Lupus is known for its protean manifestations, which affect every organ system. These are identified via symptoms, signs, and laboratory or imaging abnormalities. This section reviews the principal complaints and physical findings associated with the disease (Table 5.1).1
Chief Complaint
Half of persons with systemic lupus erythematosus present with organ-threatening disease. The remaining individuals do not present with car-diopulmonary, hepatic, or renal symptoms; central nervous system (CNS) vas-culitis; hemolytic anemia; or thrombocytopenia on initial evaluation. Organ involvement is relatively easy to diagnose—a chest radiograph, electrocardiogram, blood chemistry panel, complete blood count, and urinalysis usually point the physician in the correct direction. It takes a mean of three months from the onset of symptoms to diagnose these individuals. On the other hand, it can often take one to two years and several physician consultations before the presence of organ-sparing lupus is ascertained. Rashes can shorten the length to time of diagnosis, but young, healthy-appearing women with non-specific symptoms of fatigue and aching are often thought to have other processes or are given psychosocial explanations. A review of the chief complaint of new lupus patients revealed that the principal manifestations were arthralgia (62%) and cutaneous symptoms (especially newly discovered photosensitivity) (20%), followed by fever and malaise.
Constitutional Findings: Fever, Malaise, Fatigue, Anorexia, and Weight Loss
Constitutional complaints are generalized manifestations of the disease that do not fall into any organ-system category. They include fever, malaise, fatigue, anorexia, and weight loss.
The definition of fever is a temperature greater than 99.6°F. Low-grade fevers are often a presenting feature of SLE, and patients may not be aware of their elevated temperature. The usual source of nonfocal fever is untreated or undertreated inflammation. Often associated with tachycardia and relative hypotension, infection needs to be ruled out. Other causes of elevated temperature include medication reactions. Fevers need to be viewed seriously, especially if the patient is taking salicylates, nonsteroidal drugs, or corticosteroids that reduce body temperature.
Table 5.1 Approximate prevalence of selected symptoms, signs, and laboratory abnormalities of systemic lupus erythematosus during the course of the disease in the United States, based on a summation of findings in diverse cohorts
|
Positive antinuclear antibody |
97% |
|
Malaise and fatigue |
90% |
|
Arthralgia, myalgia |
90% |
|
Sun sensitivity, skin changes |
70% |
|
Cognitive dysfunction |
70% |
|
Low C3 or C4 complement |
61% |
|
Fever due to lupus |
57% |
|
Antibodies to dsDNA |
50% |
|
Arthritis |
50% |
|
Leukopenia |
46% |
|
Pleuritis |
44% |
|
Anemia |
42% |
|
Alopecia |
40% |
|
Nephritis, proteinuria |
40% |
|
Anticardiolipin antibody |
35% |
|
Malar rash |
35% |
|
Central nervous system |
32% |
|
Increased gamma globulin |
32% |
|
Weight loss due to lupus |
27% |
|
Raynaud’s |
25% |
|
Hypertension |
25% |
|
Sjögren’s |
25% |
|
Oral ulcerations (mouth, nose) |
20% |
|
Discoid lesions |
20% |
|
Central nervous system vasculitis |
15% |
|
Adenopathy |
15% |
|
Pleural effusion |
12% |
|
Subacute cutaneous lupus |
10% |
|
Myositis |
10% |
|
Avascular necrosis |
10% |
Lupus patients complain of a sense of malaise and fatigue. Over 90% with the disease report this to their physician, and its lack of specificity can be problematic. Loss of stamina and endurance, aching or flu-like symptoms, and a sense of “not feeling right” or “having the blahs” are examples of descriptions that might be given to an examining physician. Infection, depression, anemia, hormonal imbalance, medication reactions, and stress need to be considered in the differential diagnosis.
Half of all lupus patients report a loss of appetite with resulting weight loss upon initial presentation. Ten percent note a 10% loss of body weight over a three-month period. This nonspecific finding usually does not occur later in the disease course, especially if the patient is taking corticosteroids. Lupus with nephrosis is also associated with labile weight alterations.
Cutaneous Manifestations
Photosensitivity
Two-thirds of lupus patients self-report sensitivity to sunlight.2 Half of these (one-third of those with SLE) have reproducible rashes or a wheal-and-flare response when exposed to ultraviolet (UV) light in a controlled setting. Reactions range from a mild rash to fevers, malaise, adenopathy, arthritis, and severe rashes. Some patients have no problem going out in the sun; for others, it is dose- and time-related. UV exposure can be present on cloudy days and is greater at higher altitudes and midday. It is believed that UVA2 (320 to 340 nm) and UVB (340 to 400 nm) light are harmful in SLE; the UVA1 (290 to 320 nm) spectrum may actually have anti-inflammatory properties.
Malar (Butterfly) Rash
Present in a little more than one-third of lupus patients, the butterfly rash is one of the disease’s most recognizable features. The malar eminence is so angled as to receive more UV exposure. The rash is often worse on the left side, as exposure can be greater from reflected light when driving a vehicle in sunny weather. It needs to be differentiated from rosacea (which spares the nasolabial folds but can coexist with lupus rashes) and polymorphous light eruption in fair-skinned individuals, among other lesions.
Mucocutaneous Lesions
Oral ulcers are present in 20% of patients with SLE and need to be distinguished from herpetic lesions (Fig. 5.1). Mostly located on the buccal mucosa and hard palate, and less frequently on the soft palate or tongue, the lesions often have a sharply marginated, irregularly scalloped white border and may be painless. Empiric treatment, herpes serologies, or, if necessary, a biopsy can help consolidate the diagnosis. Other inflammatory diseases, such as Behcet’s, Crohn’s, Wegener’s, and reactive arthritis, are associated with oral ulcerations.
Alopecia (Hair Loss)
Hair thinning or loss is a common manifestation of SLE (Fig. 5.2). It can be due to inflammation; cutaneous, scarring scalp lesions; or medications such as immune-suppressive drugs or corticosteroids (which produce thinning in the male pattern of baldness). Lupus patients tend to have fine, downy, dry hair with increased fragility and may report clumps being shed after showering.
