Which diagnostic studies are utilized in the evaluation of systemic lupus

Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease characterized by multisystem involvement and the production of an array of autoantibodies. Clinical features in individual patients are highly variable, ranging from skin and joint involvement to organ-threatening and life-threatening disease. SLE is typically associated with a waxing and waning clinical course, but some patients have continuous disease activity.

++

The prevalence of SLE varies across gender, race/ethnicity, and geographic regions. SLE demonstrates a striking female predominance with a peak incidence of disease during the reproductive years. In adults, the female to male ratio is 10–15:1. In the United States, the estimated prevalence is 100 per 100,000 white women and 400 per 100,000 black women. SLE is more common in blacks in the United States but is rare among blacks in Africa. Approximately 160,000 to 320,000 people in the United States are living with SLE.

++

Although the etiology of SLE remains unclear, genetic, hormonal, and environmental influences play a role in disease pathogenesis. It is postulated that an environmental exposure triggers the onset of disease in a genetically susceptible person. Evidence of a genetic component to SLE is derived from studies showing strong familial risk. The disease concordance rate of 24–58% for monozygotic twins in comparison to the concordance rate of 2–5% for dizygotic twins confirms this strong genetic component. Multiple genes have been associated with SLE, including the genes within the major histocompatibility complex and genes that encode components of the complement pathway, Fcγ receptors, protein tyrosine phosphatase non-receptor type 22 (PTPN22), programmed cell death 1 gene (PDCD1), and cytotoxic T lymphocyte associated antigen 4 (CTLA4). The reasons for female sex predilection remain murky. Some observational data suggest that sex hormones might contribute to disease onset. For example, data from the Nurses Health Study suggest that early age at menarche (relative risk 2.1), oral contraceptive use (relative risk 1.5), and use of postmenopausal hormones (relative risk 1.9) increases the risk of SLE. In addition, the risk of SLE in men with Klinefelter syndrome (47, XXY) is 14-fold higher than in healthy male controls. In contrast, large controlled trials have shown that combined oral contraceptives do not increase the risk of flares in women with stable SLE, and studies examining serum sex hormone levels in patients with lupus compared with patients in a control group have been inconclusive. Thus, whether hormonal factors or nonhormonal aspects of sex are most important in influencing disease risk remains to be determined.

++

Various environmental factors have been examined as potential triggers for the development of SLE. Smoking is a risk factor for SLE and has been associated with anti-dsDNA production in patients with SLE. Exposure to UV light exacerbates both cutaneous and internal organ manifestations of SLE, but there is no clear evidence to suggest that UV light triggers onset of the disease.

++

Several viruses have been investigated as possible triggering factors for SLE, although there is no conclusive evidence linking one pathogen to development of disease. The virus that has received the most attention in this regard is Epstein-Barr virus (EBV). Studies in pediatric and adult patients have demonstrated a higher seroprevalence of antibodies to EBV antigens and a higher EBV viral load in SLE patients versus controls. Molecular mimicry between EBV and self proteins is postulated to play a role in SLE pathogenesis.

++

There is increasing evidence that interferon α (IFNα) plays an important role in the pathogenesis of SLE. Approximately 50% of SLE patients overexpress IFNα inducible genes, and the degree of overexpression correlates with disease activity and severity. This pattern of gene expression is referred to as the “interferon α signature.” Studies have shown that plasmacytoid dendritic cells release IFNα after stimulation with immune complexes containing nucleic acid.

++

SLE is characterized by the production of a variety of autoantibodies to nuclear antigens (antinuclear antibodies [ANA]), cytoplasmic antigens, cell surface antigens, and soluble antigens in the circulation such as IgG and phospholipids. Subtypes of ANAs can be useful for establishing a diagnosis, detecting certain disease manifestations, and sometimes in monitoring the course of the disease. Antibodies to surface antigens on red blood cells and platelets can lead to autoimmune hemolytic anemia and immune-mediated thrombocytopenia, respectively. In the majority of SLE patients, the presence of autoantibodies predates the development of symptoms or signs of SLE, and patients accrue different autoantibodies up until the time of diagnosis. One study utilizing the Department of Defense Serum Repository demonstrated that ANA, anti-Ro/SSA antibodies, anti-La/SSB antibodies, and antiphospholipid antibodies were the first to appear and did so at a mean of 3.4 years prior to the diagnosis of SLE. Antibodies to double-stranded DNA (anti-dsDNA) appeared next at a mean of 2.2 years prior to diagnosis, and anti-Smith (anti-Sm) and anti-ribonucleoprotein (anti-RNP) were the last to appear at 1 year before diagnosis. This study also showed that the autoantibody profile at the time of SLE diagnosis remained relatively constant in the years after diagnosis.

+

Clinical Findings

Listen

+++

Symptoms and Signs

+++

Constitutional

Constitutional symptoms, such as fever, fatigue, and weight changes, are common in SLE. Not infrequently, fatigue is out of proportion to other disease manifestations. In these instances, it is important to consider other factors such as deconditioning, stress, and sleep disturbance. Fever, usually low-grade, can occur in active SLE, particularly with serositis. Infection, however, is always a concern when fever develops in a lupus patient, especially in the setting of immunosuppressive therapy.

+++

Mucocutaneous

Four of the 11 American College of Rheumatology (ACR) classification criteria describe mucocutaneous manifestations, and approximately 80–90% of SLE patients will have mucocutaneous involvement at some point during the course of the disease ( and ). Photosensitivity, defined by the ACR as “skin rash as a result of unusual reaction to sunlight, by patient history, or physician observation,” occurs frequently. Patients may be sensitive to UV-A, UV-B, or visible light. Photoprovocation testing has shown that greater than 90% of lupus patients have an abnormal skin reaction to UV or visible light. SLE patients also have reported symptoms after exposure to sunlight through car glass windows and to light from fluorescent tubes and photocopiers. The majority of skin reactions occur more than 1 week after sun exposure and last for weeks to months. In addition to skin eruptions, some SLE patients report an exacerbation of systemic symptoms such as fatigue and arthralgias after sun exposure. Polymorphous light eruption and photosensitizing medications are additional diagnostic considerations when evaluating a SLE patient with a photosensitive rash. In contrast to SLE photosensitivity, polymorphous light eruption is characterized by an intensely pruritic papular, non-scarring rash developing hours after sun exposure and resolving after a few days. Polymorphous light eruption may occur in patients with known SLE.

