Systemic lupus erythematosus

I. What every physician needs to know.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can present with a constellation of symptoms, most commonly including arthritis, rash, hematologic disease, kidney disease, and inflammation of the serosal surfaces of the heart and lungs. However, SLE may target nearly any tissue in the body and mimic a number of other diseases, which adds to the challenge of making a diagnosis of SLE.

There are 11 diagnostic criteria designated by the American College of Rheumatology. Traditionally, a patient who meets 4 out of the 11 criteria is diagnosed with SLE. However, nonspecific constitutional signs such as fatigue, fever, and weight loss may be the presenting complaints. The underlying disease is thought to be mediated by autoantibodies and immune complexes that bind directly to the tissues.

II. Diagnostic Confirmation: Are you sure your patient has systemic lupus erythematosus?

The revised criteria for the diagnosis of systemic lupus erythematosus

Malar Rash
Discoid Rash
Hematologic Disorder
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Renal Disease
Abnormal Titer of anti-nuclear antibody (ANA)
Immunologic Disorder
Neurologic Disorder
Serositis
Oral Ulcers
Arthritis
Photosensitivity

Four out of eleven are confirmatory for systemic lupus erythematosus

The malar rash is a flat or raised erythematous rash over the malar eminence. It tends to spare the nasolabial folds.
The discoid rash is a raised, circular, erythematous rash with adherent keratotic scaling and follicular plugging.
Hematologic disorders that suffice to meet the diagnostic criteria for SLE include the following:

◦ Hemolytic anemia

◦ Leukopenia (< 4000/mm3)

◦ Lymphopenia (< 1500/mm3)

◦ Thrombocytopenia (< 100,000/mm3) in the absence of offending drugs.
Renal disease includes persistent proteinuria (> 500 mg per day) or cellular casts (red cell, hemoglobin, granular, tubular, or mixed).
Abnormal titers of ANA should be in the absence of drugs known to be associated with drug-induced lupus.
Immunologic disorders that suffice to meet the diagnostic criteria for SLE include the following:

◦ Anti-double-stranded DNA antibodies (Anti-DS DNA)

◦ Anti-Smith antibodies (Anti-SM)

◦ Antiphospholipid antibodies

◦ Presence of lupus anticoagulant

◦ False positive serologic test for syphilis known to be positive for at least 6 months
Neurologic disorders include seizures in the absence of offending drugs or known metabolic disturbances (e.g. ketoacidosis, uremia, electrolyte abnormalities) or psychosis in the absence of offending drugs or known metabolic disturbances (e.g. ketoacidosis, uremia, electrolyte abnormalities).
Serositis includes either pleuritis or pericarditis.
Oral ulcers are usually painless and may involve the nasopharynx as well.
Arthritis should involve two or more peripheral joints and include tenderness, swelling or effusion.
Photosensitivity is a skin rash as the result of a stronger than expected reaction to sunlight.

A. History Part I: Pattern Recognition:

SLE is a systemic disease and presents in numerous ways. There is no “typical patient” with SLE as this disease is highly variable.

B. History Part 2: Prevalence:

SLE mostly affects women during their reproductive years. There is a 9:1 female predominance. Overall prevalence of SLE in the United States is estimated to be 15-50 per 100,000. The highest prevalence has been reported in Brazil. In the United States, people of African, Hispanic or Asian ancestry have an increased prevalence of SLE and greater involvement of vital organs.