Changes in Pigmentation
Increased or decreased pigmentation is present in 10% of patients. Post-inflammatory changes and antimalarial therapies are responsible for most of this. A few patients have coexisting vitiligo. Corticosteroids may produce bruises, or ecchymoses.
Figure 5.1 Oral ulcerations in patient with systemic lupus erythematosus. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Figure 5.2 Lupus hair. Source: Wallace DJ, Hahn BH. Dubois’ Lupus Erythematosus, 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007. Reprinted with permission.
Hives and Urticaria
Seen in 10% of SLE patients, this pruritic reaction is known as “lupus urticaria.” It may be found more frequently in atopic patients. Topical or systemic steroids, antihistamines, and H2 blockers are useful; refractory cases are often responsive to a three-month course of cyclosporine.
Facial Telangiectasia
This is not a true form of lupus but is commonly seen among lupus patients who apply topical, fluorinated corticosteroids to the face, especially the cheeks, on a chronic basis. Cutaneous atrophy, cigarette-paper-thin skin, and dermal atrophy ensue, creating the appearance of small, capillary-like telangiectasias. Facial lupus rashes can be managed with the application of nonfluorinated hydrocortisone or immunophillin-binding agents (e.g., topical tacrolimus). Potent topical corticosteroids should never be used for longer than two weeks at a time.
Cutaneous Subsets Associated with Lupus Erythematosus
Acute Cutaneous Lupus
This can be a localized or generalized process that is almost always part of systemic lupus activity. Although it can be an isolated phenomenon after sun exposure, most patients have multisystem involvement and require more than topical therapy.
Subacute Cutaneous Lupus
Seen in 10% of patients with any form of lupus, this dermal reaction presents as a papulosquamous or annular lesion that is non-scarring (Fig. 5.3). Associated with anti-Ro (SSA), these lesions are more resistant to anti-malarial therapies and may respond to the addition of retinoid regimens and corticosteroids. Over 20 pharmaceutical agents can induce subacute cutaneous lupus (SCLE), particularly hydrochlorothiazide, angiotensin- converting enzyme inhibitors, calcium channel blockers, and terbinafine.
Chronic Cutaneous (Discoid) Lupus Erythematosus
This subset represents 10% of the lupus spectrum and is also observed in 20% of persons with SLE (Figs. 5.4 and 5.5). Usually appearing as a thick, plaque-like, adherent lesion in sun-exposed areas, chronic cutaneous (discoid) lupus erythematosus (CCLE) is histologically characterized by hyperkeratosis, follicular plugging, dermal atrophy, vacuolation, pigment changes, induration, and scarring. Basement membranes are thickened, and a lichenoid infiltrate and periap-pendageal inflammation are usually present. The transition rate of CCLE to SLE, if it is not present initially, is 15% over five years. Antimalarial therapies and topical regimens are usually quite effective. CCLE that appears only above the neck rarely disseminates.
Other Cutaneous Variants of Lupus
Lupus profundus is a rare form of cutaneous lupus (seen in 1 in every 200 patients), with lumpy lesions reflecting inflammatory lesions of the lower dermis and subcutaneous tissue. Exaggerated hyperkeratosis is termed hypertrophic discoid lupus erythematosus.
The presence of excessive dermal mucin in cutaneous lupus is known as lupus erythematosus tumidus. Reddish-purple patches with plaques on the fingers, toes, and face precipitated by cold, damp climates is called lupus pernio, or chilblains. Bullous lupus is a blistering variant of lupus with pemphigoid features. It is usually responsive to dapsone. Calcinosis is noted in a small number of patients, many of whom also have a scleroderma overlap (Table 5.2).
Figure 5.3 Subacute cutaneous lupus erythematosus. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Figure 5.4 Chronic cutaneous lupus erythematosus showing histopathological changes on skin biopsy and discoid lesions in a malar distribution. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Figure 5.5 Chronic cutaneous lupus erythematosus showing histopathological changes on skin biopsy and discoid lesions in a malar distribution. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Cutaneovascular Manifestations
Cutaneous Vasculitis
Vasculitis in lupus is manifested by intimal proliferation, medial necrosis, and adventitial fibrosis. SLE usually affects the small and medium-sized arterioles, but leukocytoclastic vasculitis, hypersensistivity vasculitis, and cutaneous small-vessel vasculitis are present in the skin as well. The latter affects postcap-illary venules and can present as palpable petechial areas on dependent areas. Cutaneous necrosis, ulceration, and gangrene occur infrequently (Fig. 5.6). Corticosteroids, colchicines, and dapsone may be useful in the treatment of cutaneous vasculitis. Cryoglobulinemic vasculitis has been reported in one lupus patient per 1,000. Purpura that is palpable may be associated with cutaneous vasculitis and should be differentiated from corticosteroid-induced ecchymosis.
Raynaud’s Phenomenon
Raynaud’s phenomenon in SLE represents a combination of intimal hyperplasia of the digital arterioles and autonomic-mediated vasomotor instability (Fig. 5.7). The latter promotes exaggerated vasodilatation with exposure to warmth and vasoconstriction with cold. This produces color changes in the digits, ranging from red to white to blue. Seen in 25% of persons with lupus, Raynaud’s phenomenon is often independent of disease activity, and more serious forms are associated with focal or periungual fingertip ulcerations, fingertip tuft atrophy, and gangrene. Overlap syndromes with scleroderma features and mixed connective tissue disease are found with more serious cases of Raynaud’s phenomenon.
Table 5.2 Cutaneous manifestations of lupus erythematosus
|
TYPES OF CUTANEOUS LUPUS Acute cutaneous lupus erythematosus Subacute cutaneous lupus erythematosus Chronic (discoid) cutaneous lupus erythematosus Lupus profundus Hypertrophic lupus Lupus tumidus Lupus pernio (chilblains) Bullous lupus |
|
MANIFESTATIONS OF CUTANEOUS LUPUS Sun sensitivity Oral, nasal, or genital ulcerations Butterfly rash Hair loss or thinning Changes in pigmentation Hives or welts Telangiectasias Calcinosis |
|
CUTANEO-VASCULAR MANIFESTIONS OF LUPUS Cutaneous vasculitis Cryoglobulinemic vasculitis Raynaud’s Livedo reticularis Erythromelalgia Ulceration/gangrene Purpura |
Other Cutaneovascular Manifestations
Livedeo reticularis is commonly observed in SLE and is statistically associated with the presence of antiphospholipid syndrome (termed Sneddon’s syndrome). It represents a dysautonomia and appears as a net-like, blanchable red-purple ring in a lacelike, checkerboard pattern (Fig. 5.8). Livedo reticularis does not require treatment unless it is associated with a livedoid vasculitis, where the skin breaks down. Erythromelalgia is a burning pain of the hands and feet accompanied by macular edema and warmth. Palmar erythema is usually benign and is a reflection of autonomic instability. Periungual telangiectasiasand atrophie blanche are seen in a small number of patients.
