Systemic Lupus Erythematosus

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[edit] Systemic Lupus Erythematosus

Leslie E. Kahl

Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disorder of unknown etiology.With an unpredictable clinical course and manifestations ranging from troublesome rashes and alopecia to life-threatening cerebritis and nephritis, lupus is among the most challenging disorders to treat.The physician must not only treat acute flares of disease to minimize end-organ damage, but also distinguish manifestations of lupus from those related to adverse drug effects.

The hallmark laboratory feature of idiopathic lupus is the presence of autoantibodies, which may be nonspecific (antinuclear and anti-DNA antibodies) or tissue specific (antiplatelet and antierythrocyte antibodies).Immunoglobulin and complement deposits have been identified in involved tissues, including the skin, kidney, and brain, and are thought to be pathogenic.For this reason, many investigators consider lupus the prototypic autoimmune disease.

[edit] EPIDEMIOLOGY

Idiopathic SLE occurs predominantly in women of childbearing age.The frequency of lupus in the American population is approximately 0.1%, with higher rates seen in urban areas and among African-Americans and Asians.The ratio of women to men with lupus is approximately 11:1 during the childbearing years, but only about 3:1 in children and older adults.This gender discrepancy is thought to result from hormonal effects, as evidenced by the relative rarity of the disease before menarche and after menopause, the apparent association of disease flares with pregnancy and oral contraceptive use, and the presence of altered estrogen kinetics among women with SLE.

[edit] Etiology

SLE is a heterogenous disorder with a complex etiology rather than a single cause.Current theory suggests that in the genetically predisposed host, some stimulus (or stimuli) triggers aberrant function of T and B cells and, ultimately, increased immunoglobulin and autoantibody production.Genes encoding several different proteins, including the major histocompatibility complex (MHC), complement proteinsand receptors, immunoglobulin receptors, and cytokines, are associated with an increased risk of lupus in certain ethnic groups and populations.The specific type of antibodies produced may also be influenced by these genes.The stimulus that triggers SLE probably differs from patient to patient.The potential role of sex hormones, either endogenous or exogenous, is outlined above.Environmental triggers such as ultraviolet radiation, infection, certain drugs, chemicals, and foods may play a role.Some patients associate physical or emotional stress with disease onset or with flares of established disease.

SLE is characterized by a variety of autoantibodies.Although many of the protein antigens against which these antibodies are directed play a critical role in cellular functions, little evidence indicates that the autoantibodies impede these functions.Complexes of antibodies and their antigens (immune complexes), however, may have a pathogenic role in SLE.These complexes are normally cleared from the circulation by the complement system.In lupus, however, they may be found deposited along with complement at sites of tissue injury, contributing to the inflammatory response.Complement components are consumed during immune complex clearance and tissue deposition, producing a characteristic fall in serum complement levels during disease flares.

Although the pathogenesis of most of the clinical manifestations of lupus is inflammatory, some patients also develop manifestations attributable to hypercoagulability.Vascular occlusions in both the arterial and the venous systems have been associated with antiphospholipid antibodies.Whether these antibodies are pathogenic or simply laboratory markers for this complication is unclear.

[edit] PATIENT EVALUATION

Both the presentation and the clinical course of SLE are highly variable.The initial symptoms may be nonspecific and resolve spontaneously, leading to a considerable delay in diagnosis.In many patients, only the gradual unfolding of a pattern of disease over several months leads to the correct diagnosis.In others, however, the disease is fulminant and easily recognizable at the onset.

Lupus is generally characterized by periods of remission interspersed with acute or chronic relapses.In a given patient, disease flares may involve the same organ systems each time, producing a characteristic and predictable pattern of disease.This is useful when trying to distinguish symptoms of active SLE from other conditions, such as acute infection or adverse drug reactions.However, many patients do not have such a reproducible profile of their disease flare and present a continuing diagnostic challenge.

The majority of SLE patients have fairly mild disease characterized by constitutional symptoms, arthralgias or arthritis, and rash.These individuals often lead a relatively normal life and have a normal or near-normal life span.Patients with more aggressive disease, however, may suffer considerable morbidity.The 10-year survival rate for SLE is 75% to 90%.Deaths early in the course of disease usually result from active SLE or acute infection, whereas those occurring later most often result from cardiovascular disease.

