Systemic Lupus Erythematosus

SLE is an inflammatory autoimmune disorder characterized by autoantibodies to nuclear antigens. It can affect multiple organ systems.

Many of its clinical manifestations are secondary to the trapping of antigen-antibody complexes in capillaries of visceral structures or to autoantibody-mediated destruction of host cells (eg, thrombocytopenia).

The clinical course is marked by spontaneous remission and relapses.

The severity may vary from a mild episodic disorder to a rapidly fulminant, life-threatening illness.

The incidence of SLE is influenced by many factors, including sex, environmental exposures, and genetic inheritance.

About 85% of patients are women and most cases develop after menarche and before menopause.

Among older individuals, the sex distribution is more equal.

Race is also a factor, as SLE occurs in 1:250 Black women but in 1:1000 White women.

Familial occurrence of SLE has been repeatedly documented, and the disorder is concordant in 25–70% of identical twins. If a mother has SLE, her daughters’ risks of developing the disease are 1:40 and her sons’ risks are 1:250. Serologic abnormalities (positive antinuclear antibody) are seen in asymptomatic family members, and the prevalence of other rheumatic diseases is increased among close relatives of patients.

The diagnosis of SLE should be suspected in patients having a multisystem disease with a positive test for antinuclear antibodies. It is imperative to ascertain that the condition has not been induced by a drug (see Drug-Induced Lupus below).

The traditional criteria of diagnosing SLE if at least 4 of 11 criteria in Table 1–5ck were met were updated in 2019 to require an antinuclear antibody (ANA) titer of 80 or more (Table 1–6ck), highlighting that SLE should almost never be diagnosed in the absence of an elevated ANA titer. Criteria are developed as guidelines for the inclusion of patients in research studies and do not supplant clinical judgment in the diagnosis of SLE.

Diagnostic Essentials

• Occurs mainly in young women.
• Rash over areas exposed to sunlight.
• Joint symptoms in 90% of patients.
• Anemia, leukopenia, thrombocytopenia.
• Glomerulonephritis, CNS disease, and complications of antiphospholipid antibodies are major sources of disease morbidity.
• Serologic findings: antinuclear antibodies (100%), anti–double-stranded DNA antibodies (approximately two-thirds), and low serum complement levels (particularly during disease flares).

Clinical Findings

Symptoms and Signs

The systemic features include fever, anorexia, malaise, and weight loss.

Most patients have skin lesions at some time; the characteristic “butterfly” (malar) rash affects < 50% of patients. Other cutaneous manifestations are panniculitis (lupus profundus), discoid lupus and typical fingertip lesions (periungual erythema, nail fold infarcts, and splinter hemorrhages).

Alopecia is common.

Mucous membrane lesions tend to occur during periods of exacerbation.

Raynaud phenomenon, present in about 20% of patients, often antedates other features of the disease.

Joint symptoms, with or without active synovitis, occur in > 90% of patients and are often the earliest manifestation. The arthritis can lead to reversible swan-neck deformities, but radiographic erosions and subcutaneous nodules are rare.

Ocular manifestations include keratoconjunctivitis sicca and retinal vasculopathy (cotton-wool spots, episcleritis, scleritis, and optic neuropathy).

Pleurisy and pleural effusion are common. Pneumonitis, interstitial lung disease, and pulmonary hypertension can rarely occur. Alveolar hemorrhage is uncommon but life-threatening.

The pericardium is affected in the majority of patients. Heart failure may result from myocarditis and hypertension. Cardiac arrhythmias are common. Atypical verrucous endocarditis of Libman-Sacks is usually clinically silent but occasionally can produce acute or chronic valvular regurgitation—most commonly mitral regurgitation, which can be a source of systemic emboli.

Neurologic complications of SLE include psychosis, cognitive impairment, seizures, peripheral and cranial neuropathies, transverse myelitis, and strokes. Severe depression and psychosis are sometimes exacerbated by the administration of large doses of corticosteroids.

