Systemic Lupus Erythematosus

                     Background: Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organ systems that is defined clinically and associated with antibodies directed against cell nuclei. Its multisystem manifestations and attendant complications from use of immunosuppressive agents make the diagnosis and management of this entity challenging.

Pathophysiology: Autoantibodies, circulating immune complexes, and T lymphocytes all contribute to the expression of disease. Organ systems affected include dermatologic, renal, central nervous system (CNS), hematologic, musculoskeletal, cardiovascular, pulmonary, the vascular endothelium, and gastrointestinal. The revised criteria for SLE must include 4 of the following:
Malar rash                  Discoid rash               Photosensitivity                    Oral ulcers
Arthritis                      Serositis                     Renal disorder                       Neurologic disorder
Hematologic dis        Immunologic dis       Antinuclear antibody

Frequency:
In the US: Because of variable reporting, the overall prevalence ranges from 14.6/100,000 to 50.8/100,000. Incidence varies from 1.8‑7.6/100,000 per year.
Internationally: Incidence varies worldwide. In Northern Europe, it has been reported to be 40/100,000.
Mortality/Morbidity: Recent studies in Europe and Canada have shown a reduction in mortality in lupus patients with 10‑year survival rates ranging from 75‑85%, with more than 90% of patients surviving more than 5 years.
Early deaths usually are caused by active disease. Atherosclerosis is a leading cause in late deaths. Infection and nephritis are major causes of mortality in all stages of SLE.
After dialysis or transplantation, a reduction in disease activity and flares has been reported.
Thrombosis, often secondary to antiphospholipid syndrome, carditis, pneumonitis, pulmonary hypertension, stroke, myocardial infarction, and cerebritis cause severe morbidity and mortality.
Race: SLE is more common in blacks (1:250) than in whites (1:1000). Hispanic and Asian populations are also susceptible.
Sex: Ninety percent of cases are in women. The sex distribution is more equal in those who develop SLE during childhood or when older than 50 years.
Age: Most (80%) cases have been reported to occur in women in their childbearing years.  