[edit] History

The clinical presentations of lupus are remarkably diverse.The American College of Rheumatology publishes classification criteria for SLE as a guideline for researchers (Table 135-1).Physicians typically use these criteria to assign the diagnosis of SLE.The criteria were specifically selected for their ability to distinguish patients with lupus from those with other connective tissue diseases and do not include many common but nonspecific features of lupus, such as arthralgias and alopecia.

Table 135-1 Revised Criteria for Classification of Systemic Lupus Erythematosus (SLE)

Although nonspecific constitutional symptoms (e.g., fatigue, fever, weight loss) provide few clues to the diagnosis of SLE, they may dominate the clinical picture.The fatigue that occurs in SLE can be particularly overwhelming; patients may barely be able to get up, eat, or dress themselves.Fatigue is the chief complaint of many lupus patients whose disease is otherwise in remission.

Musculoskeletal symptoms, including myalgias, arthralgias, and frank arthritis, occur at some point in nearly all SLE patients.The arthritis is inflammatory, with prominent morning stiffness, although the symptoms are frequently out of proportion to the findings on physical examination.Joint involvement is usually symmetric and may include the small joints of the hands and feet, wrists, elbows, knees, and ankles.The patient may describe swelling of the joints that waxes and wanes over a few hours, a feature rarely found in other forms of arthritis.

Mucocutaneous features of SLE are nearly as common as those involving the joints.The characteristic butterfly rash on the cheeks and nose is present at some point in up to 50% ofpatients.Approximately one third note photosensitivity, with exacerbation of the rash after sun exposure.Patients may also give a history of nonscarring alopecia or unusual breakage of hair, particularly along the hairline.This history must be interpreted with caution in women using harsh coloring or curling treatments on their hair or having a tightly-braided hairstyle.Although oral or nasal ulcers occur in up to 40% of patients, they are frequently asymptomatic.Raynaud's phenomenon is present in approximately 30% of patients but also occurs in other connective tissue diseases, including scleroderma and polymyositis.Patients usually describe aching and white or bluish discoloration of the digits on exposure to cold and may also note erythema during rewarming.

Pleurisy or pericarditis (serositis) occurs in about half of SLE patients.Although occasionally manifesting only as an asymptomatic pleural effusion or globular cardiac contour on chest radiographs, serositis generally produces a characteristic sharp or stabbing pain on one or both sides of the chest.Pain referred to the left shoulder or relieved by leaning forward is more suggestive of pericarditis, whereas exacerbation of the chest pain on deep inspiration is more common with pleurisy.Pulmonary parenchymal involvement is much rarer than pleurisy in SLE.Patients with pneumonitis usually develop dyspnea suddenly and are acutely ill.They may also give a history of hemoptysis.Cough with sputum production is not typical of lung disease in lupus and should suggest a superimposed infection.

Central nervous system (CNS) manifestations of SLE may be either functional or organic.^[1] The most common symptoms include mild depression, subtle cognitive deficits, and headaches.The patient may have simple tension-type headaches or classic migraines.Some patients present with short-lived focal neurologic deficits called “migraine equivalents” after structural abnormalities have been ruled out.Migraine headaches appear to be more common among patients experiencing Raynaud's phenomenon.Serious neurologic problems occur less frequently in lupus and include major affective disorders, seizures, and stroke.Patients with antiphospholipid antibodies are at particular risk for stroke.

Some of the most serious complications of lupus may be silent or present with nonspecific symptoms.Nephritis, which occurs in up to 40% of patients, may be manifest as fatigue, peripheral edema, or weight gain.Hypertension associated with nephritis is also frequently silent.Patients with hemolytic anemia may have fatigue or develop jaundice or dark urine.Thrombocytopenia is usually asymptomatic but may produce petechiae, bruising, or more serious bleeding complications.