C. History Part 3: Competing diagnoses that can mimic systemic lupus erythematosus.

SLE is challenging to diagnose because it can present in a myriad of ways in just about any organ. Other systemic diseases that may present similarly to SLE are the following:

Leptospirosis
Lyme Disease
Disseminated gonorrhea
HIV
Vasculitis
Post-streptoc
Syphilis
occal glomerulonephritis
Psoriasis
Atopic Dermatitis
Viral Syndromes
Mixed Connective Tissue Disease
Sjogren’s Syndrome
Rheumatoid Arthritis
Systemic Sclerosis
Lymphoma
Leukemia
Cryoglobulinemia
Thrombotic thrombocytopenic purpura (TTP)
Disseminated intravascular coagulation (DIC)
Idiopathic thrombocytopenic purpura (ITP)
Autoimmune hemolytic anemia (AIHA)
Microangiopathic hemolytic anemia (MAHA)

One of the key distinguishing features of SLE is the epidemiology. The prevalence increases in women of child-bearing age. A positive anti-nuclear antibody (ANA) AND a positive anti-DS DNA or anti-SM antibody is a distinct feature of SLE. Eighty to ninety percent of all patients with SLE have some form of mucocutaneous symptoms. It is also important to determine whether the patient is taking any medications that may induce drug-induced lupus. The most common are procainamide, hydralazine, and isoniazid.

D. Physical Examination Findings.

Dermatologic

Discoid lesions are discrete erythematous plaques covered by a scale that extends into dilated hair follicles. These tend to be found on the face, scalp, behind the ears, and on the neck. Central atrophic scarring may be seen with advanced lesions.
Subacute cutaneous lupus erythematosus (SCLE) typically affects Caucasian women. The rash is an erythematous papular rash that may progress into a papulosquamous, or psoriasiform, lesion.
The most common rash is the malar rash. It is an erythematous and edematous rash that covers the bridge of the nose and the malar eminences. It tends to spare the nasolabial folds. It does NOT involve papules or pustules.
Alopecia is commonly associated with SLE. It may be diffuse or patchy.
Oral ulcers, when present, are usually found on the buccal mucosa, tongue and palate. They tend to be painless. Similar ulcers may be found in the nose and anogenital region.
Patients with SLE may have urticaria, palpable purpura, digital ulcerations, or splinter hemorrhages due to vasculitis associated with SLE.

Musculoskeletal

Polyarthritis is a common finding. Soft tissue swelling and tenderness in the hands, wrists and knees is most often seen.
Myositis can occur, but this is unusual. Most patients have myalgias and weakness without true myositis. The weakness frequently involves the deltoids and the quadriceps.

Neurologic

SLE can present with memory loss, confusion or even psychosis.

Vascular

SLE may present with signs of vascular occlusion or insufficiency, such as stroke, myocardial infarction, deep venous thrombosis, and pulmonary embolism.
Signs of easy bruising or bleeding may be present due to thrombocytopenia.

Cardiac

The most common cardiac presentation is pericarditis. A friction rub may be present.
Libmann-Sacks endocarditis may result in valvular insufficiency. Regurgitant murmurs may be present.
Because of pulmonary hypertension, elevated jugular venous distention, lower extremity edema, a loud pulmonary component of S2, and tricuspid regurgitation may be found on exam.

Pulmonary

Pleuritis is common, but pleural rubs are usually not appreciated.
Crackles may be heard in patients with lupus pneumonitis.

Gastrointestinal (GI) tract

Involvement of the GI tract is highly variable and ranges from rebound tenderness to nausea, vomiting, and diarrhea depending on the involved structures.

Ophthalmologic

Cotton wool spots in the retina are the most common ocular lesion seen in SLE.

E. What diagnostic tests should be performed?

Antinuclear antibody (ANA)
Complete blood count (CBC)
Urinalysis
If ANA is positive, then anti-DS DNA or anti-SM antibody
If there is kidney involvement, a C3 level and a spot protein/creatinine ratio should be ordered

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Low titers of antinuclear antibodies may be found incidentally in a number of patients. In general, a titer greater than 1:80 increases the likelihood of SLE and should warrant follow-up testing.
Anti-DS DNA and anti-SM are specific for SLE.
The CBC is key. If the patient is anemic, a blood smear, fractionated bilirubin, haptoglobin, and/or an LDH can be ordered to determine whether the patient has hemolytic anemia. Many patients have anemia of chronic inflammation, but this does not meet the diagnostic criteria for SLE. However, thrombocytopenia, lymphopenia and leukopenia are part of the diagnostic criteria.
The urinalysis should show an active sediment during an acute flare, including casts and proteinuria (>2+ on dipstick). Chronic disease may show only proteinuria and minimal cells or casts.
The complement levels may be normal if the patient is not having an acute flare of SLE despite evidence of previous kidney injury, such as proteinuria or elevated creatinine. The spot protein/creatinine level is expected to be greater than 0.5 in active and untreated chronic disease.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