Figure 5.6 Digital vasculitis with gangrene in patient with lupus. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Figure 5.7 Raynaud’s phenomenon in systemic lupus erythematosus. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Musculoskeletal Manifestations
Arthralgias and Arthritis
Arthralgias are present in at least 80% of SLE patients, whereas observable inflammatory arthritis involving two or more joints is found in 50% at some point in the course of the disease. Magnetic resonance imaging suggests a bland, rheumatoid-like synovitis. Although 30% with SLE have a positive rheumatoid factor, only 10% with lupus have a rheumatoid-like arthritis. Fewer than 5% have radiographic erosions. Patients who have both rheumatoid arthritis and SLE are said to have “rhupus.” Stiffness and aching are common; they are usually associated with a morning “gel” and joint pain and are bilateral and symmetrical in distribution, especially affecting the small joints of the hands and feet. Aspirated lupus synovial fluid has a white count of 2,000 to 15,000/mm3, consistent with a low-grade inflammatory process. Concurrent osteoarthritis is common in patients over the age of 40; 25% with SLE also meet the American College of Rheumatology (ACR) criteria for fibromyalgia. Deformity is common, but grip strength and function may be impaired. Synovitis also involves the tendons and bursae; rheumatoid nodules occur in less than 5% and are usually small and pea-sized. Lupus patients often demonstrate a Jaccoud’s deformity, wherein the ulnar deviation at the metacarpal phalangeal joints is subluxable in that they can be manually straightened.6
Figure 5.8 Livedo reticularis. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Myalgias and Myositis
Myalgias are noted by 70% of lupus patients, but frank myositis raising muscle enzymes is observed in 5% to 10% during the disease process. Creatine phosphokinase levels rarely rise above 500 IU unless an overlap syndrome is present. Electromyograms confirm suspicions of a myopathic process. A several-weeks’ course of medium-dose prednisone (20 to 40 mg/day) is usually salutary for muscle inflammation associated with lupus. The differential diagnosis mandates ruling out drug-induced myalgias/myositis (as with statin therapy), hypothyroidism, fibromyalgia, or viral infections (such as influenza or hepatitis). Long-term corticosteroid therapy induces type IIa fiber atrophy, which is difficult to reverse. Tapering of corticosteroid therapy can also induce a “steroid withdrawal” myalgia, which is usually managed with agents such as clonazepam or interventions to ensure optimal sleep architecture.
Osteopenia and Osteoporosis
Inflammation from active lupus and anti-inflammatory regimens such as corti-costeroids and methotrexate are both associated with bone demineralization. The ACR recommends that any patient taking 5 mg of prednisone or more (or the equivalent) daily for longer than one month be receiving a bisphosphonate. It is prudent to measure bone densitometry every one to two years in high-risk individuals (e.g., Caucasians, smokers, those with thin body habitus or strong family history for osteoporosis). The use of calcium, vitamin D, hormonal interventions, calcitonin, bisphosphonates, or, if necessary, parathyroid hormone (parathormone) should be decided on a case-by-case basis.
Avascular Necrosis (Osteonecrosis)
One of the most feared complications of chronic corticosteroid therapy is avascular necrosis. Fatty clots produced by corticosteroids clog up the bone’s blood supply and deprive it of oxygen. Infarcted bone is most commonly noted in the hip, but any joint can be involved. In 10% of cases, avascular necrosis is found in lupus patients who are not taking corticosteroids. Magnetic resonance imaging is the gold standard for identifying the process (Fig. 5.9). Early avascular necrosis of the hip can be treated with vascular grafting or core decompression, but most patients ultimately require joint replacement along with analgesic therapies.
Pulmonary Involvement
Pleurisy
Patients with lupus may complain of pain on taking a deep breath, shortness of breath, windedness, wheezing, or chest pains. The most common problem relates to pleurisy. At autopsy, most lupus patients show evidence of pleural scarring or prior inflammation. Manifested by pain or a catching sensation on taking a deep breath, pleural symptoms are present in 60% of lupus patients, and frank effusions noted in 25%, during a lifetime. Serosal surfaces frequently become inflamed in the condition; associated pericardial and peritoneal involvement is not uncommon. It is important to note that pleurisy is not considered organ-threatening; the parenchyma is not involved. Pleuritic discomfort can also be caused by an infection or environmental exposures. Chest radiographs are normal in most patients; pleural scarring is evident in some. In the absence of pleural fluid, pleuritis is managed with nonsteroidal drugs, antimalarials, and, if necessary, a short course of corticosteroids. Some patients with concurrent fibromyalgia have pleuritic-like complaints. Acute-phase reactants (e.g., sedimentation rate, C-reactive protein) can guide the practitioner as to how active the process is. Computed tomography scanning and ultrasonography may be necessary. If present, pleural fluid obtained at thoracentesis can be an exudate (suggestive of active inflammatory disease, malignancy, or infection) or a transudate (usually seen with concurrent nephrosis or pericarditis;8 see Table 5.3).
Figure 5.9 Avascular necrosis of the right hip shown on plain film (top) and T1-weighted magnetic resonance imaging (bottom). From Wallace DJ, Hahn BH. Dubois’ Lupus Erythematosus, 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007. Reprinted with permission.
Acute Lupus Pneumonitis
Seen in 1% to 9% of persons with SLE, patients with acute lupus pneumonitis (ALP) present acutely with shortness of breath and fever. Often treated tele-phonically as a pulmonary infection with antibiotics, the process progresses rapidly if high doses of corticosteroids are not prescribed. ALP manifests as an interstitial infiltrate containing neutrophils and immune complexes. Patients should promptly undergo bronchoscopy or a bronchoalveolar lavage. Cultures are negative. ALP has an 80% mortality rate if not diagnosed within two weeks of onset; recovery is usually rapid with appropriate treatment.