CLINICAL 
History: Manifestations are protean, and the mean length of time between onset of symptoms and diagnosis is 5 years. The disease is characterized by exacerbations and remissions. Many women relate flares of their lupus to the postovulatory phase of the menstrual cycle, with resolution of symptoms at the time of menses.
Systemic symptoms include a low‑grade fever, fatigue, malaise, anorexia, nausea, and weight loss. Initial presentation may involve one or more organ systems.
Arthralgias (53‑95%) are the initial complaint in many patients. Often, the pain is out of proportion to physical findings.
Malar, butterfly rash over the cheeks and bridge of the nose (55‑90%) with photosensitivity to ultraviolet (UV) light has been reported (mostly in whites). It also often involves the chin and ears.
Painful or painless ulcers in the nose and mouth are frequent complaints.
CNS symptoms may range from mild cognitive dysfunction to a history of seizures (12‑59%). Any region of the brain, meninges, spinal cord, and cranial and peripheral nerves can be involved. CNS events often occur when SLE is active in other organ systems. Headaches are common.
Psychiatric (high‑dose steroids also can cause psychosis [5‑37%]).
Pleuritic pain (31‑57%), dyspnea, cough, fever, and chest pain are important cardiopulmonary complaints.
Patients may present with abdominal pain, diarrhea, and vomiting. Intestinal perforation and vasculitis are important diagnoses to exclude.
A number of other symptoms can be elicited by history which can help identify other pathology, including the following:
Stroke
Pulmonary embolus
Deep venous thrombosis (DVT)
Acute ischemia
Retinal vasculitis
Physical:
Temperature higher than 102°F should prompt a search for infection and may be a low‑grade temperature in patients on immunosuppressive agents.
Malar rash is a fixed erythema sparing the nasolabial folds. It is a butterfly rash that can be flat or raised over the cheeks and bridge of the nose. It also often involves the chin and ears.
Discoid rash occurs in 20% of patients with SLE and can be disfiguring secondary to scarring. It presents as erythematous patches with keratotic scaling over sun‑exposed areas of the skin.
All patients experience painless or painful oral ulcers at some time in their illness, which are helpful for making the diagnosis.
Gastrointestinal findings include vague abdominal discomfort, nausea, and diarrhea.
Acute crampy abdominal pain, vomiting, and diarrhea may signify vasculitis of the intestine.
Joints Tenderness, edema, and effusions accompany polyarthritis that is symmetric, nonerosive, and usually nondeforming. It frequently involves the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the hands, as well as the wrists and knees.
Consider avascular necrosis, which is common in patients receiving glucocorticoids.
Central nervous system All types of seizures have been reported, with grand mal being the most common. Sensory or sensorimotor neuropathies are also common.
Incidence of stroke is high in the first 5 years of disease. Patients with antiphospholipid antibodies are at higher risk for such events.
Funduscopic examination is important in patients with visual complaints. Retinal vasculitis can lead to blindness and are demonstrated by sheathed narrow retinal arterioles with white exudates adjacent to the vessels.
Cardiovascular system Pulmonary hypertension, vasculitis with digital infarcts, and splinter hemorrhages may be observed.
Systolic murmurs are reported in up to 70% of cases. They may be secondary to fever, hypoxia, anemia, or Libman‑Sacks endocarditis (associated with antiphospholipid antibodies).
Pericarditis is a frequent finding in cardiac lupus. It usually is associated with small effusions. Myocarditis can cause heart failure, arrhythmias, and sudden death.
Pulmonary Tachypnea, cough, and fever are common manifestations of lupus pneumonitis.
Hemoptysis may signify pulmonary hemorrhage. However, infection is the most common cause of infiltrates on x‑ray.
Causes:
Many of the clinical manifestations of SLE are caused by the effects of circulating immune complexes on various tissues or to the direct effects of antibodies to cell surface components.
Whether polyclonal B cell activation or a response to specific antigens exists is unclear.
A lack of immune tolerance is observed in animal models.
A genetic predisposition to the development of SLE exists. The concordance rate in monozygotic twins is approximately 25‑70%. Each patient manifests his or her disease differently.
If a mother has SLE, her daughter's risk of developing the disease is 1:40, and her son's risk is 1:250.
Photosensitivity is clearly a precipitant of skin disease. The presence of antiphospholipid antibodies in patients dictates a constellation of signs caused by thrombosis.

  DIFFERENTIALS   Other Problems to be Considered:
Metastatic malignancy          Fever of unknown origin (FUO)      Mixed connective tissue disease
Psychogenic rheumatism     Scleroderma                                      Discoid lupus
Hemoptysis                            Drug‑induced lupus

Before making a diagnosis of SLE, it is important to rule out drugs as the cause of the condition. Table 1 shows the many pharmacologic agents associated with a lupuslike syndrome. Procainamide, hydralazine, and isoniazid have been studied the best. Many patients receiving these medications have positive antinuclear antibody test results and other serologic findings. Only a few have the clinical manifestations. Drug‑induced lupus differs from SLE by the following features:
Sex ratios are nearly equal.Nephritis and central nervous system features are not commonly present.No antibodies to native DNA or hypocomplementemia are present.When the drug is discontinued, the patient has resolution of clinical manifestations and reverting of abnormal laboratory values to normal.

Table 1. Drugs associated with lupus erythematosus (Source: Tierney et al)
           