[edit] Physical Examination

The classic physical finding in SLE is the malar or butterfly rash (Fig.135-1).Along with the cheeks, the forehead, chin, and bridge of the nose may also be involved, but the nasolabial folds are generally spared.Involved skin is erythematous and may be slightly indurated.A maculopapular eruption with fine scaling may also be present.Unlike the classic butterfly rash that resolves without sequelae, discoid lupus erythematosus(DLE) involves deeper layers of the dermis and produces residual scarring.Discoid lesions are most common on the face, scalp, and ears but can also occur on the palms and soles (Figs.135-2 and 135-3).Acute discoid lesions are annular, erythematous, indurated plaques that may be covered by an adherent scale with follicular plugging.Chronic lesions generally show central atrophy and depigmentation, with an erythematous or hyperpigmented circular border.Discoid lesions occurring in the scalp may produce well-defined areas of scarring alopecia.In contrast, the nonscarring alopecia that occurs in the absence of discoid lesions is diffuse and may be associated with breakage of hairs at the hairline or fine lanugo-like hair growth.Patients with antibodies to the Ro or SS-A antigen may have annular or psoriasiform (nonscarring) rashes, termed subacute cutaneous lupus erythematosus(SCLE) (Fig.135-4).Some patients, particularly those with antiphospholipid antibodies, have livedo reticularis, a violaceous netlike pattern of vessels in the skin of the extremities.

Figure 135-1 Characteristic erythematous facial rash in systemic lupus erythematosus (SLE) may involve the forehead and chin along with the cheeks.Nasolabial fold is usually spared. (From American College of Rheumatology:Clinical slide collection on the rheumatic diseases, Atlanta, 1991, The College.)

Figure 135-2 Photodistribution of erythematous plaques in discoid lupus erythematosus (DLE).

Figure 135-3 Erythema and adherent scale in DLE. (Courtesy Frank W.Crowe, MD.)

Figure 135-4 Arcuate configuration of raised erythema and scaling in subacute cutaneous lupus erythematosus.

The musculoskeletal examination may be normal in lupus, even when the patient relates a history of joint pain suggesting inflammation.Joint swelling, tenderness, and erythema may be present, but synovial effusions are usually not large.Chronic arthritis may produce deformities, particularly in the hands.Ulnar deviation of the metacarpophalangeal (MCP) joints and flexion or swan-neck deformities of the fingers are most common.In contrast to the joint abnor malities seen in rheumatoid arthritis, however, those in SLE are usually reducible, and bony erosions rarely occur.

Patients with serositis may have no abnormal physical findings; a friction rub is sometimes heard.Atelectasis may occur, producing localized findings of consolidation at the lung bases.Dullness at the lung bases may be detected if pleural effusions are large.Pericardial effusions are rarely of hemodynamic significance, and signs of congestive heart failure are not generally seen.

The neurologic examination is normal in most patients with lupus, despite the high frequency of neuropsychiatric symptoms.However, the disease may affect virtually any portion of the CNS or peripheral nervous system.^[2] Stroke occurs in up to 15% of patients, producing focal deficits in the distribution of any of the cerebral vessels.Similarly, transverse myelitis may occur at any level of the spinal cord, although it is much less common than stroke.Patients with a history of headaches generally have a normal neurologic examination, but papilledema may occasionally be seen with pseudotumor cerebri.Neuropathy occurs in up to 15% of patients.Cranial nerve involvement is usually in the optic or trigeminal distribution.Peripheral nerve involvement may present as either a distal sensory neuropathy or a mononeuritis multiplex.Patients with a history of seizures generally have normal examinations between seizure events.Patients with mood disturbances may have findings consistent with an affective disorder, usually anxiety or depression.Formal testing may be necessary to detect more subtle cognitive defects.

In addition to these findings, which would most likely be detected by using a symptom-based approach to the patient, several potential asymptomatic abnormalities should also be sought.Adenopathy occurs in up to 25% of patients, usually in the setting of active disease elsewhere, and may suggest that the other symptoms are a manifestation of lupus rather than some unrelated problem.Hypertension may be the first indication of occult renal disease.The blood pressure must be measured each visit.The prognosis of nephritis is worse for patients with persistent hypertension, who should be treated aggressively.Similarly, patients should be checked regularly for peripheral edema, which may be the presenting sign of proteinuria.

[edit] LABORATORY STUDIES AND DIAGNOSTIC PROCEDURES

The laboratory is useful in confirming a diagnosis of SLE when the clinical picture is suggestive.The classic serologic finding for SLE is the antinuclear antibody (ANA).Since ANA is present in virtually all lupus patients, it serves as a reasonable screening test for the disease.A negative ANA test makes SLE extremely unlikely.ANA is not specific for lupus, however, and is also seen in patients with rheumatoid arthritis (RA), other connective tissue diseases, and inflammatory conditions (e.g., interstitial lung disease, chronic active hepatitis), as well as in healthy elderly individuals.