Table Graphic Jump Location

Table 21–1. The 1997 Update of the 1982 Revised American College of Rheumatology Classification Criteria for SLE.a

View Table||Download (.pdf)

Table 21–1. The 1997 Update of the 1982 Revised American College of Rheumatology Classification Criteria for SLE.aCriterionDefinitionMalar rashFixed erythema, flat or raised, over the malar eminences, sparing the nasolabial foldsDiscoid rashErythematous raised patches with adherent keratotic scale and follicular plugging; atrophic scarring may occur in older lesionsPhotosensitivitySkin rash as a result of unusual reaction to sunlight, by patient history or clinician observationOral ulcersOral or nasopharyngeal ulceration, usually painless, observed by a clinicianArthritisNonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusionSerositis

1. Pleuritis

2. Pericarditis

1. Persistent proteinuria >0.5 g/d OR

2. Cellular casts

1. Seizures OR

2. Psychosis

1. Hemolytic anemia OR

2. Leukopenia 4000/mcL OR

3. Lymphopenia <1500/mcL

4. Thrombocytopenia <100,000 mcL

1. Anti-DNA OR

2. Anti-Sm OR

3. Antiphospholipid antibodies

Table Graphic Jump Location

Table 21–2. Major Clinical Manifestations of Systemic Lupus Erythematosus.

View Table||Download (.pdf)

Table 21–2. Major Clinical Manifestations of Systemic Lupus Erythematosus.OrganManifestationMouthErythema, petechiae, or ulcers occurring most commonly on buccal mucosa, hard palate, or vermillion borderSkinMalar rash, SCLE, discoid lupus, bullous lesions, panniculitis, palpable purpura, periungal erythema, livedo reticularis, Raynaud phenomenon, chilblain lupusLymph nodesLymphadenopathy, commonly in cervical and axillary regionsJointsSymmetric, inflammatory polyarthritis, usually nonerosive; reducible Jaccoud-like arthropathyHeartPericarditis, myocarditis, Libman-Sacks endocarditis, conduction system abnormalities, premature atherosclerosisLungsPleuritis, pneumonitis, diffuse alveolar hemorrhage, pulmonary hypertensionGastrointestinalPeritonitis, hepatitis, pancreatitis, mesenteric vasculitis, intestinal pseudo-obstructionKidneyGlomerulonephritis, interstitial nephritis, antiphospholipid nephropathyBloodLeukopenia, anemia, thrombocytopenia, arterial/vein thrombosisNeuropsychiatricSeizures, headache, acute confusional state, cognitive dysfunction, myelopathy, peripheral neuropathy

Patchy or diffuse alopecia and thin, friable hair occur during active SLE flares but may also occur as a side effect of certain medications that are commonly used to treat SLE. Hair re-growth begins 6–8 weeks after disease quiescence or discontinuation of the offending drug. Permanent alopecia can occur following the development of scarring discoid lesions.

Nasal or oral ulcers, which are typically painless, commonly develop in SLE patients. This is in contrast to aphthous stomatitis which is usually painful. Lupus oral ulcers have a gradual onset and can occur anywhere on the oral mucosa. Most lesions present as erythema, petechiae, or ulcerations. They typically occur on the hard palate, buccal mucosa, and vermillion border, and are unilateral or asymmetric. Discoid lupus erythematosus (DLE) can also occur in the oral cavity and can be very painful. Oral candidiasis and oral lichen planus can resemble the oral ulcers of SLE.

Cutaneous lupus lesions are categorized as “lupus specific” versus “lupus nonspecific” based on the presence or absence of interface dermatitis on histopathology. Acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), and chronic cutaneous lupus erythematosus (CCLE) are all considered to be lupus specific lesions. ACLE lesions can be localized or generalized. The localized form produces the classic malar or “butterfly” rash, which is characterized by sharply demarcated erythema on the cheeks and bridge of the nose, sparing the nasolabial folds (). Induration and scaling may occur. The malar rash of SLE is sometimes confused with that of acne rosacea, seborrheic dermatitis, and flushing syndromes. Unlike SLE, rosacea is characterized by the predominance of telangiectasias and pustules that may sting and burn. Heat and alcohol intake worsen the erythema of rosacea. Seborrheic dermatitis is manifested by scaly erythematous plaques that occur on the eyebrows and the lateral sides of the nose. In contrast to the malar rash of SLE, seborrheic dermatitis is commonly found within the nasolabial folds. If the diagnosis remains unclear after clinical examination, biopsy of the rash can be helpful to distinguish SLE from these other dermatologic entities.

Generalized ACLE consists of maculopapular erythematosus lesions involving any area of the body in a photosensitive distribution. The dorsa of the hands and the extensor surfaces of the fingers are commonly involved. The erythema is typically found between the interphalangeal joints, which is in distinction to the Gottron papules of dermatomyositis, which occur over the joint. ACLE lesions heal without scarring, although post-inflammatory hyperpigmentation can be observed.

The rash of SCLE may be papulosquamous or annular and is believed to be the most photosensitive of all the lupus rashes. The scaly, erythematous papules are frequently located on the torso and limbs and spare the face. Neither scarring nor atrophy are present. Patients with such lesions often have anti-SSA/Ro antibody. Compared with other forms of cutaneous lupus, SCLE is more often induced by medications such as hydrochlorothiazide and terbinafine.