WORKUP
Lab Studies:
Simple laboratory tests may be helpful in making the diagnosis or in evaluating a flare. However, the diagnosis is mostly dependent on the historical and physical findings.
Rarely should autoantibody tests be ordered in the ED, unless that is done for the assistance of a secured rheumatology follow‑up.
Complete blood count (CBC)
Leukopenia, which generally is a good index for disease activity
Lymphopenia
Anemia of chronic disease (60‑80%)
Evidence of a hemolytic anemia (10%)
Cytotoxic therapy (can cause anemia or leukopenia)
Thrombocytopenia (30‑50% of cases), which may be profound secondary to antiplatelet antibodies or to antiphospholipid antibodies
The partial thromboplastin time (PTT) may be elevated secondary to lupus anticoagulant (antiphospholipid antibody), which is associated with thrombosis.
Urinalysis
Pyuria
Hematuria
Granular casts
Proteinuria
Blood urea nitrogen (BUN) and creatinine
Usually not elevated at the onset of disease
Can be useful for the determination of any progression of renal disease
Imaging Studies: Chest x‑ray
Effusion
Infiltrates
Cardiomegaly
An echocardiogram may be indicated to evaluate any effusion causing pericardial pain or any valvular pathology and to confirm any signs of pulmonary hypertension.
Magnetic resonance imaging (MRI) is most useful for assessing brain pathology.
Computed tomography (CT) is useful to rule out bleeding or mass lesions.
Other Tests:
Cerebral spinal fluid (CSF) analysis is recommended when the diagnosis of CSF lupus is in question or infection is a possible cause of symptoms.
High protein levels in 50% of patients and pleocytosis may be found.
May indicate cerebritis but is not specific for it.
Order serologies in the ED only with a secured rheumatologic consultation and follow‑up.
Antinuclear antibody, an antibody to nucleosomal DNA‑histone complexes, is very sensitive but not specific.
Anti‑ds (double stranded) DNA is more specific for lupus. This test may correlate with the degree of activity of lupus, in general, and with the level of nephritis.
Antiphospholipid antibody
Present in 30% of patients with SLE
Associated with thromboembolic complications
Associated with mild‑to‑moderate PTT elevations

  TREATMENT
Emergency Department Care: Attend to the management of individual emergencies that may be complications of SLE in the individual patient.
These can include strokes, acute myocardial infarctions, hemoptysis, respiratory distress, and pulmonary emboli.
Individual treatment plans are beyond the scope of this article and are discussed in other articles under the headings related to the particular complication (see Differentials)
Consultations:  When available, consult a rheumatologist for both patients presenting with symptoms suggestive of SLE and for patients with known disease.
Complications, such as pericardial tamponade, pulmonary hemorrhage, renal failure, or cerebritis, mandate the appropriate subspecialty consultation.

   MEDICATION 
Conservative management with nonsteroidal anti‑inflammatory drugs including salicylates is recommended for arthritis, arthralgias, and myalgias not requiring immunosuppression. Only initiate high‑dose glucocorticoids and cytotoxic agents by, or in consultation with, a rheumatologist. Patients with thrombosis require anticoagulation with warfarin for a target international normalized ratio (INR) of 3‑3.5. Antibiotics may be appropriate in the treatment of ordinary and opportunistic infections.

Drug Category: Nonacetylated salicylates ‑‑ These agents are indicated to manage the inflammatory process.
Drug Name Choline magnesium trisalicylate (Trilisate) ‑‑ An excellent initial management drug, which has less GI symptoms and less impairment of platelets and renal function than acetylated agents.
Salicylates have analgesic, antipyretic, anti‑inflammatory and antirheumatic effects. The pharmacologic effects of these agents are qualitatively similar. Their anti‑inflammatory and analgesic activity may be mediated through the inhibition of the prostaglandin synthetase enzyme complex.
 

Drug Category: Nonsteroidal anti‑inflammatory drugs (NSAIDs) ‑‑ These agents are most commonly used for the relief of mild‑to‑moderate pain. Although the effects of NSAIDs in the treatment of pain tend to be patient specific, ibuprofen is usually the DOC for initial therapy. Other options include fenoprofen, flurbiprofen, mefenamic acid, ketoprofen, indomethacin, and piroxicam.
Drug Name Ibuprofen (Motrin, Nuprin, Ibuprin, Advil) ‑‑ Usually the DOC for treatment of mild‑to‑moderate pain, if there are no contraindications.
Inhibits inflammatory reactions and pain probably by decreasing activity of the enzyme cyclo‑oxygenase, which results in inhibition of prostaglandin synthesis.
 