A positive ANA should be interpreted on the basis of the clinical setting and the titer.Titers of less than 1:160 are more likely to be false-positive results or manifestations of nonspecific immune reactivity than are higher titers.^[3] In contrast, ANA titers of 1:1280 or greater usually indicate a connective tissue disease, although not always SLE.The screening ANA detects antibody to a variety of antigenicsubstrates, which in turn may indicate the exact type of connective tissue disease.Thus, a positive screening ANA in a reasonable titer should be followed by more specific testing, including assays for Sm, ribonucleoprotein (RNP), SS-A/Ro, and SS-B/La.Patients with SLE frequently demonstrate different autoantibodies in their sera, whereas a single autoantibody is usually seen in other connective tissue diseases (Table 135-2).

Table 135-2 Frequency of Autoantibodies in Connective Diseases✢

✢Data are expressed as percentages.

Additional laboratory studies may be useful in diagnosing SLE (Table 135-3).The presence of antibody to double-stranded (native) deoxyribonucleic acid (DNA) is pathognomonic for lupus and in some patients may also be a marker of active disease, particularly nephritis.^[4] Anti-Sm is also virtually specific for SLE.Reduced serum complement levels may be seen in any disorder mediated by immune complexes but are highly suggestive of SLE when found in the presence of a positive ANA.A positive direct Coombs' test is found in up to 60% of SLE patients, but clinically evident hemolytic anemia is usually absent.Although the normochromic normocytic anemia typically seen in lupus is a nonspecific manifestation of chronic diseases, the lymphopenia is usually mediated by antilymphocyte antibodies and serves as another indicator of the diffuse immunologic hyperreactivity that characterizes SLE.Similarly, thrombocytopenia in this setting is immune mediated.The greater the number of antibodies present, the more likely the patient has SLE.

Table 135-3 Laboratory Findings Useful in Diagnosing SLE

Antiphospholipid antibodies, which may be associated with thrombosis, can be detected by three tests.The classic false-positive syphilis serology has long been recognized as a marker for SLE.The lupus anticoagulant test, in which a prolonged partial thromboplastin time (PTT) is not corrected by the addition of normal plasma, also reflects antiphospholipid antibody activity.The anticardiolipin antibody test is the third assay.Antiphospholipid antibodies may be accompanied by venous or arterial thrombosis, presenting with phlebitis, stroke, or miscarriage; the risk is highest with the lupus anticoagulant^[5](Box 135-1).Antiphospholipid antibodies are not specific for SLE and are also seen in the primary antiphospholipid syndrome, with similar vascular events.A few patients with this syndrome have low titers of ANA and thrombocytopenia and may be misdiagnosed with SLE.

A urinalysis and determination of the serum creatinine level should be performed on all new patients suspected of having SLE to screen for occult renal disease.A renal biopsy may be indicated by a rising serum creatinine, new-onset proteinuria of more than 500 mg/dl, or urinary sediment containing cellular casts or red blood cells.In these patients, new-onset hypertension, reduced serum complement levels, or a positive anti-DNA antibody test should strongly increase the clinical suspicion for nephritis and lead to consultation with a nephrologist or rheumatologist.Percutaneous renal biopsy may reveal a variety of histologic patterns that cannot be accurately predicted by routine laboratory studies.The renal biopsy also provides information on the chronicity and activity of renal disease, which may have both prognostic and therapeutic implications.

[edit] DIFFERENTIAL DIAGNOSIS

The clinical manifestations of SLE are so diverse that lupus has been dubbed one of the “great imposters.” When the initial presentation includes the malar rash and any of the more serious organ system manifestations, serologic testing is performed, and the diagnosis is relatively straightforward.More often, however, the patient may complain of nonspecific symptoms such as low-grade fever, fatigue, or arthralgias, and the clinical suspicion for lupus is not as high.SLE shouldalways be in the differential diagnosis of a multisystem disease presenting in a young woman, particularly a young Black woman, and also with apparent infection in a young woman who has negative cultures and no response to antibiotics.