Discoid lupus is the most common subtype of CCLE. The term “discoid” refers to the disc shaped appearance of the lesions. Such lesions are raised, erythematous plaques with adherent scale occurring most commonly on the scalp, face, and neck (, , and ). There is usually an erythematous ring around the lesions, which denotes the active component (). Over time, discoid lesions can lead to scarring and skin atrophy, resulting in permanent alopecia and disfigurement ( and ). DLE can also occur in the oral mucosa. Squamous cell carcinoma has been reported as a late sequela of DLE; thus, surveillance of known lesions and biopsy of changing or suspicions lesions is important.

Other subtypes of CCLE include hypertrophic lupus erythematosus and lupus panniculitis. Lupus panniculitis is a lobular panniculitis that has a predilection for the scalp, face, arms, buttocks, and thighs. When a cutaneous discoid lesion overlies the panniculitis, the entity is referred to as lupus profundus. Lupus panniculitis typically presents as a deep, firm nodule that can lead to cutaneous atrophy and rarely ulceration. Biopsy is often necessary to secure the diagnosis because there are reports of T cell lymphoma mimicking panniculitis. However, biopsy should be performed carefully because the lesions have tendency to break down. Lupus panniculitis is one of the few panniculitides that can occur above the waist.

Lupus nonspecific skin findings, such as bullous lesions, periungal erythema, chilblain lupus, and livedo reticularis, can also develop in SLE patients. Bullous lupus erythematosus is a rare cutaneous manifestation that presents as blistering skin lesions. SLE may also be associated with other bullous disorders such as bullous pemphigoid and dermatitis herpetiformis. The physical examination finding of periungal erythema represents dilatation of the capillaries at the base of the nail. These capillaries can be visualized at the bedside with a dermatoscope or ophthalmoscope. Other disorders associated with periungal erythema include scleroderma and mixed connective tissue disease. Unlike scleroderma and mixed connective tissue disease, SLE is not associated with capillary drop-out. Chilblain lupus is characterized by the presence of erythematous or violaceous macules or plaques (or both) on acral surfaces that worsen after exposure to a cold, humid weather. Livedo reticularis is characterized by an erythematous to violaceous reticular or net-like pattern of the skin. It is also highly associated with the antiphospholipid antibody syndrome.

+++

Lymphadenopathy

Lymphadenopathy is a common feature of SLE and can be localized or diffuse. The lymph nodes are soft and nontender, and the cervical and axillary chains are most frequently involved. Biopsy reveals reactive hyperplasia. A change in the pattern of a patient’s lymphadenopathy or unusually enlarging or hard lymph nodes should prompt an evaluation for lymphoma, which has an increased incidence in SLE.

+++

Musculoskeletal

Arthritis and arthralgias are noted in up to 95% of SLE patients at some time during the course of the illness and frequently involve the wrists and small joints of the hands. Swan-neck deformities and ligamental laxity are often noted. Unlike the joint findings in rheumatoid arthritis and mixed connective tissue disease, bony erosions rarely occur in SLE, and the swan-neck deformities are usually reducible (Jaccoud-like arthropathy).

+++

Lupus Nephritis

Renal involvement is common in SLE and is a significant cause of morbidity and mortality. It is estimated that up to 90% of SLE patients have pathologic evidence of nephritis on biopsy, but clinically significant nephritis develops in only 50% of people with SLE. Lupus nephritis typically develops in the first 36 months of the disease, although there are exceptions. Immune complex glomerulonephritis is the most common form of SLE renal involvement, but tubulointerstitial disease and vascular disease may also be present. The clinical presentation of lupus nephritis is highly variable, ranging from asymptomatic hematuria or proteinuria (or both) to frank nephrotic syndrome to rapidly progressive glomerulonephritis with loss of renal function.

Routine screening for the presence of lupus nephritis is a critical component of the ongoing evaluation and management of SLE patients. Screening procedures include asking about new-onset polyuria, nocturia, or foamy urine and looking for the presence of hypertension or lower extremity edema. Performance of a urinalysis with microscopy is essential. Hematuria, pyuria, dysmorphic red blood cells, and red blood cell casts may all be present. Accurate measurement of proteinuria is critical because proteinuria is a very sensitive indicator of glomerular damage. Normal daily protein excretion is <150 mg. Although the gold standard tool is an accurately collected 24-hour urine protein, many clinicians are currently using the spot urine protein to creatinine ratio out of convenience. However, the use of the spot ratio is controversial because data suggest that the spot ratio often is not representative of the findings in a timed collection, especially in the range of 0.5–3.0 (the range of most lupus nephritis flares). In addition, the spot ratio is less accurate in extremely muscular or cachectic patients. Urine dipstick should not be used for the quantification of proteinuria because it reflects protein concentration and varies depending on the volume of the sample. Screening SLE patients at regular intervals for the presence of proteinuria and hematuria is recommended; in patients with active SLE, screening at 3-month intervals is prudent. Hematuria in the absence of proteinuria might also be due to urolithiasis, menstrual contamination, or bladder pathology, particularly transitional cell carcinoma in a patient with previous cyclophosphamide exposure.

Renal biopsy is a critical part of the evaluation of a patient with possible lupus nephritis. The International Society of Nephrology/Renal Pathology Society system classifies the glomerular pathology into six categories () based on light microscopic, immunofluorescent, and electron-micrographic findings. An individual biopsy might exhibit just one of the pathologic classes or a combination of classes. In class I lupus nephritis, glomeruli appear normal on light microscopy and, on immunofluorescence, immune deposits are limited to the mesangium. Class II disease is characterized by mesangial proliferation on light microscopy and mesangial deposits on immunofluorescence.

Table Graphic Jump Location

Table 21–3. International Society of Nephrology/Renal Pathology Society Classification of Lupus Nephritis.