An electrocardiography (EKG) may be helpful to establish a diagnosis of pericarditis. Diffuse ST elevation and/or PR depression are the expected findings. The voltage may be low depending on the amount of fluid in the pericardial sac.

III. Default Management.

Management depends on the organ involvement and severity.

NSAIDs are used to treat the following:

Mild arthritis
Myalgias
Serositis
Headaches

Systemic corticosteroids, the equivalent dose of 5mg to 30mg of prednisone are used the treat the following:

Moderate arthritis
Skin manifestations of SLE
Serositis

Systemic corticosteroids, the equivalent dose of 1 to 2mg/kg/day of prednisone, are use to treat the following more serious manifestations:

Pericarditis
Myocarditis
Glomerulonephritis
Hemolytic anemia
Alveolar hemorrhage
CNS symptoms
Systemic vasculitis

Pulse methyprednisolone (1g intravenous) can be given for up to three days for life-threatening manifestations of SLE. Cyclophosphamide, mycophenolate mofetil or azathioprine can be used for patients resistant to corticosteroids. Cyclophosphamide or mycophenolate mofetil is used for severe lupus nephritis. These should be administered by physicians experienced in their use.

Antimalarial agents, specifically hydroxychloroquine, are the first-line treatment for the treatment of mild SLE.

Hydroxychloroquine is used for the following:

Constitutional symptoms
Mild cutaneous symptoms
Mild musculoskeletal symptoms

Hydroxycholoroquiine is usually started at 200mg/day and increased to 200mg BID.

Coumadin titrated to an INR of 2.0-3.0 is used to treat antiphospholipid antibody syndrome. Low-molecular-weight heparin plus aspirin is used for pregnant women with antiphospholipid antibody syndrome and recurrent fetal loss.

Rituximab, a monoclonal antibody, that targets the cell-surface antigen, CD20, on B cells, has been shown to have beneficial effects for patients with SLE. Further studies are currently underway.

A. Immediate management.

Pulse methylprednisolone (1g intravenous) should be given for any life-threatening manifestations of SLE. Otherwise, see default management for further details.

B. Physical Examination Tips to Guide Management.

A detailed mucocutaneous exam including the oropharynx, nasopharynx and skin should be performed. Oral ulcers, malar rash, discoid rash, or evidence of photosensitivity indicate pharmacologic therapy. A non-blanching rash characteristic of vasculitis indicates the use of systemic corticosteroids.

A detailed musculoskeletal exam assessing for arthritis, joint effusions and joint tenderness should be performed. Mild symptoms can be treated with NSAIDs. More severe symptoms require systemic corticosteroids.

A pericardial friction rub indicates pericarditis and the necessity for systemic corticosteroids.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Creatinine should be closely monitored in patients with glomerulonephritis. During the initiation of treatment, the creatinine should be checked every day.

Anti-DS DNA antibodies correlate to disease activity in some patients with glomerulonephritis. The titer will increase with disease flares and decrease with response to therapy.

Erythrocyte sedimentation rate and C-reactive protein decrease with appropriate treatment of an SLE flare. These may remain elevated in patients who are corticosteroid resistant. An alternative agent such as hydrochloroquine or azathioprine should be considered in corticosteroid resistant patients depending on the severity of symptoms.

D. Long-term management.

Hydroxychloroquine is used to treat mild constitutional, cutaneous and musculoskeletal symptoms and may reduce the number of disease flares. The dose is either 200mg or 400mg per day. Patients receiving hydroxychloroquine should have annual monitoring for retinal changes.