A lupus diagnosis is most likely to be missed when the disease presents in a single organ system.Pleurisy or pericarditis is usually attributed to a viral infection unless the ANA test is performed.The pleural fluid in SLE is typically an exudate with lymphocytic predominance in the cell count, which may be helpful in the differential diagnosis.Isolated thrombocytopenia or hemolytic anemia is generally considered idiopathic unless an ANA test is done.CNS involvement is particularly challenging to diagnose, since it often occurs without other signs or symptoms of SLE.In this setting, seizure or stroke may be regarded as idiopathic, and optic neuritis or transverse myelitis may be attributed to multiple sclerosis.Isolated synovitis may be misdiagnosed as RA.The articular findings in the two disorders have a similar character and distribution, and up to 30% of patients with RA may have positive ANA tests.Patients with these clinical scenarios may remain undiagnosed until, with time, the multisystemic nature of the disease is revealed.

Although the most common diagnostic error involving SLE is overlooking it as a clinical possibility, cutaneous lesions are probably overdiagnosed as lupus.The erythematous rash of acne rosacea may assume a malar distribution but can be differentiated from SLE by the presence of pustules.Seborrheic dermatitis also typically occurs in a malar distribution but, unlike SLE, involves the nasolabial folds.Superficial fungal infections may resemble cutaneous lupus but give positive results on examination of skin scrapings with potassium hydroxide.Photoallergic contact dermatitis and polymorphous light eruption may be difficult to distinguish from lupus clinically, but they have distinctive histopathologic pictures.Similarly, the rash of dermatomyositis may closely resemble lupus; in dermatomyositis, however, the color of the rash is more purple than red, and its scaling lesions (Gottron's papules) occur over the knuckles, whereas those of lupus occur on the dorsum of the hand between the joints.Features of other lupuslike rashes can be differentiated from SLE (Table 135-4).

Table 135-4 Differential Diagnosis of SLE

Lupus must also be differentiated from other systemic inflammatory disorders, such as necrotizing vasculitis.Although cutaneous vasculitis may be a manifestation of SLE, widespread vascular involvement is unusual.Serologic studies are generally negative in vasculitis.The arthralgias or arthritis, fever, malaise, and cutaneous lesions of bacterial endocarditis may also be confused with SLE.Again, serologic studies, along with blood culture results, should clarify the diagnosis.Among the connective tissue diseases, lupus shares cutaneous features with dermatomyositis, synovitis with RA, serositis with RA and Sjögren's syndrome, and Raynaud's phenomenon with all of these disorders.In general, the clinical picture and active serologic profile of lupus are sufficient to distinguish it from these disorders.Occasionally a patient has features characteristic of several of these diseases but diagnostic of none.Antibodies to RNP are generally present, and this constellation of findings is termed mixed connective tissue disease(MCTD) or overlap syndrome.

After making the lupus diagnosis, the physician often must decide whether a new symptom represents SLE, an adverse drug effect, or an unrelated problem.For example, a patient with longstanding lupus who develops fever and pleuritic chest pain may have lupus-related serositis but may also have pneumonia or a pulmonary embolus.Signs or symptoms of active SLE in other organs may help clarify the diagnosis, along with judicious use of laboratory studies and radiographs.Similarly, a rise in the serum creatinine or new-onset hypertension is probably related to the development of nephritis, but nephrotoxicity from nonsteroidal antiinflammatory drugs (NSAIDs) must also be considered.Fatigue may be caused by SLE but also by superimposed fibromyalgia, depression, hypothyroidism, or obstructive sleep apnea from steroid-induced weight gain.

In a patient with suspected SLE the distinction must also be made between spontaneous and drug-induced lupus.Medications implicated in drug-induced lupus do not cause exacerbations of spontaneous lupus (Box 135-2).Patients with drug-induced lupus are older, are more likely to be men, and usually present with fever, malaise, serositis, and arthralgias or arthritis.Weight loss may be a prominent feature, raising the diagnostic suspicion for malignancy.More serious organ system involvement (e.g., cerebritis, nephritis, thrombocytopenia, hemolytic anemia) is rare.Serologic abnormalities are usually limited to a positive ANA test in a homogenous pattern and an elevated erythrocyte sedimentation rate (ESR); hypocomplementemia and the plethora of autoantibodies typically seen in spontaneous SLE are absent.When the offending medication is discontinued, the signs and symptoms of lupus generally resolve over several weeks, although the ANA may persist much longer.Patients who develop a positive ANA test during treatment with a lupus-inducing drug but who remain asymptomatic may continue taking the medication.