Interstitial Lung Disease
Unlike ALP, interstitial lung disease (ILD) is a chronic process, and many years often elapse without the patient’s making any complaint. Most symptomatic patients describe being mildly short of breath or easily winded on exertion. Strongly associated with Sjögren’s syndrome, mixed connective tissue disease, and overlap syndromes, ILD causes a lymphocytic infiltrate. Infection and lym-phoproliferative processes need to be ruled out. Pulmonary-function testing demonstrates restrictive findings, and respirations can be rapid and shallow. The gold standard of diagnosis is a high-resolution computed tomography scan. A ground-glass appearance tends to suggest reversibility, while honeycombing goes against it. If the process is not scarred down, anti-inflammatory regimens are indicated. Respiratory failure is extremely uncommon.
Table 5.3 Pleural fluid in systemic lupus erythematosus
|
Transudate of exudates Color: yellow to amber Protein: >3g if exudate and pH >7.35 WBC: 3000 to 5000 cells/mL, monocyte and lymphocyte predominance Glucose: near serum levels ANA > serum titer, C3 and C4 decreased Sediment: LE cells on Wright stain |
Pulmonary Embolus
Almost all lupus patients who sustain a pulmonary embolus have antiphospho-lipid antibodies. Seen in 5% to 10% of lupus patients in their lifetime, pulmonary emboli present acutely with shortness of breath, chest pains, tachycardia, and low-grade fever. Thrombophlebitis may be evident. Oxygen saturations are decreased, and elevated D-dimer levels along with mismatching on a ventila-tion/perfusion lung scan usually confirm the diagnosis. Pulmonary emboli are managed with the same regimen of anticoagulation as is used in any non-lupus patient with this condition: heparin followed by warfarin. If antiphospholipid antibodies are present, lifelong warfarin may be advised, as the recurrence rate for thromboembolic disease is high.
Pulmonary Hemorrhage
Less than 1% of lupus patients experience bleeding into their air sacs, but this represents up to 10% of all lupus deaths. Usually of acute onset, patients appear ill and complain of hemoptysis along with evidence for multisystem activity. Suggested by alveolar infiltrates on chest radiography and confirmed at bronchoscopy by inflammation without infection and staining for immune complexes, pulmonary hemorrhage is managed with combination anti-inflammatory regimens (Fig. 5.10).
Pulmonary Hypertension
Most lupus patients who develop clinically significant elevations in pulmonary pressures have antiphospholipid syndrome (with recurrent pulmonary emboli), mixed connective tissue disease (anti-RNP positive), or a scleroderma overlap. The pathological stimulus is thought to be related to endothelial cell dysfunction with abnormal vascular responses. Complaints of breathlessness are common; chest radiographs may be normal. Pulmonary pressures are estimated with a 2-D Doppler echocardiogram and precisely quantitated at right-heart catheterization. Readings above 50 mm Hg are usually managed more aggressively, with approaches that will be reviewed in Chapter 11. The heretofore dismal prognosis for pulmonary hypertension is slowly improving, and heart/lung transplantation has led to some cures.
Figure 5.10 Hemosiderin granules in a patient with alveolar hemorrhage.
Shrinking Lung Syndrome
Elevated hemidiaphragms seen on chest radiographs are usually due to chronic pleural scarring and can result in shortness of breath. The condition is termed “shrinking lung syndrome.” This rare manifestation may respond to corticosteroids and occasionally but infrequently necessitates pleural decortication.
Reversible Hypoxemia
Active disease is rarely associated with hypoxemia and hypocapnea with a wide alveolar-arterial gradient. Chest radiographs are normal. Inflammation or complement split products may play a role, and the process is responsive to corticosteroids.
The cardiopulmonary manifestations of SLE are summarized in Table 5.4.
Table 5.4 Prevalence of principal cardiopulmonary manifestations of systemic lupus erythematosus
|
Pleuritic discomfort |
60% |
|
Myocardial dysfunction |
40% |
|
Hypertension |
25% |
|
Pleural effusion |
25% |
|
Pericardial effusion |
25% |
|
Interstitial lung disease |
10% |
|
Pulmonary embolus |
7% |
|
Acute lupus pneumonitis |
5% |
|
Pulmonary hypertension |
5% |
|
Libman-Sacks endocarditis |
3% |
|
Shrinking lung syndrome |
1% |
|
Pulmonary hemorrhage |
1% |
Cardiovascular Manifestations
A cardiac history may reveal chest pains, pressure, palpitations, or shortness of breath. The cardiac examination should include measuring pulse and blood pressure, pressing the chest wall for tenderness, and auscultation. Tachycardia can be a sign of inflammation or fever; it may be associated with relative hypotension. Dysautonomic responses (e.g., tilt-table testing) are not uncommon. The most common chest complaint in a lupus patient is chest pain. Costochondritis and gastroesophageal reflux disease (GERD) are typically the sources of this, with pericardial irritation frequently noted. Other causes include myocarditis or angina.7
The Pericardium
Pericardial involvement is found in 60% of lupus patients at autopsy and incidentally, and asymptomatically in 25% on 2-D echocardiogram. Frank effusions are seen in 25% during the course of disease but in fewer than 5% of patients at any given point in time. The effusions can be exudates (active inflammation) or transudates (as with concurrent nephrosis or ascites). Patients note a pressure-like discomfort relieved by leaning forward. Chronic inflammation leads to pericardial scarring, and individuals note ongoing pressure sensations.