View Table||Download (.pdf)

Table 21–3. International Society of Nephrology/Renal Pathology Society Classification of Lupus Nephritis.ClassDescriptionIMinimal mesangialIIMesangial proliferativeIIIFocal nephritisIVDiffuse nephritisVMembranousVIAdvanced sclerosing

Class III and IV lupus nephritis are highly inflammatory lesions with immune complex deposition in the subendothelial space. These forms of lupus nephritis are described as “proliferative” because of the presence of proliferating endocapillary cells within the glomeruli. Class III denotes that <50% of glomeruli are involved and class IV denotes that ≥50% of glomeruli are involved. Class IV lesions are subcategorized according to whether the majority of glomeruli show focal (<50% of the glomerular tuft) or global (>50% of the glomerular tuft) involvement. Class IV lesions are further described as active (A), chronic (C), or a mixture of both (A/C). Class V lupus nephritis is characterized by immune complex deposition in the subepithelial space resulting in thickened capillary loops. This lesion commonly manifests clinically as nephrotic range proteinuria. Class V nephritis may occur in a pure histopathologic form or in combination with features of class III or class IV nephritis. Class VI nephritis is defined by the presence of >90% globally sclerotic glomeruli. In addition to glomerular pathology, renal histopathologic changes may include tubulointerstitial inflammation or fibrosis and a variety of vascular lesions including hyaline thrombi and thrombotic microangiopathy. Thrombotic microangiopathy is highly associated with the presence of antiphospholipid antibodies and should prompt the consideration of antiphospholipid nephropathy.

When an SLE patient has clinical or laboratory features that suggest the presence of nephritis, a renal biopsy should be performed in order to confirm the diagnosis, evaluate the degree of disease activity, and determine an appropriate course of treatment. A biopsy is especially important because urinary parameters, such as hematuria and the degree of proteinuria, imperfectly predict the underlying renal pathology. Hematuria might be absent in patients with severe class IV nephritis, and proteinuria can be modest in patients with class V nephritis. Each histopathologic class portends a different renal prognosis. Class I and class II nephritis have an excellent renal prognosis and do not require any specific therapy. In contrast, the long-term renal prognosis of class III–IV nephritis is extremely poor in the absence of immunosuppression. The long-term prognosis of class V nephritis is more favorable than class III–IV nephritis and is largely defined by the presence of associated proliferative lesions, which portend a worse prognosis. A repeat renal biopsy may be indicated in certain clinical settings, eg, if a patient is not responding appropriately to therapy or if a patient unexpectedly worsens after having achieved a good response to therapy. Repeat renal biopsy also can detect class transformation, which occurs in 15–50% of lupus nephritis patients during the course of the disease.

+++

Cardiovascular

Cardiovascular disease is a frequent complication of SLE and may involve the pericardium, valves, myocardium, and coronary arteries. Raynaud phenomenon affects approximately 30% of SLE patients and is characterized by vasospasm of the digital arteries and arterioles after exposure to cold temperature or stress.

Pericarditis may be asymptomatic; pericardial effusions are typically small and usually do not lead to hemodynamic compromise. However, on occasion lupus pericarditis can lead to life-threatening hemodynamic complications. Valvular heart disease predominantly affects the mitral and aortic valves as valve leaflet thickening, with or without nonbacterial vegetations (Libman-Sacks endocarditis). One echocardiographic study in SLE patients cited a prevalence of valvular abnormalities of 61% compared to 9% of controls. The presence of valvular disease was not associated with other clinical or serologic features of lupus disease activity. Myocarditis and conduction defects are rarer manifestations. SLE is associated with accelerated atherosclerosis and is itself a risk factor for cardiovascular disease (see below, ).

+++

Pulmonary

SLE frequently involves the pulmonary system, with pleural involvement being the most common manifestation. Pleural effusions, which are typically small, develop in up to 50% of patients during the course of the disease. Many patients experience pleuritic chest pain, but some effusions are asymptomatic. When evaluating an SLE patient with a pleural effusion, it is important to rule out other potential etiologies such as infection, malignancy, and heart failure.

Lupus pneumonitis, characterized by an acute respiratory illness with fever, cough, and pulmonary infiltrates, is very rare and is associated with a high mortality.

Chronic interstitial lung disease, also a very rare complication of SLE, can develop in an insidious fashion or after one or more episodes of acute lupus pneumonitis.

Chest radiography may be normal early in the disease course, but high-resolution CT may show characteristic findings of lung fibrosis. Pulmonary function studies reveal a restrictive pattern.

Diffuse alveolar hemorrhage is extremely rare and frequently fatal. Presenting symptoms include dyspnea and cough; hemoptysis is not universally present at the onset of diffuse alveolar hemorrhage. Clinicians should suspect diffuse alveolar hemorrhage in the setting of acute pulmonary infiltrates, a falling hematocrit, and a hemorrhagic bronchoalveolar lavage. Lupus nephritis frequently occurs concomitantly with diffuse alveolar hemorrhage. Isolated pulmonary arterial hypertension is an uncommon manifestation of SLE but is more frequently detected in mixed connective tissue disease. Lastly, the rare manifestation of vanishing lung syndrome is characterized by progressive dyspnea and decrease in lung volume with elevated diaphragms in the absence of parenchymal or pleural abnormalities on imaging studies.

+++

Gastrointestinal

SLE may involve any part of the gastrointestinal system. Abdominal pain has been reported in up to 40% of SLE patients and can be due to SLE-related causes, medication side effects, and other non–SLE-related etiologies such as infection. When evaluating an SLE patient with abdominal pain, it is critical to rule out non-SLE conditions first and to bear in mind treatment with glucocorticoids or other immunosuppressives can mask the clinical signs of an acute abdomen.

SLE-related causes of abdominal pain include peritonitis, pancreatitis, mesenteric vasculitis, and intestinal pseudo-obstruction. Pancreatitis is uncommon and is usually associated with active SLE in other organs. When considering the potential diagnosis of pancreatitis, it is important to note that elevated serum amylase may be misleading in that it has been observed in SLE patients in the absence of pancreatitis. Although glucocorticoids and azathioprine have been associated with the development of pancreatitis in patients who do not have SLE, these medications do not seem to play a major role in the development of pancreatitis in patients who do have SLE. Mesenteric vasculitis is a very rare manifestation of SLE, usually occurs in the presence of active SLE elsewhere, and typically involves the small vessels (arterioles and venules) of the small bowel submucosa. Thus, mesenteric angiography is usually nondiagnostic.