[edit] MANAGEMENT

Because SLE is not well understood by the public, treatment must begin with education.Common misconceptions about lupus are that it is always fatal, may be either contagious or strongly familial, and is a form of acquired immunodeficiency syndrome (AIDS).Reassuring lupus patients and their families about these issues may relieve many unspoken anxieties.SLE patients often look well despite overwhelmingfatigue and arthralgias.Frequently, this disparity leads to a lack of understanding and unrealistic expectations of family, friends, and co-workers, who also may need education.Both the Arthritis Foundation and the Lupus Foundation of America are excellent sources for educational materials regarding SLE.Many local chapters also sponsor patient support groups, allowing patients and their families to share their fears, frustrations, and successful strategies.

[edit] Nonpharmacologic Treatment

Although medications are frequently indicated in the management of lupus, several nonpharmacologic approaches also have merit.Many patients associate flares of their disease with periods of excessive fatigue.Rest is important in the daily management of SLE.Patients must learn to prioritize their daily schedules, plan ahead, and pace themselves.Because the disease tends to vary from day to day, many patients save up their chores or activities until they feel well, overdo it on that day, and are exhausted for the next several days.Other patients observe that emotional rather than physical stress is a disease precipitant, and counseling for stress management may be particularly useful.

Environmental manipulations may also help some lupus patients.The 30% to 40% of patients who are photosensitive can avoid the sun by staying indoors during midday or by wearing long sleeves and a hat.Topical sunscreens that include coverage against UVA also provide considerable protection.Patients with Raynaud's phenomenon need to avoid the cold.Most patients do not realize, however, that they must keep the whole body warm, not just the digits.Wearing a warm hat and using potholders for cold items and insulated holders for cold drinks can be helpful.They must also refrain from smoking.

[edit] Pharmacologic Treatment

No single medication is appropriate for all SLE patients (Table 135-5).Rather, the disease is managed by a problem-oriented approach.NSAIDs are the medications most widely prescribed, although the efficacy and toxicity of a particular drug in an individual patient are unpredictable.NSAIDs should generally be prescribed at the upper end of the recommended dose range.If one preparation does not provide relief after a 2-to 3-week trial, another may be prescribed.Lupus patients are subject to all the toxicities of the NSAIDs seen in other patients but to others as well.Because of subclinical or undiagnosed nephritis, SLE patients are at increased risk for NSAID-induced nephrotoxicity.This usually presents with a rise in serum creatinine, and may be accompanied by hyperkalemia and hypertension.These abnormalities are reversible once the drug is stopped but occur with sufficient frequency to merit monitoring of the serum creatinine in any patient after an NSAID is begun.Lupus patients are also probably at increased risk of mild hepatitis from NSAIDs, particularly salicylates, and serum transaminases should be monitored along with the creatinine.Aseptic meningitis, a rare complication of NSAID use, appears to be much more common in SLE and may also be caused by use of sulfa-containing antibiotics in these patients.No data are yet available on either the efficacy or the toxicity of selective cyclooxygenase II (COX-II) inhibitors in SLE but should be similar to those in RA.

Table 135-5 Drug Treatment for SLE

The antimalarial drug hydroxychloroquine is useful in the management of photosensitivity, rash, articular symptoms, alopecia, and oral ulcers in lupus.^[6] Some patients also experience less fatigue.The usual starting dose is 400 mg daily.Clinical response may not occur for 3 months.Once symptoms are under control, the drug may be continued at a lower dose.The most common toxicity, gastrointestinal intolerance, may be ameliorated if the drug is taken before bedtime.The most serious toxicity, retinal damage, occurs in less than 1% of patients.Patients should be monitored every 6 months by an ophthalmologist.Retinal changes are generally not reversible but usually do not progress once the drug is discontinued.

