Definition

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that is associated with autoantibody production and complement-fixing immune complex deposition. The immune system triggers an inflammatory process, resulting in tissue damage. SLE is the prototype of an autoimmune disease that can cause a wide spectrum of clinical presentations and is characterized by remissions and exacerbation. Periods of active illness are sometimes called flares. The course of the disease is unpredictable, but can sometimes be triggered by environmental factors such as ultraviolet light and certain drugs. Although the cause of SLE is not yet fully elucidated, there are known to be a variety of genes that makes individuals susceptible to the disease and to its flares. SLE can affect skin, joints, kidneys, lungs, heart, blood vessels, liver, and the nervous system. The disease occurs nine times more often in women than in men, especially in the childbearing years between the ages of 15 and 45 years. The disease can also be found in pediatric and geriatric populations. The prevalence in the general population is approximately 1 in every 2000 persons, but it varies according to race, ethnicity, and socioeconomic background. From population-based studies, the prevalence of SLE is higher than previously recognized, especially in black female patients, which is 1 in 537 persons. However, the annual incidence and prevalence of SLE in Turkey is lower than North America but similar to European countries.

The American College of Rheumatology (ACR) formulated the classification criteria of SLE. They are designed for investigators recruiting SLE patients into clinical trials and have been updated from the American Rheumatism Association 1982 criteria and the ACR 1997 criteria to the Systemic Lupus International Collaborating Clinics (SLICC) 2012 criteria. The SLICC 2012 criteria ( Table 161.1 ) are more sensitive than the ACR 1997 criteria and can be applied to childhood-onset SLE and early disease. The criteria can also be used in clinical practice. The patient must satisfy at least four criteria, including at least one clinical criterion and one immunologic criterion, or the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies (ANA) or anti-double-stranded DNA antibodies.

Symptoms

SLE can cause a variety of symptoms ranging from mild to severe. Patients can present with constitutional symptoms and organ-specific symptoms. Constitutional symptoms include fever, weight loss, and fatigue, which are typically present at some time during the course of the disease in most SLE patients. Mucocutaneous manifestations are common. Skin lesions can be burning, tender, or itching. Rashes such as the classic malar (butterfly) rash and discoid lesions are characteristic. Patients may experience photosensitivity after a period of sun exposure. Photosensitivity is clinically defined as an abnormal response to ultraviolet light. These responses are manifested as exaggerated sunburn reactions and are often associated with systemic symptoms including fever, weakness, fatigue, and joint pain. Photosensitivity seems to correlate strongly with the presence of Ro/SSA antibodies. Oral ulcerations are common and may be asymptomatic. They are commonly on the hard palate and usually indicate active disease. The location and often asymptomatic nature of lupus-related oral ulcerations help differentiate them from non-lupus ulcerations, including aphthous stomatitis, lichen planus, herpes simplex, and drug-related lesions such as thrush due to corticosteroids and mucositis due to methotrexate. Nasal ulcers can also be found during disease activity and are often painful.

Patients may note thin hair, alopecia, or bald spots. Diffuse alopecia is nonspecific and can be caused by many systemic illnesses as well as by drugs such as cyclophosphamide and steroids. Focal bald spots, known as alopecia areata, are almost always due to autoimmune reactions and are characteristic of SLE. Painful red eyes from episcleritis, scleritis, or uveitis can be seen in SLE patients. Visual loss can occur in SLE patients with retinitis, vasculitis, optic neuritis, or thrombosis due to the antiphospholipid antibody syndrome (APS). Some SLE patients experience sicca symptoms of dry eyes and dry mouth due to secondary Sjögren syndrome.

Patients may present with pleuritic chest pain related to serositis or pulmonary embolism. In addition, SLE patients have a very high incidence of premature atherosclerosis, and myocardial infarctions and strokes are not uncommon in young women with SLE. The authors have seen such events in a number of women in their late teens and 20s.

Epigastric pain in SLE patients can be due to nonsteroidal anti-inflammatory drugs, but the differential diagnosis must include pancreatitis, a life-threatening complication of SLE, or of drugs used to treat it, such as azathioprine.

Patients presenting with dependent edema must be evaluated for lupus nephritis, which can cause the nephrotic syndrome. In the case of unilateral leg swelling, deep venous thrombosis needs to be ruled out. The hypercoagulable state in SLE patients is often associated with the APS. Antiphospholipid antibodies, including the lupus anticoagulant, are seen in approximately one fourth of SLE patients. Many remain asymptomatic, but the antibodies are associated with a number of clinical manifestations, including deep venous thrombosis and pulmonary embolism, arterial clots, recurrent spontaneous abortions, and strokes that may present in the form of transient ischemic attacks, ischemic strokes, or hemorrhagic strokes. Symptoms of strokes range from mild to severe of muscle weakness, language deficits, amaurosis fugax, or vertigo.

Articular symptoms are quite common in SLE patients. Typical joint involvement in SLE affects the small joints of the hands as well as the wrists, feet, and knees. The joint symptoms are inflammatory in nature; therefore, they tend to be worse in the morning and are often accompanied by generalized stiffness. Patients generally experience significant joint pain out of proportion to objective physical findings. In patients who have received high doses of corticosteroids, avascular necrosis (osteonecrosis) needs to be in the differential diagnosis of severe joint pain, especially in the hips, knees, and shoulders. Raynaud phenomenon is an additional risk factor for this complication in SLE.