Several forms of glomerulonephritis may occur, including mesangial, focal proliferative, diffuse proliferative, and membranous. Some patients may also have interstitial nephritis. With appropriate therapy, the survival rate even for patients with serious kidney disease (proliferative glomerulonephritis) is favorable, albeit a substantial portion of patients with severe lupus nephritis develop ESKD.

Hematologic manifestations include leukopenia, autoimmune hemolytic anemia, immune thrombocytopenia, and thrombotic thrombocytopenic purpura.

Laboratory Findings

SLE is characterized by the production of many different autoantibodies (Tables 1–7ck and 1–8ck). Antinuclear antibody tests based on immunofluorescence assays using HEp-2 cells (a human cell line) as a source of nuclei are nearly 100% sensitive for SLE but not specific—ie, they are positive in low titer in up to 20% of healthy adults and also in many patients with other immune-mediated conditions such as rheumatoid arthritis, thyroid disease, systemic sclerosis (scleroderma), and Sjögren syndrome. False-negative results can occur with tests for antinuclear antibodies based on multiplex assays that use specific nuclear antigens rather than cell lines. Antibodies to double-stranded DNA and to Sm are specific for SLE but not sensitive, since they are present in only 60% and 30% of patients, respectively.

Depressed serum complement—a finding suggestive of disease activity—often returns toward normal in remission. Anti–double-stranded DNA antibody levels also correlate with disease activity in some patients; anti-Sm levels do not.

Other autoantibodies commonly seen in SLE include antibodies to SS-A/Ro, SS-B/La, ribonucleoprotein (RNP), and phospholipid. Antibodies to SS-A/Ro are associated with subacute cutaneous lupus; during pregnancy these autoantibodies can cross the placenta and damage the developing fetal conduction system, producing congenital heart block.

During disease flares, elevations in the ESR are common, but the serum CRP is usually normal unless there is serositis or arthritis. An elevated CRP in the absence of these manifestations should increase clinical suspicion for infection.

Abnormality of urinary sediment, including hematuria with or without casts, and proteinuria (varying from mild to nephrotic range) can indicate active lupus nephritis.

Differential Diagnosis

The differential diagnosis is broad, including drug-induced lupus, rheumatoid arthritis, systemic vasculitis, systemic sclerosis, primary antiphospholipid syndrome, inflammatory myopathies, viral hepatitis, sarcoidosis, acute drug reactions, and infections or malignancies with multisystem involvement.

Treatment

Since the various manifestations of SLE affect prognosis differently and since SLE activity often waxes and wanes, drug therapy—both the choice of agents and the intensity of their use—must be tailored to match disease severity.

Patients should be cautioned against sun exposure and should apply broad-spectrum UVA/UVB sunscreen while outdoors.

Milder skin lesions often respond to the topical administration of corticosteroids.

Minor joint symptoms can usually be alleviated by NSAIDs.

Antimalarials (hydroxychloroquine) may be helpful in treating lupus rashes or joint symptoms. They also reduce the incidence of disease flares and prolong survival in SLE. The dose of hydroxychloroquine is 200 or 400 mg/day orally and should not exceed 5 mg/kg/day; annual monitoring for retinal toxicity is recommended. Neuropathy and myopathy are rare adverse effects of hydroxychloroquine and may be erroneously ascribed to the underlying disease.

Corticosteroids are required for the control of certain complications. (Systemic corticosteroids rarely are given for minor skin rashes, leukopenia, or the anemia associated with chronic disease.) Glomerulonephritis, hemolytic anemia, myocarditis, alveolar hemorrhage, CNS involvement, and severe thrombocytopenia all require corticosteroid treatment and often other interventions. For serious manifestations, either methylprednisolone 250–1000 mg given intravenously over 30 minutes daily for 3 days or prednisone 40–60 mg orally is needed initially; however, the lowest dose of corticosteroid that controls the condition should be used over time (Table 26–17).