Abnormalities of liver tests occur frequently in SLE patients during the course of the illness (see below, ). Once medications and infections have been ruled out as possible culprits, persistent liver test abnormalities should prompt an investigation with an abdominal ultrasound and possibly a liver biopsy. Lupus hepatitis is believed to be a distinct entity from autoimmune hepatitis. Lupus hepatitis is typically characterized by the presence of lobular inflammation with a paucity of lymphoid infiltrates. These findings contrast with those of autoimmune hepatitis in which periportal inflammation and dense lymphoid infiltrates usually dominate. Although ANA is frequently seen in both disorders, anti-smooth muscle antibody is more frequently noted in autoimmune hepatitis than in SLE-associated hepatitis. Lastly, vascular disorders of the liver, such as Budd-Chiari syndrome, hepatic veno-occlusive disease, and hepatic infarction, can occur in SLE, especially in the setting of antiphospholipid antibodies.

+++

Neuropsychiatric

Neuropsychiatric manifestations can involve any aspect of the central or peripheral nervous system. Involvement of the nervous system is associated with a poorer prognosis.

The ACR categorized the neuropsychiatric manifestations of SLE into 19 distinct syndromes encompassing both the central and peripheral nervous system (). Headaches, cerebrovascular disease, seizures, mood changes, and cognitive dysfunction are the most frequent manifestations. The pathogenic mechanisms underlying these manifestations are varied and may, in some cases, involve small vessel vasculopathy, thrombosis of arteries and veins, atherosclerotic disease, demyelination, or intrathecal production of proinflammatory cytokines.

Table Graphic Jump Location

Table 21–4. American College of Rheumatology Classification of Neuropsychiatric Syndromes in SLE.

View Table||Download (.pdf)

Table 21–4. American College of Rheumatology Classification of Neuropsychiatric Syndromes in SLE.Central Nervous SystemPeripheral Nervous SystemAseptic meningitisGuillain-Barré syndromeCerebrovascular diseaseAutonomic disorderDemyelinating syndromeMononeuropathy, single/multiplexHeadacheMyasthenia gravisMovement disorderCranial neuropathyMyelopathyPlexopathySeizurePolyneuropathyAcute confusional stateAnxiety disorderCognitive dysfunctionMood disorderPsychosis

Central nervous system events occur more frequently than peripheral nervous system events. There are several types of histopathologic changes including small vessel vasculopathy (vascular hyalinization, perivascular lymphocytosis, or endothelial proliferation), multifocal infarctions, hemorrhage, cortical atrophy, and demyelinating lesions similar to those found in multiple sclerosis. True vasculitis is rare. The most common findings on brain MRI include T2 hyperintense focal lesions in the periventricular and subcortical white matter that can appear identical to the lesions seen in multiple sclerosis. Newer imaging techniques, such as magnetic resonance spectroscopy, have demonstrated abnormalities in brains of some SLE patients that appear normal on conventional MRI. A lumbar puncture should be performed in any patient with suspected CNS involvement. Cerebrospinal fluid findings are often entirely within normal limits, but some patients may demonstrate a pleocytosis or elevated protein (or both). The primary role of lumbar puncture is to rule out central nervous system infection; cerebrospinal fluid findings are not sensitive or specific enough to confirm a diagnosis of neuropsychiatric SLE. Cognitive dysfunction, manifested primarily by deficits in thinking, memory, and concentration, is being increasingly recognized in SLE patients. Some experts have estimated a prevalence of up to 80%, although serious impairment is much less common. Cognitive dysfunction may be associated with the presence of antiphospholipid antibodies. Acute myelopathy is an uncommon but devastating neuropsychiatric manifestation characterized by the onset of bilateral lower extremity paresthesia, numbness, and weakness that can rapidly progress to involve the upper limbs and the muscles of respiration. A sensory level is usually present. MRI of the spinal cord is important to confirm the diagnosis of myelopathy; T1 and T2 signal abnormalities and widening of the cord from edema are observed. Urgent treatment is necessary to try to prevent permanent neurologic damage. SLE myelopathy should be distinguished from neuromyelitis optica (NMO), which causes myelitis and optic neuritis in the setting of a positive anti-NMO IgG antibody.

Some of the most dramatic and devastating central nervous system manifestations of SLE may reflect systemic rather than localized abnormalities. Specifically, the sudden appearance of a stroke in a patient with SLE most likely reflects thrombosis due to antiphospholipid antibodies without any inflammatory or immunologic pathology within the central nervous system.

Peripheral neuropathy has been observed in up to 20% of SLE patients and is typically characterized by a symmetric, length dependent sensory or sensorimotor polyneuropathy. Because small diameter nerve fibers are likely involved, the results of nerve conduction studies and the clinical neurologic examination may be normal. Patients typically have fluctuating numbness and tingling of the upper extremities and hands. A large fiber vasculitic neuropathy can also occur in patients with SLE. This manifestation warrants urgent treatment to prevent ongoing and irreversible nerve damage. Autonomic neuropathies and cranial neuropathies may also develop in patients with SLE.

When evaluating an SLE patient with possible neuropsychiatric manifestations, it is important to distinguish if the neurologic symptoms are due to SLE-mediated damage or to secondary factors (such as metabolic abnormalities; severe hypertension; infection; or adverse effects of medications, such as glucocorticoids). No laboratory or imaging study is sufficiently sensitive or specific to confirm the diagnosis of neuropsychiatric SLE. Instead, the diagnosis is based on a thorough clinical evaluation that is corroborated by findings (or lack thereof) on brain imaging, serologic testing, lumbar puncture, and neuropsychiatric assessment.

+++

Laboratory Findings

+++

Hematology

All three blood cell lines can be affected in SLE. Anemia can be due to anemia of chronic disease (most common cause), autoimmune hemolytic anemia (AIHA), microangiopathic hemolytic anemia (MAHA), blood loss, renal insufficiency, pure red cell aplasia, and aplastic anemia.