Topical corticosteroids are the mainstay of treatment for cutaneous lupus.Mild to potent topical steroids may be used depending on the severity and thickness of the lesions and their location.Intralesional injections of betamethasone (6 mg/ml) or triamcinolone (5 mg/ml) may be required in well-established lesions of DLE.Antimalarial drugs are the second line of treatment of cutaneous lupus, unless lesions are widespread or occur in concert with other disease manifestations.

Systemic corticosteroids should be reserved for the more serious manifestations of lupus; however, they are also effective for milder symptoms if other therapies fail or have unacceptable toxicities.Fig.135-5 provides a general guide line to the appropriate dose of prednisone according to disease manifestation.The lowest dose that provides control of the problem at hand should be used.Once the problem comes under control, the dose of prednisone should be gradually tapered and, if possible, discontinued.A schedule that reduces the dose by 25% every 3 to 4 weeks is generally appropriate.If the disease flares during this process, the next higher dose that controlled symptoms should be resumed and a taper reattempted once the disease has stabilized.The addition of an NSAID, hydroxychloroquine, topical steroids, or methotrexate may have steroid-sparing effects in certain patients.^[7] Some manifestations of lupus, including thrombosis, end-stage or pure membranous nephritis, and occasionally thrombocytopenia or hemolytic anemia, do not respond to steroid therapy.

Figure 135-5 Problem-oriented guide to corticosteroid dosage: suggested minimum prednisone doses (solid lines) with ranges (broken lines). Arthritis, rash, and serositis can often be managed without steroids.

Rarely, when the illness is particularly fulminant or life threatening, high-dose “pulse” intravenous (IV) steroid therapy is used.This approach has met with some success in nephritis, cerebritis, pneumonitis, vasculitis, and thrombocytopenia.Methylprednisolone is generally given in a single IV dose of 500 to 1000 mg daily for 3 to 6 days, followed by 60 mg of oral prednisone daily.Patients requiring this aggressive approach should be managed with the consultation of an appropriate specialist.

Although corticosteroids may be lifesaving treatment in SLE, their use, particularly at high doses, is fraught with complications.Hypertension, weight gain, glucose intolerance, and acne are among the most common adverse effects.Osteoporosis is a major problem, especially during prolonged use.Many lupus patients also avoid the sun, and some experience premature menopause resulting from cytotoxic use, placing them at particular risk for osteoporosis.Calcium supplementation of 1500 mg daily should be prescribed when steroids are begun, along with 800 IU of vitamin D.^[8]

Lupus patients are at particular risk of three potentially serious adverse effects of steroid use. Infections of all types occur more frequently in patients taking prednisone, particularly at higher doses.Infection is a primary or contributing factor in 30% to 50% of all deaths in SLE patients.Bacterial infections are most common, but fungal and opportunistic infections also occur and must be sought aggressively.The second unusual toxicity of steroid use in SLE is atherosclerosis. Both coronary artery and peripheral vascular diseases occur more often in SLE, even in young female patients, and appear to be related to long-term steroid use.Patients at highest risk are males and those with hypertension, renal disease, diabetes, hyperlipidemia, and the lupus anticoagulant.These risk factors should be vigorously addressed. Ischemic necrosis of bone, also referred to as avascular necrosis or aseptic necrosis, is the third type of steroid toxicity that is a particular problem in SLE.The femoral head is most often involved, although many patients have multiple sites, including the humeral heads, femoral condyles, and tali.The pain of avascular necrosis, unlike that of lupus-related synovitis, is exacerbated by use and relieved by rest.Joint stiffness is minimal.

Cytotoxic drugs are generally reserved for serious or potentially life-threatening manifestations of disease.They should be prescribed in consultation with an appropriate specialist experienced in their use.Cyclophosphamide is probably more effective than azathioprine for SLE but is also more toxic.Monthly boluses of IV cyclophosphamide are used primarily for diffuse proliferative glomerulonephritis.The initial dosage of 500 to 750 mg/m²is adjusted to achieve a nadir white blood cell count of 3500 to 4500, 10 to 14 days after infusion.Mesna is used with each infusion to minimize bladder irritation.Although IV therapy is associated with less bladder toxicity and a lower risk of malignancy than daily oral therapy, the risk of serious infection is similar.Cyclophosphamide or azathioprine can be used in a daily oral dose of 1 to 3 mg/kg when the clinical situation is serious enough to warrant the toxicity.Patients must be monitored for marrow suppression and are at risk of infection, malignancy, infertility, and menopause.