The Myocardium: Myocarditis and Myocardial Dysfunction
Myocardial dysfunction (often from subclinical inflammation) is found on stress echocardiography in 40% with SLE, but only 5% to 10% ever experience frank myocarditis. Lupus myocarditis presents similarly to, and is often confused with, viral myocarditis. Patients complain of chest discomfort, cough, and dyspnea along with constitutional symptoms of extracardiac systemic inflammation. Concurrent features may include angina pectoris (classical), microvascular angina (small vessel disease, or “Raynaud’s of the heart”) and elevated muscle enzymes. The diagnosis is solidified by traditional angiog-raphy, a 64-slice computed tomography “virtual angiogram,” or myocardial biopsy. Although congestive heart failure (CHF) was common 40 to 50 years ago, only a small percentage of lupus patients with significant myocardial dysfunction ever evolve to this point now. Brought on or aggravated by the long-term administration of corticosteroids, hypertension, anemia, or disorders of the heart valves, CHF in lupus patients is managed with traditional remedies (e.g., digitalis, angiotensin-converting enzyme inhibitors, diuretics, β-blockers).
The Endocardium: Valvular Heart Disease
Materials such as cellular debris, proliferative cells, and immune complexes averaging 1 mm to 4 mm in diameter may form vegetations on cardiac valves in 1% to 5% of patients with SLE (Fig. 5.11). These sterile aggregates, termed “Libman-Sacks endocarditis,” are especially observed in patients with antiphospholipid antibodies, as well as those who have been on long-term corticoste-roid therapy. Morbidity ensues when these vegetations fleck off and travel to the brain, or become infected (especially after a dental procedure), becoming bacterial endocarditis. Identified by 2-D Doppler echocardiogram 30% of the time, the lesions can be demonstrated by transesophageal echocardiography in 70% of patients.
Figure 5.11 Libman-Sacks endocarditis. Note the valvular vegetation. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Tricuspid regurgitation is a harbinger and symptom of pulmonary hypertension; mitral valve prolapse is slightly more frequent in SLE.
Hypertension
Patients with renal impairment, as well as those who have been on long-term corticosteroid therapy, are especially prone to blood pressure elevations. Hypertension is found in 25% to 30% of patients with SLE; it is also a contributing factor in accelerated atherogenesis (see next section).
Accelerated Atherogenesis
Coronary artery disease, hypertension, insulin resistance, metabolic syndrome, hyperhomocystinemia, and hyperlipidemia are more common in lupus patients, even in those for whom corticosteroids were never prescribed (Fig. 5.12). Several mechanisms may account for this, among them the presence of a recently described proinflammatory high-density lipoprotein (HDL) in 40% with SLE, the atherogenic effects of systemic inflammation, corticosteroids, and obesity related to lupus therapies. Recent work has concentrated on the dys-lipidemia of lupus, oxidative stress, endothelial apoptosis, proinflammatory cytokines, adiponectin, leptin, and endothelial progenitor cells combined with traditional risk factors. Proactive screening for atherosclerotic disease (e.g., blood pressure monitoring, blood sugar and lipid testing, carotid duplex ultrasound, 2-D echocardiography, stress testing) with appropriate interventions (e.g., diet, exercise, smoking cessation, medication) can greatly diminish the morbidity and mortality of SLE.
Figure 5.12 Incidence of myocardial infarction in 498 women with systemic lupus erythematosus. Source: Manzi S, Meilahn EN, Rairie JE, 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;145:408–415. Reprinted with permission, Oxford University Press, 1997.
The Nervous System
Lupus can involve the central, peripheral, and autonomic nervous systems. It produces myriad symptoms and signs that can be difficult to diagnose, to manage, and to differentiate from infection, psychological distress, or medication side effects. The 1982/1997 ACR criteria for nervous system involvement (seizures, psychosis) are obsolete. As a result, the ACR has delineated 19 different forms of nervous system lupus. Most lupus patients complain of at least some intermittent cognitive impairment; at least one of the 18 nervous system manifestations is noted in 30% of patients during the course of disease, and ongoing morbidity from such manifestations occurs in 10%3 (Table 5.5).
Neurological Manifestations of Lupus
Memory impairment, confusion, and difficulty in articulating thoughts and remembering names or dates is termed cognitive dysfunction. “Lupus fog” is usually the result of a vascular-mediated process (e.g., bifrontal and bitemporal hyperperfusion on imaging studies) but can occur with headache, vasculitis, infection, and organic brain syndromes. Headaches are also usually autonomic/vascular in etiology but may be a manifestation of infection, medication, hypertension, vasculitis, or a cerebral bleed. Seizures result from inflammation, medication, fevers, or scar foci. Altered consciousness includes stupor, excessive sleepiness, or coma and is usually a consequence of active inflammation, medication, or infection. Paralysis or strokes can be sequelae of antiphospholipid antibodies or related to inflammation or atherosclerosis. Movement disorders include ataxia and chorea, resulting from infarction or inflammation of the cerebellum or basal ganglia. Corticosteroids, psychosocial distress, inflammation, and infection lead to altered behavior patterns. Visual changes may be produced by optic neuritis, pseudotumor cerebri, corticosteroids, cranial neuropathies, and other medications. Additional complaints include burning, numbness, and tingling from peripheral neuritis, cranial neuritis, dysautonomias, fibromyalgia, medication, or mechanical compression.
Table 5.5 Neuropsychiatric syndromes in systemic lupus erythematosus as defined by the American College of Rheumatology Research Committee
|
1. Central a. Aseptic meningitis b. Cardiovascular disease c. Demyelinating syndrome d. Headache e. Movement disorder f. Myelopathy g. Seizure disorders h. Acute confusional state i. Anxiety disorder j. Cognitive dysfunction k. Mood disorder l. Psychosis |
|
2. Peripheral a. Guillain-Barré syndrome b. Autonomic neuropathy c. Mononeuropathy d. Myasthenia gravis e. Cranial neuropathy f. Plexopathy g. Polyneuropathy |
The Principal Lupus Syndromes of the Nervous System
Eighty percent of CNS vasculitis takes place in the first five years of disease. Seen in 10% of patients with SLE, it may be the initial presentation of the disorder. The typical patient experiences fevers, seizures, meningismus, and altered behavior patterns. If untreated, CNS vasculitis can progress to stupor, coma, status epilecticus, and death. Blood testing is unhelpful, brain imaging is nonspecific, and angiography has a less than 10% yield. Infection needs to be ruled out. Electroencephalograms and evoked responses are usually nonspecific and occasionally misleading. Spinal fluid evaluation is the gold standard: one-third of patients have pleocytosis, one-third have elevated protein, many have LE cells, and 80% demonstrate antineuronal antibodies. The most helpful test is the “multiple sclerosis panel”; the positive patient has oligoclo-nal bands and an increased IgG synthesis rate. Etiopathogenetic factors include perivascular or endothelial inflammation, vasculitis, hyalinization, infarction, hemorrhage, cytokine dysfunction, choroid plexus dysfunction, abnormal hypothalamic-pituitary-adrenal stress responses, and CNS tissue injury.