Raynaud phenomenon occurs in at least a third of SLE patients and may be the presenting manifestation. Raynaud phenomenon is caused by episodic vasospasm and ischemia of the extremities in response to cold or emotional stimuli. Typical color change is triphasic from white to blue to red, but many patients do not go through all three phases. Instead, they may just have periods of blanching followed by a return to normal color. In severe cases, digital ulcers may occur and can lead to shortening of the distal phalanx.

Neurologic symptoms, including headaches, numbness, tingling, and weakness, can vary from mild to severe. Strokes are found at an increased incidence in SLE because of both the accelerated atherosclerosis mentioned before and the hypercoagulable state due to associated antiphospholipid antibodies. SLE can also affect the spinal cord with rapidly progressive transverse myelitis, a consideration in any patient with lower extremity neurologic symptoms plus bladder or bowel incontinence.

Proximal muscle weakness involving the upper arms and thighs can be seen in SLE patients as a result of concomitant inflammatory muscle disease. SLE patients are also at risk for steroid myopathy, which is typically much worse in the proximal lower extremities. Patients with myopathy generally present with significant muscle weakness rather than with muscle pain. They have difficulty in using their arms for over-the-shoulder tasks and difficulty in getting up from a chair or a low position as well as using stairs.

Physical Examination

A thorough physical examination is important in evaluating SLE patients, given the nature of their multisystem involvement ( Table 161.2 ). Articular manifestations can present as painful, non-erosive symmetric synovitis. Patients who have had repeated bouts of arthritis in their fingers can also develop Jaccoud arthropathy, which is clinically characterized by reversible joint deformities including swan-neck changes, thumb subluxations, ulnar deviation, and boutonnière deformities along with an absence of articular erosions on plain radiographs ( Fig. 161.1 ). In general, the prevalence of Jaccoud arthropathy in SLE is around 5% to 10%.

Reversible swan-neck deformities in a patient with systemic lupus erythematosus (Jaccoud arthropathy).

The skin is second only to the joints as the most frequently affected organ system, and skin disease is the second most common way that SLE initially is manifested clinically. There are three major types of lupus-specific skin disease.

• 1.
  

  The typical malar or butterfly rash involves the cheeks and bridge of the nose. Photosensitive lupus dermatitis is generalized throughout sun-exposed areas.

  
  
• 2.
  

  Subacute cutaneous lupus erythematosus. This is a distinct clinical subset of SLE. It is characterized by recurrent, erythematous, photosensitive, non-scarring skin lesions in a characteristic distribution involving the face, trunk, and arms and by mild systemic disease. Anti-Ro/SSA antibodies are found in 63% to 90% of patients with subacute cutaneous lupus erythematosus. The major anti-Ro/SSA response in subacute cutaneous lupus erythematosus is directed against the native 60-kDa Ro protein. Many drugs can induce SLE skin reactions, including photosensitizers such as spironolactone, angiotensin-converting enzyme inhibitors, calcium channel blockers, and hydrochlorothiazide. The skin lesions begin between 4 and 20 months after the initiation of drugs, and the lesions typically improve 6 to 12 weeks after the offending drug is withdrawn.

  
  
• 3.
  

  Chronic cutaneous lupus erythematosus. The most common form is classic discoid lupus erythematosus (DLE). Clinical features of DLE are induration, scarring, pigment changes, follicular plugging, and hyperkeratosis. Involvement of hair follicles is a prominent clinical feature of DLE lesions. Typical DLE lesions occur most often on the face, scalp, ears, V-neck area of the neck, and extensor aspects of the arms. Scarring alopecia is often observed in patients with scalp involvement. Other forms of chronic cutaneous lupus erythematosus include lupus profundus or panniculitis, mucosal DLE, and chilblain lupus or lupus pernio.

There are generally two common types of alopecia in SLE patients: irreversible scarring alopecia due to persistent DLE activity on the scalp; and the more widespread and often reversible non-scarring focal areas of alopecia that are often present during periods of disease activity. Hair in areas of alopecia is dry and coarse with increased fragility, making it break easily. This is often prominent over the frontal hairline.

Because of the nature of painless oral ulceration in SLE, the lesions are often found by a physician on a thorough physical examination, and patients may not recognize them. In patients with inflammatory eye disease such as uveitis or retinitis, a careful examination by an ophthalmologist is needed.

Parotid gland enlargement, several dental cavities, very dry buccal mucosa, or oral thrush can be found in patients with secondary Sjögren syndrome. Oral thrush can also be found in patients who are treated with steroids.

Cardiac examination may reveal a pericardial rub or distant heart sounds in SLE patients with pericardial effusion from pericarditis. Heart murmurs due to noninfectious endocarditis can be detected in SLE patients. Split P ₂ , loud P ₂ , or right-sided heart heave may suggest pulmonary hypertension, a complication of SLE associated with a high mortality rate. Crackles can also be found in SLE patients from interstitial lung disease, which is treatable if it is detected early.

Splenomegaly is occasionally seen in SLE patients with or without overt hematologic complications of the disease. Focal neurologic deficits and altered mental status can be found in SLE patients with central nervous system involvement including central nervous system vasculitis or stroke from associated APS. The peripheral nervous system can also be involved in SLE patients, including peripheral stocking-glove neuropathies as well as mononeuritis due to vasculitis. In SLE patients with secondary Raynaud phenomenon, abnormal nail fold capillaries can be detected with the presentation of dilated, unorganized capillaries or dropout lesions. Digital ulcers may be evident, and they may be difficult to heal.