AIHA should be considered in the setting of the following laboratory abnormalities: increased serum unconjugated bilirubin, increased lactate dehydrogenase, increased reticulocyte count, and reduced serum haptoglobin. The direct Coombs test is typically positive and is usually mediated by warm reacting IgG antierythrocyte antibodies. The peripheral blood smear often shows spherocytosis. There is an association between AIHA and the presence of anticardiolipin antibodies. AIHA may be the presenting manifestation of SLE but also may predate full blown SLE by many years.

MAHA, characterized by the presence of schistocytes on peripheral blood smear, should prompt the consideration of thrombotic thrombocytopenic purpura—a syndrome that consists of MAHA, thrombocytopenia, fever, neurologic symptoms, and renal involvement and that is associated with SLE. Because MAHA, thrombocytopenia, neurologic symptoms, and renal involvement can also occur in catastrophic antiphospholipid antibody syndrome, antiphospholipid antibodies should always be measured as part of the evaluation.

Leukopenia occurs in approximately 50% of SLE patients and can be secondary to lymphopenia or neutropenia or both. The presence of lymphocytoxic antibodies in some SLE patients correlates with lymphopenia. Thrombocytopenia is noted in up to 25% of SLE patients and can manifest in a severe fashion similar to immune thrombocytopenia. Chronic, low level thrombocytopenia is also a characteristic feature of the antiphospholipid antibody syndrome. Similar to AIHA, isolated immune thrombocytopenia has been shown to predate the development of complete SLE by several years. When evaluating a patient with the hematologic abnormalities described above, it is always important to consider the potential of bone marrow suppression from such medications as methotrexate, azathioprine, mycophenolate mofetil, and cyclophosphamide. In addition, glucocorticoids are a common cause of lymphopenia.

+++

Chemistry

Hyperkalemia can occur as part of renal tubular acidosis in a patient with lupus nephritis. Also, hyperkalemia may be encountered in lupus nephritis patients with renal insufficiency, especially if they are being treated with an angiotensin-converting enzyme inhibitor. Serum creatinine may be elevated in lupus nephritis patients.

+++

Liver Tests

Liver test abnormalities have been described in up to 60% of SLE patients at some point during the course of the illness, but clinically significant liver disease is rarely a direct manifestation of SLE. For this reason, the presence of liver disease should prompt a search for other causes, including medications such as nonsteroidal anti-inflammatory drugs, methotrexate, and azathioprine, all of which can cause hepatotoxicity. Glucocorticoids can lead to hepatic steatosis. Elevated transaminases also can be seen in the setting of SLE-associated hepatitis and pancreatitis.

+++

Muscle Enzymes

Creatine kinase can be elevated in the setting of SLE-associated myositis but is more commonly elevated in patients with mixed connective tissue disease.

+++

Acute Phase Reactants

The erythrocyte sedimentation rate (ESR) sometimes correlates with SLE disease activity, but the test is very nonspecific. The presence of anemia and renal disease (both common in SLE patients) can lead to elevations in the ESR. The majority of SLE patients have a mild elevation in the C-reactive protein (CRP) level, but very few have a marked elevation. Notable exceptions are those patients with serositis or concomitant infection in which the CRP level can be quite high (>60 mg/L). In contrast to ESR, CRP levels are not thought to correlate well with SLE disease activity.

+++

Special Tests

+++

Autoantibodies

The standard method for the detection of ANA is via indirect immunofluorescence using a human tumor cell line substrate (the HEp-2 cell line). When this method is used, ANA are present in virtually all SLE patients (). More recently, enzyme-linked immunosorbent assays (ELISA) containing a mixture of nuclear antigens are being used to detect ANA. These ELISA tests have a lower sensitivity for the detection of ANA than the HEp-2 cell immunofluorescence technique. Thus, in the appropriate clinical setting, a negative ANA by ELISA should be repeated using the immunofluorescent technique. The ANA is a nonspecific test and may be positive in a variety of other conditions including infection, malignancy, and other autoimmune diseases such as scleroderma and autoimmune thyroid disease. Approximately 30% of healthy people have an ANA titer of 1:40 and 3% have a titer of 1:320. Thus, while a negative ANA typically excludes SLE, a positive ANA does not secure the diagnosis. Once a patient with a positive ANA and characteristic symptoms receives a diagnosis of SLE, there is usually no need to repeat the ANA test.

Table Graphic Jump Location

Table 21–5. Autoantibodies and Clinical Significance in Systemic Lupus Erythematosus (SLE).

View Table||Download (.pdf)

Table 21–5. Autoantibodies and Clinical Significance in Systemic Lupus Erythematosus (SLE).AutoantibodyPrevalence in SLEClinical SignificanceANAAnti-dsDNA70%95% specificity for SLE; fluctuates with disease activity; associated with glomerulonephritisAnti-Sm20%99% specificity for SLE; associated with anti-U1RNP antibodiesAnti-U1RNP30%Defining antibody in MCTD; associated with lower frequency of glomerulonephritisAnti-Ro/SSA30%Associated with Sjögren syndrome, photosensitivity, SCLE, neonatal lupus, congenital heart blockAnti-La/SSB20%Associated with Sjögren syndrome, SCLE, neonatal lupus, congenital heart block, anti-Ro/SSAAnti-histone70%Associated with drug-induced lupusAntiphospholipid30%Associated with arterial and venous thrombosis, pregnancy morbidity

Anti-dsDNA antibodies are highly specific for SLE and may fluctuate with disease activity. Anti-dsDNA antibodies correlate well with the presence of lupus nephritis. Anti-Sm and anti-RNP antibodies are antibodies to small ribonucleoprotein particles that are found in some SLE patients. Anti-Sm is highly specific for the diagnosis of SLE. High titers of anti-RNP strongly suggest mixed connective tissue disease. Anti-Ro/SSA and anti-La/SSB antibodies are associated with the development of neonatal lupus and congenital heart block. In SLE patients, it is very rare to detect anti-La/SSB antibodies in the absence of anti-Ro/SSA antibodies. Anti-Ro/SSA antibodies are also associated with SCLE. Both antibodies are also commonly detected in patients with primary Sjögren syndrome.