Drug Category: Anti‑malarials ‑‑ These agents are an alternative conservative therapy with both sunblocking and anti‑inflammatory effects. Initiation of antimalarial therapy usually does not take place in the ED setting.
Drug Name Hydroxychloroquine (Plaquenil) ‑‑ Inhibits chemotaxis of eosinophils, locomotion of neutrophils, and impairs complement‑dependent antigen‑antibody reactions.
Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate. Used for the treatment of discoid and systemic lupus erythematosus and rheumatoid arthritis.
 
Drug Category: Glucocorticoids ‑‑ Have both anti‑inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli. High‑dose glucocorticoids are used for severe SLE complications, such as hematologic or CNS disease, serositis, vasculitis, or glomerulonephritis.
Drug Name Prednisone (Deltasone) ‑‑ Used as an immunosuppressant in the treatment of autoimmune disorders. By reversing increased capillary permeability and suppressing PMN activity, it may decrease inflammation.
Drug Name Methylprednisolone (Solu‑Medrol, Depo‑Medrol, Adlone) ‑‑ Useful in the treatment of inflammatory and autoimmune reactions. By reversing increased capillary permeability and suppressing PMN activity, it may decrease inflammation.
 
Drug Category: Immunosuppressives/cytotoxic agents ‑‑ These agents are used in active SLE cases resistant to corticosteroids. Patients should be monitored closely because of the adverse effects, and these agents should be administered by experienced specialist physicians. These drugs are more beneficial when used in conjunction with glucocorticoids. Treatment with glucocorticoids plus cyclophosamide is more beneficial, although more toxic, than treatment with glucocorticoids plus azathioprine.
Drug Name Cyclophosphamide (Cytoxan, Neosar) ‑‑ Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross‑linking of DNA, which may interfere with growth of normal and neoplastic cells. Pediatric dosing is controversial and not first line.
Drug Name Azathioprine (Imuran) ‑‑ Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. Pediatric dosing is controversial and not first line.
 
  FOLLOW‑UP   Further Inpatient Care:
Patients may require admission for treatment of severe complications, such as lupus nephritis (for pulse steroids, cytotoxic agents) or other entities responsive to high‑dose steroids.
Admit patients with neuropsychiatric presentation or stroke syndromes.
Admit patient to appropriate service (rheumatology if available) with subspecialty consultations as needed.
Further Outpatient Care:
Conservative management is indicated for the symptomatic relief of arthralgias, arthritis, or myalgias with nonacetylated salicylates, NSAIDs, or low‑dose glucocorticoids.
In/Out Patient Meds:Nonacetylated salicylates or NSAIDs
Deterrence/Prevention:Advise patients to use a sunscreen.

Complications:
Vasculitis and its various complications (eg, intestinal perforations)
Pericarditis
Myocarditis
Lupus pneumonitis
Pulmonary hemorrhage, pulmonary hypertension
Proliferative glomerulonephritis
Hemolytic anemia, thrombocytopenia
Intravascular thrombosis (eg, stroke and myocardial infarctions)
Complications of high dose glucocorticoid therapy
Complications of cytotoxic agents
Prognosis: Prognosis has improved over the last few years. Mortality typically is due to renal failure or infection.
Patient Education: Protection from the sun Compliance with medications and follow‑up appointments

  MISCELLANEOUS 
Medical/Legal Pitfalls: Failure to evaluate for ordinary or opportunistic infections
Failure to involve rheumatologist or primary physician in the management and disposition of a case
Special Concerns: It is controversial whether flares of SLE are more frequent during pregnancy. The flares do not seem to be exceedingly more serious compared to those in nonpregnant patients. Pre‑eclampsia, fetal wastage, prematurity, and intrauterine growth retardation are more frequent. Predictors for fetal loss include active nephritis at conception and the presence of antiphospholipid (aPL) antibodies.
High‑dose aspirin and NSAIDs should be avoided in the last few weeks of pregnancy. Hydroxychloroquine has not been shown to induce congenital malformations. Furthermore, unnecessary discontinuation of hydroxycholorquine during pregnancy may result in lupus flares. Prednisone, prednisolone, and methylprednisolone are the corticosteroids of choice, if necessary, during pregnancy because of their minimal placental transfer.