Azathioprine (2-2.5mg/kg/day) is used as corticosteroid sparing agent for patients with mild to moderate disease activity. It is an alternative to cyclophosphamide for patients needing maintenance therapy for lupus nephritis.

The duration of cyclophosphamide for lupus nephritis is varied. One recommendation is monthly doses (500mg/m²) of intravenous cyclophosphamide for 6 months, then 2 quarterly doses of cyclophosphamide followed by daily azathioprine for 2 years.

Coumadin titrated to an INR of 2.0-3.0 is used to treat antiphospholipid antibody syndrome.

SLE patients require a significant amount of education about their disease and how to recognize the signs of a flare and seek medical treatment.

E. Common Pitfalls and Side-Effects of Management

Short-term use of corticosteroids may result in hyperglycemia, emotional liability and even psychosis. Long-term use may result in glaucoma, cataracts, osteoporosis, immunosuppression and Cushing’s syndrome (central obesity, abdominal striae, hypertension, diabetes mellitus, and lipid abnormalities).
Antimalarials, such as hydroxychloroquine, may result in gastrointestinal side effects such as abdominal pain, nausea, vomiting, diarrhea, or bloating. They may also cause retinopathy and require annual ophthalmologic screening. These medications may cause hyperpigmentation of the nails, mucous membranes, and skin (particularly on sun-exposed areas). Hydroxychloroquine may cause hypoglycemia and may decrease the insulin requirement in diabetic patients with SLE. Antimalarials may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Azathioprine may cause myelosuppression. It should not be used in patients taking allopurinol for gout as this also results in myelosuppression. Azathioprine is metabolized by the liver and excreted by the kidneys. It requires periodic monitoring of renal and liver function and dosage may need to be adjusted accordingly.
Cyclophosphamide may cause bone marrow suppression, nausa, vomiting, immunosuppression, and bladder carcinoma. There is an association with hemorrhagic cystitis and cervical dysplasia as well.
Mycophenolate mofetil may result in gastrointestinal side effects such as nausea, diarrhea and bloating. It also causes immunosuppression and myelosuppression.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

Drug dose reduction of azathioprine. Avoidance of NSAIDs.

B. Liver Insufficiency.

Close monitoring of azathioprine, cyclophosphamide, and hydroxychloroquine use.

C. Systolic and Diastolic Heart Failure

No adjustment.

D. Coronary Artery Disease or Peripheral Vascular Disease

Avoid long-term use of NSAIDs.

E. Diabetes or other Endocrine issues

Hydroxychloroquine has hypoglycemic properties and may result in hypoglycemia or decreased insulin requirements for diabetic patients.

Corticosteroid use will result in hyperglycemia and increased insulin requirements.

J. Hematologic or Coagulation Issues

Cyclophosphamide, mycophenolate mofetil and azathioprine may cause bone marrow suppression.

V. Transitions of Care

N/A

B. Anticipated Length of Stay.

Variable depending on organ involvement and severity.

C. When is the Patient Ready for Discharge.

When no longer requiring intravenous medications and is able to perform activities of daily living without issue.

D. Arranging for Clinic Follow-up

N/A

1. When should clinic follow up be arranged and with whom.

Rheumatology within 2-4 weeks.
Nephrology for patients with lupus nephritis. If admitted for lupus nephritis, follow-up within 2-4 weeks.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Not applicable.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

If the patient has lupus nephritis, a basic metabolic panel and a phosphorus is appropriate.
For patients on azathioprine, mycophenolate mofetil or cyclophosphamide, a complete metabolic panel should be ordered to follow liver and kidney function.
SLE causes accelerated atherosclerosis and these patients are at risk of coronary artery disease. Consider checking serum lipid levels.

F. Prognosis and Patient Counseling.

10-year survival rate is approximately 85%. Most patients have a remitting and relapsing course. However, a small number of patients have severe impairment of key organs resulting in increased morbidity and mortality.

VI. Patient Safety and Quality Measures

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients with SLE should be up to date on all immunizations. They should receive the pneumovax and annual influenza vaccines.

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