Antiphospholipid antibodies are antibodies that are directed against phospholipids or to plasma proteins that bind to phospholipids. They are present in up to 50% of SLE patients and are associated with venous and arterial thrombosis and fetal loss. Some reports suggest an association between antiphospholipid antibodies, AIHA, and immune thrombocytopenia.

+++

Complement

Hypocomplementemia may occur during SLE flares as a result of complement activation and consumption, resulting in low C4, C3, and CH50. Because other diseases that cause hypocomplementemia are uncommon, low complement levels can be a very useful clinical indicator. It is important to remember that hereditary deficiencies of the early components of the classical pathway occur with increased frequency in patients with SLE. Thus, complement deficiencies should be considered before attributing hypocomplementemia to active SLE. This distinction is most relevant when evaluating a patient with low C4. C4 is encoded by two genes: C4A and C4B. Partial deficiency of C4 is common; it is estimated that 1% of whites are homozygous for C4A null alleles and 3% of whites are homozygous for C4B deficiency. Up to 15% of whites with SLE are C4A deficient. Thus, it may be difficult to discern if low C4 in a patient with SLE is due to complement consumption or to an inherited deficiency of C4. Ongoing complement consumption due to active SLE is more likely to result in reduced levels of multiple complement components (eg, reduction in the levels of C3 as well as C4) and the levels of C4 fluctuate with disease activity. In contrast, an inherited deficiency of C4 results in a fixed low level of C4 that does not vary with disease activity. Although rare, C1q deficiency is the complement deficiency that is most highly associated with SLE. Homozygous deficiency of C2 also confers increased risk of the development of SLE.

+++

Biopsy

A skin biopsy can aid in the diagnosis of cutaneous lupus in the setting of an atypical clinical presentation. Immunofluorescence should always be performed along with conventional histology. Histopathologic findings include basal layer vacuolar degeneration of keratinocytes and interface dermatitis. Dermal mucinosis is often observed. Discoid lupus lesions show follicular plugging. Immunofluorescence demonstrates deposition of IgG, IgA, IgM, and complement components along the dermoepidermal junction. IgM is the most frequent and IgA the least frequent immunoglobulin class deposited. It is important to remember that the skin biopsy of dermatomyositis can appear identical to that of SLE.

+++

Imaging Studies

Chest radiography is the initial study to detect pleural effusions or alveolar infiltrates in the evaluation of pleuritic chest pain or dyspnea. However, high-resolution CT has a higher sensitivity for the diagnosis of lupus pneumonitis or diffuse alveolar hemorrhage. Echocardiography is useful for the detection of pericardial effusions, valvular lesions, and as a screening test for pulmonary hypertension. Transesophageal echocardiography provides better resolution in the evaluation of valvular abnormalities.

+

Diagnostic Criteria

Listen

++

Establishing the diagnosis of lupus can be quite challenging because of the remarkable heterogeneity in clinical presentation and the lack of a definitive diagnostic test. The ACR has developed classification criteria for SLE (see ) that are often cited to support a lupus diagnosis. A person must fulfill 4 of 11 criteria in order to be classified as having SLE, all other reasonable diagnoses having been excluded. It should be emphasized, however, that these classification criteria were developed in an effort to standardize patients being enrolled into clinical trials, and they do not always meet the diagnostic challenge in individual patients. For example, a person with unequivocal biopsy proven lupus nephritis might only meet two of the classification criteria. At the other end of the spectrum, a person might have acute erythrovirus (parvovirus B19) infection and meet 4 criteria. Although these criteria cannot always be relied upon for diagnostic purposes, they serve as useful reminders of the myriad of symptoms and signs that can be seen in SLE.

+

Differential Diagnosis

Listen

++

Because of the involvement of multiple organ systems and the lack of specificity of some of the early symptoms, SLE can be readily mimicked by a variety of systemic diseases. A thorough evaluation for infectious, malignant, and other autoimmune diseases must be undertaken before SLE is diagnosed in a patient.

++

A number of viral infections can produce a constellation of symptoms and signs similar to SLE and, to complicate matters further, trigger the production of autoantibodies. A careful patient history and appropriate serologic testing for the potential offending virus should lead to the correct diagnosis. Erythrovirus (parvovirus B19) presents with fever, rash, anemia, and a symmetric inflammatory polyarthritis. ANA and anti-dsDNA antibodies and hypocomplementemia have been reported. Cytomegalovirus and EBV can present with constitutional symptoms; cytopenias; and gastrointestinal, hepatic, and lung abnormalities that can mimic an SLE flare. Acute HIV infection typically presents with fever, lymphadenopathy, and mucosal ulcers. Hepatitis B and C infection can also cause an inflammatory arthritis with positive autoantibodies.

++

Malignancy, particularly non-Hodgkin lymphoma, can present with constitutional symptoms, arthralgias, cytopenias, rash, and a positive ANA. Clinicians must be especially concerned about the possibility of malignancy in an older patient who has a new lupus-like syndrome. It is critical to ensure that the patient is up-to-date on all of their age appropriate malignancy screening tests.

++

Other autoimmune diseases, such as rheumatoid arthritis and dermatomyositis, can share similar features with SLE. A symmetric inflammatory arthritis with a predilection for the wrists and small joints of the hands develops in patients with rheumatoid arthritis and SLE. ANA and rheumatoid factor may be elevated in both disorders, although anti-cyclic citrullinated peptide antibody is usually absent in SLE. The photosensitive, erythematous rashes of dermatomyositis and SLE can appear clinically and histopathologically identical. A careful patient history and supporting serologic tests aid in making the correct diagnosis. Mixed connective tissue disease must also be considered when evaluating a patient for possible SLE. Mixed connective tissue disease is a syndrome characterized by a high titer anti-RNP antibody in conjunction with clinical features that are often present in SLE, scleroderma, and polymyositis. Patients frequently have puffy, swollen hands and Raynaud phenomenon. In contrast to SLE, an erosive arthritis that resembles rheumatoid arthritis can develop in patients with mixed connective tissue disease. Pulmonary arterial hypertension is a leading cause of morbidity and mortality in mixed connective tissue disease.