Immunosuppressive agents (such as cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate, or tacrolimus) are used for long-term control of disease.

Belimumab, a monoclonal antibody that inhibits the activity of a B-cell growth factor, is FDA-approved for treating antibody-positive SLE patients with active non-renal lupus that has not responded to standard therapies (eg, antimalarials or immunosuppressive therapies). Belimumab is also approved for the treatment of active lupus nephritis.

Anifrolumab, a type 1 interferon receptor antagonist, is approved to treat non-renal lupus that has not responded to standard therapies.

Voclosporin, a novel calcineurin inhibitor, is approved to treat active lupus nephritis when used in combination with mycophenolate mofetil.

Treatment of lupus nephritis includes an induction phase and a maintenance phase.

Mycophenolate mofetil (1000 mg or 1500 mg orally twice daily) and cyclophosphamide are first-line induction treatments for lupus nephritis and are generally given with corticosteroids to achieve disease control.

Cyclophosphamide is usually administered using the Euro-Lupus regimen (500 mg intravenously every 2 weeks for six doses) but can also be administered according to the National Institutes of Health regimen (3–6 monthly intravenous pulses [0.5–1 g/m2]) for induction.

Evidence increasingly suggests that renal response can be enhanced with combination immunosuppressive therapy.

For example, belimumab can improve renal response when added to cyclophosphamide or mycophenolate mofetil.

Similarly, voclosporin can improve renal response when added to mycophenolate; voclosporin can be helpful in nephrotic syndrome as the drug stabilizes renal podocytes and can quickly reduce proteinuria.

Mycophenolate mofetil or azathioprine is typically used for maintenance therapy for lupus nephritis; patients who were induced with combination therapy using belimumab or voclosporin should generally continue these therapies for at least 1–2 years during the maintenance phase of treatment.

Close follow-up is needed to watch for potential side effects when immunosuppressants are given; these agents should be administered by clinicians experienced in their use.

When higher doses of cyclophosphamide are required, gonadotropin-releasing hormone analogs can be given to protect a woman against the risk of premature ovarian failure.

Rituximab is usually reserved for life-threatening or organ-threatening manifestations that have failed conventional therapies.

Course & Prognosis

Ten-year survival rates exceeding 85% are routine. In most patients, the illness pursues a relapsing and remitting course.

Prednisone, often needed in doses of 40 mg/day orally or more during severe flares, can usually be tapered to low doses (5–10 mg/day) or be discontinued when the disease is inactive.

However, there are some in whom the disease pursues a virulent course, leading to serious impairment of vital structures such as lungs, heart, brain, or kidneys, and the disease may lead to death.

Mortality in SLE shows a bimodal pattern. In the early years after diagnosis, infections—especially with opportunistic organisms—are the leading cause of death, followed by active SLE, chiefly due to kidney or CNS disease. In later years, accelerated atherosclerosis, linked to chronic inflammation, becomes a major cause of death. Indeed, the incidence of MI is five times higher in persons with SLE than in the general population. Therefore, SLE patients should avoid cigarette smoking and minimize other conventional risk factors for atherosclerosis (eg, hypercholesterolemia, hypertension, obesity, and inactivity).

Fertility is normal in SLE. Women are advised to pursue pregnancy under close supervision and when SLE is well-controlled and no teratogenic medications are being used.

With more patients living longer, avascular necrosis of bone, affecting most commonly the hips and knees, is responsible for substantial morbidity.

Nonetheless, the outlook for most patients with SLE is increasingly favorable.

When to Refer

Appropriate diagnosis and management of SLE requires the active participation of a rheumatologist.

The severity of organ involvement dictates referral to other subspecialists, such as nephrologists and pulmonologists.

When to Admit

Rapidly progressive glomerulonephritis, pulmonary hemorrhage, transverse myelitis, and other severe organ-threatening manifestations of lupus usually require in-patient assessment and management.

Severe infections, particularly in the setting of immunosuppressant therapy, should prompt admission.