present.9

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Genitourinary

Menstrual irregularities, early onset menopause, and worsening or improvement of lupus symptoms corresponding to menstrual cycle, pregnancy, or hormonal therapy may be part of the initial patient presentation.30,31 Repeated miscarriages may indicate the presence of aPLs.32 Hyperprolactinemia occurs in 20% to 30% of patients and rarely may cause galactorrhea.33 Physiologic problems related to sexual or genitourinary function in males have not been reported.

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Laboratory findings

Table Lupus-associat...
Table Lupus-associat...
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When evaluating a patient for SLE, the following laboratory tests are indicated: complete blood count with platelets, erythrocyte sedimentation rate (ESR), dipstick of urine and urinalysis, and ANA.34 The ACR recommends ANA testing in patients who have two or more signs suggestive of SLE that are unexplained by other disorders. A positive ANA titer of 1:40 or greater is the most sensitive of the ACR criteria, but it is nonspecific.8 As many as 13% of healthy individuals will have positive ANA by indirect immunofluorescence at 1:80 dilution;35 ANA-negative SLE is rare.

The College of American Pathologists recommend no further laboratory tests in patients who meet diagnostic criteria for SLE and have a positive ANA test result.36 However, further autoantibody testing may be helpful in patients with a positive ANA test who fail to meet 4 of the 11 ACR criteria SLE (see Lupus-associated autoantibodies).

Antidouble-stranded DNA (ds-DNA) and anti-Sm antibodies are specific for SLE but have low sensitivity, occurring in only 40% to 60% of patients.14 Approximately 30% of patients have elevated titers of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-beta2 glycoprotein-1), and about half of those will develop antiphospholipid syndrome. This disorder is characterized by the presence of aPLs plus the occurrence of a thrombotic event.37 In the presence of an autoimmune disease, aPLs at least doubles the risk of thrombosis.

It is worth noting that a new diagnostic blood test—a platelet-bound complement activation product with 99% specificity and 18% sensitivity—has recently been made commercially available for assisting in the diagnosis of SLE.38,39

Hematologic abnormalities (very often the initial presentation) are common and can mimic blood dyscrasias.14 Anemia, leukopenia, and thrombocytopenia can occur together or in isolation. Leukopenia is usually mild, while thrombocytopenia, in particular, may herald SLE years in advance of other symptoms. Complement components C3 and C4 may be reduced but are nonspecific for SLE.40

ESR and/or C-reactive protein (CRP) may be elevated, but both are nonspecific. CRP is a poor acute-phase responder in SLE flares.40 Researchers have located gene polymorphisms associated with lower CRP levels on a locus linked to SLE.41 Markedly elevated CRP levels are found in SLE patients with infections but otherwise are only moderately elevated, even in patients with very active disease.42

Urinalysis may reveal proteinuria (alone or with red blood cells or casts) and can signal lupus nephritis.22 Isolated hematuria without other urine abnormalities is unlikely SLE and should prompt a search for other causes.

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Other diagnostics

Diagnostic imaging is not routine in the initial diagnosis of SLE unless CNS involvement or osteonecrosis is suspected; it should be under the direction of a rheumatologist or other subspecialist. The same holds true for skin and renal biopsies, which are helpful in diagnosing cutaneous SLE and lupus nephritis, respectively.8

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Differential diagnosis

Drug-induced lupus should be excluded first (see Drugs with potential to cause lupus-like disease). It differs from SLE in that males and females are equally affected, nephritis and CNS symptoms are not usually present, and symptoms most often resolve when the offending medication is withdrawn.43

Likewise, infections should be excluded. Parvovirus, hepatitis B, and hepatitis C may mimic SLE. Anemia, elevated ESR, positive ANA, vasculitis, and other autoimmune phenomena are associated with some malignancies.14

Patients with multisystem manifestations and positive ANA titers may have rheumatic conditions other than SLE. Initial presentation of the patient with SLE and the patient with RA may be similar, but arthritis in SLE is rarely erosive.25 Scleroderma has serologies associated with SLE, but familial occurrence is rare. Polymyositis and dermatomyositis are less common in women, and most often, patients lack a familial history of autoimmune disorders. Autoimmune disorders marked by vasculitis—polyarteritis nodosa, Behçet syndrome, and Wegener granulomatosis—can be confused with SLE, but they frequently have a negative ANA.9 Fibromyalgia may be mistaken for SLE, and many patients with SLE have fibromyalgia. Although the ANA is positive in 20% to 30% of patients with fibromyalgia, other blood tests are normal.44 A malar rash should be distinguished from seborrhea or rosacea, which do not spare the nasolabial folds. Oral ulcers are more common on the hard palate in SLE, and persistent blue or cyanotic discoloration of the extremities is more likely to be observed.9

Clinical manifestations of multiple sclerosis (MS) resemble those of SLE and often follow a similar course.28 The McDonald criteria used to diagnose MS do not help in differentiating the two disorders.45

There are some signs and/or symptoms that should raise suspicion: fever, joint aches, and rash in a young woman; recurrent infections (especially lung, skin, and urinary tract); thrombotic events such as stroke and pulmonary embolism in individuals without known risk factors; new onset menstrual irregularities and/or galactorrhea in young women; and cardiac events in men and women before age 45.

Patients with positive autoantibodies who fulfill less than four of the ACR criteria are sometimes classified as having undifferentiated connective tissue disorder or incomplete/latent lupus. Their disease may never progress, it may evolve slowly into well-defined SLE, or the patients may become part of a subset with mild SLE.9 Nonetheless, they warrant follow-up in order to assess disease progression and prevent organ damage.

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Implications for practice

Early diagnosis of SLE is critical to prevent organ damage that adversely affects prognosis and quality of life. SLE should be suspected in any patient who fulfills two or more of the ACR critieria.8 The nurse practitioner (NP) is an important contributor to the early identification of lupus patients. The complexity of SLE requires the active participation of a rheumatologist since some diagnostic tests and medical treatments extend beyond the scope of NP practice. A missed SLE diagnosis or failure to refer to a rheumatologist when SLE is suspected may delay treatment and increases the risk of organ damage. A misdiagnosis of SLE can have equally unfavorable consequences as it potentially subjects the patient to unnecessary procedures and treatments; these include corticosteroids (which have consequential adverse reactions), needless lifestyle modifications, and emotional distress. Successful diagnosis and management of the patient with SLE depends upon collaboration among the NP, rheumatologist, subspecialists, and other members of the healthcare team.

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Drugs with potential to cause lupus-like disease

High risk

Hydralazine

Procainamide

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Moderate risk

Quinidine

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Low risk

Acebutolol

Captopril

Carbamazepine

Chlorpromazine

D-Penicillamine

Isoniazid

Methyldopa

Minocycline

Propylthiouracil

Sulfasalazine

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Very Low Risk

Amiodarone

Atenolol

Atorvastatin

Clonidine

Disopyramide

Enalapril

Ethosuximide

Hydrochlorothiazide

Interferon

Lisinopril

Lithium carbonate

Lovastatin

Mesalamine

Nitrofurantoin

Perphenazine

Phenelzine

Phenytoin

Pindolol

Prazosin

Primidone

Propafenone

Simvastatin

Ticlopidine

Timolol eye drops

Trimethadione

Tumor necrosis factor inhibitors (such as infliximab, etanercept)

Zafi rlukast

*This list is not all-inclusive and drugs that exclusively induce skin manifestations or antibody production are not included.

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Keywords:

autoimmune disease; lupus nephritis; mucocutaneous manifestations; systemic lupus erythematosus

© 2012 Lippincott Williams & Wilkins, Inc.

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