++

Drug-induced lupus usually manifests as polyarthritis, myalgia, fever, and serositis. A wide variety of drugs have been implicated in the development of drug-induced lupus; minocycline, procainamide, hydralazine, isoniazid, interferon α, and anti-tumor necrosis factor (TNF) agents are well known culprits. Hydrochlorothiazide is associated with SCLE. All these drugs cause a positive ANA and, with the exception of minocycline, anti-histone antibodies. Although characteristic of drug-induced lupus, anti-histone antibodies also are present in up to 80% of idiopathic SLE patients and cannot be used to distinguish drug-induced lupus from idiopathic SLE. Minocycline and hydralazine also can trigger production of perinuclear-staining antineutrophil cytoplasmic antibodies (pANCAs); anti-TNF agents can cause anti-dsDNA antibodies.

+

Complications

Listen

+++

Accelerated Atherosclerosis

SLE patients are at increased risk for the development of premature atherosclerotic coronary artery disease with an estimated prevalence of 6–10% of SLE patients. Myocardial infarction in women with SLE is 50-fold more common than in age-matched controls. Traditional cardiovascular risk factors do not explain this increased risk of coronary artery disease. Thus, SLE itself is thought to be an independent risk factor. Evaluation for and treatment of modifiable cardiovascular risk factors such as obesity, smoking, hypertension, and hyperlipidemia are important in mitigating the development of atherosclerotic disease.

+++

End-Stage Renal Disease

It is estimated that up to 10% of lupus nephritis patients progress to end-stage renal disease requiring dialysis. Some patients experience a decrease in SLE activity, while others continue to have active extrarenal manifestations and elevated serologies. SLE patients are typically good candidates for renal transplantation, although it is recommended that patients are given a 3-month dialysis period in order to allow for the possibility of recovery of renal function. The incidence of recurrent lupus nephritis in the allograft is low and does not universally result in allograft loss.

+++

Infection

Infections are a major cause of illness and death in patients with SLE. Immunosuppressive medications (especially glucocorticoids and cyclophosphamide) and immunologic abnormalities of SLE itself most likely contribute to the increased risk of infection. Bacterial, viral, and opportunistic pathogens have all been described.

Progressive multifocal leukoencephalopathy (PML) is a very rare and usually fatal demyelinating disease caused by reactivation of the JC polyomavirus. Although PML has been well recognized in patients with HIV and in patients receiving heavy immunosuppression for treatment of malignancy, it has also been described in patients with rheumatic disease. The majority of reported cases of PML in the setting of rheumatic diseases have occurred in patients with SLE. Recently, PML was diagnosed in two SLE patients after they received the biologic agent rituximab. It remains to be determined whether biologic therapy poses a greater risk than conventional immunosuppressive treatments for SLE, but it should be emphasized that PML has also been reported in lupus patients whose immunosuppressive therapy was quite mild. Therefore, new, progressive neurologic deficits and white matter lesions on brain imaging should prompt an evaluation for PML in any lupus patient. The diagnosis of PML is confirmed by the detection of JC virus by polymerase chain reaction of the cerebrospinal fluid.

Vaccination with inactivated vaccines such as the Pneumovax and the inactivated influenza vaccine is an important practice to reduce risk of certain infections. Prophylaxis against Pneumocystis jiroveci should be offered to selected patients, particularly those being treated with cyclophosphamide.

+++

Osteoporosis and Avascular Necrosis

Glucocorticoids are a major risk factor for the development of osteoporosis and avascular necrosis in SLE patients; it is important to use the lowest possible dose to control SLE disease activity. Patients should be routinely screened for low bone mineral density, and daily calcium and vitamin D supplementation should be emphasized. The use of bisphosphonates in women of childbearing age remains highly controversial due to the prolonged half-life of those agents. Avascular necrosis often involves multiple joints in SLE patients with the femoral head being most commonly affected. SLE is an independent risk factor for avascular necrosis, even in the absence of glucocorticoid therapy. Thus, the diagnosis should be considered in any SLE patient with persistent pain in any joint that is not explained by SLE activity. Raynaud phenomenon and hyperlipidemia may be additional risk factors for avascular necrosis in patients with SLE. MRI is the most sensitive imaging modality to detect early avascular necrosis.

+++

Malignancy

Patients with SLE have an increased risk of malignancy, the most common types being non-Hodgkin lymphoma, Hodgkin lymphoma, lung cancer, and cervical cancer. Interestingly, the increased cancer risk is highest in the early years after SLE diagnosis rather than after many years of disease. SLE patients should undergo age appropriate cancer screening including yearly cervical cancer screening.

+

Prognosis

Listen

++

The prognosis of SLE patients has improved dramatically over the past 50 years from a 50% survival at 2 years in the 1950s to 90% survival at 10 years in developed countries in the current era. The reasons for this improvement are likely multifactorial and include earlier diagnosis, more effective treatment (glucocorticoids were introduced in the 1950s), and better medical management of such complications as infection and renal disease. However, as SLE patients live longer, complications from long-standing disease and side effects of treatments emerge. The bimodal mortality pattern in SLE was first described over 30 years ago; patient deaths early in the course of the disease are from active disease or infection, while deaths in long-standing disease are due to atherosclerotic coronary disease. Malignancy also is a cause of excess mortality in patients with long-standing disease. One study showed that the survival curve of patients with mild disease is similar to that of patients with severe disease up until 10–15 years after diagnosis at which time there is a decline in survival in the severe group. Recognition of long-term complications of disease and implementation of appropriate preventive strategies to prevent and screen for atherosclerosis and malignancy are imperative in the ongoing care of SLE patients.

Which diagnostic studies are utilized in the evaluation of SLE?

What is the most specific test for the diagnosis of systemic lupus erythematosus?

How many diagnostic criteria must be present to diagnose a patient with systemic lupus erythematosus?