Lupus patients who develop sudden, nonpainful neurological deficits akin to a cerebrovascular accident (and these patients can be young) have antiphospholipid syndrome. Focal infarction is identified by neuroimaging and confirmed at physical examination. Nearly all patients will have an anticardiolipin antibody, prolonged clotting times, or a lupus anticoagulant. It is treated with anticoagulation. Other coagulopathies found in lupus and affecting the nervous system include cryoglobu-linemia, hyperviscosity, or thromboembolic or bleeding complications from throm-botic thrombocytopenic purpura or idiopathic thrombocytopenic purpura. Pseudotumor cerebri (benign intracranial hypertension) is more common in SLE, as is posterior reversible encephalopathy syndrome (PRES), which manifests itself with severe hypertension and headache in patients who have received immune suppressive therapies.
Autonomic dysfunction in SLE involves vasomotor instability, which may produce migraine (lupus headache), or, conversely, transient cognitive impairment (lupus fog) resulting from excessive vasodilatation or vasoconstriction. Akin to “Raynaud’s of the brain,” dysautonomias are often mistaken or misinterpreted as lupus cerebritis, which they are not. Single-photon emission computed tomography, positron emission tomography, and functional magnetic resonance imaging demonstrate subtle flow abnormalities in the temporal-parietal, or watershed, regions. Extracranial manifestations of dysautonomia include palmar erythema, burning and tingling sensations, Raynaud’s phenomenon, mitral valve prolapse, and livedo reticularis. Fibromyalgia needs to be ruled out. Myelitis may ensue from spinal cord inflammation or a coagulopathy that leads to paralysis or weakness. Normal spinal fluid findings with myelitis warrant anticoagulation, while corticosteroids are used if there is evidence for vasculitis.
CNS vasculitis, inflammation, or infarction heals but leaves scarring in the brain. Patients can have seizures or demonstrate cognitive dysfunction years after the incident episode. This is termed organic brain syndrome. It is managed with anticonvulsants, psychotropic drugs, and emotional support. Anti-inflammatory therapy in the absence of evidence for acute inflammation is contraindicated (Table 5.6).
The peripheral nervous system can become inflamed in 10% of persons with SLE. Manifesting itself as polyneuritis, cranial neuritis, myasthenia gravis, mononeuritis multiplex, or acute or chronic demyelinating inflammatory neuropathies (Guillain-Barré or Chronic inflammatory demyelinating polyneuropathy (CIDP)), peripheral inflammation can induce motor or sensory deficits identifiable on electromyography or nerve (especially sural) biopsy. Corticosteroids, immunosuppressive therapies, gabapentin derivatives, and, if necessary, intravenous immunoglobulin are the treatments of choice.
Head and Neck Manifestations, Including Sjögren’s Syndrome
The Eye
Discoid lesions around the eye are not uncommon. Conjunctivitis and episcleritis are more frequently noted in SLE. Uveitis is statistically associated with lupus but seen in only 1% to 2% of patients. Corticosteroid therapy is the source of most cataracts and glaucoma diagnosed in lupus patients. Antimalarial therapies can produce retinal changes in 3% of patients taking hydroxychloroquine and 10% of patients taking chloroquine for 10 years. Between 1% and 2% of patients with SLE develop retinal vasculitis or optic neuritis (Fig. 5.13). Antiphospholipid antibody-mediated clots in the retina need to be considered in the differential diagnosis.
Table 5.6 Major central nervous system (CNS) syndromes and their management
|
Syndrome |
Prevalence in lupus (%) |
Treatment |
|
Cerebral vasculitis |
10 |
High-dose IV steroids, immunosuppressants |
|
Antiphospholipid syndrome |
5 to 10 |
Platelet inhibition, anticoagulants with brain clots |
|
Lupus headache |
15 |
Migraine therapy, steroids |
|
Cognitive dysfunction |
50 |
Antimalarials, psychotropics, biofeedback counseling, cognitive-behavioral therapy |
|
Fibromyalgia |
10 to 20 |
Nonsteroidals, counseling, psychotropics, physical therapy |
|
CNS infection |
1 |
Antibiotics |
|
Cryoglobulinemia or |
1 |
Steroids, apheresis, |
|
hyperviscosity |
immunosuppressants |
|
|
Bleed due to low platelets |
2 |
Steroids, apheresis, chemotherapy, factor replacement, transfusion |
The Ear, Nose, and Throat
One lupus patient in 500 develops autoimmune vestibulitis, which presents with a sudden onset of hearing deficits that are steroid-responsive. Lupus chondritis inflames the ear cartilage and is rapidly responsive to moderate-dose corticosteroids. Mucocutaneous lesions are discussed in an earlier section of this chapter. A hoarse voice is noted when the synovially lined cricoarytenoid joint is inflamed. Patients with SLE who undergo dental work should receive routine antibiotic prophylaxis if they are immune-suppressed or have additional risk factors (e.g., Libman-Sacks endocarditis).
Periodontal disease is more common in lupus patients who also have Sjögren’s and scleroderma overlaps.
Sjögren’s Syndrome
Characterized by dry eyes and dry mouth (keratoconjunctivitis sicca), Sjögren’s is diagnosed when these manifestations are related to an immunological dysfunction of the exocrine (lacrimal and salivary) glands. Secondary Sjögren’s is found in 10% to 20% of persons with SLE and is diagnosed by a combination of factors, including parotid enlargement; Lissimine green or Rose-Bengal staining or Schirmer testing of the cornea; positive anti-SSA (Ro) antibodies; and evidence for a dry mouth by lip biopsy, salivary imaging, or flow tests. Dry lungs (bronchitis sicca), vaginal dryness, and renal tubular acidosis are associated features. Sjögren’s-specific remedies, in addition to lupus therapies, include topical replacement of lubrication, sialogogues, cyclosporine eye drops, and pilocar-pine. These are summarized in Table 5.7.