Anticoagulants are used in the subset of patients whose disease manifestations can be attributed to thrombosis.These patients usually have one or more forms of antiphospholipid antibody.Initial therapy of the thrombosis is with IV heparin, followed by oral warfarin with a target international normalized ratio (INR) of at least 2.5.Patients with antiphospholipid antibodies who have had clear-cut thrombotic episodes are at increased risk of recurrent thrombosis.Lifelong anticoagulation must be considered, particularly if the initial event was a stroke or large-vessel occlusion.Management in this setting is the same whether the patient has SLE or the primary antiphospholipid syndrome.

[edit] Monitoring

Several laboratory tests useful in making the diagnosis of lupus are also helpful in monitoring patients with established disease.Some patients have their own distinctive pattern of laboratory abnormalities that track with clinical disease activity.For example, levels of anti-DNA antibodies may rise with flares of disease and return to negative when disease is under control.ANA titers, in contrast, are rarely useful in monitoring disease activity and should not be followed serially.Some patients reproducibly demonstrate a fall in serum complement levels or a rise in ESR or quantitative immunoglobulin levels just before a disease flare.These markers should be surveyed when the lupus is quiescent to establish each patient's normal baseline profile.When a disease flare is suspected, studies may be repeated and compared with original values.As long as the lupus is inactive, it is unnecessary to repeat these measurements.Urinalysis, serum creatinine, and complete blood count should be performed at least twice yearly, however, even if the lupus appears to be in remission, to screen for occult disease.

[edit] Reproductive Issues

One of the most problematic management areas in lupus involves issues of reproduction.Patients with active SLE should avoid becoming pregnant because of definite risks to both the mother and the fetus.Use of estrogen-containing oral contraceptive preparations may induce a disease flare.Patients taking them without difficulty are generally permitted to continue, but most rheumatologists are reluctant to allow their lupus patients to begin oral contraceptives.Barrier methods of contraception, including the diaphragm and condom with contraceptive spermicide, or progesterone-based implantable devices may be preferable.If pregnancy occurs when the disease is under control, controversy surrounds the risk of lupus flare.^[9] Hypertension, proteinuria, or thrombocytopenia developing in a pregnant woman with lupus may be difficult to distinguish from preeclampsia.Serial monitoring of renal function and serum complement levels may be useful in tracking the course of the lupus.Lupus patients should be observed through their pregnancy in consultation with a high-risk obstetrician or perinatologist.

The fetus is also subject to potential dangers related to the mother's SLE.Mothers with antiphospholipid antibodies have an increased frequency of second-trimester miscarriage and stillbirth; early miscarriages may also be increased.Some women have multiple recurrent miscarriages and are unable to carry a pregnancy to term.Heparin treatment, with or without concomitant aspirin therapy, may reduce pregnancy loss in these patients but should be undertaken only with the guidance of an experienced perinatologist.

The other major risk to the fetus is neonatal lupus.This occurs in some fetuses whose mothers have anti-SSA/Ro, an immunoglobulin G that crosses the placenta to the fetus.Congenital heart block may develop, becoming evident between weeks 20 and 22 of the pregnancy.Structural cardiac defects may also occur and carry a poorer prognosis.Infants of mothers with lupus may also experience a temporary neonatal lupus syndrome, manifesting as a positive ANA test and photosensitive dermatitis.The rash and serologic abnormalities gradually disappear over the first fewmonths of life as the infant metabolizes the maternal immunoglobulins.

[edit] Consultation and Referral

The physician caring for a patient with suspected SLE may need to consult various specialists, both to confirm the diagnosis and to assist in treatment decisions.In a patient with probable lupus and a rash, a dermatologist may be able to provide clinical or histologic confirmation of the diagnosis.For patients with more generalized problems or with a confusing serologic picture, a rheumatologist may be more appropriate.Consultation should also be sought when serious or potentially life-threatening complications develop (e.g., cerebritis, nephritis, thrombocytopenia, hemolysis).Any patient being considered for high-dose steroid therapy or cytotoxic use should also be referred for subspecialty input into management.

[edit] REFERENCES