Figure 5.13 Retinal vasculitis in systemic lupus erythematosus. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Endocrinopathies
Autoimmune thyroiditis, type 1 diabetes, autoimmune adrenalitis, premenstrual disease flares, and elevated prolactin levels have increased prevalence in SLE.
Gastrointestinal Manifestations
The gastrointestinal tract is rarely directly involved in SLE. Dysphagia and esophageal motility disorders are seen in scleroderma and inflammatory myo-sitis overlaps. Comorbidities such as GERD or gastritis (due to corticosteroids or nonsteroidal therapies), nausea or diarrhea (due to steroids, nonsteroidals, antimalarials, or immune suppressives), and peptic ulcer disease (due to medication) are prevalent in lupus. SLE is statistically associated with ulcerative colitis, biliary cirrhosis, celiac disease, autoimmune hepatitis, and autoimmune pancreatitis. Direct lupus involvement of the gastrointestinal tract manifests as ascites (especially with nephrosis—seen at some point in 10%), protein-losing enteropathy (almost always limited to children and adolescents), and pancreatitis. The latter results from medications (e.g., diuretics, azathioprine, corticosteroids), biliary cirrhosis, usual causes of pancreatitis (e.g., gallstones, alcohol abuse), or frank pancreatic vasculitis (found in 1% of those with SLE). Mesenteric vasculitis with ensuing infarction is a life-threatening complication of SLE noted in 1% to 2% with the disease. An antiphospholipid-mediated process should first be ruled out, and aggressive high-dose corticosteroids should be administered, along with close surgical coordination.
Table 5.7 Clinical features of Sjögren’s syndrome
|
COMMON: Dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), arthralgias FOUND IN 10%-50% WITH SJOGREN’S: Parotid gland enlargement, dry cough (bronchitis sicca), vaginal dryness, atrophic gastritis, hypothyroidism FOUND IN <10% OF PATIENTS: Peripheral nerve disease, pancreatitis, renal tubular acidosis, interstitial lung disease, lymphoma |
Low-level liver enzyme abnormalities may ensue from nonsteroidal anti-inflammatory drugs, salicylates, methotrexate, and fatty livers exacerbated by corticosteroid therapy. Usually, no treatment is necessary. Hepatitis due to SLE is diagnosed once viral etiologies are ruled out. Autoimmune hepatitis can coexist with or be part of lupus and responds to corticosteroid and immuno-suppressive regimens (e.g., azathioprine, 6mercaptopurine). Budd-Chiari syndrome is associated with antiphospholipid antibodies.
Lupus in the Kidneys and Urinary Tract
Pathophysiology
Classic chronic immune complex glomerulonephritis, as defined in experimental models, is strikingly similar to what is seen in human SLE. Autoantibodies bind to nonglomerular autoantigens, intrinsic glomerular antigens, and preformed circulating immune complexes, which are deposited in the glomerulus. Nucleosomes in the form of DNA bound to histone have an affinity for anionic components of the glomerular basement membrane such as heparan sulfate, which bind to negatively charged cell surfaces or matrix components of the glomerulus in the course of filtration. Nucleosomal antigen interacts with circulating autoantibody, leading to the formation of immune complexes in situ. This results in activation of the complement cascade, procoagulant factors, mono-cyte and neutrophil infiltration, release of proteolytic enzymes, elaboration of various cytokines and adhesion molecules, and consequent glomerular and vascular damage. Hypertension further accelerates this.
Lupus Nephritis
Thirty percent of individuals with SLE have some form of renal involvement; in half of these cases, it mandates organ-specific therapy. Unless one has nephrosis or is uremic, lupus nephritis is usually asymptomatic. It may be present in concert with multisystem complaints or found incidentally via routine urinalysis. The report of urinary casts (hyaline or granular) and/or hematuria along with proteinuria should lead one to suspect renal involvement. Most lupus specialists now agree that a renal biopsy is the gold standard that guides the diagnosis and treatment of lupus. First, it usually rules out diabetes, hypertension, other forms of vasculitis, amyloidosis, hepatitis, and lymphoma, among other conditions that can mimic lupus nephritis. The advent of interventional radiology and ultrasonography has made the biopsy procedure much safer. The World Health Organization’s 1982 histopathological classifications have given way to the 2004 International Society of Nephrology and Renal Pathology Society (ISN/RPS) revisions, which take into account damage and activity indices evolved by the National Institutes of Health in the mid-1980s.4(See Tables 5.8 and 5.9 and Figs. 5.14 through 5.17.) Whereas nil disease (Class I) and mesangial disease (Class II) have excellent prognoses, patients with proliferative or membranous nephritis have a 50% and 30% risk of evolving end-stage renal disease within 10 years, respectively. Lupus nephritis is associated with high morbidity and mortality. In addition to renal failure, the potential for hypertension, hy-perlipidemia, Cushing’s disease, electrolyte disorders, insulin resistance, and nephrotic syndrome mandates extra vigilance. Patients should be proactively screened and treated for these complications. Diet, angiotensin-converting enzyme inhibitors, weight control, exercise, and specific attention to medication adherence are important in the management of lupus nephritis. Renal lupus is monitored by C3 complement and anti-DNA (usually abnormal with proliferative nephritis but normal in burnt-out disease or membranous nephritis), serum albumin levels, monitoring of vital signs, 24-hour urinary protein or protein-to-creatinine determinations, glomerular filtration rate calculations, and blood chemistry panels. Individuals with antiphospholipid antibodies and nephritis often demonstrate pathological evidence for microthrombi and ath-eroembolic events; renal vein thrombosis is associated with these antibodies and membranous nephritis. Sjögren’s patients may have coexisting renal tubular acidosis and interstitial disease.
Table 5.8 Histopathological directed treatment approaches for lupus nephritis
Table 5.9 International Society of Nephrology and Renal Pathology Society (ISN/RPS) classification of lupus nephritis (2004)
|
Class I |
Minimal mesangial: normal glomeruli by light microscopy (LM), mesangial immune deposits by immunofluorescence |
|
Class II |
Mesangial proliferative: mesangial hypercellularity or matrix expansion by LM with mesangial immune deposits |
|
Class III |
Focal proliferative: focal, segmental, and/or global endo- and/or extra-capillary involvement of <50% of glomeruli, with or without mesangial alterations |
|
III (A): purely active lesions |
|
|
III (A/C): active and chronic lesions |
|
|
III (C): Chronic inactive with scarring |
|
|
Class IV |
Diffuse proliferative: same as Class III but involving >50% of glomeruli |
|
IV-S (A) or IV-G (A): purely active, diffuse segmental or global proliferative |
|
|
IV-S (A/C) or IV-G (A/C): above with active and chronic lesions |
|
|
IV-S (C) or IV-G (C): inactive with scarring |
|
|
Class V |
Membranous: global or segmental subepithelial immune deposits with or without mesangial alteration |
|
Class VI |
Advanced sclerosing: >90% of glomeruli sclerosed with no activity |
Figure 5.14 Class II mesangial disease. Source: Wallace DJ, Hahn BH. Dubois’ Lupus Erythematosus, 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007. Reprinted with permission.
Lupus Cystitis and Bladder Disturbances
Urinary tract infections are extremely common in young women with SLE. Sulfa antibiotics used by practitioners to manage these may lead to a disease flare or sun sensitization and should be carefully prescribed, or avoided. Hemorrhagic cystitis can be a manifestation of active lupus or cyclophosphamide therapy.
Figure 5.15 Class III focal proliferative nephritis. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Figure 5.16 Class IV diffuse proliferative nephritis. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
The Hemic-Lymphatic System
Anemias
Over 80% of lupus patients are anemic at some point in time. Most have anemia as a chronic disease. Young women with heavy menses lose iron as well. Lupus medications ranging from nonsteroidal anti-inflammatory agents to immunosuppressive regimens further contribute to the anemia cauldron. Renal impairment is an additional anemogenic contributor. Autoimmune disease is associated with atrophic gastritis with resulting vitamin B12 deficiency. The management of anemia in lupus depends on its source.9
Autoimmune hemolytic anemia (AIHA) occurs in up to 10% of individuals with SLE. AIHA is suspected when lupus patients are anemic and have elevated serum lactate dehydrogenase (LDH) and reticulocyte counts, decreased serum haptoglobin, or a positive Coombs’ direct test, and diagnosis is confirmed when the peripheral blood smear is viewed (see Table 5.10).
Figure 5.17 Class V membranous nephritis. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Leukopenia, Leukocytosis, and Adenopathy
Leukopenia is seen in almost all lupus patients at some time. A consequence of antilymphocyte antibodies, viral infection, medication, or bone marrow suppression, this benign finding is considered to be a marker of disease activity and very rarely mandates a specific intervention. Leukocytosis with lymphopenia results from corticosteroid therapy. Granulocytopenia is rare in SLE and warrants consideration of other diagnoses (e.g., Felty’s syndrome).
Adenopathy and reactive lymphadenitis are markers of active disease and are found in half of all lupus patients at some point in the disease course. Sometimes the glands are so large (Kikuchi’s syndrome) that a biopsy may be performed to rule out other conditions. Ten percent of lupus patients have an enlarged spleen on CT of the abdomen.
Table 5.10 Sources of anemia in SLE
|
1. Anemia of chronic disease 2. Iron deficiency 3. Folic acid or B12 deficiency 4. Bone marrow suppression 5. Drugs (e.g., NSAIDs, immune suppressives) 6. Sickle-cell anemia 7. Renal impairment 8. Immune anemias (e.g., hemolytic, thrombotic thrombocytopenic purpura) 9. Heavy menses |
Platelet Defects, Including Idiopathic Thrombocytopenic Purpura and Thrombotic Thrombocytopenic Purpura
Qualitative platelet defects are noted in a few lupus patients not taking any medication, but are primarily induced by aspirin, nonsteroidal drugs, and corti-costeroids. Some patients manifest purpura or ecchymoses. Prolonged clotting times are found with the lupus anticoagulant and antiphospholipid antibodies.
Low platelet counts are observed in lupus patients taking immunosuppres-sive medication and in those with infections, idiopathic thrombocytopenic purpura (ITP), and thrombotic thrombocytopenic purpura (TTP). ITP is a common immune thrombocytopenia in that 20% with SLE have antiplatelet antibodies, and in 20% of these patients, platelet counts drop below 100,000/mm3. Most lupus specialists treat thrombocytopenia when counts decrease to 60,000/mm3 or fewer.
TTP is a rare, life-threatening complication of SLE consisting of a pentad of fever, nephritis, hemolysis, renal impairment, and neurological compromise that mimics or can be brought on by an infection. The diagnosis is confirmed by assessing the functional activity of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (a von Willebrand factor protease) and viewing the peripheral blood smear.
References
1. Wallace DJ, Hahn BH. Sections IV and V: The skin in lupus and clinical aspects of lupus. In: DJ Wallace and BH Hahn, eds. Dubois’ Lupus Erythematosus. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:551–1130.
2. Patel P, Werth V. Cutaneous lupus erythematosus: a review. Dermatol Clin. 2002;20:373–385.
3. Hanly JG. ACR classification criteria for systemic lupus erythematosus: limitations and revisions to neuropsychiatric variables. Lupus. 2004;13:861–864.
4. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15:241–250.
5. van Vugt R, Derksen R, Kater L, et al. Deforming arthropathy or lupus and rhupus hands in patients with systemic lupus erythematosus. Ann Rheum Dis. 1998;57:540–544.
6. McMahon M, Skaggs B, Grossman J. Pathogenesis and treatment of atherosclerosis in lupus. In: DJ Wallace and BH Hahn, eds. Dubois’ Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia, PA: Elsevier; 2013:341–351.
7. Keane MP, Lynch JP. Pleuropulmonary manifestations of systemic lupus erythe-matosus. Thorax. 2000;55:159–166.
8. Karpouzis GA. Hematologic and lymphoid abnormalities in SLE. In: DJ Wallace and BH Hahn, eds. Dubois’ Lupus Erythematosus and Related Syndromes. 8th edition. Philadelphia, PA: Elsevier; 2013:426–437.